WO2015121230A1 - 2,3-benzodiazépines substituées en position 9 - Google Patents

2,3-benzodiazépines substituées en position 9 Download PDF

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WO2015121230A1
WO2015121230A1 PCT/EP2015/052709 EP2015052709W WO2015121230A1 WO 2015121230 A1 WO2015121230 A1 WO 2015121230A1 EP 2015052709 W EP2015052709 W EP 2015052709W WO 2015121230 A1 WO2015121230 A1 WO 2015121230A1
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alkyl
alkoxy
halogen
amino
unsubstituted
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PCT/EP2015/052709
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German (de)
English (en)
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Stephan Siegel
Stefan BÄURLE
Arwed Cleve
Bernard Haendler
Amaury Ernesto FERNÁNDEZ-MONTALVÁN
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Bayer Pharma Aktiengesellschaft
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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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to bromodomain protein-inhibiting, in particular BET protein-inhibiting and preferably BRD4-inhibitory, 9-substituted 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: 10.1002 / cmdc.201300434).
  • the bromodomains are protein regions that recognize acetylated 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 acetylation patterns recognized by BET proteins in histones have been well studied (Umehara et al., J. Biol. Chem., 2010, 285: 7610-7618; Filippakopoulos et al., Cell, 2012, 149: 214- 231). In addition, you can
  • BRD4 binds to RelA, resulting in the stimulation of NF- ⁇ and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell Biol., 2009, 29: 1375-1387; Zhang et al., J. Biol Chem., 2012, doi / 10.1074 / jbc.M112.359505).
  • the extra-terminal domain of BRD2, BRD3 and BRD4 interacts with several proteins that have a role in chromatin modification 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 transcription elongation and recruitment of the elongation complex P-TEFb
  • 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).
  • BET proteins play an important role in various tumor types.
  • 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 (Fihppakopoulos et al., Nature, 2010, 468: 1067-1073).
  • Screening for therapeutic targets in an acute myeloid leukemia cell line (AML) showed that BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, doi: 10.1038). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis.
  • Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo.
  • Amplification of the DNA region containing the BRD4 gene 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 also interacts with various 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).
  • P-TEFb BRD4 also plays an important role in the replication of HIV (Bisgrove et al., Proc Natl Acad., USA, 2007, 104: 13690-13695).
  • BET proteins are also involved in inflammatory processes.
  • BRD2-hypomorphic mice show reduced inflammation in adipose tissue (Wang et al., Biochem J., 2009, 425: 71-83).
  • the infiltration of macrophages into white adipose tissue is also reduced in BRD2-deficient mice (Wang et al., Biochem J., 2009, 425: 71-83).
  • BRD4 regulates a number of genes involved in inflammation.
  • Macrophages prevent a BRD4 inhibitor from expression of inflammatory genes, such as IL-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1119-1123).
  • Apolipoprotein AI (ApoAl) is a major component of high density
  • 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 WO201 1/143669 (Dana Farber Cancer Institute). Replacement of the thieno by a benzo moiety also results in active inhibitors (J. Med. Chem. 201 1, 54, 3827-3838, E. Nicodeme et al., Nature 2010, 468, 1119).
  • WO2012 / 075383 describes 6-substituted 4i7-isoxazolo [5,4-cf] [2] benzazepines and 4H-isoxazolo [3,4-cf] [2] benzazepines, including compounds optionally substituted at position 6
  • phenyl as BRD4 inhibitors and also analogs with alternative heterocyclic fusion partners instead of the benzo moiety, eg Thieno or pyridoazepines.
  • WO2013 / 184876 and WO2013 / 184878 describe further benzoisoxazoloazepine derivatives as inhibitors of bromodomain-containing proteins.
  • BRD4 inhibitors is 7-isoxazoloquinolines and related quinolone derivatives (WO201 1/054843, Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967, GlaxoSmithKline).
  • Pyridinones and pyridazinones (WO 2013/185284, WO 2013/188381, Abbott Laboratories) and isoindolones (WO 2013/155695 and WO 2013/158952; Abbott Laboratories) are proteins inhibiting binding of bromodomains of the BET proteins to 7V-acetylated lysine residues described.
  • W094 / 26718 and EP0703222A1 are substituted 3-amino-2,3-dihydro-li7-l-benzazepin-2-ones or the corresponding 2-thiones and analogs in which the benzo moiety is replaced by alternative substituted monocyclic systems and in which the 2-ketone or the 2-thione can form a heterocycle together with the substituted nitrogen atom of the azepine ring, as CCK and gastrin antagonists for the therapy of diseases of the CNS, such as anxiety and depression, and of Diseases of the pancreas and gastrointestinal ulcers 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.
