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WO2017005711A1 - Dérivés de benzodiazépine substitués par du phosphore et du soufre - Google Patents

Dérivés de benzodiazépine substitués par du phosphore et du soufre Download PDF

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Publication number
WO2017005711A1
WO2017005711A1 PCT/EP2016/065756 EP2016065756W WO2017005711A1 WO 2017005711 A1 WO2017005711 A1 WO 2017005711A1 EP 2016065756 W EP2016065756 W EP 2016065756W WO 2017005711 A1 WO2017005711 A1 WO 2017005711A1
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alkyl
phenyl
dimethoxy
carboxamide
benzodiazepine
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PCT/EP2016/065756
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German (de)
English (en)
Inventor
Stephan Siegel
Bernard Haendler
Antonius Ter Laak
Amaury Ernesto FERNANDEZ-MONTALVAN
Detlef STÖCKIGT
Norbert Schmees
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Bayer Pharma Aktiengesellschaft
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Publication of WO2017005711A1 publication Critical patent/WO2017005711A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/02—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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms

Definitions

  • the present invention relates to bromodomain protein inhibitor cells, in particular to BET protein-inhibiting and preferably BRD4-inhibitory phosphorus- and sulfur-substituted benzodiazepine derivatives, to pharmaceutical agents containing the compounds according to the invention and to their prophylactic and therapeutic use in hyperproliferative
  • this invention relates to the use of BET protein inhibitors in benign hyperplasia, atherosclerotic diseases, sepsis, autoimmune diseases, vascular diseases, viral infections, in HIV-associated kidney diseases, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic erotic diseases, in heart failure Muscular dystrophies such as fazioskapulohumeral muscular dystrophy and in male fertility control.
  • the bromodomain protein belonging to the bromodomain protein family has four members (BRD2, BRD3, BRD4 and HR DT), the two related bromodomains ([BRD4 (1)] and [BRD4 (2) ] and an extra-terminal domain (Gallenkamp et al., Chem. Med. Chem., 2014, 9: 438-464; Filippakopoulos and Knapp, Nature Reviews, 2014, 13: 337-356; Haendler et al, Epigenomics, 2015 , 7: 487-501).
  • the bromodomains are protein regions that recognize acylated lysine residues.
  • 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
  • the various acylation patterns recognized by BET proteins in histones have been well studied (Umehara et al., J. Biol. Chem., 2010, 285: 7610-761 8;
  • bromodomains can recognize additional acetylated proteins.
  • BRD4 binds to RelA, resulting in the stimulation of NF-B 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, 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 "
  • RNA polymerase 11 Chromatin amplify and promote transcription by RNA polymerase 11 (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).
  • c-Myc expression an essential factor in cell proliferation, following BRD4 inhibition was demonstrated
  • 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).
  • BRDT has an essential function in spermatogenesis (Berkovits and Wolgemuth, Curr., Top. Dev. Biol., 2013, 102: 293-326).
  • BET proteins play an important role in various tumor types.
  • the fusion between the BET proteins BRD3 or BRD4 and NUT a protein normally only expressed in the testes, 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, 286: 27663-27675).
  • the growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073).
  • 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 was detected in primary breast tumors (Kadota et al., Cancer Res, 2009, 69: 7357-7365). Also for "
  • BRD2 has data on 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 inhibitors used in various preclinical in vitro and in vivo tumor models suggest an essential role of BET proteins, especially BRD4, in hematological tumors such as AML, multiple myeloma, and lymphomas ( Delmore et al., Cell, 201 1, 146: 904-917; Zuber et al., Nature, 2011, 478: 524-528; Merz et al., Proc. Natl.
  • Tumors such as prostate cancer (Asangani et al., Nature, 2014, 510: 278-282), breast cancer (Nagarajan et al., Cell Reports, 2014, 8: 460-469; Shi et al., Cancer Cell, 2014; 25: 210-225), lung cancer (Shimamura et al., Clin. Cancer Res., 2013, 19: 6183-6192, Lockwood et al., Proc Natl Acad., USA, 2012, 109: 19408-19413 ), Melanoma (Gallagher et al., J. Invest. Dermatol.
  • pancreatic cancer Sahai et al., Mol. Cancer Ther., 2014, 13: 1907-1917
  • glioblastoma Pastori et al., Epigenetics, 9: 61-620
  • Neuroblastoma Wyce et al., PLOS One, 2013, 8: e72967
  • medulloblastoma Henssen et al., Oncotarget, 2013, 4: 2080-2095.
  • 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 O cells (Wu et al., Genes Dev., 2006, 20: 2383-2396, Vosa et al., J. Viral. 2012, 86: 348-357;
  • herpesvirus responsible for Kaposi's sarcoma also interacts with various BET proteins
  • 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). A role of BRD4 in the control of the latency of H IV proviruses has also been demonstrated (Boehm et al., Cell Cycle, 2013, 1 2: 452-462). Human T-cell leukemia virus 1 (HTLV-1) is also controlled by BRD4 via the NF- ⁇ B pathway (Wu et al., J. Biol.
  • 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.
  • a BRD4 inhibitor prevents the expression of inflammatory genes, such as II.-I or IL-6 (Nicodeme et al., Nature, 2010, 468: 1179-1123).
  • BET proteins also regulate the expression of the ApoAl gene, which plays an important role in atherosclerosis and in inflammatory processes (Chung et al., J. Med. Chem., 2011, 54: 3827-3838).
  • 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., 201 1, 32: 1345-1361).
  • Increased expression of BRD4 was observed during cardiac hypertrophy and attributed to the regulation of atrial natriuretic factor expression (Spiltoir et al., J. Mol. Cell. Cardiol., 2013, 63: 175-179). Accordingly, BRD4 could also play an important role in heart failure.
  • BET proteins play an essential role in various pathologies and also in male fertility. It is therefore desirable to find potent and selective inhibitors which prevent the interaction between the BET proteins, for example BRD2, BRD3, BRD4 and BRDT, and acetylated proteins, especially acetylated histone H4 peptides.
  • L-aryl-4,5-dihydro-3i7-2,3-benzodiazepines have long been known, inter alia, as modulators or antagonists excitatory shear amino acid receptors, such as the AMPA receptor and are, among other things as a potential therapeutic agents for diseases central nervous Origin described.
