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WO2015121227A1 - 1-phényl-3h-2,3-benzodiazépines disubstituées en position 6,9 et leur utilisation comme inhibiteurs de bromodomaine - Google Patents

1-phényl-3h-2,3-benzodiazépines disubstituées en position 6,9 et leur utilisation comme inhibiteurs de bromodomaine Download PDF

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WO2015121227A1
WO2015121227A1 PCT/EP2015/052705 EP2015052705W WO2015121227A1 WO 2015121227 A1 WO2015121227 A1 WO 2015121227A1 EP 2015052705 W EP2015052705 W EP 2015052705W WO 2015121227 A1 WO2015121227 A1 WO 2015121227A1
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alkyl
alkoxy
halogen
unsubstituted
amino
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Stephan Siegel
Stefan BÄURLE
Arwed Cleve
Bernard Haendler
Amaury Ernesto FERNÁNDEZ-MONTALVÁN
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Bayer Pharma AG
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    • C07D243/02—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention relates to bromodomain protein-inhibiting, in particular BET protein-inhibiting and preferably BRD4-inhibitory 6,9-disubstituted 2,3-benzodiazepines, pharmaceutical compositions containing the compounds of the invention and their
  • this invention relates to the use of BET protein inhibitors in benign hyperplasia, atherosclerotic diseases, sepsis, autoimmune diseases, vascular diseases, viral infections, in neurodegenerative disorders
  • the bromodomain protein belonging to the bromodomain protein 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; Gallenkamp et al., Chem. Med. Chem., 2014, DOI:
  • 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 of open chromatin structure and active gene transcription (Kuo and Allis, Bioessays, 1998, 20: 615). 626).
  • histones eg, histone H3 or histone H4
  • 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, 28: 967-976). 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 the transcription elongation and recruitment of the elongation complex P-TEFb 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.
  • RNA polymerase II Chromatin regions and promote transcription by RNA polymerase II (LeRoy et al., Mol. Cell, 2008, 30: 51-60).
  • 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).
  • BRD2 and BRD4 knockout mice die prematurely during embryogenesis (Gyuris et al., Biochim Biophys Acta, 2009, 1789: 413-421, Houzelstein et al., Mol. Cell Biol., 2002, 22: 3794-3802 ).
  • Heterozygous BRD4 mice have various growth defects attributable to reduced cell proliferation (Houzelstein et al., Mol. Cell. Biol., 2002, 22: 3794-3802).
  • BET proteins play an important role in various tumor types.
  • the fusion between the BET proteins BRD3 or BRD4 and NUT results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet, Cytogenet., 2010, 203: 16 -20).
  • the fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 2011,
  • 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 arrest of the cell cycle 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 was 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).
  • the herpesvirus 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. Virol., 2006, 80: 8909-8919).
  • 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 (ApoAl) is a major component of high density
  • HDL Lipoproteins
  • ApoAl Lipoproteins
  • Elevated HDL levels are associated with a decreased risk of atherosclerosis (Chapman et al., Eur. Heart J., 2011, 32: 1345-1361).
  • the first published BRD4 inhibitors are phenyl-thieno-triazolo-l, 4-diazepine (4-phenyl-6-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 describes 6-substituted 4i7-isoxazolo [5,4-cf] [2] benzazepines and AH- rsoxazolo [3,4-uf] [2] benzazepines, including compounds optionally substituted with phenyl at position 6, as BRD4 inhibitors and also analogs with alternative heterocyclic fusion partners in place of the benzo moiety, eg, thieno or pyridoazepines.
  • WO2013 / 184876 and WO2013 / 184878 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 are proteins inhibiting binding of bromodomains of the BET proteins to 7V-acetylated lysine residues described.
  • Cholecystokinin receptors are described in WO2006 / 051312 (James Black Foundation). They also include substituted 3,5-dihydro-4i7-2,3-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. It would therefore be desirable to find new compounds that have prophylactic and therapeutic properties.
  • the present invention provides compounds and pharmaceutical compositions containing these compounds for a prophylactic and therapeutic use in hyperproliferative diseases, especially in tumor diseases and as BET protein inhibitors in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and used in male fertility control.
  • the compounds of the invention are novel, at C-6 and C-9 obligate substituted phenyl-2,3-benzodiazepines (l-phenyl-4,5-dihydro-3i7-2,3-benzodiazepine), which does not merge with the Benzodiazepingerüst with a second heterocyclic unit, especially an isoxazole or triazole, and, surprisingly, are still BRD4 inhibitors.
  • novel compounds differ, inter alia, by the substitution at C-6 and C-9 of known 2,3-benzodiazepines such as the numerous published AMPA antagonists (WO 1997/28135 (Schering AG), US Pat. No. 5,807,851, WO 0097000688, WO 2002 Res. Rev. 2007, 27 (2), 239-278) as well as antagonists of the MT2 receptors and inhibitors of the adenosine transporter (WO 2008 / 124075, Teva Pharmaceuticals).
  • AMPA antagonists WO 1997/28135 (Schering AG)
  • antagonists of the MT2 receptors and inhibitors of the adenosine transporter WO 2008 / 124075, Teva Pharmaceuticals.
  • WO 1997/034878 discloses 2,3-benzodiazepine-4-ones which may also be substituted at C-6 and C-9, but from the compounds of the present invention by the oxo substitution at C-4 of the benzodiazepine scaffold, as antagonists or positive modulators of the AMPA receptor.
  • WO 2001/098280 discloses further 1-phenyl-4,5-dihydro-3 # -2,3-benzodiazepines as antagonists of the non-NMDA ionotropic excitatory amino acid (EAA) receptor.