  • the compounds according to the invention are novel phenyl-2,3-benzodiazepines (1-phenyl-4,5-dihydro-3i7-2,3-benzodiazepines) which are obligately substituted at C-9 and which do not fuse to the benzodiazepine skeleton 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-9 of known 2,3-benzodiazepines such as the numerous published AMPA antagonists (WO 1997/28135 (Schering AG), US Pat. No. 5,807,851, HU 0097000688, WO 2002/050044 and WO 2007/077469 (Egis Gyogyszergyar), for a review see also Med. 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).
  • WO 1997/034878 discloses 2,3-benzodiazepin-4-one, which may also be substituted at C-9, but differ from the compounds of the present invention by the oxo substitution at C-4 of the benzodiazepine skeleton, 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 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.
  • R 1a represents hydrogen, halogen, cyano, -SF 5 , hydroxy, -NR 7 R 8 , C 1 -C 6 -alkoxycarbonyl-,
  • Ci-Ce-alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C6 alkylcarbonyl, GC 6 - alkoxy, Ci-COE-alkylthio, Ci-COE Alkylsulfinyl- or Ci-Cö-alkylsulfonyl stands, which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, with halogen, cyano, nitro, hydroxyl, amino, oxo, carboxy, ci-ce-alkyl, C 1 -C 6 -alkoxy, ci C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C
  • phenoxy-, phenylthio-, phenylsulfinyl- or phenylsulfonyl- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, nitro, hydroxy, amino, carboxy, C 1 -C 6 -alkyl - 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 6 -alkylamino-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -
  • C 3 -C 10 -cycloalkyl- which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, carboxyl, C 1 -C 4 -cycloalkyl-
  • Alkyl C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 Alkyl, halo-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy or monocyclic heterocyclyl having 4 to 8 ring atoms, or
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, and is substituted by halogen, hydroxyl, amino, cyano, nitro, carboxy, C 1 -C 6 -alkyl, GG-alkoxy, C 6 alkoxy-C 1 -C 6 -alkyl, hydroxy-GG-alkyl, GG-alkylamino, amino-GG-alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halogeno-GG-alkyl -, halogen-GG-alkoxy, C3-Cio-cycloalkyl-,
  • R 2 is C 1 -C 3 -alkyl-, trifluoromethyl- or C 3 -C 4 -cycloalkyl-,
  • R 3 is cyclopropyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino, cyclopropylamino or
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino,
  • Ci-COE-alkyl, Ci-COE-alkoxy, Ci-COE-alkylamino, phenylamino, C I -C ⁇ - alkylcarbonylamino, Ci-COE-Aikylaminocarbonyl- or C I -C ⁇ - alkylaminosulfonyl, which are unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, are substituted by halogen, amino, hydroxy, carboxy, ci-ce-alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, -C ( O) -NR 9 R 10 ,
  • Heteroaryl- with 5 or 6 ring atoms which in turn are unsubstituted or monosubstituted with Ci-C 3 alkyl,
  • C 3 -C 10 -cycloalkyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, is substituted by halogen, amino, hydroxyl, carboxy, C 1 -C 10 -alkyl,
  • halogen cyano, hydroxyl, amino, carboxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, G-C 2 -alkoxy-C 1 -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, halogeno-C 1 -C 3 -alkyl-, halogeno-G-C 3 Alkoxy or GG-cycloalkyl-,
  • C 1 -C 6 -alkyl is C 1 -C 6 -alkyl, GG-alkenyl, GG-alkynyl, C 1 -C 6 -alkylcarbonyl, C 3 -C 6 -cycloalkylsulfonyl or C 1 -C 6 -alkylsulfonyl-, which are unsubstituted or mono-, di- - or triply, identically or differently, are substituted by halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, Ce-Ce-alkoxy-Ci-Ce-alkyl -, hydroxy-Ci-C6-alkyl, Ci-COE-alkylamino, amino-Ci- Ce-alkyl, Ci-C 6 -alkylamino-Ci-C 6 alkyl, halo-C iC 6 -
  • C3-Cio-cycloalkyl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituted with halogen, amino, hydro xy, carboxy, CI-C ⁇ - alkyl, Ci-COE-alkoxy , C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino
  • Halogen hydroxy, amino, cyano, nitro, 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 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, hydroxyl, amino, cyano, nitro, carboxy, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, Ci-Ce-alkoxy-Ci-Ce-alkyl, hydroxy-Ci-Ce-alkyl,
  • Ci-Cö-alkylamino amino-Ci-Cö-alkyl, Ci-Ce-alkylamino-Ci-Cö-alkyl, halogen-Ci-Cö-alkyl, halogen-Ci-Cö-alkoxy, C 3 - Cio-cycloalkyl,
  • 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 are hydrogen, C 1 -C 3 -alkyl, cyclopropyl or di-C 1 -C 3 -alkyl-amino-C 1 -C 3 -alkyl,
  • R 11 is hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen-C 1 -C 3 -alkyl, hydroxy-C 1 -C 4 -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, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.
