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Definitions

• the present invention relates to BET protein-inhibiting, in particular BRD4-inhibitory bicyclo- and spirocyclic-substituted 2,3-benzodiazepines, pharmaceutical compositions containing the compounds of the invention and their prophylactic and therapeutic use in hyper-proliferative diseases, especially in tumor diseases. Furthermore, this invention relates to the use of BET protein inhibitors in benign hyperplasia, atherosclerotic diseases, sepsis, autoimmune diseases, vascular diseases, viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.
• the human BET family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and BRDT) containing two related bromodomains and one extra-terminal domain (Wu and Chiang, J. Biol. Chem., 2007 , 282: 13141-13145).
• the bromodomains are protein regions that recognize acetylated lysine residues. Such acetylated lysines are often found at the N-terminal end of histones (eg, histone H3 or histone H4) and are features for an open chromatin structure and active gene transcription (Kuo and Allis, Bioessays, 1998, 20: 615). 626).
• the various acetylation patterns recognized by BET proteins in histones have been well studied (Umehara et al., J. Biol. Chem., 2010, 285: 7610-7618;
• bromodomains can recognize additional acetylated proteins.
• BRD4 binds to RelA, resulting in the stimulation of NF- ⁇ and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell Biol., 2009, 29: 1375-1387; Zhang et al., J. Biol Chem., 2012, doi / 10.1074 / jbc.Ml 12.359505).
• the extra-terminal domain of BRD2, BRD3 and BRD4 interacts with several proteins that have a role in chromatin modulation and regulation of gene expression (Rahman et al., Mol. Cell Biol., 2011, 31: 2641-2652).
• BET proteins play an important role in cell growth and cell cycle. Biol. Cell, 2009, 20: 4899-4909, Yang et al., Mol. Cell. Biol., 2008,
• BRD4 is important for the post-mitotic reactivation of gene transcription (Zhao et al., Nat Cell Biol., 2011, 13: 1295-1304). It has been shown that BRD4 is essential for transcription elongation and recruitment of the elongation complex P-TEFb, which consists of CDK9 and cyclin Tl, resulting in the activation of RNA polymerase II (Yang et al., Mol. Cell, 2005, 19 : 535-545, Schröder et al., J. Biol. Chem., 2012, 287: 1090-1099). Consequently, the Expression of genes involved in cell proliferation, such as c-myc and aurora B (You et al., Mol. Cell. Biol., 2009, 29: 5094-5103; Zuber et al., Nature, 2011 , 478: 524-528). BRD2 and BRD3 bind to transcribed genes in hyperacetylated
• RNA polymerase II RNA polymerase II
• BRD4 binds to promoter regions of several genes activated in the Gl phase, such as cyclin D1 and D2 (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040- 9048).
• cyclin D1 and D2 activated in the Gl phase
• inhibition of c-Myc expression, an essential factor in cell proliferation, following BRD4 inhibition has been demonstrated (Dawson et al., Nature, 2011, 478: 529-533, Delmore et al., Cell, 2011, 146: 1-14, Mertz et al., Proc Natl Acad., USA, 2011, 108: 16669-16674).
• BET proteins play an important role in various tumor types.
• the fusion protein prevents cell differentiation and requires proliferation (Yan et al., J. Biol. Chem., 2011, 286: 27663-27675).
• the growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073).
• Screening for therapeutic targets in an acute myeloid leukemia cell line (AML) showed that BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, doi: 10.1038). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis.
• Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo.
• Amplification of the DNA region containing the BRD4 gene has been detected in primary breast tumors (Kadota et al., Cancer Res, 2009, 69: 7357-7365). Also for BRD2 there is data related to a role in tumors. A transgenic mouse that selectively overexpressing BRD2 in B cells develops B-cell lymphomas and leukemias (Greenwall et al., Blood, 2005, 103: 1475-1484).
• BET proteins are also involved in viral infections.
• BRD4 binds to the E2 protein of various papillomaviruses and is important for survival of the viruses in latently infected cells (Wu et al., Genes Dev., 2006, 20: 2383-2396; Vosa et al., J. Virol., 2012 , 86: 348-357). That too Herpesviras, which is responsible for Kaposi's sarcoma, interacts with various BET proteins, which is important for disease resistance (Viejo-Borbolla et al., J. Virol., 2005, 79: 13618-13629, You et al. J.
• BRD4 By binding to P-TEFb, BRD4 also plays an important role in the replication of HIV (Bisgrove et al., Proc Natl Acad., USA, 2007, 104: 13690-13695).
• BET proteins are also involved in inflammatory processes.
• BRD2-hypomorphic mice show reduced inflammation in adipose tissue (Wang et al., Biochem J., 2009, 425: 71-83).
• the infiltration of macrophages into white adipose tissue is also reduced in BRD2-deficient mice (Wang et al., Biochem J., 2009, 425: 71-83).
• BRD4 regulates a number of genes involved in inflammation.
• Macrophages prevent a BRD4 inhibitor from expression of inflammatory genes, such as IL-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1119-1123).
• BET proteins also regulate the expression of the ApoAl gene, which plays an important role in
• Apolipoprotein AI is a major component of high density lipoproteins (HDL) and increased expression of ApoAl results in elevated blood cholesterol levels (Degoma and Rader, Nat. Rev. Cardiol., 2011, 8: 266-277). Elevated HDL levels are associated with a decreased risk of atherosclerosis (Chapman et al., Eur. Heart J., 2011, 32: 1345-1361). All of these studies show that the BET proteins play an essential role in different
• the first published BRD4 inhibitors are phenyl-thieno-triazolo-l, 4-diazepine (4-phenyl-6H-thieno [3,2-] [l, 2,4] triazolo [4,3-a] [l, 4] diazepines) as described in WO2009 / 084693 (Mitsubishi Tanabe Pharma Corporation) and with the compound JQ1 in WO2011 / 143669 (Dana Farber Cancer Institute). Replacement of the thieno by a benzo moiety also results in active inhibitors (J. Med. Chem., 2011, 54, 3827-3838, E. Nicodeme et al., Nature 2010, 468, 1119).
• WO2012 / 075383 (Constellation Pharmaceuticals) describes 6-substituted-4H-isoxazolo [5,4-i] [2] benzazepines and 4H-isoxazolo [3,4-i] [2] benzazepines, including compounds optionally substituted at position 6 Have phenyl, as BRD4 inhibitors and also analogs with alternative heterocyclic fusion partners instead of the benzo moiety, eg Thieno or pyridoazepines.
• WO2013 / 184876 and WO2013 / 184878 (Constellation Pharmaceuticals) describe further benzoisoxazoloazepine derivatives as inhibitors of bromodomain-containing proteins.
• BRD4 inhibitors Another structural class of BRD4 inhibitors is 7-isoxazoloquinolines and related quinolone derivatives (WO2011 / 054843, Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967, GlaxoSmithKline). Pyridinones and pyridazinones (WO 2013/185284, WO 2013/188381, Abbott Laboratories) and isoindolones (WO 2013/155695 and WO
• Ligands of the gastrin and the cholecystokinin receptor are described in WO2006 / 051312 (James Black Foundation). They also include substituted 3,5-dihydro-4H-2,3-benzodiazepin-4-ones, which differ from the compounds of the invention mainly by the obligatory oxo group in position 4 and by a mandatory, carbonyl-containing alkyl chain in position 5. Finally, substituted 3,5-dihydro-4H-2,3-benzodiazepin-4-ones are also described as AMPA antagonists in WO97 / 34878 (Cocensys Inc.). Despite a very broad generic claim regarding the possible substitution patterns on the benzodiazepine skeleton, the embodiments are limited to a narrow range.
• the compounds according to the invention are novel phenyl-2,3-benzodiazepines (1-phenyl-4,5-dihydro-3H-2,3-benzodiazepines) and heteroaryl-2,3-benzodiazepines (1-heteroaryl-4,5-dihydroxy) 3H-2,3-benzodiazepines) that on the benzodiazepine backbone do not fuse with a second heterocyclic one
• the compounds according to the invention differ from known 2,3-benzodiazepines such as the numerous published AMPA antagonists (WOO 198280, Annovis Inc, WO 9728135, Schering AG, for an overview see Med. Res. Rev. 2007, 27 (2) , 239-278) or analogous diazepines in which the benzo moiety is replaced by another monocyclic moiety, by their substitution pattern on the phenyl group or on the benzo moiety or other monocyclic moiety: at least one substituent on the phenyl group or at the benzo unit is cyclic ((hetero) aromatic, (hetero) cyclic) or is new at the appropriate position such as Trifluoromethoxy or alkylaminosulfonylphenyl on the benzo moiety.
• AMPA antagonists WOO 198280, Annovis Inc, WO 9728135, Schering AG, for an overview see Med. Res. Rev. 2007, 27 (2) , 239-278
• analogous diazepines in which the be
• the compounds according to the invention also differ from the known compounds psychopharmacological 2,3-benzodiazepine derivatives which are inhibitors of the adenosine transporter and the MT2 receptor (WO2008 / 124075, Teva Pharm).