  • EAA excitatory amino acid
  • the compounds of the present invention differ, inter alia, by the substitution at C-6 and C-9 as well as the phenyl ring linked to C-1 of the benzodiazepine skeleton.
  • the compounds of the invention inhibit the interaction between BET proteins, especially BRD4, and an acetylated histone H4 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.
  • Ci-Ce-alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, G-Ce-alkylcarbonyl, GC 6 - alkoxy, C I -C ⁇ - alkyl thio, G -Cö-alkylsulfinyl or G-Cö-alkylsulfonyl-, which are unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, Ce Ce Alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl-, C 1 -C 4 -alkyl, -C
  • Ci-C is the same or different substituted with halogen, amino, hydroxy, carboxy, Ci-Ce-alkyl, G-Ce-alkoxy, Ci-6 alkoxy-C 6 alkyl, G-Ce-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 or monocyclic heterocyclyl with 4 up to 8 ring atoms,
  • C 1 -C 6 -alkyl, GG-alkoxy, GG-alkylamino, phenylamino, GG-alkylcarbonylamino, GG-alkylaminocarbonyl or GG-alkylaminosulphonyl, which are unsubstituted or mono-, di- or trisubstituted, identical or variously substituted with halogen, amino, hydroxy, carboxy, G-Ce-alkyl, hydroxy-G-Ce-alkyl, GG-alkoxy, GG-alkoxy-G-G-alkyl, G-Ce-alkylamino , Amino-GG-alkyl, -C ( O) -NR 9 R 10 ,
  • C 3 -C 10 -cycloalkyl- which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by 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,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, is halogen, amino, hydroxy, cyano, nitro,
  • R 4 and R 5 can each also be hydrogen
  • R 6b is halogen, cyano, hydroxy, amino, carboxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C
  • Ci-Ce-alkyl C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, G-Ce-alkylcarbonyl, C 3 -C 6 - is Cycloalkylsulfonyl- or Ci-COE-alkylsulfonyl, which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, 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, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alky
  • C 3 -C 10 -cycloalkyl- which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by 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, aminoC 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halogeno-C i-C ⁇ -alkyl, halogeno-C 1 -C 6 -alkoxy or monocyclic heterocyclyl having 4 to 8 ring atoms,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, hydroxyl, amino, cyano, nitro, carboxy, C 1 -C 6 -alkyl, G-C 1 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-G-C 6
  • R 8 represents hydrogen, C 1 -C 6 -alkyl, C 5 -C 6 -alkenyl, C 5 -C 6 -alkynyl, phenyl-C 1 -C 4 -alkyl,
  • Alkyl- or C 3 -C 10 -cycloalkyl- which are unsubstituted or mono-, di- or trisubstituted, identically or differently, with halogen, cyano, hydroxy, C 1 -C 3 -alkoxy- or C 1 -C 3 - alkyl,
  • R 9 and R 10 independently of one another represent hydrogen, C 1 -C 3 -alkyl, cyclopropyl or C 1 -C 3 -alkyl-amino-C 1 -C 3 -alkyl,
  • R 11 is hydroxy, C 1 -C 6 -alkyl, G-C 1 -alkoxy, halogen-C 1 -C 3 -alkyl, hydroxy-G
  • phenyl is phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted or disubstituted, identical or different, are substituted by halogen, Ci-C3-alkoxy- or ci C 3 alkyl,
  • bromodomain protein inhibitors in particular as BET protein inhibitors and preferably as BRD4 inhibitors are particularly well suited for a variety of prophylactic and therapeutic uses, especially in hyperproliferative diseases, tumors and viral infections, neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases and male fertility control.
  • C6-Ci 2 -Heterospirocycloalkyl-, C6-Ci 2 -Heterobicycloalkyl-, bridged Ce- Ci is 2 heterocycloalkyl, bicyclic heteroaryl, partially saturated bicyclic aryl or bicyclic partially saturated heteroaryl, which are unsubstituted or mono-, di- or triply, the same or different, are substituted with halogen,
  • Ci-Ce-alkyl, Ci-Ce-alkoxy, halogen-Ci-Ce-alkyl or halogen-Ci-Ce alkoxy stand,
  • R 2 is methyl
  • R 3 is cyclopropyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino, cyclopropylamino or
  • R 4 , R 5 and R 6 independently of one another represent hydroxyl, cyano, amino, aminocarbonyl,
  • C 3 -C 10 -cycloalkyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, carboxy,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, is substituted by halogen, amino, hydroxyl, cyano, carboxy, G-Cö-alkyl, Ci-Cö-alkoxy, Ci-Cö Alkylamino, amino-Ci-Cö-alkyl, G-C ⁇ -alkylaminocarbonyl, GG-alkylaminosulfonyl, hydroxy-GG-alkyl, halogen-Ci-Cö-alkyl or halogen-Ci-Cö-alkoxy,
  • R 9 and R 10 independently of one another represent hydrogen, C 1 -C 3 -alkyl-, cyclopropyl-, or di-
  • R 11 represents hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno-C 1 -C 3 -alkyl-, hydroxy-G-
  • phenoxy-, phenylthio- or phenylsulfonyl- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, are substituted by halogen, cyano, hydroxyl, amino, carboxy, Ci-C3-alkyl, Ci-C3 Alkoxy, hydroxy-GG-alkyl, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, fluoro-G
  • Halogen hydroxy, amino, cyano, carboxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl -, fluoro-GC 3 - alkyl, fluoro-Ci-C 3 -alkoxy,
  • C6-Ci 2 -Heterospirocycloalkyl-, C6-Ci 2 -Heterobicycloalkyl-, bridged Ce- Ci is 2 heterocycloalkyl, bicyclic heteroaryl, partially saturated bicyclic aryl or bicyclic partially saturated heteroaryl, which are unsubstituted or mono-, di- or triply, the same or different, are substituted with halogen,
  • R lb and R lc independently of one another represent hydrogen, halogen, hydroxyl, cyano,
  • R 2 is methyl
  • R 3 is cyclopropyl, Ci-C 3 alkyl, cyclopropylamino or
  • R 4 , R 5 and R 6 independently of one another represent hydroxyl, cyano, amino, aminocarbonyl,