  • WO 2001/098280 discloses 1-phenyl-4,5-dihydro-377-2,3-benzodiazepines as antagonists of the non-NMDA ionotropic excitatory amino acid (EAA) receptor.
  • EAA excitatory amino acid
  • the compounds according to the invention furthermore differ, inter alia, by the substitution on the aromatics associated with Cl of the B enzodiazepine skeleton of other known 2,3-benzodiazepines such as the numerous published AMPA antagonists (see, for example, WO 1997/28135 (Schering AG), US Pat. No. 5,807,851 , HU 0097000688, WO
  • WO 1997/034878 and US 5,891,871 disclose 2,3-benzodiazepine-4-ones which differ from the compounds of the present invention by the oxo substitution at C -4 of the benzodiazepine skeleton Antagonists or positive modulators of the AMPA receptor.
  • Ligands of the gastrin and the cholecystokinin receptor are described in WO2006 / 051312 (James Black Foundation). They also include substituted 3,5-dihydro-417-2,3-benzodiazepine-4-ones, which differ from the compounds of the invention mainly by the obligatory oxoglobin in position 4 and by a mandatory carbonyl-containing alkyl chain in position 5.
  • WO 2008/121877 discloses cyclic and acyclic hydrazone derivatives as inhibitors of the functional transmembrane conductance regulatory polypeptide in cystic fibrosis (CFTR), inter alia, for the treatment of diarrhea and polycystic kidney disease (PKD).
  • WO 2014/026997, WO 2014/128067 and WO 2014/202578 disclose 1-phenyl- and 1-heteroaryl-4,5-dihydro-3i7-2,3-benzodiazepines as inhibitors of ET Prot, in particular of BRD4 for the treatment of hyperproliferative diseases.
  • the compounds of the present invention differ by substitution on the phenyl or heteroaryl ring attached to C-1 of the benzodiazepine skeleton.
  • Fertility control can be used.
  • the compounds according to the invention inhibit the interaction between BET proteins, in particular BRD4, and an acetylated histone H4 peptide.
  • they inhibit the growth of cancer or tumor cells and can also be used in viral infections, in HIV-associated diseases, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic erotic diseases, in heart failure, in muscular dystrophies such as, for example, the fazioskapulohumeral
  • R is C 1 -C 3 -alkyl, trifluoromethyl or C 3 -C 4 -cycloalkyl, R is cyclopropyl, C 1 -C 3 -alkyl, C 1 -C 8 -alkoxy, amino, cyclopropylamino or
  • R 4 and R 3 are independently
  • C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulphonyl which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, by halogen, amino, hydroxyl,
  • Carboxy C 1 -C 6 -acyl, 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 4 -alkyl, C6-alkyl,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, nitro, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1-Ce-alkoxy-C 1 -Ce-alkyl,
  • R 15 independently of one another, is hydrogen, halogen, hydroxyl, cyano, nitro or C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-,
  • monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, Ci-C 3 alkyl, fluoro-GC 3 alkyl, Cs -Ce-cycloalkyl, cyclopropylmethyl, C i -C3 alkylcarbonyl or C 1 -C 4 alkoxycarbonyl -, for hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno-C 1 -C 3 alkyl,
  • Ci-C 3 alkoxy or GC 3 alkyl is C Ce-alkyl, which is unsubstituted or GC is monosubstituted with cyano, 3 alkoxy, C 1 -C 3 alkylamino, phenyl, C 3 -Cs-cycloalkyl , or with monocyclic heterocyclyl having 4 to 8 ring atoms,
  • phenyl in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted identically or differently with halogen, cyano, G-C4-alkyl-, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci-C 4 alkoxy, halo-Ci-C 4 alkyl or halo-C i -C 4 alkoxy, and
  • phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 - Alkoxy, trifluoromethyl or trifluoromethoxy,
  • bromodomain protein inhibitors in particular as BET protein inhibitors and preferably as BRD4 inhibitors, for a variety of prophylactic and therapeutic uses, in particular in hyperproliferative diseases, in cancer or
  • Tumor diseases as well as in viral infections, in HTV-associated kidney diseases, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases, in heart failure, in muscular dystrophies such as the
  • the present invention furthermore relates to compounds of the general formula (I) in which
  • R 4 and W are independent of each other
  • Ci-Ce-Alkylaminosuifonyl- which are unsubstituted or mono-, di- or trisubstituted, identically or differently, are substituted by halogen, amino, hydroxy, carboxy, O-Ce-alkyl, hydroxy-C i -Cö-alkyl- , Ci-Cö-alkoxy,
  • C 3 -C 10 -cycloalkyl- or C 4 -C 1 -cycloalkenyl- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, carboxy, C 1 -C 6 -cycloalkyl- Alkyl, Ci-Ce-alkoxy,
  • Ci-Ce-alkylamino amino-Ci-Ce-alkyl, Ci-Ce-alkylaminocarbonyl, Ci-Ce-alkylaminosulfonyl, Ci-Ce-Aikylamino-Ci-alkyl,
  • monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl , Cs-Ce-cycloalkyl, cyclopropylmethyl, Ci-Cs-alkylcarbonyl or Ci-C4-alkoxycarbonyl, for hydroxy, Ci-Ce-alkyl, G-Ce-alkoxy, halogen-C i-C3-alkyl -
  • 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 mono- or di-substituted, same or different, substituted are halogen, O-Cs-alkoxy or O-Cs-alkyl, is O-Ce-alkyl which is unsubstituted or monosubstituted with cyano, G -C -alkoxy, C i -C 3 -alkylamino, Phenyl, C 3 -C 8 -cycloalkyl- or monocyclic heterocyclyl having 4 to 8 ring atoms,
  • phenyl in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl-, Ci-C 4 alkoxy, halo-Ci-C 4 alkyl or halogen-C 1 -C 4 alkoxy, and
  • phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl- in turn are unsubstituted or one or two times, same or different are substituted with halogen, cyano, GC 3 alkyl, GC 3 alkoxy, trifluoromethyl or trifluoromethoxy,
  • R 1 and R 15 together represent C 2 -C 8 -alkylene
  • R 16 represents G-C 1 -C 4 -alkyl or phenyl-C 1 -C 3 -alkyl, and also their polymorphs, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • R 3 is cyclopropyl, Ci-C3-alkyl, cyclopropylamino or
  • R 4 and R 5 are independently
  • C 1 -C 6 -alkyl G-C 1 -C -alkoxy, C 1 -C 6 -alkylamino, phenylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulfonyl, which unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, halogen, amino, hydroxy, carboxy, C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 3 -C 3 -alkoxy, C1-C3-alkoxy-C1-C.
  • monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by identical or different substituted with halogen, amino, hydroxy, cyano, carboxy, C1-C3 alkyl, GC 3 alkoxy -, C 1 -C 3 alkoxy-C 1 -C 3 -alkyl, hydroxy-C iC 3 alkyl, C iC 3 alkylamino,
  • R 15 is hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or GC 3 alkyl, GC 3 - Alkoxy, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, fluoro-GC 3 -alkyl-,
  • Fluorine-GC 3 -alkoxy- or GC 3 -alkylsulfonyl stands independently of one another for hydrogen, GC 3 -alkyl, acetyl, propionyl or for fluorine-C 1 -C 3 -alkyl- stand,
  • monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, cyano, GC 3 alkyl, C 3 -C 6 cycloalkyl, GC 3 alkylcarbonyl or C 1 -C 4 alkoxy carbonyl, for hydroxy, C 1 -C 3 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 3 -alkyl,
  • phenyl represents phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or mono- or disubstituted, identical or different, are substituted by halogen, Ci-C 3 alkoxy or C 1 -C 3 -alkyl-, C 1 -C 6 -alkyl-, which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl, C 3 - Cs-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms,
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluorine-GC 3 -alkyl or fluorine C 1 -C 3 -alkoxy- and in which C 3 -C 8 -cycloalkyl- and monocyclic heterocyclyl having 4 to 8 ring atoms are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with GC 3 -alkyl-,
  • R 14 and R 15 independently of one another are C 1 -C 3 -alkyl, phenyl-G-Cs-alkyl,
  • phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C -alkoxy- , Trifluoromethyl or trifluoromethoxy,
  • R 14 and R 15 together represent C 2 -C 8 -alkylene
  • R 16 is C 1 -C 3 -alkyl or benzyl, and their polymorphs, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically tolerated salts and solvates of these salts.
  • Ci-Ce-Alkylaminosulfonyl- which are unsubstituted or mono-, di- or trisubstituted, identical or different, are substituted by halogen, amino, hydroxy, carboxy, G-C3-alkyl, hydroxy-C i -C 3 alkyl -, Ci-C3-alkoxy,
  • R 15 represents hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or GC 3 alkyl, Ci-C 3 alkoxy, C 1 -C 3 alkoxy C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl,
  • Fluoro-Ci-C 3 alkoxy or C 3 is alkylsulfonyl, independently of one another represent hydrogen, GC 3 -Aikyl-, acetyl, propionyl or fluoro-C 1 -C 3 alkyl are,
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, cyano, Ci-C3-alkyl, Cs-Ce-cycloalkyl, Ci-C3-alkylcarbonyl - or C i -C4-alkoxycarbonyl, for hydroxy, C 1 -C 3 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 3 -alkyl,
  • Ci-C 3 alkoxy or C 1 -C 3 -alkyl- represents C 1 -C 6 -alkyl-, which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl, C 3 - Cs-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms,
  • phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, GC 3 alkyl, Ci-C 3 alkoxy, fluoro-Ci-C 3 alkyl or fluorine C 1 -C 3 -alkoxy- and in which C 3 -C 8 -cycloalkyl- and monocyclic heterocyclyl having 4 to 8 ring atoms are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with GC 3 -alkyl-,
  • R 14 and R 15 independently of one another represent G-Cs-alkyl-, phenyl-C 1 -C 3 -alkyl-,
  • phenyl and the phenyl contained in phenyl-C 1 -C 3 -alkyl- are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, G-Cs-alkyl, G-Cs-alkoxy- , Trifluoromethyl or trifluoromethoxy,
  • R 14 and R 15 together represent C 2 -C 8 -alkylene
  • R 16 is C 1 -C 3 -alkyl or benzyl, and their polymo he, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • R ' is Ci-Cs-alkylamino-, R 4 and R 5 are independently
  • R is hydrogen, fluorine, C 1 -C 3 -alkoxy- or C 1 -C 3 -alkylsulfonyl-, R 9 and R 10 are each independently hydrogen, methyl, ethyl or acetyl, or
  • monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluoro, oxo, methyl, ethyl, cyclopropyl, acetyl or terf-butoxycarbonyl,
  • R is hydroxy, C 1 -C 3 -alkyl or C 1 -C 4 -alkoxy
  • R 12 is GG-alkyl- which is unsubstituted or monosubstituted with G-C 3 alkylamino, phenyl, or with monocyclic heterocyclyl of 4 to 7
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, G-G-alkyl, GG-alkoxy, trifluoromethyl or trifluoromethoxy, and wherein the monocyclic heterocyclyl having 4 to 7 ring atoms in turn is unsubstituted or monosubstituted by methyl, or
  • Ci-C3-alkyl is C3-6 cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted with Ci-C3-alkyl or
  • R 14 and R 15 independently of one another for C 1 -C 3 -alkyl, benzyl, trifluoromethyl or for
  • R 16 is C 1 -C 3 -alkyl-, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which represented by the carbon atom bound to R 2 center of asymmetry ( ⁇ -configured, as well as their stereoisomeric mixtures in which those stereoisomers predominate in which the represented by the carbon atom bound to R 2 asymmetric center (S) - is configured.
  • R 2 is methyl
  • R 3 is Ci-Cs-alkylamino
  • R 4 and R 5 are independently
  • R is hydrogen, fluorine, GC 3 -alkoxy- or C 1 -C 3 -alkylsulfonyl-,
  • R 9 and R 10 are independently hydrogen, methyl, ethyl or acetyl, or
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, Oxo, methyl, ethyl, cyclopropyl, acetyl or ferf-butoxycarbonyl, is hydroxy, Ci-C3-alkyl or Ci-C4-alkoxy, is Ci-Ce-alkyl- which is unsubstituted or is monosubstituted by G-C3-alkylamino, phenyl, or monocyclic heterocyclyl having 4 to 7 ring atoms,
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, G-G-alkyl, GG-alkoxy, trifluoromethyl or trifluoromethoxy, and wherein the monocyclic heterocyclyl having 4 to 7 ring atoms in turn is unsubstituted or monosubstituted by methyl,
  • phenyl and the benzyl-containing phenyl in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, GC 2 alkyl, GC 2 alkoxy, trifluoromethyl or trifluoromethoxy -, and represents GC 3 -alkyl-, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, as well as their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R- is ( ⁇ -configured, as well as their mixtures of stereoisomers, in which those stereoisomers in which the asymmetric center (5) - represented by the carbon atom bound to R predominate - are configured.