  • R l is hydrogen, halogen, cyano, hydroxy, -NR 7 R 8 , C 1 -C 6 -alkoxycarbonyl-,
  • C 1 -C 6 -alkyl for C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy, G-C 1 -C 6 -alkyl, or -alkyl
  • C 1 -C 6 -alkylsulfonyl radicals which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, being substituted by halogen, cyano, hydroxyl, amino, oxo, carboxy, C 1 -C 6 -alkyl-, C 1 -C 6 -alkyl-, Alkoxy, hydroxy-Ci-Cö-alkyl,
  • phenoxy-, phenylthio- or phenylsulfonyl- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, with halogen,
  • Ci-Cö-alkyl Ci-Cö-alkoxy, hydroxy-Ci-Cö-alkyl, Ci-Cö-alkylamino, amino
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, hydroxyl, amino, cyano, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxyl C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyl , -
  • R lb and R lc independently of one another represent hydrogen, halogen, hydroxyl, cyano,
  • Ci-Cö-alkyl, Ci-Cö-alkoxy, halogen-Ci-Cö-alkyl or halogen-Ci-Cö-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 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, amino,
  • 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-, Ci-Cö-alkylamino, amino-Ci-Cö-alkyl, halogen-Ci-Cö-alkyl or halogen-Ci-Cö-alkoxy,
  • phenyl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, is substituted by halogen, amino, hydroxy, cyano, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl alkylamino, amino-Ci-COE-alkyl, C I -C ⁇ - alkylaminocarbonyl, Ci-COE-alkylaminosulfonyl, hydroxy-Ci-COE-alkyl, halo-Ci-COE-alkyl or halogen-Ci -Cö alkoxy,
  • C6-G 2 -spirocycloalkyl for C6-G 2 -spirocycloalkyl, C6-G 2 -heterospirocycloalkyl, C6-G 2 -bicycloalkyl, C6-G 2 -heterobicycloalkyl, bridged C6-G 2 -cycloalkyl, bridged C6-G2-
  • R 9 and R 10 independently of one another are 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
  • Ci-COE-alkyl Ci-COE-alkoxy, Ci-COE-alkylamino, phenylamino, CI-C ⁇ - Alkylcarbonylamino, Ci-Cö-alkylaminocarbonyl or CI-C ⁇ -alkylaminosulfonyl, which are unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, Ci-C 3 alkyl , Hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl or monocyclic heterocyclyl having 4 to 6 ring atoms or monocyclic heteroaryl with 5 or 6 ring atoms,
  • 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 mono-, di- or Ci-C is three times, identically or differently substituted with halogen, amino, hydroxy, cyano, carboxy, Ci- C3 alkyl, 3 alkoxy, C -C 3 alkylamino, amino-Ci-C 3 alkyl, C 1 -C 3 - alkylaminocarbonyl, Ci-C3 alkylaminosulfonyl, hydroxy-Ci-C 3 alkyl, fluoro Ci-C 3 Alkyl or fluoro-C 1 -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,
  • 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,
  • C6-Ci 2 is heterocycloalkyl, which are unsubstituted or mono-, di- or trisubstituted by identical or different substituted with halogen, cyano, oxo,
  • halogen for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, hydroxyl, cyano, oxo, C 1 -C 3 -alkyl-, C 1 -C 3 - Alkoxy- or trifluoromethyl- represents halogen, cyano, hydroxyl, amino, methyl, methoxy- 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 C 1 -C 3 -alkyl, trifluoromethyl, C 3 -C 6 -cycloalkyl-,
  • R la is -NR 7 R 8 ,
  • Cycloalkyl phenyl or monocyclic heterocyclyl having 4 to 8 ring atoms, or
  • R 1b and R lc independently of one another represent hydrogen, fluorine or chlorine
  • R 2 is methyl
  • R 3 is methylamino, independently of one another represent hydrogen, hydroxyl, cyano, amino,
  • halogen, hydroxyl, cyano, oxo, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy or trifluoromethyl- represents halogen, cyano, hydroxyl, amino, methyl, methoxy- 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-,
  • Ci-C3-alkyl is monocyclic heteroaryl- with 5 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by Ci-C3-alkyl, or
  • Ci-C3-alkyl is monocyclic heteroaryl- with 5 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by Ci-C3-alkyl, or
  • phenyl which is unsubstituted or monosubstituted by halogen, is hydrogen or C 1 -C 3 -alkyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically tolerated salts and solvates of these salts.