  • Ci-Cö-alkyl Ci-Cö-alkoxy, Ci-Cö-alkylamino, phenylamino, CI-C ⁇ -alkylcarbonylamino, Ci-Cö-alkylaminocarbonyl or GC ⁇ - alkylaminosulfonyl, which are unsubstituted or -, two- or three-fold, same or different, are substituted by halogen, amino, hydroxy, carboxy, GC 3 alkyl, hydroxy-Ci-C 3 alkyl, GC 3 alkoxy, GC 3 - Alkylamino, amino-C 1 -C 3 -alkyl or monocyclic heterocyclyl having 4 to 6 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, or
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, C 1 -C 3 -alkyl-, Ci-C 3 alkoxy, C 1 -C 3 - alkylamino, amino-Ci-C 3 alkyl, hydroxy-C 3 alkyl, fluoro-Ci-C 3 alkyl or fluoro-Ci-C 3 alkoxy,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, is substituted by halogen, amino, hydroxyl, cyano, carboxy, C 1 -C 6 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -synyl -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 or fluorine -Ci-C 3 alkoxy,
  • Ci 2 -Heterocycloalkyl- or bicyclic heteroaryl- which are unsubstituted or mono-, di- or trisubstituted by identical or different substituents
  • C 1 -C 3 -alkyl is hydrogen, C 1 -C 3 -alkyl, phenyl-C 1 -C 2 -alkyl or C 3 -C 5 -cycloalkyl, independently of one another represent hydrogen or C 1 -C 3 -alkyl-,
  • Alkyl C 3 -C 6 cycloalkyl, phenyl,
  • R 1 is hydrogen, halogen, cyano, hydroxy or -NR 7 R 8 ,
  • C 1 -C 6 -alkyl- or C 1 -C 6 -alkoxy- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, hydroxyl, amino, C 1 -C 3 -alkoxy-, C 1 -C 3 -alkylamino, C 3 -C 7 -cycloalkyl, phenyl or monocyclic heterocyclyl- having 4 to 8 ring atoms,
  • R 1b and R lc independently of one another represent hydrogen, fluorine or chlorine
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, amino,
  • C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, with fluorine,
  • phenylamino which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, is substituted by halogen, Ci-C3-alkyl or Ci-C3-alkoxy, or
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, hydroxyl, oxo, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- , or trifluoromethyl, or
  • phenyl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, is substituted by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy or trifluoromethyl-,
  • Ci-Cö-alkyl Ci-Cö-alkyl, Ci-Cö-alkylcarbonyl, Cs-Cö-cycloalkylsulfonyl or CI-C ⁇ -alkylsulfonyl-, which are unsubstituted or mono-, di- or trisubstituted, identical or different, are substituted by halogen , Cyano, hydroxy, amino or C 1 -C 3 -alkylamino,
  • phenylsulfonyl which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- or trifluoromethyl-,
  • phenyl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, being substituted by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- or trifluoromethyl-,
  • R 8 is hydrogen or C 1 -C 3 -alkyl-
  • R 11 is G-Cs-alkyl, trifluoromethyl, C 3 -C 6 -cycloalkyl, phenyl-,
  • Ci-C 3 alkoxy stands for Ci-C, which are mono-substituted with C 3 -C 7 cycloalkyl, phenyl or monocyclic heterocyclyl with 4 to 8 ring atoms, or
  • trifluoromethyl is hydroxy, cyano, amino, fluorine, chlorine or bromine,
  • phenylamino which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, or
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, hydroxyl, oxo, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- , or trifluoromethyl, or
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy or trifluoromethyl-,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- or trifluoromethyl-,
  • R 8 is hydrogen or C 1 -C 3 -alkyl-
  • R 11 is Ci-Cs-alkyl, trifluoromethyl, Cs-Ce-cycloalkyl, phenyl,
  • R la is halogen or -NR 7 R 8 ,
  • phenyl which is unsubstituted or monosubstituted by halogen, or
  • R lb and R lc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen, fluorine, chlorine or bromine,
  • R 6 is cyano, fluorine, chlorine or bromine
  • R 6b is halogen, cyano or methoxy
  • R 7 is C 3 -C 6 -cycloalkylsulfonyl or C 1 -C 6 -alkylsulfonyl-,
  • R 8 is hydrogen or C 1 -C 3 -alkyl-, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts ,
  • R la is -NR 7 R 8 ,
  • phenyl which is unsubstituted or monosubstituted by halogen, or
  • R lb and R lc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen, fluorine, chlorine or bromine, or
  • R 6 is cyano, fluorine, chlorine or bromine
  • R 6b is halogen, cyano or methoxy
  • R 7 is monocyclic heteroaryl- with 5 ring atoms which is unsubstituted or monosubstituted or disubstituted by C 1 -C 3 -alkyl-,
  • R 8 is hydrogen or C 1 -C 3 -alkyl-, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts ,
  • R la represents chlorine, bromine or -NR 7 R 8,
  • azetidinyl is azetidinyl, pyrrolidinyl, 1,2-thiazolidinyl, piperidinyl or piperazinyl, which are unsubstituted or monosubstituted or disubstituted by fluorine, hydroxyl, oxo or methyl,
  • phenyl which is unsubstituted or monosubstituted by fluorine, or
  • R lb and R lc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen or methoxy, R 6 is fluorine or chlorine,
  • R 6b is chlorine, cyano or methoxy
  • R 7 is cyclopropylsulfonyl or methylsulfonyl
  • R 8 is hydrogen or methyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • R la is -NR 7 R 8 ,
  • azetidinyl is azetidinyl, pyrrolidinyl, 1,2-thiazolidinyl, piperidinyl or piperazinyl, which are unsubstituted or monosubstituted or disubstituted by fluorine, hydroxyl, oxo or methyl,
  • phenyl which is unsubstituted or monosubstituted by fluorine, or
  • R lb and R lc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen or methoxy
  • R 6 is fluorine or chlorine
  • R 6b is chlorine, cyano or methoxy
  • R 7 is isoxazolyl, which is unsubstituted or monosubstituted or disubstituted by methyl,
  • R 8 is hydrogen or methyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • R la represents chlorine, bromine or -NR 7 R 8,
  • R lb and R lc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen or methoxy
  • R 6a is fluorine or chlorine
  • R 6b is chlorine or methoxy
  • R 7 is cyclopropylsulfonyl or methylsulfonyl
  • R 8 represents hydrogen or methyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically tolerated salts and solvates of these salts.