  • R - is methyl
  • R 3 is methylamino or dimethylamino
  • R 4 is methoxy
  • R 3 is methoxy
  • R is hydrogen, fluorine, methoxy- or methylsulfonyl-, R 'and R 10 independently of one another represent hydrogen, methyl or ethyl,
  • R 9 and R 10 together with the nitrogen atom to which they are attached, for monocyclic heterocyclyl having 5 to 7 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, methyl or ethyl, R "is hydroxy, methyl, ethyl, methoxy or ethoxy .
  • R 12 is C 1 -C 3 -alkyl which is unsubstituted or monosubstituted with
  • phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, cyano, methyl, methoxy or trifluoromethyl, or
  • butoxycarbonyl with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ", or
  • R ' 4 and R' 5 independently of one another represent methyl, ethyl or phenyl
  • phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, and
  • R 16 is methyl, as well as their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the by R in ; bonded carbon atom represented asymmetry center ( ⁇ -konfiguriert is, as well as their stereoisomeric mixtures in which those stereoisomers predominate, in which is the asymmetric center (S) - represented by the carbon atom bonded to R : -.
  • R is methyl, R 'is methylamino,
  • R 4 is methoxy
  • R 5 is methoxy
  • R 7 is hydrogen, fluorine, methoxy- or methylsulfonyl-
  • R ' is hydrogen, methyl or ethyl
  • phenyl is in turn unsubstituted or monosubstituted with Fluorine, chlorine, cyano, methyl, methoxy or trifluoromethyl, or
  • phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, and
  • R 16 is methyl, as well as their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R 2 is ( ⁇ -configured , and their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetry center (S) - represented by the carbon atom bound to R 2 - is configured.
  • R 3 is methylamino or dimethylamino
  • R 4 is methoxy
  • R 7 is hydrogen, fluorine or methylsulfonyl-
  • R 12 is methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or a group
  • R 13 is hydrogen or methyl
  • R 14 and R independently of one another are methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically tolerated salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which by R bound carbon atom represented center of asymmetry ( ⁇ is configured, as well as their stereoisomeric mixtures in which predominate those stereoisomers in which the represented by the carbon atom bound to R 2 asymmetry center (5) - is configured.
  • R 4 is methoxy
  • R 5 is methoxy
  • R is hydrogen, fluorine or methylsulfonyl
  • R 12 is methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or one of a group
  • R 13 is hydrogen or methyl
  • R 14 and R ' 5 are each independently methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which by the center of asymmetry centered on R (5) is conglomerated, as well as their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetric center (5) represented by the carbon atom bound to R 2 is configured.
  • R 4 is methoxy
  • R 5 is methoxy
  • R 7 is hydrogen, fluorine, or methylsulfonyl-
  • R 12 is methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or one
  • R 13 is hydrogen
  • R 14 and R 15 are independently methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which by the carbon center attached to R 2 represents the center of asymmetry ( ⁇ -configured and their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetry center (S) - represented by the carbon atom bound to R " - is configured.
  • R 13 is hydrogen
  • R 14 and R 15 are independently methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which by the and the stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetric center (S) - represented by the carbon atom bound to R - is configured.
  • R 3 is methylamino-
  • R 4 is methoxy
  • R 5 is methoxy-, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R 2 ( ⁇ -konfiguriert ist , and their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetry center (5) represented by the carbon atom bound to R is configured. Also highly preferred are those compounds of general formula (I), in R a for a group
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R is methyl, R 3 is methylamino,
  • R 4 is methoxy
  • R 3 is methoxy
  • (4S) -7,8-dimethoxy-N 4-dimethyl-1- [4- (methylsulfonyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide
  • (4S) -7,8-dimethoxy-N 4-dimethyl-1- ⁇ 4 - [(1-methylpiperidin-4-yl) sulfanyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;
  • (4S) -7,8-dimethoxy-N 4-dimethyl-1- [4- (phenylsulfmyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide
  • (4S) -7,8-dimethoxy-N 4-dimethyl-1- (4 - ⁇ [4- (2-oxo-pyi-tolidin-1-yl) -phenyl] -sulfonyl ⁇ -phenyi) -4,5-dihydro-3H-2 , 3-benzodiazepin-3-carboxamide;
  • R 1 is preferably a group
  • R 1 particularly preferably represents a group
  • R is hydrogen, and wherein "*" is the point of attachment to the rest of the molecule.
  • R ! most preferably for a group a
  • R 1 most preferably represents a group
  • R 1 most preferably represents a group
  • R is hydrogen
  • "*" is the point of attachment to the rest of the molecule.
  • R is hydrogen
  • "*" is the point of attachment to the rest of the molecule.
  • R 1 is more preferably a group
  • R 1 is more preferably a group
  • R 1 is more preferably a group
  • R 1 is more preferably a group
  • 1 is more preferably a group
  • R 1 is more preferably a group or for a group
  • R is preferably methyl or ethyl.
  • R 2 is preferably methyl.
  • R 3 is preferably cyclopropyl, C 1 -C 8 -alkyl, cyclopropylamino or C 1 -C 3 -alkylamino.
  • R 3 is particularly preferably GC 3 alkylamino.
  • R 3 is particularly preferably C 1 -C 2 -alkylamino.
  • R 3 is very particularly preferably methylamino or
  • R 3 very particularly preferably represents methylamino.
  • R 4 and R 5 are each independently preferably
  • R 4 and IV independently of one another are particularly preferably
  • R 4 particularly preferably represents hydrogen, hydroxy, cyano,
  • R 4 particularly preferably stands for C 1 -C 3 -alkoxy- and R 5 particularly preferred for hydrogen, hydroxy, cyano, fluorine, chlorine or bromine,
  • R 4 particularly preferably represents hydrogen, hydroxyl, cyano, fluorine, chlorine or bromine,
  • R 4 and R 5 particularly preferably represents G-C3-alkoxy-.