• the compounds of the invention inhibit the interaction between BET proteins, in particular BRD4, and an acetylated histone 4 peptide and inhibit the growth of cancer cells. They thus represent new structures for the therapy of human and animal diseases, in particular of cancers.
• X is an oxygen or sulfur atom
• A is a monocyclic heteroaryl ring with 5 or 6 ring atoms
• R la 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 be on or may be monosubstituted, identically or differently substituted by halogen, cyano, nitro, hydroxyl, amino, oxo, carboxy, 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, C 1 -C 6 -alkylcarbonylamino, amino-C 1 -C 6
• n 0, 1 or 2
• R 1b is halogen, hydroxy, cyano, nitro or a C 1 -C 6 -alkyl-,
• Ci-Ce-alkoxy Ci-C 6 alkoxy-C 6 alkyl, halo-Ci-Ce-alkyl, halo-Ci-C 6 - alkoxy, C3-Cio-cycloalkyl radical or an monocyclic heterocyclyl radical with 3 to
• R 2 is a C 1 -C 3 -alkyl or trifluoromethyl or a C 3 or C 1 -cycloalkyl radical
• R 3 is cyclopropyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino, cyclopropylamino or
• R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino,
• 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 -alkylaminosulfonyl, which may be mono- or polysubstituted, may be the same or different substituted with halogen, amino,
• C 3 -C 10 -cycloalkyl- which may optionally be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, 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, halogeno-C 1 -C 6 -alkyl-, halogen-C 1 -C 6 -alkyl- Alkoxy, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
• monocyclic heteroaryl having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, cyano, nitro, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy , Ci-Ce-alkoxy-Ci-Ce-alkyl,
• phenyl which may optionally be monosubstituted or polysubstituted by identical or different substituents, is halogen, amino, hydroxyl, cyano, nitro, carboxy, 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 -alkylaminosulfonyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl-, Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkoxy, C 3 -C 10
• R 8 represents hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy-C 1 -C 3 Alkyl, Cs-Cg-cycloalkyl, phenyl, monocyclic
• R 9 is C 1 -C 6 -alkyl-
• physiologically acceptable salts and solvates of these salts are particularly well suited for a variety of prophylactic and therapeutic uses, especially in
• hyperproliferative diseases in tumor diseases and as BET protein inhibitors, in particular as inhibitors of BRD4, in viral infections, in neurodegenerative disorders
• X is an oxygen atom, represents a monocyclic heteroaryl ring having 6 ring atoms, which may contain one or two nitrogen atoms,
• 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 -alkylaminosulfonyl, which may be mono- or polysubstituted, may be identical or different substituted with halogen, amino, hydroxy, carboxy, 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- or amino-C 1 -C 6 -alkyl, monocyclic heterocyclyl having 3 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, wherein said monocyclic heterocyclyl and heteroaryl radicals in
• eC3-Cio-cycloalkyl which may optionally be monosubstituted or polysubstituted by identical or different substituents, with halogen, amino, hydroxyl, carboxy, 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, halogeno-C 1 -C 6 -alkyl-, halogeno-C 1 -C 4 -alkyl-, -C6-alkoxy, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
• monocyclic heteroaryl having 5 or 6 ring atoms which may be monosubstituted or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, cyano, nitro, carboxy, Ci-C6-alkyl, Ci-C6-alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, 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, Halogen-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
• monocyclic heterocyclyl having 3 to 8 ring atoms which may be monosubstituted or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, oxo, carboxy, 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-, Halogen-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
• phenyl which may optionally be monosubstituted or polysubstituted by identical or different substituents, is halogen, amino, hydroxyl, cyano, nitro, carboxy, 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 -alkylaminosulfonyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl , Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or
• R 9 is C 1 -C 6 -alkyl-
• X is an oxygen atom
• A is a phenyl ring
• R la for a Heterospirocycloalkyl-, Heterobicycloalkyl- or a
• n 0 or 1
• R 1b is halogen, hydroxy, cyano, nitro or a C 1 -C 3 -alkyl-,
• R 2 is methyl
• R 3 is cyclopropyl, C 1 -C 3 -alkyl, cyclopropylamino or C 1 -C 3 -alkylamino-,
• R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino,
• 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 -alkylaminosulfonyl, which may be mono- or polysubstituted, may be the same or different substituted with halogen, amino, hydroxy, carboxy, Hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino or amino-C 1 -C 3 -cycloalkyl
• C 3 -C 7 -cycloalkyl- which may optionally be monosubstituted or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, carboxy, C 1 -C 5 -alkyl-, C 1 -C 3 -alkoxy-, C 1 -C 3 - Alkylamino, aminoCi-Cs-alkyl, fluoro-C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkoxy, or a monocyclic heterocyclyl radical having 5 or 6 ring atoms,
• monocyclic heterocyclyl having 3 to 8 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, oxo, carboxy, Ci-C3-alkyl, Ci-C3-alkoxy, C1-C3-alkylamino, amino-Ci-C3-alkyl, hydroxy-Ci-C3-alkyl, fluoro-Ci-C3-alkyl, fluoro-Ci-C3-alkoxy, C3-C 7 -cycloalkyl- , or a monocyclic heterocyclyl radical having 5 or 6 ring atoms,
• phenyl which is optionally mono- or may be multiple, identical or different substituents selected from halogen, amino, hydroxy, cyano, nitro, carboxyl, Ci- C 3 alkyl, Ci-C 3 alkoxy, C 3 -Alkylamino, amino-C 1 -C 3 -alkyl, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulphonyl, hydroxy-C 1 -C 3 -alkyl-, fluoro-C 1 -C 3 -alkyl-, fluoro-C 1 -C 3 -alkyl Alkoxy, C 3 -C 7 -cycloalkyl, or a monocyclic heterocyclyl radical having 5 or 6 ring atoms,
• X is an oxygen atom
• A is a phenyl ring
• R la for a Heterospirocycloalkyl-, Heterobicycloalkyl- or a
• n 0 or 1
• R 1b is halogen, hydroxy, cyano, nitro or a C 1 -C 3 -alkyl-,
• R 2 is methyl
• R 3 is cyclopropyl, C 1 -C 3 -alkyl, cyclopropylamino or C 1 -C 3 -alkylamino-,
• R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino,
• Alkylaminosulfonyl which may optionally be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino or amino-C 1 -C 3 -alkyl,
• monocyclic heteroaryl having 5 or 6 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, carboxy, Ci-C3-alkyl, Ci-C3-alkoxy, hydroxy-Ci-C3-alkyl, Ci-C3-alkylamino , Amino-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkoxy, C 3 -C 7 -cycloalkyl, or a monocyclic heterocyclyl radical having 5 or 6 ring atoms,
• monocyclic heterocyclyl having 3 to 8 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, oxo, carboxy, Ci-C3-alkyl, Ci-C3-alkoxy, C1-C3-alkylamino, amino-Ci-C3-alkyl, hydroxy-Ci-C3-alkyl, fluoro-Ci-C3-alkyl, fluoro-Ci-C3-alkoxy, C3-C 7 -cycloalkyl- , or a monocyclic
• phenyl which is optionally mono- or may be multiple, identical or different substituents selected from halogen, amino, hydroxy, cyano, nitro, carboxyl, Ci- C 3 alkyl, Ci-C 3 alkoxy, C 3 -Alkylamino, amino-C 1 -C 3 -alkyl, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulphonyl, hydroxy-C 1 -C 3 -alkyl-, fluoro-C 1 -C 3 -alkyl-, fluoro-C 1 -C 3 -alkyl alkoxy, C3-C 7 cycloalkyl, or
• monocyclic heterocyclyl radical having 5 or 6 ring atoms, independently of one another, being hydrogen, C 1 -C 3 -alkyl-, cyclopropyl-, or di-C 1 -C 3 -alkyl-amino-C 1 -C 3 -alkyl-,
• R is hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 3 -alkyl, hydroxy-C 1 -C 4 -alkyl
• R 9 is C 1 -C 4 -alkyl-
• X is an oxygen atom
• A is a phenyl ring
• R la for a Heterospirocycloalkyl-, Heterobicycloalkyl- or a
• C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkyl or fluoro-C 1 -C 3 -alkoxy radical represents methyl
• Ci-C4-alkyl Ci-C 4 alkoxy, Ci-Ce-alkylamino, Ci-C 4 - alkylcarbonylamino, Ci-C4-alkylaminocarbonyl or C1-C4 alkylaminosulfonyl, optionally containing one - or polysubstituted, identically or differently, with halogen, amino, hydroxyl, carboxy, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino or amino-C 1 -C 3 -alkyl- .