  • R la is -NR 7 R 8 ,
  • R lb and R lc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen or methoxy
  • R 6a is fluorine or chlorine
  • R 6b is chlorine or methoxy
  • (+) - 6-Fluoro-8,9-dimethoxy-N 4-dimethyl-1- [4- (2-oxa-7-azaspiro [3,5] non-7-yl) -phenyl] -4,5-dihydro -3H-2,3-benzodiazepine-3-carboxamide; (4S) -6-fluoro-8,9-dimethoxy-N, 4-dimethyl-1- [4- (2-oxa-7-azaspiro [3,5] non-7-yl) -phenyl] -
  • (+) - 6-Fluoro-8,9-dimethoxy-N 4-dimethyl-1- ⁇ 4- [methyl (methylsulfonyl) -amino] -phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine-3 -carboxamide
  • - (+) - 6-Fluoro-8,9-dimethoxy-N 4-dimethyl-1- ⁇ 4 - [(phenylsulfonyl) amino] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine-3 -carboxamide;
  • (+) - 6-Fluoro-8,9-dimethoxy-N 4-dimethyl-1- [4- (morpholin-4-ylmethyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3 -carboxamide;
  • C 1 -C 6 -alkyl- or C 1 -C 6 -alkoxy- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, hydroxyl, amino, oxo, carboxy,
  • R 1 particularly preferably represents hydrogen, halogen, cyano,
  • C 1 -C 6 -alkyl- or C 1 -C 6 -alkoxy- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, hydroxyl, amino, C 1 -C 3 -alkoxy-, Ci-C 3 - alkylamino, C 3 -C 7 cycloalkyl, phenyl or monocyclic heterocyclyl with 4 to 8 ring atoms,
  • R 1 particularly preferably represents hydrogen, halogen, cyano, hydroxy or -NR 7 R 8 .
  • R l is particularly preferred for Ci-COE-alkyl or CI-C ⁇ - alkoxy, which are unsubstituted or mono-, di- or trisubstituted by identical or different substituted with halogen, cyano , Hydroxy, amino, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, C 3 -C 7 -cycloalkyl, phenyl or monocyclic heterocyclyl having 4 to 8 ring atoms.
  • R 1 particularly preferably represents -NR 7 R 8 ,
  • C 1 -C 3 -alkyl- or C 1 -C 3 -alkoxy- which are monosubstituted by C 1 -C -cycloalkyl-, phenyl- or monocyclic heterocyclyl- having 4 to 8 ring atoms,
  • R 1 particularly preferably represents -NR 7 R 8 .
  • R 1 is particularly preferably C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, which are monosubstituted by C 3 -C 7 -cycloalkyl, phenyl or monocyclic heterocyclyl- 4 to 8 ring atoms.
  • R 1 very particularly preferably represents halogen or -NR 7 R 8 , or
  • R 1 very particularly preferably represents halogen or -NR 7 R 8 .
  • R 1 very particularly preferably represents halogen.
  • R 1 is C 1 -C 3 -alkyl, which is unsubstituted or monosubstituted by monocyclic heterocyclyl- with 6
  • R 1 is very particularly preferably monocyclic
  • R 1 very particularly preferably represents monocyclic heteroaryl having 5 ring atoms which is unsubstituted or monosubstituted or disubstituted by C 1 -C 3 -alkyl-.
  • R 1 most preferably represents phenyl which is unsubstituted or monosubstituted by halogen.
  • R l is very particularly preferably represents C ⁇ -CIO Heterospirocycloalkyl- or bicyclic heteroaryl, which are unsubstituted or mono- or disubstituted by identical or different substituted with oxo, or Ci-C3 alkyl.
  • R 1 very particularly preferably represents -NR 7 R 8 ,
  • R 1 very particularly preferably represents -NR 7 R 8 ,
  • R 1 very particularly preferably represents C 1 -C 3 -alkyl which is monosubstituted by monocyclic heterocyclyl having 6 ring atoms.
  • R 1 is very particularly preferably monocyclic
  • Heterocyclyl having 4 to 6 ring atoms which is unsubstituted or monosubstituted or disubstituted, identical or different, with halogen, hydroxy, oxo or C 1 -C 3 -alkyl,
  • R 1 very particularly preferably represents chlorine, bromine or -NR 7 R 8 , or
  • azetidinyl pyrrolidinyl, 1,2-thiazolidinyl, piperidinyl or piperazinyl, which are unsubstituted or monosubstituted or disubstituted by fluorine, hydroxyl, oxo or methyl, or
  • isoxazolyl which is unsubstituted or monosubstituted or disubstituted with methyl, or
  • R 1 very particularly preferably represents chlorine, bromine or -NR 7 R 8 .