  • R 4 and R 5 independently of one another particularly preferably represent G-C 3 -alkoxy.
  • R 4 and R 5 very particularly preferably each represent methoxy.
  • R ' is preferably a group SR 1 ".
  • R "preferably represents a group ⁇ S ( O) R 12.
  • R" preferably represents a group
  • R preferably represents hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or for GC 3 alkyl, Ci-C 3 alkoxy, C 1 -C 3 alkoxy-C 1 -C 3 alkyl, fluoro-Ci-C 3 alkyl, fluoro-C 1 -C 3 alkoxy - or C 1 -Cs-alkylsulfonyl.
  • R is preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or methyl, methoxy, methoxymethyl, methoxyethyl, difluoromethyl, Trifluoromethyl, trifluoromethoxy or methylsulfonyl.
  • R preferably represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or methylsulfonyl.
  • R is particularly preferably hydrogen, fluorine, C 1 -C 3 -alkoxy or C 1 -C 8 -alkylsulfonyl-.
  • R very particularly preferably represents hydrogen, fluorine, methoxy- or methylsulfonyl-.
  • R very particularly preferably represents hydrogen, fluorine or methylsulfonyl. In the general formula (I), R very particularly preferably represents hydrogen or fluorine.
  • R is very particularly preferably fluorine.
  • R is very particularly preferably methylsulfonyl.
  • R is very particularly preferably hydrogen.
  • R 9 and R 10 are independently of each other preferably
  • R 9 and R 10 together with the nitrogen atom to which they are attached are monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluoro, oxo, cyano, C 1 C 3 alkyl, Cs-Ce cycloalkyl, C 1 -C 3 alkylcarbonyl or C 1 -C 4 alkoxycarbonyl.
  • R 9 and R 10 independently of one another are preferably
  • R 9 and R 10 are preferably taken together with the nitrogen atom to which they are bonded, for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents Fluorine, oxo, Cyan, Ci-C3-alkyl, Cs-Cö-cycloalkyl, G-Cs-alkylcarbonyl or G-C4-alkoxycarbonyl-.
  • R 9 and R 10 independently of one another particularly preferably represent hydrogen, methyl, ethyl or acetyl
  • R 'and R 10 are taken together with the nitrogen atom to which they are attached, for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, oxo. Methyl, ethyl, cyclopropyl, acetyl or tert. -Butoxycarbonyl-.
  • R 9 and R 10 independently of one another particularly preferably represent hydrogen, methyl, ethyl or acetyl.
  • R 9 and R 10 are particularly preferably together with the
  • Ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, methyl, ethyl, cyclopropyl, acetyl or tert. -Butoxycarbonyl-.
  • R 9 and R 10 independently of one another very particularly preferably represent hydrogen, methyl or ethyl
  • R 9 and R 10 together with the nitrogen atom to which they are attached, monocyclic heterocyclyl having 5 to 7 ring atoms which is unsubstituted or mono- or disubstituted by identical or different substituted with oxo, methyl or ethyl ,
  • R 9 and R 10 independently of one another very particularly preferably represent hydrogen, methyl or ethyl.
  • R 9 and R 10 are particularly preferably together with the
  • Ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, methyl or ethyl.
  • R 9 and R 10 independently of one another very particularly preferably represent hydrogen or methyl. In the general formula (I), R 9 and R 10 very particularly preferably each represent hydrogen. In the general formula (I), R 'and R ! "very particularly preferably for methyl.
  • R 11 preferably represents hydroxyl, C 1 -C 3 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 3 alkoxy-C 1 -C 3 -alkyl or C 3 -C 7 -cycloalkyl, or for phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or a - or doubly, the same or different, are substituted by halogen, Ci-Cj-alkoxy or Ci-C3-alkyl-.
  • R 11 particularly preferably represents hydroxy, C 1 -C 3 -alkyl or C 5 -O-alkoxy-.
  • R ! i very particularly preferably for hydroxy, methyl, ethyl, methoxy or ethoxy.
  • R 11 is very particularly preferably hydroxy, methoxy or ethoxy.
  • R 11 very particularly preferably represents methyl or ethyl.
  • R 11 very particularly preferably represents hydroxyl, methyl or methoxy.
  • R 11 is very particularly preferably hydroxyl.
  • R i2 is preferably C 1 -C 6 -alkyl which is unsubstituted or monosubstituted with cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl, C C 3 -C 5 cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms,
  • phenyl in which phenyl is in turn unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl, C 3 -C 3 -alkoxy-,
  • C3-C8-cycloalkyl and monocyclic heterocyclyl having 4 to 8 ring atoms are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl or for fluorine-C 1 -C 3 -alkyl-,
  • C 3 -C 8 -cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 8 -alkyl or C 1 -C 4 -alkoxycarbonyl, with the proviso that that the monocyclic
  • R 12 preferably represents G-Ce-alkyl, which is unsubstituted or is monosubstituted by cyano , C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl, C 3 -C 8 -cycloalkyl or monocyclic heterocyclyl with 4 to 8 ring atoms,
  • phenyl in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, G-C3-alkyl-, C 1 -C 3 -alkoxy-,
  • Cs-Cs-cycloalkyl and monocyclic heterocyclyl having 4 to 8 ring atoms in turn are unsubstituted or mono- or disubstituted by identical or different substituents with GC 3 alkyl or
  • R 12 is particularly preferably C 1 -C 6 -alkyl which is unsubstituted or monosubstituted by C 1 -C 3 -alkylamino, phenyl or monocyclic
  • phenyl in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted, identically or differently, by fluorine, chlorine, bromine, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, trifluoromethyl- or trifluoromethoxy-, and
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, trifluoromethyl, trifluoromethoxy,
  • R 12 is particularly preferably C 1 -C 6 -alkyl which is unsubstituted or monosubstituted by C 1 -C 3 -alkylamino, phenyl or monocyclic
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, O-Cs-alkyl, Ci-Cs-alkoxy, trifluoromethyl or trifluoromethoxy, and
  • C3-C6-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted with Ci-C3-alkyl or Ci-C4-alkoxycarbonyl, with the proviso that the monocyclic heterocyclyl with 4 until 7 ring atoms are not bonded via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C 3 alkyl, Ci-C 3 alkoxy, trifluoromethyl or
  • R 12 particularly preferably represents C 1 -C 4 -alkyl which is unsubstituted or monosubstituted by C 1 -C 3 -alkylamino, phenyl or monocyclic
  • phenyl in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-,
  • R 12 particularly preferably represents Cs-Ce-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted by C 1 -C 3 -alkyl or C 1 -C 4 -alkoxycarbonyl -, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms is not bound via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R '.