• monocyclic heteroaryl having 5 or 6 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, carboxy, Ci-C3-alkyl, Ci-C3-alkoxy-, Fluoro-C 1 -C 3 -alkyl-, or fluoro-C 1 -C 3 -alkoxy-,
• monocyclic heterocyclyl having 3 to 8 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, oxo, carboxy, Ci-C3-alkyl, Ci-C3-alkoxy, Fluoro-C 1 -C 3 -alkyl-, or fluoro-C 1 -C 3 -alkoxy-,
• phenyl which may optionally be mono- or polysubstituted by identical or different substituents, is halogen, amino, hydroxy, cyano, nitro, carboxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl, fluorine-C 1 -C 3 -alkyl-, or fluoro-C 1 -C 3 -alkoxy-, for hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 4 -alkyl, 3 alkyl, hydroxy-C 3 - alkyl, C3-C8-cycloalkyl, phenyl, monocyclic heterocyclyl having 4 to 7 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, as well as
• X is an oxygen atom
• A is a phenyl ring
• n 0 or 1
• R 1b represents fluorine, chlorine or cyano
• R 2 is methyl
• R 3 is methyl or C 1 -C 3 -alkylamino
• R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano,
• C 1 -C 1 -alkyl-, C 1 -C -alkoxy- which may optionally be mono- or polysubstituted by the same or different substituents with fluorine, amino, hydroxyl, carboxy, C 1 -C 3 -alkoxy,
• monocyclic heterocyclyl having 4 to 7 ring atoms which may optionally be monosubstituted or polysubstituted by identical or different substituents, with halogen, cyano, oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoro-ci C 3 alkyl, fluoro C 1 -C 3 alkoxy,
• phenyl which may optionally be monosubstituted or polysubstituted by identical or different substituents, with halogen, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkyl, fluoro Ci-C 3 -alkoxy,
• R 8 is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
• A is a phenyl ring
• n 0 or 1
• R 1b represents fluorine, chlorine or cyano
• R 2 is methyl
• R 3 is methyl or C 1 -C 3 -alkylamino
• R 4 is hydrogen or C 1 -C 3 -alkoxy
• R 5 is hydrogen, C 1 -C 3 -alkoxy or fluoro-C 1 -C 3 -alkoxy
• R 8 is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy - stands,
• X is an oxygen atom
• A is a phenyl ring
• R la represents the radicals 2-azabicyclo [2.2.1] heptyl, 2,5-diazabicyclo [2.2.1] heptyl,
• n 0 or 1
• R lb is fluorine
• R 2 is methyl
• R 3 is methyl or C 1 -C 3 -alkylamino
• R 4 is hydrogen or C 1 -C 3 -alkoxy
• R 5 is hydrogen, C 1 -C 3 -alkoxy or fluoro-C 1 -C 3 -alkoxy
• R 8 is Ci-C 4 Alkyl or C 1 -C 4 -alkoxy -
• X is an oxygen atom
• A is a phenyl ring
• R lb is fluorine
• R 2 is methyl
• R 3 is C 1 -C 3 -alkylamino
• R 4 is hydrogen or methoxy
• R 5 is methoxy, trifluoromethoxy or 3,5-dimethylpyrazol-1-yl
• R 8 is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
• X is an oxygen atom
• A is a phenyl ring
• n 0 or 1
• R lb is fluorine
• R 2 is methyl
• R 3 is C 1 -C 3 -alkylamino
• R 4 is hydrogen or methoxy
• R 5 is methoxy, trifluoromethoxy, or 3,5-dimethylpyrazol-1-yl
• R 8 is methyl or tert. -Butoxy- stands,
• X is an oxygen atom
• A is a phenyl ring
• n 0 or 1
• R lb is fluorine
• R 2 is methyl
• R 3 is methylamino
• R 4 is hydrogen or methoxy
• R 5 is methoxy, trifluoromethoxy or 3,5-dimethylpyrazol-1-yl, and also their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates,
• spirocycloalkyl is 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 be mono- or polysubstituted, may be identical or different substituted with halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, hydroxy C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, amino-C 1 -C 6 -alkyl-,
• Ci-Ce-alkoxy Ci-C 6 alkoxy-C 6 alkyl, halo-Ci-Ce-alkyl, halo-Ci-C 6 - alkoxy, C3-Cio-cycloalkyl radical, and / or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
• R 3 represents cyclopropyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino, cyclopropylamino or ci
• R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino,
• 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 -alkylaminosulfonyl which may be mono- or polysubstituted, may be identical or different substituted with halogen, amino, hydroxy, carboxy, hydroxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl
• C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, monocyclic heterocyclyl having 3 to 8 ring atoms and / or monocyclic heteroaryl having 5 or 6 ring atoms, wherein said monocyclic heterocyclyl and heteroaryl radicals in turn may be optionally monosubstituted can be represented by C 1 -C 3 -alkyl,
• C 3 -C 10 -cycloalkyl- which may optionally be mono- or polysubstituted by the same or different substituents with halogen, amino, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -cycloalkyl- C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy , and / or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
• phenyl which may be mono- or polysubstituted by identical or different substituents may be halogen, amino, hydroxy, cyano, nitro, carboxy, Ci-C6-alkyl, CI-C ⁇ -alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-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-, halogeno-C 1 -C 6 -Alkyl, halogen-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl and / or a monocyclic heterocyclyl radical having 3 to 8 ring
• R 6 and R 7 independently of one another are hydrogen, C 1 -C 3 -alkyl, cyclopropyl or C 1 -C 1 -C 3 -alkylamino-C 1 -C 3 -alkyl-,
• R 8 is hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen-C 1 -C 3 -alkyl-, hydroxy-C 1 -C 3 -
• Ring atoms is in which phenyl, heteroaryl and heterocyclyl may optionally be mono- or disubstituted by halogen, Ci-C3-alkoxy or C1-C3-alkyl, and
• R 9 is C 1 -C 6 -alkyl-
• X is an oxygen atom
• A is a phenyl ring
• R la is a group selected from bicyclo [2.2.1] heptyl
• Halogen, cyano, hydroxyl, Ci-C i-alkyl, fluoro Ci-C i-alkyl, Ci-C i-alkoxy, fluoro-Ci-C i-alkoxy, C3-C8-cycloalkyl, monocyclic heterocyclyl with 3 to 8 ring members, phenyl, halophenyl, phenyl-C 1 -C 2 -alkyl, phenoxy-, and / or -C ( O) -R 8 ,
• n 0 or 1
• R 1b represents fluorine, chlorine or cyano
• R 2 is methyl
• R 3 is methyl or C 1 -C 3 -alkylamino
• R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano,
• C 1 -C 4 -alkyl-, C 1 -C 4 -alkoxy- which may optionally be monosubstituted or polysubstituted by identical or different substituents with fluorine, amino, hydroxyl, carboxy,
• a monocyclic heteroaryl radical having 5 or 6 ring atoms which may optionally be monosubstituted or polysubstituted by identical or different substituents, with halogen, cyano, nitro, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoroC 1 -C 3 Alkyl, fluoro-C 1 -C 3 -alkoxy,
• a monocyclic heterocyclyl radical having 4 to 7 ring atoms which may optionally be monosubstituted or polysubstituted by identical or different substituents, with halogen, cyano, oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoroC 1 -C 3 Alkyl, fluoro-C 1 -C 3 -alkoxy,
• phenyl radical which may be monosubstituted or polysubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkyl, fluoro-C 1 -C 4 -alkyl, C3 alkoxy, and
• R 8 is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
• X is an oxygen atom
• A is a phenyl ring
• R la is a group selected from bicyclo [2.2.1] heptyl
• each of the abovementioned groups may optionally be substituted once or twice, identically or differently, by oxo, halogen, cyano, hydroxyl, C 1 -C 4 -alkyl, fluorine-C 1 -C 4 -alkyl-, C 1 -C 4 - alkoxy,
• Fluorine-Ci-C t-alkoxy, C3-C8-cycloalkyl, monocyclic heterocyclyl having 3 to 8 ring members, phenyl, halophenyl, phenyl-Ci-C 2 alkyl, phenoxy, and / or - C ( 0 ) -R 8 ,
• n 0 or 1
• R 1b represents fluorine, chlorine or cyano
• R 2 is methyl
• R 3 is methyl or C 1 -C 3 -alkylamino
• R 4 is hydrogen or C 1 -C 3 -alkoxy
• R 5 is hydrogen, Ci-C3-alkoxy or fluoro-Ci-C3-alkoxy- stands, or for one
• Heteroaryl radical having 5 or 6 ring atoms which may be monosubstituted or disubstituted by Ci-C3-alkyl, Ci-C3-alkoxy and / or halogen, and R 8 is Ci-C 4 -alkyl or Ci-C 4 Alkoxy - stands,
• A is a phenyl ring
• R la is a group selected from 2-azabicyclo [2.2.1] heptyl, 1-thia-6-azaspiro [3.3] heptyl, 8-oxa-3-azabicyclo [3.2.1] octyl, 2-oxa-6-azaspiro [3.3] heptyl, 8-azabicyclo [3.2.