  • R 1 very particularly preferably represents chlorine or bromine.
  • R 1 most preferably represents methyl, which is unsubstituted or monosubstituted with N-morpholinyl.
  • R 1 very particularly preferably represents azetidinyl, pyrrolidinyl, 1,2-thiazolidinyl, piperidinyl or piperazinyl, which are unsubstituted or mono- or disubstituted by fluorine, hydroxyl, oxo or Methyl-.
  • R 1 is very particularly preferably isoxazolyl, which
  • R l is very particularly preferably represents phenyl, which is unsubstituted or monosubstituted with fluorine.
  • R 1 most preferably represents 2-oxa-7-azaspiro [3.5] nonyl, 1-thia-6-azaspiro [3.3] hept-6-yl or indolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents are substituted by oxo or Ci-C3-alkyl.
  • R 1 very particularly preferably represents -NR 7 R 8 ,
  • azetidinyl pyrrolidinyl, 1,2-thiazolidinyl, piperidinyl or piperazinyl, which are unsubstituted or monosubstituted or disubstituted by fluorine, hydroxyl, oxo or methyl,
  • R 1 very particularly preferably represents -NR 7 R 8 ,
  • R 1 most preferably represents methyl which is monosubstituted with N-morpholinyl-.
  • R 1 very particularly preferably represents azetidinyl, pyrrohdinyl, 1,2-thiazolidinyl, piperidinyl or piperazinyl, which are unsubstituted or mono- or disubstituted by fluorine, hydroxyl, oxo or Methyl-,
  • isoxazolyl which is unsubstituted or monosubstituted or disubstituted with methyl, or
  • R 1 is more preferably
  • R 1b and R lc are preferably and independently of one another
  • R 1b and R lc are particularly preferably and independently of one another hydrogen, halogen, hydroxy, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy- or trifluoromethyl-.
  • R 1b and R lc are particularly preferably and independently of one another hydrogen, fluorine or chlorine.
  • R 1b and R lc most preferably represent hydrogen.
  • R 2 may be C 1 -C 3 -alkyl, trifluoromethyl or C 3 -C 4 -cycloalkyl.
  • R 2 is preferably methyl.
  • R 3 is preferably cyclopropyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino, cyclopropylamino or C 1 -C 3 -alkylamino.
  • R 3 particularly preferably represents cyclopropyl, C 1 -C 3 -alkyl, cyclopropylamino or C 1 -C 3 -alkylamino.
  • R 3 particularly preferably represents C 1 -C 3 -alkylamino.
  • R 3 is particularly preferably methylamino.
  • R 4 , R 5 and R 6 are particularly preferably and independently of one another hydroxyl, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine,
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, C 1 -C 3 -alkyl-, GC 3 - Alkoxy, C 1 -C 3 -alkylamino, aminoCi-C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl or fluorine-GC 3 -alkoxy, or
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, carboxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, C 1 -C 3 -alkyl Alkylamino, amino-C 1 -C 3 -alkyl, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulphonyl, hydroxy-C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkyl or fluoro-C 1 -C 4 -alkyl- or fluoro-C 1 -C 4 -alkyl- -C 3 alkoxy,
  • R 4 and R 5 can each also be hydrogen.
  • R 4 and R 5 are particularly preferably and independently of one another hydrogen, hydroxyl, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine, or
  • monocyclic heteroaryl having 5 or 6 ring atoms which is unsubstituted or mono-, di- or Ci-C is three times, identically or differently substituted with halogen, cyano, 3 alkyl, C 1 -C 3 - alkoxy or trifluoromethyl,
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, hydroxy, cyano, oxo, C 1 -C 3 -alkyl-, Ci-C 3 Alkoxy- or trifluoromethyl-.
  • R 4 and R 5 are particularly preferably and independently of one another hydrogen, hydroxyl, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine, or
  • monocyclic heteroaryl having 5 or 6 ring atoms which is unsubstituted or mono-, di- or Ci-C is three times, identically or differently substituted with halogen, cyano, 3 alkyl, C 1 -C 3 - alkoxy or trifluoromethyl.
  • R 4 and R 5 are particularly preferably and independently of one another hydrogen, hydroxyl, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine, or
  • R 4 and R 5 are particularly preferably and independently of one another hydrogen, hydroxyl, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine, or
  • C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy which are unsubstituted or mono-, di- or trisubstituted by fluorine.
  • R 4 and R 5 are very particularly preferably and independently of one another hydrogen, fluorine, chlorine or bromine or C 1 -C 3 -alkoxy-.
  • R 4 and R 5 are most preferably and independently of one another hydrogen or methoxy.
  • R 6 particularly preferably represents hydroxyl, cyano, amino, fluorine,
  • C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, with fluorine,
  • phenylamino which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, C 1 -C 3 -alkyl- or C 1 -C 3 -alkoxy-,
  • monocyclic heteroaryl having 5 or 6 ring atoms which is unsubstituted or mono-, di- or Ci-C is three times, identically or differently substituted with halogen, cyano, 3 alkyl, C 1 -C 3 - alkoxy or trifluoromethyl,
  • phenyl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, is substituted by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy or trifluoromethyl-.
  • R 6 particularly preferably represents hydroxyl, cyano, amino, fluorine, Chlorine or bromine,
  • C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy which are unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, with fluorine.
  • R 6 very particularly preferably represents cyano, fluorine, chlorine or bromine.
  • R 6 very particularly preferably represents fluorine or chlorine.
  • R 6 very particularly preferably represents fluorine.