  • R 12 particularly preferably represents phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano,
  • R 12 particularly preferably represents phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano,
  • R 12 very particularly preferably represents C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by phenyl,
  • phenyl is in turn unsubstituted or monosubstituted with fluorine, chlorine,
  • Nitrogen atom is bonded to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',
  • R 12 very particularly preferably represents C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by phenyl,
  • phenyl in which phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, cyano, methyl, methoxy or trifluoromethyl,
  • C3-C6 cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted with methyl or terf-butoxycarbonyl, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms does not have a
  • Nitrogen atom is bonded to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',
  • R 12 very particularly preferably represents O-Cs-alkyl which is unsubstituted or monosubstituted with phenyl,
  • phenyl is in turn unsubstituted or monosubstituted with fluorine, chlorine,
  • R i2 very particularly preferably represents C 1 -C 3 -alkyl- which is unsubstituted or monosubstituted by phenyl-,
  • phenyl is in turn unsubstituted or monosubstituted with fluorine, chlorine,
  • R 12 very particularly preferably represents Cs-Ce-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms, which are unsubstituted or monosubstituted by methyl or fer-butoxycarbonyl, with the proviso that that the monocyclic heterocyclyl having 4 to 7 ring atoms is not bound via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ".
  • R 12 very particularly preferably represents C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by phenyl,
  • piperidinyl is unsubstituted or monosubstituted with methyl or feri-butoxycarbonyl, with the proviso that the piperidinyl is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R 6 , or
  • R 12 very particularly preferably represents C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by phenyl,
  • piperidinyl is unsubstituted or monosubstituted with methyl or butoxy-butoxycarbonyl, with the proviso that the piperidinyl is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',
  • R 12 very particularly preferably represents C 1 -C 8 -alkyl, which is unsubstituted or monosubstituted with phenyl.
  • R 12 very particularly preferably represents C 3 -C 8 -cycloalkyl, T-undehydropyranyl or piperidinyl,
  • piperidinyl is unsubstituted or monosubstituted with methyl or ieri-butoxycarbonyl, with the proviso that the piperidinyl is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R '.
  • R 12 very particularly preferably represents methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or one or more groups
  • R 12 very particularly preferably represents methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or one or more groups
  • R is preferably hydrogen, cyano, C 1 -C 6 -alkyl-,
  • R 13 is particularly preferably hydrogen or C 1 -C 3 -alkyl-.
  • R 13 is particularly preferably C 1 -C 8 -alkyl-.
  • R " is very particularly preferably hydrogen or methyl.
  • R 13 is very particularly preferably hydrogen. In the general formula (I) R 13 is very particularly preferably methyl. In the general formula (I), R 14 and R 15 are each independently preferably
  • R 14 and R 15 together are preferably C 1 -C 8 -alkylene.
  • R 14 and R 15 are each independently preferably
  • phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen,
  • R ! 4 and R 15 together are preferably C 2 -C 8 -alkylene.
  • R 14 and R ! 5 independently of one another are particularly preferably C 1 -C 3 -alkyl-, benzyl-, trifluoromethyl- or phenyl-,
  • phenyl and the benzyl-containing phenyl are in turn unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C 2 alkyl, Ci-C2-alkoxy, trifluoromethyl - or trifluoromethoxy.
  • R 14 and R 15 independently of one another very particularly preferably represent methyl, ethyl or phenyl
  • phenyl is in turn unsubstituted or monosubstituted with fluorine, chlorine,
  • R 14 and R 15 independently of one another very particularly preferably represent methyl, ethyl or phenyl.
  • R i4 and R i5 independently of one another very particularly preferably represent methyl or ethyl.
  • R 14 and R are very particularly preferably each methyl.
  • R 14 and R 15 very particularly preferably each represent ethyl, ⁇
  • R 16 is preferably Ci-Cs-alkyl or benzyl.
  • R 16 is particularly preferably C 1 -C 3 -alkyl-.
  • R i6 is very particularly preferably methyl.
  • R 2 is more preferably methyl, R 3 is methylamino, R 4 is C 1 -C 3 -alkoxy and R 5 is C 1 -C 3 -alkoxy.
  • R 3 is methylamino
  • B enzo diazep in scaffold represented stereocenters preferentially either racemic or predominantly or fully in the ( ⁇ configuration
  • B enzo diazep in framework represented stereocenters preferentially either racemic or predominant or at least 95% in the (. ⁇ - configuration.
  • Benzodiazepine scaffold represented stereocenter preferentially racemic.
  • Benzodiazepine skeleton represented stereocenter particularly preferably predominantly or completely in the ( ⁇ configuration before.
  • B enzodiazepine framework represented stereocentre most preferably predominantly in the (S) configuration.
  • Benzodiazepine skeleton represented particularly preferred stereocenter of at least 5% in the (. ⁇ - configuration.
  • the stereocenter represented by the carbon atom of the benzodiazepine skeleton bonded to R 2 is particularly preferably completely in the (S) configuration.
  • Alkyl stands for a linear or branched, saturated, monovalent hydrocarbon radical with generally 1 to 6 (C 1 -C 6 -alkyl), preferably 1 to 4 (C 1 -C 6 -alkyl), and particularly preferably 1 to 3 carbon atoms (C 1 -C 4 -alkyl). C3-Alk1-).
  • C 2 -C -alkylene, or a C 2 -C 5 -alkylene group is to be understood as meaning a linear or branched, saturated, divalent hydrocarbon radical, such as, for example, an ethylene, propylene, butylene,
  • Cycloalkyl- stands for a monocyclic, saturated, monovalent hydrocarbon radical having generally 3 to 10 (C 3 -C 10 -cycloalkyl), preferably 3 to 8 carbon atoms
  • Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.