  • R la represents chlorine, bromine or -NR 7 R 8,
  • pyrazolyl or isoxazolyl which are unsubstituted or monosubstituted, disubstituted or trisubstituted by methyl
  • phenyl which is unsubstituted or monosubstituted by fluorine, is hydrogen or methyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • pyrazolyl or isoxazolyl which are unsubstituted or monosubstituted, disubstituted or trisubstituted by methyl
  • 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, amino or bromine
  • R 6 is fluorine, chlorine or bromine
  • R 7 is imidazolyl which is unsubstituted or monosubstituted with
  • 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 1b and R independently of one another represent hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen, amino or bromine
  • R 6 is fluorine, chlorine or bromine
  • R 7 is cyclopropylsulfonyl or methylsulfonyl
  • R 8 is hydrogen or methyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and .Solvate of these salts.
  • R is -NR 7 R 8 ,
  • R 1b and R stand for hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen, amino or bromine
  • R 6 is fluorine, chlorine or bromine
  • R 8 is hydrogen or methyl, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • (+) - 9-fluoro-7,8-dimethoxy-N 4-dimethyl-1- ⁇ 4 - [(phenylsulfonyl) amino] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine-3 carboxamide; - (+) - 9-fluoro-7,8-dimethoxy-N, 4-dimethyl-1- [4- (morpholin-4-ylmethyl) phenyl] -4,5-dihydro-
  • 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, hydroxyl 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-, GC 3 - Alkylamino, Cs-C 4 -cycloalkyl, phenyl or monocyclic heterocyclyl having 4 to 8 ring atoms,
  • C6-Ci 2 -Heterospirocycloalkyl-, C6-Ci 2 -Heterobicycloalkyl- or bridged C 6 -C 12 - heterocycloalkyl which are unsubstituted or mono-, di- or trisubstituted by identical or different substituted with halogen, cyano, oxo , C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, trifluoromethyl,
  • R 1 particularly preferably represents hydrogen, halogen, cyano, hydroxy or -NR 7 R 8 .
  • R 1 particularly preferably represents C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, which are unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, with halogen, Cyano, hydroxy, amino, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, C 3 -C 4 -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 3 -C 7 -cycloalkyl, phenyl or monocyclic heterocyclyl having 4 to 8 ring atoms,
  • C6-Ci 2 -Heterospirocycloalkyl-, C6-Ci 2 -Heterobicycloalkyl- or bridged C 6 -C 12 - heterocycloalkyl which are unsubstituted or mono-, di- or trisubstituted by identical or different substituted with halogen, cyano, oxo , C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, trifluoromethyl,
  • 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 3 -C 7 -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 with C 3 -C 7 -cycloalkyl, phenyl or monocyclic heterocyclyl having 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 very particularly preferably represents C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by monocyclic heterocyclyl having 6 ring atoms.
  • R 1 very particularly preferably represents monocyclic heterocyclyl having 4 to 6 ring atoms, which is unsubstituted or monosubstituted or disubstituted, identical or different, with halogen, hydroxy or C 1 -C 3 -alkyl-.
  • R 1 very particularly preferably represents monocyclic heteroaryl with 5 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by C 1 -C 3 -alkyl-.
  • R 1 very particularly preferably represents bridged C 6 -C 10 -heterocycloalkyl-.
  • R 1 very particularly preferably represents -NR 7 R 8 ,
  • C 1 -C 3 -alkyl which is monosubstituted by monocyclic heterocyclyl with 6 ring atoms, or
  • R 1 very particularly preferably represents monocyclic heterocyclyl having 4 to 6 ring atoms, which is unsubstituted or monosubstituted or disubstituted, identical or different, with halogen, hydroxy or C 1 -C 3 -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 very particularly preferably represents chlorine, bromine or -NR 7 R 8 , or
  • azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl which are unsubstituted or monosubstituted with fluoro, hydroxy or methyl
  • 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, pyrrohdinyl, piperidinyl or piperazinyl, which are unsubstituted or monosubstituted by fluorine, hydroxyl or methyl.