  • R 6 most preferably represents chlorine.
  • R 6b may be halogen, cyano, hydroxy, amino, carboxy, GC 3 - alkyl, Ci-C 3 alkoxy, Ci-C 2 alkoxy-Ci-C 2 alkyl, Hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl, C 1 -C 2 -alkylamino-C 1 -C 2 -alkyl, or halogen-C 3 -C 3 -alkyl- , Halogen-GC 3 - alkoxy- or C 3 -C 5 -cycloalkyl- stand.
  • R 6b is preferably halogen, cyano, hydroxyl, amino, carboxy, C 1 -C 2 -alkyl, C 2 -C 4 -alkoxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy or
  • R 6b particularly preferably represents halogen, cyano, hydroxyl, amino, C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, hydroxymethyl, trifluoromethyl or trifluoromethoxy.
  • R 6b is particularly preferably halogen, cyano, hydroxy, amino, methyl, methoxy or trifluoromethyl.
  • R 6b very particularly preferably represents halogen, cyano or methoxy.
  • R 6b very particularly preferably represents halogen or methoxy. In the general formula (I), R 6b very particularly preferably represents halogen.
  • R 6b very particularly preferably represents chlorine, cyano or methoxy. In the general formula (I), R 6b very particularly preferably represents chlorine or methoxy. In the general formula (I), R 6b very particularly preferably represents chlorine.
  • R 6b very particularly preferably represents methoxy.
  • R 7 is particularly preferably C 1 -C 6 -alkyl-, C 1 -C 4 -alkyl-
  • phenylsulfonyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy-, or trifluoromethyl-, or -
  • monocyclic heteroaryl having 5 or 6 ring atoms which is unsubstituted or mono-, di- or Ci-C is three times, identically or differently substituted with halogen, cyano, 3 alkyl, C 1 -C 3 - alkoxy or trifluoromethyl,
  • phenyl which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- or trifluoromethyl-, or
  • R 7 is particularly preferred for Ci-COE-alkyl, C I -C ⁇ - alkylcarbonyl, C 3 -C 6 Cycloalkylsulfonyl- or Ci-COE-alkylsulfonyl which are unsubstituted or mono- , two or three times, identical or different, are substituted by halogen, cyano, hydroxyl, amino or C 1 -C 3 -alkylamino, or
  • phenylsulfonyl which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, or trifluoromethyl-, or -
  • monocyclic heteroaryl having 5 or 6 ring atoms which is unsubstituted or mono-, di- or Ci-C is three times, identically or differently substituted with halogen, cyano, 3 alkyl, C 1 -C 3 - alkoxy or trifluoromethyl,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, is substituted by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- or trifluoromethyl-.
  • R 7 is particularly preferred for Ci-COE-alkyl, C I -C ⁇ - alkylcarbonyl, Cs-COE-Cycloalkylsulfonyl- or Ci-COE-alkylsulfonyl which are unsubstituted or mono-, two or three times, identically or differently, are substituted by halogen, cyano, hydroxy, amino or Ci-C 3 alkylamino.
  • R 7 is particularly preferably phenylsulfonyl which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 4 -alkyl 3 alkoxy, or trifluoromethyl.
  • R 7 is particularly preferably monocyclic Heterocyclyl- having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identical or different, with halogen, hydroxy, oxo, Ci-C 3- alkyl, Ci-C 3 -alkoxy- or trifluoromethyl-.
  • R 7 particularly preferably represents monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 - Alkyl, Ci-C 3 -alkoxy- or trifluoromethyl-.
  • R 7 particularly preferably represents phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C3-alkoxy- or trifluoromethyl-.
  • R 7 is particularly preferably monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, hydroxy, oxo, Ci-C3 -Alkyl, C 1 -C 3 -alkoxy- or trifluoromethyl-,
  • phenyl which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- or trifluoromethyl-, or
  • R 7 is particularly preferably monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 - Alkyl, Ci-C 3 alkoxy or trifluoromethyl, or
  • phenyl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, is substituted by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy- or trifluoromethyl-.
  • R 7 is very particularly preferably C 3 -C 6 -cycloalkylsulfonyl or
  • phenyl which is unsubstituted or monosubstituted with halogen.
  • R 7 very particularly preferably represents C 3 -C 6 -cycloalkylsulfonyl or C 1 -C 6 -alkylsulfonyl-.
  • R 7 is very particularly preferably phenylsulfonyl.
  • R 7 very particularly preferably represents monocyclic heteroaryl with 5 ring atoms which is unsubstituted or monosubstituted or disubstituted by C 1 -C 3 -alkyl-.
  • R 7 very particularly preferably represents phenyl which is unsubstituted or monosubstituted by halogen.
  • R 7 very particularly preferably represents monocyclic heteroaryl having 5 ring atoms, which is unsubstituted or monosubstituted or disubstituted by
  • phenyl which is unsubstituted or monosubstituted with halogen.
  • R 7 is very particularly preferably cyclopropylsulfonyl or
  • isoxazolyl which is unsubstituted or monosubstituted or disubstituted with methyl, or
  • R 7 very particularly preferably represents isoxazolyl which is unsubstituted or monosubstituted or disubstituted by methyl
  • R 7 very particularly preferably represents isoxazolyl which is unsubstituted or monosubstituted or disubstituted by methyl.
  • R 7 very particularly preferably represents phenyl which is unsubstituted or monosubstituted by fluorine.
  • R 7 is more preferably cyclopropylsulfonyl or
  • R 7 is very preferably
  • R 8 particularly preferably represents hydrogen, C 1 -C 3 -alkyl, phenyl-C 1 -C 2 -alkyl or C 3 -C 5 -cycloalkyl.