  • Cycloalkenyl C4-C6-cycloalkenyl, C4-C8-cycloalkenyl, C4-Cio-cycloalkenyl, or Cs-Cs-cycloalkenyl- is a monocyclic, mono- or polyunsaturated, non-aromatic, composed exclusively of carbon atoms Ring system with 4 to 6 atoms, 4 to 8 atoms, 4 to 10 atoms, or 5 to 8 atoms to understand. Examples are cyclobutene-1-yl,
  • phenyl-Ci-Cs-alkyl- is meant a group which is composed of an optionally substituted phenyl radical and a C 1 -C 3 alkyl group, and the via the C 1 -C 3 alkyl group to the rest of the molecule is bound.
  • the alkyl radical here has the meanings given above under alkyl.
  • 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.
  • Alkoxyalkvl- alkoxyalkyl stands for a substituted alkoxy radical, for example C 1 -C 6 alkoxy-C 1 - Ce alkyl or C iC 3 alkoxy-C 1 -C 3 alkyl.
  • Ci-Ce-alkoxy-Ci-Ce-Allcyl- 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 valency, for example to a saturated carbon atom or to sulfur.
  • the bond to carbon to form a carbonyl group Preferably, the bond to carbon to form a carbonyl group, and the
  • Binding of two double-bonded oxygen atoms to sulfur to form a sulfonyl group -S ( 0) 2 -.
  • Alkylaminoalkylamino stands for 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 represents, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms each
  • Examples include:
  • Phenylamino- represents a radical Ph-NH- or a radical Ph-N (Ci-C3-alkyl) -.
  • Examples include:
  • N-phenylamino N-methyl-N-phenylamino and N-ethyl-N-phenylamino. Preference is given to N-phenylamino.
  • Heteroatoms are oxygen, nitrogen or sulfur atoms.
  • heteroaryl
  • Heteroaryl means a monovalent, mono- or bicyclic, aromatic ring system having at least one heteroatom. As heteroatoms, it is possible for stoichi atoms, oxygen atoms or sulfur atoms to 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 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:
  • Monocyclic heterocyclyl means a saturated or mono- or polyunsaturated but not aromatic monocyclic ring system having at least one heteroatom.
  • Heteroatoms can occur as sto ffatoms, oxygen atoms or sulfur atoms.
  • a monocyclic heterocyclyl ring according to the present invention may have 4 to 8, preferably 4 to 7, more 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 tetrahydrofuryl radicals.
  • Exemplary and preferred for monocychic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl.
  • azepanyl By way of example and with preference for monocychic heterocyclyl radicals having 7 ring atoms, mention may be made of azepanyl, oxepanyl, 1,3-diazepanyl, 1,4-diazepanyl-.
  • Exemplary and preferred for monocychsche Heterocyclylreste with 8 ring atoms are called: Oxocanyl-, Azocanyl-.
  • monocyclic heterocyclyl radicals preference is given to 4 to 7-membered, saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl represents an alkyl radical having at least one halogen substituent.
  • a halo-C 1 -C 6 -alkyl radical is an alkyl radical having 1 to 6 carbon atoms and at least one halogen substituent. If several halogen substituents are present, they may also be different. Preference is given to fluoro-C 1 -C 6 -alkyl and fluoro-C 1 -C 4 -alkyl radicals, particular preference to fluorine-C 1 -C 3 -alkyl radicals. Examples and also preferred are:
  • Trifluoromethyl 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,5,5,5-pentafluoropentyl or
  • Haloalkoxy stands for an alkoxy radical with at least one halogen substituent.
  • a halo-C 1 -C 6 alkoxy radical is an alkoxy radical having 1 to 6 carbon atoms and at least a halogen substituent. If several halogen substituents are present, they may also be different. Preference is given to fluoro-C 1 -C 6 -alkoxy, fluoro-C 1 -C 4 -alkoxy, particularly preferably fluoro-C 1 -C 3 -alkoxy radicals. Examples and preferred are:
  • Hydroxyalkyl represents 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. Preference is given to hydroxy-C 1 -C 3 -alkyl radicals, particularly preferably hydroxymethyl- and 2-hydroxyethyl-.
  • Aminoalkylaminoalkyl- stands for an alkyl radical having at least one amino substituent.
  • amino-C 1 -C 6 -alkyl radical is an alkyl radical consisting of 1 -6 carbon atoms and at least one amino substituent. Preference is given to amino-C 1 -C 3 -alkyl radicals, particular preference is given to aminomethyl- and 2-aminoethyl-. alkylaminoalkyl
  • Alkylaminoalkyl- represents a substituted with alkylamino as defined above
  • Alkyl radical for example, Ci-Ce-alkylamino-Ci-Ce-alkyl or Ci-Cs-alkylamino-Ci-Cs-alkyl.
  • Ci-Ce-alkylamino-Ci-Ce-alkyl means here that the alkylaminoalkyl group on the alkyl
  • alkylaminoalkyl examples include N, N-dimethylaminoethyl, N, N-dimethylaminomethyl, N, N-
  • leaving group refers to an atom or group of atoms that is displaced in a chemical reaction as a stable species with entrainment of the bonding electrons.
  • leaving groups are halogen, in particular fluorine, chlorine, bromine or iodine, (methylsulfonyl) oxy, [(trifluoromethyl) sulfonyl] oxy, [(nonafluorobutyl) sulfonyl] oxy, (phenylsulfonyl) oxy, [(4-methylphenyl) sulfonyl] oxy,
  • Salts which are preferred 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 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 from 1 to 16 carbon atoms, such as for example, methylamine, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methylglucamine, dimethylglucamine, ethylglucamine, 1 , 6-hexadiamine, glucosamine, sarcosine, serinol,
  • alkali metals such as sodium or potassium
  • the compounds according to the invention can form base addition salts with quaternary ammonium ions which, for example, by Qarternmaschine 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 can be obtained.
  • quaternary ammonium ions are examples of such quaternary ammonium ions.
  • Tetramethylammonium T etraethylammonium, tetra (.propropyl) 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 can be present either as a single polymorph or as a mixture of several polymorphs in all concentration ranges.
  • 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 inventive compounds can, depending on their structure in
  • the compounds according to the invention have an asymmetric center on the carbon atom to which R 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 dural carbon atom.
  • the present invention therefore also encompasses diastereomers and their respective mixtures.
  • 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 dural 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 the one in which the center of asymmetry represented by the carbon atom attached to R is (-configured.