• Alkyl, fluoro-Ci-C4-alkyl, Ci-C 4 alkoxy, fluoro-Ci-C 4 alkoxy, C 3 -C 8 - cycloalkyl, monocyclic heterocyclyl having 3 to 8 ring members, phenyl, halophenyl, Phenyl-C 1 -C 2 -alkyl-, phenoxy-, and / or -C ( O) -R 8 , n is 0 or 1, R lb is fluorine,
• R 2 is methyl
• R 3 is methyl or C 1 -C 3 -alkylamino
• R 4 is hydrogen or C 1 -C 3 -alkoxy
• R 5 is hydrogen, Ci-C3-alkoxy or fluoro-Ci-C3-alkoxy- stands, or for one
• Heteroaryl radical having 5 ring atoms, which contains at least one nitrogen atom, via which it is bonded to the rest of the molecule, and which may be mono- or disubstituted by Ci-C3-alkyl and / or halogen, and
• R 8 is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
• X is an oxygen atom
• A is a phenyl ring
• R la for a group is selected
• R 8 is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
• X is an oxygen atom
• A is a phenyl ring
• R la for a greeting is selected
• n 0 or 1
• R lb is fluorine
• R 2 is methyl
• R 3 is C 1 -C 3 -alkylamino
• R 4 is hydrogen or methoxy
• R 5 is methoxy, trifluoromethoxy, or 3,5-dimethylpyrazol-1-yl
• R 8 is methyl or tert. -Butoxy- stands,
• A is a phenyl ring
• R la for a group is selected
• R 4 is hydrogen or methoxy
• R 5 is methoxy, trifluoromethoxy, or 3,5-dimethylpyrazol-1-yl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
• X is an oxygen atom
• A is a phenyl ring
• R la for a group is selected
• n 0 or 1
• R lb is fluorine
• R 2 is methyl
• R 3 is methylamino
• R 4 is hydrogen or methoxy
• R 5 is methoxy, trifluoromethoxy, or 3,5-dimethylpyrazol-1-yl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates,
• (4S) -7,8-dimethoxy-N 4-dimethyl-1- [4- (2-oxa-6-azaspiro [3.3] hept-6-yl) -phenyl] -4,5-dihydro-3H-2 , 3-benzodiazepin-3-carboxamide
• (4R) -7,8-dimethoxy-N 4-dimethyl-1- [4- (2-oxa-6-azaspiro [3.3] hept-6-yl) -phenyl] -4,5-dihydro-3H- 2,3-benzodiazepin-3-carboxamide;
• X may represent an oxygen or sulfur atom.
• X is preferably an oxygen atom.
• A may represent a monocyclic heteroaryl ring having 5 or 6 ring atoms or a phenyl ring.
• A preferably represents a monocyclic, 6-membered heteroaryl ring which may contain one or two nitrogen atoms, or a phenyl ring.
• A is more preferably a phenyl ring.
• R 1a is preferably a heterospirocycloalkyl-
• R la is more preferably a Heterospirocycloalkyl-, Heterobicycloalkyl- or a bridged heterocycloalkyl radical, a naphthyl radical or a bicyclic heteroaryl, or a partially saturated bicyclic aryl group, where the radicals mentioned may optionally be mono- or polysubstituted by identical or may be substituted differently with halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, Ci-C i-alkyl, Ci-C i-alkoxy, hydroxy-Ci-C i-alkyl, Ci-C4-alkylamino , C 1 -C 4 -alkylcarbonylamino, amino-C 1 -C -alkyl, fluoro-C 1 -C -alkyl, fluoro C 1 -C 4 -alkoxy, C 3 -C 8 -cycloalkyl, pheny
• R 1a very particularly preferably represents the radicals
• Heterocyclyl- with 3 to 8 ring members, phenyl, halophenyl, phenyl-Ci-C2-alkyl, phenoxy, or -C ( 0) -R 8 .
• R la also very particularly preferably represents the radicals
• R la is further very particularly preferably represents a group which is selected from bicyclo [2.2.1] heptyl, spiro [3.3] heptyl, bicyclo [3.2.1] octyl, spiro [3.4 ] octyl-, spiro [4.5] decyl-, wherein said groups independently contain at least one, optionally also two heteroatoms selected from oxygen, nitrogen and sulfur, which may be identical or different,
• each of the abovementioned groups may optionally be substituted, independently of one another, once or twice, identically or differently, by oxo, halogen, cyano, hydroxyl, C 1 -C 1 -alkyl-, fluoro-C 1 -C 4 -alkyl-, C 1 -C 4 -alkyl i-alkoxy, fluoro-Ci-C i-alkoxy, C3-C8-cycloalkyl, monocyclic
• Heterocyclyl- with 3 to 8 ring members, phenyl, halophenyl, phenyl-Ci-C2-alkyl, phenoxy, or -C ( 0) -R 8 .
• R la is extremely preferred for the radicals 2- azabicyclo [2.2.1] heptyl, 2,5-diazabicyclo [2.2.1] heptyl, 2-oxa-5-azabicyclo [2.2.
• R 1a is furthermore exceptionally preferably the radicals
• R preferably represents halogen, hydroxy, cyano, nitro or a C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl- , halo-Ci-C 6 -alkyl, halo-C 6 - alkoxy, C3-Cio-cycloalkyl radical or a monocyclic heterocyclyl radical having 3 to 8
• R 1b is particularly preferably halogen, hydroxy, cyano, or a C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkyl or fluorine C 1 -C 3 -alkoxy radical.
• R 1b very particularly preferably represents fluorine, chlorine or cyano.
• R 1b is extremely particularly preferably fluorine.
• n may be 0, 1 or 2.
• n is more preferably 0 or 1. In the general formula (I), n is more preferably 1.
• n is particularly preferably 0.
• R 2 may be a C 1 -C 3 -alkyl or trifluoromethyl or a C 3 - or C 1 -cycloalkyl radical.
• R 2 is preferably a methyl radical.
• R 3 may be a cyclopropyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino, cyclopropylamino or a C 1 -C 3 -alkylamino radical.
• R 3 particularly preferably represents a Ci-C 3 alkyl or a Ci-C 3 - alkylamino.
• R 3 very particularly preferably represents a methyl or a C 1 -C 3 -alkylamino radical.
• R 3 very particularly preferably represents a methyl radical.
• R 3 very particularly preferably represents a C 1 -C 3 -alkylamino radical.
• R 3 is a methylamino radical.
• R 4 and R 5 may independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine,
• C 3 -C 10 -cycloalkyl- which may optionally be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, carboxy, 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, halogeno-C 1 -C 6 -alkyl-, halogeno-C 1 -C 6 -alkyl- Alkoxy, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
• monocyclic heteroaryl having 5 or 6 ring atoms which may be monosubstituted or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, cyano, nitro, carboxy, Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-C 6 alkoxy-C 6 -alkyl, hydroxy-C 6 alkyl, Ci-C 6 - alkylamino, amino-Ci-C6-alkyl, Ci-C6-alkylamino-Ci C6-alkyl, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
• monocyclic heterocyclyl having 3 to 8 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, cyano, oxo, carboxy, Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-C 6 alkoxy-C 6 alkyl, Ci-Ce-alkylamino, amino-Ci-Ce-alkyl, Ci-Ce-alkylamino-Ci-Ce-alkyl, hydroxy-Ci-C 6 -Alkyl, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or
• phenyl which may optionally be monosubstituted or polysubstituted by identical or different substituents, is halogen, amino, hydroxy, cyano, nitro, carboxy, 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 -alkylaminosulfonyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl-, Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl or a monocyclic
• R 4 and R 5 independently of one another more preferably represent hydrogen, hydroxyl, 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 -alkylaminosulfonyl which may be mono- or polysubstituted, may be monosubstituted or differently substituted by halogen, amino, hydroxy, carboxy, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino or amino-C 1 -C 3 -alkyl-,
• C 3 -C 7 -cycloalkyl which may optionally be mono- or polysubstituted by identical or different substituents, with halogen, amino, hydroxy, carboxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino , Amino-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkoxy, or a monocyclic heterocyclyl radical having 5 or 6 ring atoms,
• monocyclic heteroaryl having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, carboxy, Ci-C 3 alkyl, Ci-C 3 alkoxy , C 1 -C 4 -alkyl, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkoxy, C 3 -C 4 -alkyl, C 7 cycloalkyl, or a monocyclic
• monocyclic heterocyclyl having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, oxo, carboxy, Ci-C 3 alkyl, Ci-C 3 alkoxy -, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkoxy, C 3 - C 7 cycloalkyl, or a monocyclic
• phenyl which may optionally be monosubstituted or polysubstituted by identical or different substituents, is halogen, amino, hydroxyl, cyano, nitro, carboxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino , Amino-C 1 -C 3 -alkyl, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl, hydroxy-C 1 -C 3 Alkyl, fluoro-C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkoxy, C 3 -C 7 -cycloalkyl, or a monocyclic heterocyclyl radical having 5 or 6 ring atoms.
• R 4 and R 5 independently of one another are very particularly preferably hydrogen, hydroxyl, cyano, aminocarbonyl, fluorine, chlorine, bromine,
• C 1 -C 4 -alkyl-, C 1 -C 4 -alkoxy which may optionally be mono- or polysubstituted by identical or different substituents, with fluorine, amino, hydroxyl, carboxy, C 1 -C 3 -alkoxy,
• monocyclic heteroaryl having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents with halogen, cyano, nitro, Ci-C3-alkyl, C 1 -C3-alkoxy, fluoro-Ci-Cs Alkyl, fluoro-C 1 -C 3 -alkoxy,
• monocyclic heterocyclyl having 4 to 7 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents with halogen, cyano, oxo, Ci-C3-alkyl, Ci-C3-alkoxy, fluoro-Ci-C 3 Alkyl, fluoro-C 1 -C 3 -alkoxy,
• phenyl which may optionally be mono- or polysubstituted by identical or different substituents selected from halogen, cyano, Ci-C 3 alkyl, Ci-C 3 alkoxy, fluoro-Ci-C 3 alkyl, fluoro Ci-C 3 -alkoxy.