  • R 8 is particularly preferably hydrogen or C 1 -C 3 -alkyl-.
  • R 8 very particularly preferably represents hydrogen or methyl.
  • R 9 and R 10 are particularly preferably and independently of one another hydrogen or C 1 -C 3 -alkyl-.
  • R 11 is particularly preferably hydroxy, C 1 -C 3 -alkyl, C 1 -C 4 -alkoxy, trifluoromethyl, hydroxy-C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, or
  • phenyl or monocyclic heterocyclyl having 4 to 6 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms.
  • R 11 is particularly preferably C 1 -C 3 -alkyl-, trifluoromethyl-C 1 -C 6 -cycloalkyl-, or
  • R 11 is particularly preferably C 1 -C 3 -alkyl-, trifluoromethyl-, C 3 -C 6 -cycloalkyl-.
  • R 11 is particularly preferably phenyl or
  • Benzodiazepine skeleton preferably represented stereocenter either racemic or predominantly or completely in the (S) -configuration.
  • Benzodiazepine skeleton represented preferred stereocenter stereocenter before.
  • Benzodiazepine skeleton represented stereocenter particularly preferably predominantly or completely in the ( ⁇ configuration before.
  • Benzodiazepine skeleton represented stereocentre most preferably predominantly in the (S) configuration. In the general formula (I), this is due to the carbon atom of the carbon atom bonded to R 2
  • Benzodiazepine skeleton most preferably represented stereocenter completely in the (S) configuration.
  • 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) 3- alkyl).
  • Particularly preferred is a methyl, ethyl, propyl, isopropyl or tert-butyl radical.
  • C 2 -C 6 -alkenyl or a C 2 -C 6 -alkenyl group
  • C 2 -C 6 -alkynyl or a C 2 -C 6 -alkynyl group
  • Preference is given to C 3 -C 6 -alkynyl or C 2 -C 4 -alkynyl, particular preference being given to ethynyl and propargyl.
  • Cycloalkyl is a monocyclic, saturated, monovalent hydrocarbon radical having generally 3 to 10 (C 3 -C 10 -cycloalkyl), preferably 3 to 7 carbon atoms
  • Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.
  • phenyl-Ci-C6-alkyl- is a group which is composed of an optionally substituted phenyl radical and a Ci-Cö-alkyl group, and the via the C I -C ⁇ - alkyl group to the rest of the Molecule is bound.
  • the alkyl radical here has the above alkyl given meanings.
  • 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 4 -alkoxy), and particularly preferably 1 to 3 (C 1 -C 3 -alkoxy) carbon atoms.
  • Phenoxy- represents a radical of the formula -O-phenyl. alkoxyalkyl
  • Alkoxyalkyl is an alkoxy-substituted alkyl radical, for example C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl or C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl.
  • C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl here means that the alkoxyalkyl group is bonded via the alkyl part 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 amino radical having one or two (independently selected) alkyl substituents with generally 1 to 6 (C 1 -C 6 -alkylamino), preferably 1 to 3 carbon atoms (C 1 -C 3 -alkylamino).
  • (C 1 -C 3) -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms per molecule
  • Examples include:
  • Phenylamino is a radical Ph-NH- or a radical Ph-N (Ci-C3-alkyl) -. Examples include:
  • Phenylamino methylphenylamino and ethyl-phenylamino. Preference is given to N-phenylamino.
  • Alkylthio represents a linear or branched, saturated radical of the formula -S-alkyl having generally 1 to 6 (C 1 -C 6 -alkylthio), preferably 1 to 4 (C 1 -C 4 -alkylthio), and particularly preferably 1 to 3 (C 1 -C 3 -alkylthio) carbon atoms.
  • Methylsulfonyl ethylsulfonyl, propylsulfonyl.
  • Hydrocarbon radical having usually 3 to 6 carbon atoms (C3-C6-Cycloalkylsulf onyl-).
  • Phenylthio is a radical of the formula -S-phenyl.
  • 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 at least one heteroatom. 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.
  • 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:
  • Benzothienyl Benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl, indolinyl.
  • 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 is fused via two immediately adjacent ring atoms to an aliphatic cyclic radical having 4 to 7 ring atoms, respectively optionally contain one or two heteroatoms can 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:
  • Monocyclic heterocyclyl means a non-aromatic monocyclic ring system having at least one heteroatom. As heteroatoms nitrogen atoms, oxygen atoms or sulfur atoms can occur.
  • a monocyclic heterocyclyl ring according to the present invention may have 4 to 8, preferably 4 to 6, particularly preferably 5 or 6 ring atoms.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 4 ring atoms are: azetidinyl, oxetanyl.
  • azetidinyl imidazolidinyl, pyrazolidinyl, pyrrolinyl, dioxolanyl, thiazolidinyl and tetrahydrofuranyl radicals.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl.
  • monocyclic heterocyclyl radicals having 7 ring atoms 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-. Exemplary and preferred for monocyclic heterocyclyl radicals having 8 ring atoms are: oxocanyl, azocanyl.
  • monocyclic heterocyclyl radicals preference is given to 4 to 6-membered, saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S.
  • Carbon atoms through heteroatoms as defined above in any combination is to be understood as meaning a fusion of two saturated ring systems sharing in common two directly neighboring atoms.
  • 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 [5.2.0] nonyl, bicyclo [6.2.0] decyl, bicyclo [4.3.0] nonyl, bicyclo [5.3.0] decyl, bicyclo [6.3.0] undecyl and bicyclo [5.4.0] undecyl, including variants modified by heteroatoms such as Azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl,
  • 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.
  • both a bridged carbocycle arise as well as a bridged heterocycle (bridged Heterocycloalkyl-) with a replacement of 1-4 carbon atoms by heteroatoms as defined above in any combination.