  • Another object of the present invention are stereoisomeric mixtures of (45) - configured compounds of the invention with their (4i?) - isomers, in particular the corresponding racemates, the other 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 compounds according to 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 in a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as : H (deuterium), ⁇ (tritium), "C, 13 C, 14 C, 15 N, 17 0, ls O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br,! 23 1, 124 1, 129 I and 131 I.
  • isotopic variants of a compound according to the invention in particular those in which one or more radioactive isotopes are incorporated, may be of use, for example for the investigation of the mechanism of action or distribution of active substance in the body the comparatively slight manufacturing and detectability for this purpose are in particular * H - or 14 C isotopes suitable labeled compounds
  • isotopes such as deuterium
  • some specific therapeutic benefits as a result of greater metabolic stability of the compound. lead, such as an extension of the half-life in the body or a reduction of the required effective dose;
  • modifications of the compounds of the invention may therefore optionally 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 those 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
  • 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.
  • For oral administration are functioning according to the prior art
  • 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
  • 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 can be accomplished by bypassing a ⁇ ⁇ (e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a ⁇ ⁇ e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and
  • fusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines i.a.
  • Eye preparations vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as Plasters), milk, pastes, foams, powder, 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
  • flavor and / or odoriferous agents e.g., ascorbic acid
  • dyes e.g., inorganic pigments such as iron oxides
  • flavor and / or odoriferous agents e.g., 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 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 fillers, 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.
  • excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • oral or oral administration in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question.
  • 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 according to the invention are particularly suitable for the prophylaxis and therapy of hypersoluble diseases such as, for example
  • 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
  • treatable as breast tumors are:
  • Her-2 positive breast cancers Hormone receptor and 2 negative breast cancers are Her-2 positive breast cancers Hormone receptor and 2 negative breast cancers.
  • tumors of the respiratory tract are treatable
  • non-small cell lung carcinomas such as squamous cell carcinoma, adenocarcinoma, large cell carcinoma and
  • tumors of the brain are treatable.
  • tumors of the male reproductive organs are treatable:
  • Prostate cancers such as androgen receptor-positive prostate cancers and androgen receptor-negative prostate cancers,
  • Penis cancer For example, tumors of the female reproductive organs are treatable:
  • tumors of the gastrointestinal tract are treatable:
  • tumors of the urogenital tract are treatable:
  • renal carcinomas such as renal cell carcinomas
  • tumors of the eye are treatable:
  • tumors of the liver are treatable:
  • tumors of the skin are treatable:
  • Melanomas for example malignant melanomas
  • tumors of the head and neck are treatable:
  • Carcinomas of the midline structures such as NMC, CA French, Annu Rev. Pathol.
  • sarcomas are treatable:
  • treatbax As lymphomas, for example, treatbax:
  • AIDS-associated lymphomas For example, treatable as leukemias are:
  • the compounds according to the invention can be used for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias,
  • Prostate cancer especially androgen receptor-positive prostate cancer
  • Hormone receptor-positive or BRCA-associated breast cancers pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung cancers, endometrial carcinomas and colorectal
  • the compounds according to the invention can be used particularly advantageously for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • the compounds according to the invention can furthermore be used for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and
  • lymphomas especially B cell lymphomas
  • Prostate cancer especially androgen receptor-positive prostate cancer, Ovarian carcinoma, choriocarcinoma, bladder carcinoma, renal carcinoma, melanoma, lung carcinoma and rhabdomyosarcoma.
  • the compounds according to the invention can also be used with particular advantage for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and lymphoblastic leukemias, B-cell lymphomas, androgen receptor-positive
  • 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 fertility control of the male.
  • the compounds according to the invention are also suitable for the prophylaxis and 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:
  • Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatous s, in particular Boeck's disease
  • Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic 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 in degenerative joint disease
  • 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.
  • Ni diseases that are associated with inflammatory, allergic and / or proliferative processes nephrotic syndrome; all nephritis
  • 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.
  • Proctological diseases associated with inflammatory, allergic and / or proliferative processes analgesic; fissures; Hemorrhoids; idiopathic proctitis Eye diseases associated with inflammatory, allergic or proliferative processes: allergic keratitis, uveitis, ulceris; conjunctivitis; blepharitis; Neuritis nervi optici; Chlorioditis; Opthalmia sympathica

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Abstract

L'invention concerne des dérivés de benzodiazépine substitués par du phosphore et du soufre inhibant les protéines à bromodomaine, en particulier les protéines BET, et de préférence la BRD4, lesdits dérivés étant représentés par la formule générale (I) dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans la description. L'invention concerne également des substances pharmaceutiques renfermant les composés selon l'invention, 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 d'inhibiteurs de protéines BET dans les hyperplasies bénignes, les maladies athérosclérotiques, le sepsis, les maladies auto-immunes, les maladies vasculaires, les infections virales, les maladies rénales associées au VIH, les maladies neurodégénératives, les maladies inflammatoires, les maladies athérosclérotiques, l'insuffisance cardiaque, les dystrophies musculaires, comme par exemple la dystrophie musculaire fascio-scapulo-humérale et dans les contrôles de la fertilité masculine.
PCT/EP2016/065756 2015-07-09 2016-07-05 Dérivés de benzodiazépine substitués par du phosphore et du soufre WO2017005711A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006051312A1 (fr) * 2004-11-15 2006-05-18 James Black Foundation Limited Ligands de récepteur de la gastrine et de la cholécystokinine
WO2014026997A1 (fr) * 2012-08-16 2014-02-20 Bayer Pharma Aktiengesellschaft 2,3-benzodiazépines
WO2014202578A1 (fr) * 2013-06-17 2014-12-24 Bayer Pharma Aktiengesellschaft Phényl-2,3-benzodiasépine substituée

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006051312A1 (fr) * 2004-11-15 2006-05-18 James Black Foundation Limited Ligands de récepteur de la gastrine et de la cholécystokinine
WO2014026997A1 (fr) * 2012-08-16 2014-02-20 Bayer Pharma Aktiengesellschaft 2,3-benzodiazépines
WO2014202578A1 (fr) * 2013-06-17 2014-12-24 Bayer Pharma Aktiengesellschaft Phényl-2,3-benzodiasépine substituée

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US12122833B2 (en) 2016-05-11 2024-10-22 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors

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