• R 4 is also very particularly preferably hydrogen or C 1 -C 3 -alkoxy.
• R 5 is also very particularly preferably hydrogen, C 1 -C 3 -alkoxy or fluoro-C 1 -C 3 -alkoxy, or a heteroaryl radical having 5 or 6 ring atoms which is monosubstituted or disubstituted may be C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or halogen.
• R 5 is particularly preferably hydrogen, C 1 -C 3 -alkoxy or fluoro-C 1 -C 3 -alkoxy, or a heteroaryl radical with 5 ring atoms, which contains at least one nitrogen atom, via which it is bonded to the rest of the molecule, and which may be mono- or disubstituted by Ci-C3-alkyl or halogen.
• R 5 is for Methoxy, trifluoromethoxy, or 3,5-dimethylpyrazol-1-yl.
• R 6 and R 7 are preferably hydrogen, C 1 -C 3 -alkyl-,
• Cyclopropyl or di-C 1 -C 3 -alkyl-amino-C 1 -C 3 -alkyl-.
• R 8 is preferably hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 3 -alkoxy-C 1 -C 3 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, monocyclic heterocyclyl having 3 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms.
• R 8 particularly preferably represents hydroxyl, C 1 -C -alkyl-, C 1 -C 4 -alkoxy, fluoro-C 1 -C 3 -alkyl-, hydroxy-C 1 -C 3 -alkyl-, C 3 -C 8 cycloalkyl, phenyl, monocyclic heterocyclyl having 4 to 7 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms.
• R 8 very particularly preferably represents C 1 -C 1 -alkyl or C 1 -C 4 -alkoxy.
• R 9 is preferably C 1 -C 6 -alkyl-.
• R 9 is more preferably Ci-C / i-alkyl-.
• Benzodiazepine skeleton preferably represented stereocenter either racemic or predominantly or completely in the (S) -configuration.
• Benzodiazepine skeleton represented preferred stereocenter stereocenter before. In the general formula (I), this is due to the carbon atom of the carbon atom bonded to R 2
• Benzodiazepine skeleton represented stereocenter particularly preferably predominantly or completely in the (S) configuration.
• Benzodiazepine skeleton represented stereocentre most preferably predominantly in the (S) configuration.
• Benzodiazepine skeleton most preferably represented stereocenter completely in the (S) configuration.
• radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced, irrespective of the particular combinations of radicals indicated, by any definitions of radicals of other combinations. Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.
• ring may be synonymous with the term “radical”, which then also denotes a cyclic radical.
• radical which then also denotes a cyclic radical.
• Alkyl is a linear or branched, saturated, monovalent hydrocarbon radical having generally 1 to 6 (C 1 -C 6 -alkyl), preferably 1 to 4 (C 1 -C 4 -alkyl), and particularly preferably 1 to 3 carbon atoms (C 1 -C 4 -alkyl). C3 alkyl).
• cycloalkyl a methyl, ethyl, propyl, isopropyl or tert-butyl radical.
• Cycloalkyl is a monocyclic, saturated, monovalent hydrocarbon radical having generally 3 to 10 (C 3 -C 10 -cycloalkyl), preferably 3 to 8
• phenyl-Ci-C6-alkyl- is meant a group which is composed of a
• alkyl radical here has the meanings given above under alkyl.
• benzyl examples which may be mentioned are benzyl, phenethyl, phenylpropyl, phenylpentyl, benzyl being preferred.
• Alkoxy represents a linear or branched, saturated alkyl ether radical of the formula -O-alkyl having generally 1 to 6 (C 1 -C 6 -alkoxy), preferably 1 to 4 (C 1 -C 1 -alkoxy), and particularly preferably 1 to 3 (C 1 -C 3 -alkoxy) carbon atoms.
• Alkoxyalkyl is an alkoxy-substituted alkyl radical, for example C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl or C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-.
• Ci-C6-alkoxy-Ci-C6-alkyl- means that the alkoxyalkyl group is bonded via the alkyl moiety to the rest of the molecule.
• Oxo may be attached to atoms of suitable valence, for example to a saturated carbon atom or to sulfur.
• Alkylamino represents an Arninorest with one or two (chosen independently of one another) alkyl substituents having generally 1 to 6 (CI-C ⁇ - alkylamino), preferably 1 to 3 carbon atoms (Ci-C3-AJJ ⁇ ylamino).
• (C 1 -C 3) -Alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent. Examples include:
• alkyl moiety. alkylaminosulfonyl
• Methylaminosulfonyl ethylaminosulfonyl, dimethylaminosulfonyl.
• Heteroatoms are oxygen, nitrogen or sulfur atoms.
• Aryl is a monovalent, mono- or bicyclic carbon atom aromatic ring system. Examples are naphthyl and phenyl; preferred is phenyl or a phenyl radical.
• Halophenyl- denotes a mono- or polysubstituted by identical or different fluorine, chlorine or bromine substituted phenyl radical.
• Heteroaryl means a monovalent, mono- or bicyclic, aromatic ring system having one, two, three or four heteroatoms, which may be the same or different. As heteroatoms nitrogen atoms, oxygen atoms or sulfur atoms can occur. The bond valency may be at any aromatic carbon atom or at a nitrogen atom.
• a monocyclic heteroaryl group according to the present invention has 5 or 6 ring atoms. Preference is given to those heteroaryl radicals having one or two heteroatoms. Particularly preferred are one or two nitrogen atoms.
• heteroaryl radicals having 5 ring atoms include the rings:
• Heteroaryl radicals having 6 ring atoms include, for example, the rings:
• a bicyclic heteroaryl group according to the present invention has 9 or 10 ring atoms.
• heteroaryl radicals having 9 ring atoms include the rings:
• Heteroaryl radicals with 10 ring atoms include, for example, the rings:
• a partially saturated bicyclic aryl radical or heteroaryl radical represents a bicyclic group consisting of a phenyl radical or a monocyclic, 5- or 6-membered heteroaryl radical which, via two immediately adjacent ring atoms, in each case to an aliphatic cyclic radical with 4 to 7 ring atoms is condensed, which may optionally contain one or two heteroatoms, which may be the same or different.
• heteroatoms nitrogen atoms, oxygen atoms or sulfur atoms can occur.
• Partially saturated bicyclic aryl radicals include, for example, the groups:
• Partially saturated bicyclic heteroaryl radicals include, for example, the groups:
• Monocychic heterocyclyl means a non-aromatic monocyclic ring system having one, two or three heteroatoms which may be the same or different. As heteroatoms nitrogen atoms, oxygen atoms or sulfur atoms can occur.
• a monocyclic heterocyclyl ring according to the present invention may have 3 to 8, preferably 4 to 7, particularly preferably 5 or 6 ring atoms.
• Exemplary and preferred for monocyclic heterocyclyl radicals having 3 ring atoms are: aziridinyl-.
• Exemplary and preferred for monocyclic heterocyclyl radicals having 4 ring atoms are: azetidinyl, oxetanyl.
• azepanyl By way of example and with preference for monocyclic heterocyclyl radicals having 7 ring atoms, mention may be made of azepanyl, oxepanyl, 1,3-diazepanyl, 1,4-diazepanyl-.
• monocyclic heterocyclyl radicals having 8 ring atoms are: oxocanyl, azocanyl.
• Preferred monocyclic heterocyclyl radicals are 4 to 7-membered, saturated
• C5-C12-spirocycloalkyl or C5-C12-heterospirocycloalkyl having a replacement of one, two, three or four carbon atoms by heteroatoms as defined above in any combination a fusion of two saturated ring systems is to be understood, which is a common Share the atom.
• Combination is a fusion of two saturated ring systems that share two atoms directly adjacent to each other. Examples are selected from bicyclo [2.2.0] hexyl, bicyclo [3.3.0] octyl, bicyclo [4.4.0] decyl, bicyclo [5.4.0] undecyl, bicyclo [3.2.0] heptyl, bicyclo 4.2.0] octyl,
• Bicyclo [6.3.0] undecyl and bicyclo [5.4.0] undecyl including heteroatom modified variants such as e.g. Azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl, diazabicyclo [4.3.0] nonyl, oxazabicyclo [4.3.0] nonyl, thiazabicyclo [4.3.0] nonyl or azabicyclo [4.4.0 ] decyl and radicals derived from other possible combinations as defined.
• heteroatom modified variants such as e.g. Azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl, diazabicyclo [4.3.0] nonyl, oxazabicyclo [4.3.0] nonyl, thiazabicyclo [4.3.0] nonyl or azabicyclo [4.4.0 ] decyl and radicals derived from other possible combinations as defined.