  • Examples are bicyclo [2.2.1] heptyl, azabicyclo [2.2.1] heptyl, oxazabicyclo [2.2.1] heptyl, thiazabicyclo [2.2.1] heptyl,
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is an alkyl radical having at least one halogen substituent.
  • a halo-Ci-Cö-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, fluorine-C 1 -C 4 -alkyl, and fluorine 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 fluoro 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.
  • An amino-Ci-Cö-alkyl radical is an alkyl radical consisting of 1-6 carbon atoms and at least one amino substituent.
  • Alkylaminoalkyl- represents an alkyl radical substituted with 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 examples include -Dimethylaminoefhyl-, A ⁇ -Dimethylaminomefhyl-, N, N-diethylaminoethyl, A ⁇ -Dimefhylaminopropyl-, -Mefhylaminoefhyl-, -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 the compounds of formula (I), the compounds mentioned below 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, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds of this 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 from 1 to 16 carbon atoms, such as Example methylamine, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, -methylpiperidine, -methylglucamine, dimethylglucamine, ethylglucamine, 1,6-hexadiamine , Glucosamine, sarcosine, serinol,
  • alkali metals such as sodium or potassium
  • alkaline earth metals
  • the compounds according to the invention can form base addition salts with quaternary ammonium ions, which are obtained, for example, by quaternization of corresponding amines with etches 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 can be obtained.
  • quaternary ammonium ions are examples of such quaternary ammonium ions.
  • Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs can be present either as a single polymorph or 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
  • Solvent molecules form a complex. 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 can, depending on their structure in
  • the compounds according to the invention have an asymmetric center on the carbon atom to which R 2 is bonded (C-4). They can 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, for example a chiral carbon atom.
  • 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 (-configured.
  • Another object of the present invention are stereoisomer mixtures of (45) - configured compounds according to the invention with their (4R) isomers, in particular the corresponding racemates, the further Diastereomeren- and Enantiomerengemische in which outweighs the (45) form. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • 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.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ⁇ (deuterium), ⁇ (tritium), n C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 1, 124 L 129 I and 131 I.
  • isotopic variants of a compound of the invention may be useful, for example, for the study of the mechanism of action or distribution of active ingredient 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.
  • the incorporation of 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;
  • modifications of the compounds according to the invention may therefore possibly also constitute a preferred embodiment of the present invention.
  • 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 corresponding isotopic modifications of the respective reagents and / or
  • 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. To this end it may be administered in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • a suitable manner such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds of the invention can be used in suitable
  • Administration forms are administered.
  • Forms of administration which deliver the compounds according to the invention rapidly and modified, and which may contain the compounds according to the invention in crystalline, amorphized or dissolved form, such as e.g. Tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), in
  • Oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, pellets, powders,
  • Emulsions, suspensions, aerosols or solutions Emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption 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.
  • Other routes of administration are suitable, for example 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 for example, polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers eg
  • Antioxidants such as ascorbic acid
  • dyes e.g., inorganic pigments such as iron oxides
  • flavor and / or odoriferous agents are pharmaceutical 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 is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
  • excipients for example, vehicles, 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.
  • 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.
  • the compounds of the invention 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 gliomas
  • tumors of the male reproductive organs are treatable:
  • tumors of the female reproductive organs are treatable:
  • Vulvar Carcinomas As tumors of the gastrointestinal tract, for example, are treatable:
  • tumors of the urogenital tract are treatable:
  • tumors of the eye are treatable:
  • Intraocular melanomas For example, tumors of the liver are treatable:
  • tumors of the skin are treatable:
  • tumors of the head and neck are treatable:
  • Carcinomas of the midline structures (such as NMC, CA French, Annu Rev. Pathol., 2012, 7: 247-265)
  • sarcomas are treatable:
  • lymphomas are treatable:

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Abstract

L'invention concerne des 2,3-benzodiazépines disubstituées en position 6,9, inhibant les protéines à bromodomaine, en particulier les protéines BET et de préférence la BRD4, lesdites benzodiazépines étant représentées par la formule générale (I), dans laquelle R1a, R1b, R1c, R2, R3, R4, R5, R6a et R6b sont tels que définis dans la description. L'invention concerne également des substances pharmaceutiques renfermant lesdits composés ainsi que leur utilisation prophylactique et thérapeutique dans le cas de maladies hyperprolifératives, en particulier dans le cas de maladies tumorales. L'invention concerne en outre l'utilisation des inhibiteurs de protéines BET dans le traitement des hyperplasies bénignes, des maladies athérosclérotiques, des sepsis, des maladies auto-immunes, des maladies vasculaires, des infections virales, des maladies neurodégénératives, des maladies inflammatoires et pour le contrôle de la fertilité masculine.
PCT/EP2015/052705 2014-02-14 2015-02-10 1-phényl-3h-2,3-benzodiazépines disubstituées en position 6,9 et leur utilisation comme inhibiteurs de bromodomaine Ceased WO2015121227A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012075456A1 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals Inhibiteurs de bromodomaines et leurs utilisations
WO2012075383A2 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals, Inc. Inhibiteurs de bromodomaines et leurs utilisations

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2012075456A1 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals Inhibiteurs de bromodomaines et leurs utilisations
WO2012075383A2 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals, Inc. Inhibiteurs de bromodomaines et leurs utilisations

Non-Patent Citations (1)

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Title
JEAN-MARC GARNIER ET AL: "BET bromodomain inhibitors: a patent review", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 24, no. 2, 1 February 2014 (2014-02-01), pages 185 - 199, XP055121821, ISSN: 1354-3776, DOI: 10.1517/13543776.2014.859244 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués

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