• C 1 -C 10 -heterobicycloalkyl Preference is given to C 1 -C 10 -heterobicycloalkyl, by way of example and more preferably perhydrocyclopenta [c] pyrrolyl, perhydrofuro [3,2-c] pyridinyl, perhydropyrrolo [1,2-a] pyrazinyl, perhydropyrrolo [3,4-c] pyrrolyl.
• Preferred examples of C 6 -C 12 bicycloalkyl are perhydronaphthalenyl (decalinyl),
• Bridged cycloalkyl and bridged heterocycloalkyl A bridged C6-Ci2- ingsystem such as bridged C6-Ci2-cycloalkyl or bridged C6-Ci2-Heterocycloalkyl- is to understand a fusion of at least two saturated rings, which share two atoms that are not directly adjacent to each other.
• a bridged carbocycle bridged cycloalkyl
• bridged heterocycle bridged heterocycloalkyl
• halogen includes fluorine, chlorine, bromine and iodine.
• Haloalkyl is an alkyl radical having at least one halogen substituent.
• a halo-C 1 -C 6 -alkyl radical is an alkyl radical having 1-6 carbon atoms and at least one halogen substituent. If several halogen substituents are present, they may also be different. Preference is given to fluorine-C 1 -C 6 -alkyl, fluoro-C 1 -C -alkyl, and fluoro-C 1 -C 3 -alkyl radicals.
• Trifluoromethyl 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,5,5,5-pentafluoropentyl or
• perfluorinated alkyl radicals such as trifluoromethyl or pentafluoroethyl.
• Haloalkoxy is an alkoxy radical having at least one halogen substituent.
• a halo-C 1 -C 6 alkoxy radical is an alkoxy radical having 1-6 carbon atoms and at least one halogen substituent. If several halogen substituents are present, they may also be different. Preference is given to fluorine-C 1 -C 6 -alkoxy, fluorine-C 1 -C 4 -alkoxy, and fluorine-C 1 -C 3 -alkoxy radicals.
• Hydroxyalkyl is an alkyl radical having at least one hydroxy substituent.
• a hydroxy-C 1 -C 6 -alkyl radical is an alkyl radical consisting of 1 -6 carbon atoms and at least one hydroxy substituent.
• Aminoalkyl is an alkyl radical having at least one amino substituent.
• amino-Ci-C6-alkyl radical is an alkyl radical consisting of 1-6 carbon atoms and at least one amino substituent. alkylaminoalkyl
• Alkylaminoalkyl- represents an alkyl radical substituted by alkylamino as defined above, for example C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl or C 1 -C 3 -alkylamino-C 1 -C 3 -alkyl-.
• Ci-C6-alkylamino-Ci-C6-alkyl- means that the alkylaminoalkyl group is bound via the alkyl moiety to the rest of the molecule.
• Di-alkyl-amino-alkyl for example di-Ci-C3-alkyl-amino-Ci-C3-alkyl-, means that the aforementioned alkylamino part obligatorily contains two alkyl groups, which may be the same or different.
• alkylaminoalkyl are N, N-dimethylaminoethyl, N, N-dimethylaminomethyl, N, N-diethylaminoethyl, N, N-dimethylaminopropyl, N-methylaminoethyl, N-methylaminomethyl.
• Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as in the case of the compounds of formula (I), the following compounds are not already Salts, solvates and solvates of the salts.
• Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
• Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic,
• Physiologically acceptable salts of the compounds of the invention further include base addition salts of, for example, alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, or ammonium salts derived from ammonia or organic amines containing 1 to 16 carbon atoms, such as Example methylamine,
• the compounds according to the invention can form base addition salts with quaternary ammonium ions which can be obtained, for example, by Q -emization of corresponding amines with agents such as lower alkyl halides, for example methyl, ethyl, propyl and butyl chlorides, bromides and iodides, dialkyl sulfates such as dimethyl , Diethyl dibutyl and diamyl sulfate, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, or arylalkyl halides such as benzyl bromide or phenethyl bromide.
• agents such as lower alkyl halides, for example methyl, ethyl, propyl and butyl chlorides, bromides and iodides, dialkyl sulfates such as dimethyl , Diethyl dibutyl
• quaternary ammonium ions examples include tetramethylammonium, tetraethylammonium, tetra (n-propyl) ammonium, tetra (n-butyl) ammonium, and benzyltrimethylammonium.
• Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs either as individual polymorphs or may be present as a mixture of several polymorphs in all concentration ranges.
• Another object of the present invention are pharmaceutical compositions containing the compounds of the invention and at least one or more other active ingredients, in particular for the prophylaxis and / or therapy of tumor diseases.
• Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
• the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers.
• the compounds according to the invention have an asymmetric center on the carbon atom to which R 2 is bonded (C-4). They may therefore be present as pure enantiomers, racemates but also as diastereomers or mixtures thereof, if one or more of the substituents described in the formula (I) contains a further asymmetric element,
• the present invention therefore also encompasses diastereomers and their respective mixtures. From the mixtures mentioned, the pure enantiomers and diastereomers can be isolated in a known manner; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on chiral or achiral phase.
• the stereoisomers according to the invention inhibit the target to different degrees and are active in different ways in the cancer cell lines investigated.
• the more active stereoisomer is preferred, which is often that in which the center of asymmetry represented by the carbon atom bound to R 2 is (S) -configured.
• Another object of the present invention are stereoisomeric mixtures of the (45) -configured compounds of the invention with their (4R) isomers, in particular the corresponding racemates, diastereomer and Enantiomerengemische in which outweighs the (45) form.
• the present invention encompasses all tautomeric forms.
• the present invention also includes all suitable isotopic variants of the invention Links.
• An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of
• Certain isotopic variants of a compound of the invention in particular those in which one or more radioactive isotopes are incorporated, may be useful, for example, to study the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
• isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
• isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
• the present invention also includes prodrugs of the compounds of the invention.
• prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
• the compounds according to the invention can act systemically and locally.
• it may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
• the compounds of the invention can be used in suitable forms.
• Administration forms are administered.
• working compounds which release the compounds according to the invention and which contain the compounds according to the invention in crystalline or amorphized or dissolved form are rapidly and functionally modified in accordance with the state of the art.
• tablets or films / wafers rapidly breaking down in the oral cavity films / lyophilisates
• capsules e.g. Soft gelatin capsules
• dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration can be done by bypassing a resorption step (e.g.
• intravenously, intraarterially, intracardially, intraspinally or intralumbarally) or with the involvement of resorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
• parenteral administration are suitable as application forms u.a. Injection and
• Infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhalation medicines i.a.
• Ophthalmic preparations vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, scattering powders, implants or stents.
• the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• adjuvants include, among others.
• Carriers e.g., microcrystalline cellulose, lactose, mannitol
• solvents e.g., liquid polyethylene glycols
• emulsifiers e.g., emulsifiers and dispersing or wetting agents
• binders e.g., polyvinylpyrrolidone
• synthetic and natural polymers e.g., albumin
• stabilizers e.g., antioxidants such as ascorbic acid
• dyes e.g., inorganic pigments such as iron oxides
• compositions containing the compounds of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
• the formulation of the compounds according to the invention into pharmaceutical preparations takes place in in a manner known per se, by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
• excipients examples include excipients, fillers, disintegrants, binders, humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants,
• Preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers are used. Reference may be made to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).
• the pharmaceutical formulations can be any suitable pharmaceutical formulations.
• auxiliaries may be, for example, salts, saccharides (mono-, di-, tri-, oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils,
• Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically.
• the present invention relates to the compounds of the invention.
• They can be used for the prophylaxis and treatment of human diseases, in particular tumors.
• the compounds of the invention can be used in particular to the
• the compounds of the invention are particularly suitable for the prophylaxis and therapy of hyper-proliferative diseases such as
• BPH benign prostatic hyperplasia
• tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland are treatable Bone and connective tissue and metastases of these tumors.
• hematological tumors are treatable
• Leukemias For example, treatable as breast tumors are:
• tumors of the respiratory tract are treatable.
• non-small cell bronchial carcinomas such as squamous cell carcinoma
• Adenocarcinoma large cell carcinoma
• tumors of the brain are treatable.
• tumors of the male reproductive organs are treatable:
• Treatable as tumors of the female reproductive organs for example: endometrial carcinomas
• tumors of the gastrointestinal tract are treatable:
• tumors of the urogenital tract are treatable:
• tumors of the eye are treatable:
• tumors of the liver are treatable:
• tumors of the skin are treatable: Malignant melanomas
• tumors of the head and neck are treatable:
• sarcomas are treatable:
• lymphomas are treatable:
• Treatable as leukemias for example:
• the compounds according to the invention can be used for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas,
• breast cancer in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinoma, pancreatic carcinoma, renal cell carcinoma,
• Bronchial carcinoma, endometrial carcinoma and colorectal carcinoma are particularly advantageous compounds of the invention.
• Prophylaxis and / or therapy of leukemias in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
• the compounds according to the invention are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as, for example, endometriosis, leiomyoma and benign prostatic hyperplasia.
• the compounds according to the invention are also suitable for the fertility control of the man.
• the compounds according to the invention are also suitable for the prophylaxis and / or therapy of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.
• the compounds according to the invention are also suitable for the prophylaxis and therapy of inflammatory or autoimmune diseases such as, for example:
• Lung diseases especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatoses, especially Boeck's disease
• Rheumatoid arthritis / autoimmune disorders / joint diseases associated with inflammatory, allergic and / or proliferative processes all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms of degenerative joint disease (arthrosis); traumatic arthritis; Collagenoses of any genesis, e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Still's syndrome, Felty syndrome
• Vasculitis Panarteritis nodosa, temporal arteritis, erythema nodosum
• Dermatological disorders associated with inflammatory, allergic and / or proliferative processes atopic dermatitis; Psoriasis; Pityriasis rubra pilaris;
• erythematous diseases induced by different noxae e.g. Blasting, chemicals, burns etc .
• bullous dermatoses Diseases of the lichenoid type; pruritus; Seborrheic dermatitis; rosacea; Pemphigus vulgaris; Erythema exudative multiforme; balanitis; vulvitis; Hair loss such as alopecia areata; cutaneous T-cell lymphomas
• Kidney diseases associated with inflammatory, allergic and / or proliferative processes nephrotic syndrome; all nephritis
• Liver diseases associated with inflammatory, allergic and / or proliferative processes acute liver cell decay; acute hepatitis of different causes, e.g. viral, toxic, drug-induced; chronically aggressive and / or chronic intermittent
• Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, e.g. native sprue
• allergic rhinitis hay fever
• External otitis e.g. due to contact problems, infection, etc .
• Neurological diseases associated with inflammatory, allergic and / or proliferative processes brain edema, especially tumor-related cerebral edema; Multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, e.g. BNS
• Blood disorders associated with inflammatory, allergic and / or proliferative processes acquired hemolytic anemia; idiopathic thrombocytopenia
• Tumor diseases associated with inflammatory, allergic and / or proliferative processes acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen;
• lymphosarcoma extensive metastases, especially in mammary, bronchial and prostate cancer
• Endocrine disorders associated with inflammatory, allergic and / or proliferative processes endocrine orbitopathy; thyrotoxic crisis; Thyreoditis de Quervain; Hashimoto's thyroiditis; Graves' disease
• Severe states of shock e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
• SIRS systemic inflammatory response syndrome
• Emesis associated with inflammatory, allergic and / or proliferative processes e.g. in combination with a 5-HT3 antagonist in cytostatic vomiting - pain of inflammatory genesis, e.g. lumbago
• the compounds according to the invention are also suitable for the treatment of viral
• Diseases such as infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.
• the compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, periferous vascular diseases, cardiovascular diseases, angina, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.
• the compounds of the invention are also useful in the treatment of neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease.
• Another object of the present application are the compounds of the invention for use as medicaments, in particular for the prophylaxis and / or therapy of
• a further subject of the present application are the compound according to the invention prophylaxis and therapy of leukemias, in particular acute myeolemic leukemias, Prostate cancer, especially androgen receptor-positive prostate cancer,
• Hormone receptor-positive or BRCA-associated breast carcinomas pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal carcinomas.
• a further subject of the present application are the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
• Another object of the invention is the use of the compounds of the invention for the manufacture of a medicament.
• Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and therapy of
• Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of
• Leukemias in particular acute myeolemic leukemias, prostate cancers, especially androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas .
• Endometrial carcinomas and colorectal carcinomas are endometrial carcinomas and colorectal carcinomas.
• Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and therapy of leukemias, especially acute myeloid leukemias, prostate cancer, in particular androgen receptor-positive prostate cancer, breast cancer, in particular estrogen receptor-negative breast cancer, melanoma or multiple myeloma.
• Another object of the present application is the use of the compounds of the invention for the prophylaxis and therapy of tumor diseases.
• the present application further relates to the use of the compounds according to the invention for the prophylaxis and therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular of hormone receptor negative,
• Hormone receptor-positive or BRCA-associated breast carcinomas pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal carcinomas.
• the present application further relates to the use of the compounds according to the invention for the prophylaxis and therapy of leukemias, in particular acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, breast cancers, in particular estrogen receptor-alpha-negative breast carcinomas,
• the present application further relates to pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular of hormone receptor-negative, hormone receptor positive or BRCA-associated breast cancers, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas,
• leukemias in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular of hormone receptor-negative, hormone receptor positive or BRCA-associated breast cancers, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas,
• Another object of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of leukemias, especially acute myeloid leukemias, prostate cancer, especially androgen receptor-positive prostate cancer, breast cancer, especially estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
• Another object of the invention is the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.
• Another object of the invention is the use of the compounds of the invention for the treatment of benign hyperplasia, inflammatory diseases, autoimmune Diseases, sepsis, viral infections, vascular diseases and neurodegenerative conditions
• the compounds of the invention may be used alone or as needed in combination with one or more other pharmacologically active substances, as long as they are
• Another object of the present invention are therefore pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the prophylaxis and / or therapy of the aforementioned diseases.
• the compounds according to the invention can be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancers.
• the combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.
• Anastrozole Anzmet, Apatinib, Aranesp, Arglabin, Arsenic trioxide, Aromasin, Arzoxifen, Asoprisnil, L-asparaginase, Atamestan, Atrasentan, Avastin, Axitinib, 5-Azacytidine, Azathioprine, BCG or tice-BCG, Bendamustine, Bestatin, Beta methasone acetate, betamethasone sodium phosphate, bexarotene, bicalutamide, bleomycin sulfate, broxuridine, bortezomib, bosutinib, busulfan,
• Doxorubicin (adriamycin), dronabinol, dSLIM, dutasteride, DW-166HC, edotecarin, eflornithine, eligard, elitek, ellence, emend, enzalutamide, epirubicin, epoetin-alfa, epogen, epothilone and its derivatives, eptaplatin, ergamisole, erlotinib, erythrocytes Hydroxynonyladenine, estrace, estradiol, estramustine sodium phosphate, ethinyl estradiol, ethylol, etidronic acid, etopophos, etoposide,
• Hydroxyprogesterone caproate ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, iniparib, interferon-alpha, interferon-alpha-2, interferon-alpha-2a, interferon-alpha-2 ⁇ , interferon-alpha-nl, interferon-alpha-n3, interferon -beta, interferon-gamma- ⁇ , interleukin-2, intron A, Iressa, irinotecan, ixabepilone, keyhole limpet hemocyanin, cytril, lanreotide, lapatinib, lasofoxifen, lentinan sulfate, lestaurtinib, letrozole, leucovorin, leuprolide, leuprolide acetate , Levamisole, Levofolic Acid Calcium Salt, Levoth
• the compounds of the invention may also be treated with biological therapeutics such as antibodies (eg, aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, ofatumumab, panitumumab, pertuzumab, rituximab, tositumumab, trastuzumab ) and recombinant proteins.
• biological therapeutics such as antibodies (eg, aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, of
• the compounds of the invention may also be used in combination with others, against the
• Angiogenesis-targeted therapies such as bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib or thalidomide. Combinations with antihormones and steroidal metabolic enzyme inhibitors are because of their favorable
• the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.
• 4,5-Dihydro-3H-2,3-benzodiazepines of the general formula (I) can be prepared analogously to processes described in the literature. Depending on the substituents present, it may be necessary to use protecting group strategies which are well known to those skilled in the art.
• Scheme 1 describes the synthesis of 4,5-dihydro-3H-2,3-benzodiazepines using a 3,4-dihydro-1H-2-benzopyran intermediate (III) wherein A, n and the residues R la , R 1b , R 2 , R 4 and R 5 have the meanings given in the general formula (I).
• Corresponding approaches are described, for example, in F. Gatta et al. II Farmaco - Ed. Sc. 1985, 40, 942 or in WO2008124075 or WO200198280.
• aldehydes (IIa) used are commercially available or their preparation is known to the person skilled in the art.
• R 1a and R 1b can also be introduced at a later stage in the synthesis, for example as described in Scheme 5.
• the 1-aryl-2-propanols (II) used are either commercially available or are prepared by reduction of the corresponding ketones (Ia), e.g. by reduction with lithium aluminum hydride in THF.
• This synthetic route is preferably used in the case of electron-rich substituted arylpropanols (II) (for example with alkoxy).
• 3,4-Dihydro-1H-2-benzopyrans are obtained by condensation of the 1-aryl-2-propanols (II) with aromatic or heteroaromatic aldehydes (IIa) under acidic conditions.
• the reaction is preferably carried out at elevated temperature (about 100 ° C) in hydrochloric dioxane in
• Chromium (VI) oxide / sulfuric acid provides the diketone (IV) which is reacted with hydrazine to give 4-methyl-1-aryl-5H-2,3-benzodiazepine or 4-methyl-1-heteroaryl-5H-2,3-benzodiazepine ( V) can be cyclized (see US5288863). Reduction with, for example, sodium cyanoborohydride (Synthetic Communications, 2002, 32, 527) then provides the desired 4,5-dihydro-3H-2,3-benzodiazepine derivative (VI).
• This may, for example, be cyclized by mesylation and subsequent base treatment to the Boc-protected 4,5-dihydro-3H-2,3-benzodiazepine derivative (IX), which in turn is converted into the corresponding 4,5-dihydro by acid deprotection in a well-known manner -3H-2,3-benzodiazepine derivative (VI) can be converted.
• Scheme 2 describes the synthesis of 4,5-dihydro-3H-2,3-benzodiazepines from indanones (X).
• Scheme 2 4,5-Dihydro-3H-2,3-benzodiazepines from indanones
• the indanone (X) can be converted to the corresponding 3-aryl-1H-indene or 3-heteroaryl-1H-indene (XII).
• XII 3-heteroaryl-1H-indene
• the indanone derivative (X) can e.g. in a generally known manner in the corresponding enol nonaflate (XI) transferred, and then by a palladium-catalyzed Suzuki coupling with the corresponding boronic acid derivatives (IIb) to indene (XII) are reacted.
• the indanone derivative (X) can be converted into the corresponding indanols (XIII) by addition of organomagnesium reagents (IIc) in a generally known manner, which readily form the corresponding indenes (XII) by acid-catalyzed elimination.
• the 3-aryl-lH-indenes and 3-heteroaryl-lH-indenes (XII) can be prepared by oxidative methods, for example with ruthenium (III) chloride / sodium periodate (Bioorganic and Medicinal Chemistry Letters, 2011, 21, 2554) in the convert corresponding diketones (IV). These can be converted into the corresponding 4,5-dihydro-3H-2,3-benzodiazepine derivatives (VI) analogously to Scheme 1.
• the indanones (X) used for the preparation of the embodiments are either commercially available or can be prepared, for example, as shown in Scheme 3, wherein the radicals R 2 , R 4 and R 5 have the meanings given in the general formula (I).
• Scheme 4 illustrates the preparation of the example compounds of the invention starting from 4,5-dihydro-3H-2,3-benzodiazepines (VI) by means of well-known reactions, for example with acid chlorides, anhydrides, chloroformates or isocyanates or isothiocyanates, where A, n and Radicals R 1a , R 1b , R 2 , R 3 , R 4 and R 5 have the meanings given in the general formula (I).
• the corresponding alkylureas (XIX) can also be obtained by reacting a reactive intermediate, such as 4-nitrophenyl carbamate, with alkylamines.
• R 1a , R 4 and R 5 may also be introduced at a later stage of the synthesis, for example as described in Scheme 5.
• Scheme 5 illustrates the preparation of embodiments which are characterized by palladium-catalyzed coupling reactions well known to those skilled in the art starting from e.g. of bromine-substituted aryl or heteroaryl derivatives (XXI, XXIIIa and XXIIIb) by reaction with the corresponding boronic acid derivatives (Chem. Rev. 1995, 95, 2457-2483, Angewandte Chemie, International Edition (2002), 41 (22), 4176-421 1 ) or make amines.
• the intermediates XXI, XXIIIa and XXIIIb can be prepared analogously to the synthesis routes shown.
• Method 1 Instrument: Waters Acquity LCT; Column: Phenomenex Kinetex C18, 50mm x 2.1mm, 2.6 ⁇ ; Eluent A: water / 0.05% AS, eluent B: ACN / 0.05% AS; Gradient: 0.0 min 98% A -> 0.2 min: 98% A ⁇ 1.7 min: 10% A ⁇ 1.9 min: 10% A - »2 min: 98% A -» 2.5 min: 98% A; Flow: 1.3 ml / min; Column temperature: 60 ° C; UV detection: 200-400 nm.
• Method 2 Instrument: Waters Acquity Platform ZQ4000; Column: Waters BEHC 18, 50 mm x 2.1 mm, 1.7 ⁇ ; Eluent A: water / 0.05% AS, eluent B: ACN / 0.05% AS; Gradient: 0.0 min 98% A -> 0.2 min: 98% A ⁇ 1.7 min: 10% A ⁇ 1.9 min: 10% A - »2 min: 98% A -» 2.5 min: 98% A; Flow: 1.3 ml / min; Column temperature: 60 ° C; UV detection: 200-400 nm.
• Method 3 UPLC-SQD-HCOOH; Instrument: Waters Acquity UPLC-MS SQD; Column: Acquity UPLC BEH C18 1,7 50x2,1mm; Eluent A: water + 0.1% by volume formic acid (99%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 ml / min; Temperature: 60 ° C; Injection: 2 ⁇ ; DAD scan: 210-400 nm.
• Method A System: Waters: Alliance 2695, DAD 996; Column: Chiralpak ID-3 3 ⁇ 100x4.6 mm; Eluent: hexane / IPA 50:50 (v / v) + 0.1% DEA; Flow: 1.0 ml / min; Column temperature: 25 ° C; Detection: DAD 254 nm.
• Method B System: Agilent: 1260 AS, MWD, Aurora SFC Module; Column: Chiralpak IA 5 ⁇ 100x4.6 mm; Eluent: C0 2 / methanol 8: 2; Flow: 4.0 ml / min; Pressure (outlet): 100 bar;
• Method C System: Agilent: 1260 AS, MWD, Aurora SFC Module; Column: Chiralpak IA 5 ⁇ 100x4.6 mm; Eluent: C0 2 / methanol 7: 3; Flow: 4.0 ml / min; Pressure (outlet): 100 bar;
• Method D System: Agilent: 1260 AS, MWD, Aurora SFC Module; Column: Chiralpak ID 5 ⁇ 100x4.6 mm; Eluent: C0 2 / ethanol 6: 4; Flow: 4.0 ml / min; Pressure (outlet): 100 bar;
• Method E System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak ⁇ > 3 ⁇ 100x4.6 mm; Eluent: ethanol / methanol / diethylamine 50: 50: 0.1 (v / v / v); Flow: 1.0 ml / min;
• Method G System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak ⁇ -3 ⁇ 100x4.6 mm; Eluent: hexane / 2-propanol / diethylamine 70: 30: 0.1 (v / v / v); Flow: 1.0 ml / min;
• Method H System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak ⁇ -3 ⁇ 100x4.6 mm; Eluent: hexane / 2-propanol / diethylamine 70: 30: 0.1 (v / v / v); Flow: 1.0 ml / min;
• Method J System: Agilent: 1260 AS, MWD, Aurora SFC Module; Column: Chiralpak ID 3 ⁇ 100x4.6 mm; Eluent: C0 2 / ethanol 65:35 + 0.2% by volume diethylamine; Flow: 4.0 ml / min; Pressure (outlet): 100 bar; Column temperature: 37.5 ° C; Detection: DAD 254 nm.
• Method K System: Agilent: 1260 AS, MWD, Aurora SFC Module; Column: Chiralpak IC 3 ⁇ 100x4.6 mm; Eluent: C0 2 /2-propanol 60:30 + 0.2% by volume diethylamine; Flow: 4.0 ml / min; Pressure (outlet): 100 bar; Column temperature: 37.5 ° C; Detection: DAD 254 nm.
• Method I System: Agilent: Prep 1200, 2x Prep Pump G1361A, DLA G2258A, MWD G1365D, Prep FC G1364B; Column: Chiralpak ID 5 ⁇ 250x20 mm; Eluent: hexane / IPA 50:50 (v / v) + 0.1% DEA; Flow: 30 ml / min; Temperature: RT; Detection: UV 254 nm.
• Method III System: Agilent: Prep 1200, 2x Prep Pump, DLA, MWD, Prep FC; Column: Chiralpak ID 5 ⁇ 250x20 mm; Eluent: hexane / 2-propanol 70:30 (v / v) + 0.1% DEA; Flow: 40 ml / min;
• Method V System: Sepiatec: Prep SFC 100, Prep FC; Column: Chiralpak ID 5 ⁇ 250x30 mm; Eluent: C0 2 / ethanol 6/4; Flow: 80 ml / min; Temperature: 40 ° C; Detection: UV 254 nm.
• Method VI System: Agilent: Prep 1200, 2x Prep Pump, DLA, MWD, Prep FC; Column: Chiralpak IA 5 ⁇ 250x30 mm; Eluent: hexane / 2-propanol / diethylamine 70: 30: 0.1 (v / v / v); Flow: 20 ml / min; Temperature: RT; Detection: UV 254 nm.
• Method VII System: Agilent: Prep 1200, 2x Prep Pump, DLA, MWD, Prep FC; Column: Chiralpak ID 5 ⁇ 250x30 mm; Eluent: hexane / 2-propanol / diethylamine 70: 30: 0.1 (v / v / v); Flow: 50 ml / min; Temperature: RT; Detection: UV 280 nm.
• Method VIII System: Sepiatec: Prep SFC 100; Column: Chiralpak IC 5 ⁇ 250x20 mm; Eluent: C0 2 /2-propanol / diethylamine 60: 40: 0.4 (v / v / v); Flow: 80 ml / min; Temperature: 40 ° C; Detection: UV 254 nm.

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