  • R 1 very particularly preferably represents pyrazolyl or isoxazolyl, which are unsubstituted or mono-, di- or trisubstituted by methyl.
  • R 1 very particularly preferably represents 8-oxa-3-azabicyclo [3.2.1] octyl-.
  • R 1 very particularly preferably represents -NR 7 R 8 ,
  • azetidinyl, pyrrohdinyl, piperidinyl or piperazinyl which are unsubstituted or monosubstituted by fluoro, hydroxy or methyl
  • R 1 very particularly preferably represents methyl which is monosubstituted with N-morpholinyl
  • azetidinyl, pyrrohdinyl, piperidinyl or piperazinyl which are unsubstituted or monosubstituted by fluoro, hydroxy or methyl
  • R 1 most preferably represents methyl, which is simple is substituted with N-morpholinyl-.
  • R 1 is more preferably chlorine, bromine or -NR 7 R 8 , or
  • R 1 is most preferably for
  • R 1b and R Lc are preferably and independently of one another hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno-C 1 -C 6 -alkyl or halogen -C i -Cö alkoxy.
  • 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 particularly preferably methyl.
  • R 3 may be 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 and R 5 are particularly preferably and independently of one another hydrogen, hydroxyl, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, halogen, amino, hydroxy, cyano, carboxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl, hydroxy-C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl - or fluorine-GC 3 -alkoxy.
  • 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
  • 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 particularly preferably and independently of one another hydrogen, hydroxyl, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine.
  • R 4 and R 5 are particularly preferably and independently of one another 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 most preferably and independently each other for hydrogen, amino, fluorine, chlorine or bromine,
  • R 4 and R 5 are very particularly preferably and independently of one another hydrogen, amino or bromine,
  • R 6 may be halogen, cyano, hydroxy, amino, carboxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 2 -alkoxy-C 1 -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, halogeno-C 1 -C 4 -alkyl, C 3 alkyl, halogen-GC 3 alkoxy or C 3 -C 5 cycloalkyl stand.
  • R 6 is preferably halogen, cyano, hydroxyl, amino, carboxy, C 1 -C 2 -alkyl, C 2 -C 4 -alkoxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy or
  • R 6 particularly preferably represents halogen, cyano, hydroxyl, amino, C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, hydroxymethyl, trifluoromethyl or trifluoromethoxy.
  • R 6 particularly preferably represents halogen, cyano, hydroxyl, amino, methyl, methoxy or trifluoromethyl.
  • R 6 very particularly preferably represents fluorine, chlorine, bromine or cyano.
  • R 6 very particularly preferably represents fluorine, chlorine or bromine.
  • R 7 particularly preferably represents C 1 -C 6 -alkoxycarbonyl-
  • R 7 is particularly preferably GG-alkyl, GG-
  • Alkylcarbonyl, G-G-cycloalkylsulphonyl or G-G-alkylsulphonyl- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, hydroxy, amino or G-G-alkylamino-,
  • phenylsulfonyl which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, G-G-alkyl-, G-G-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, 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 C 1 -C 3 -alkylamino,
  • 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 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 preferably C 1 -C 6 -alkyl-, C 1 -C 6 -alkyl-
  • R 7 is particularly preferably C 1 -C 6 -alkyl-, C 1 -C 8 -alkyl-
  • R 7 particularly preferably represents 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-.
  • R 7 particularly preferably represents phenylsulfonyl which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkyl- 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-, C 3 alkoxy- or trifluoromethyl-.
  • R 7 particularly preferably represents 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-,
  • 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 7 is particularly preferably 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-C3-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 very particularly preferably represents C 3 -C 4 -cycloalkylsulfonyl or C 1 -C 8 -alkylsulfonyl-,
  • phenyl which is unsubstituted or monosubstituted with halogen.
  • R 7 very particularly preferably represents C 3 -C 4 -cycloalkylsulfonyl or C 1 -C 3 -alkylsulfonyl-,
  • R 7 very particularly preferably represents C 3 -C 4 -cycloalkylsulfonyl or C 1 -C 8 -alkylsulfonyl-.
  • R 7 is very particularly preferably phenylsulfonyl.
  • R 7 very particularly preferably represents monocyclic heteroaryl having 5 ring atoms, which is unsubstituted or mono- or disubstituted by Ci-C3-alkyl, or
  • phenyl which is unsubstituted or monosubstituted with halogen.
  • R 7 very particularly preferably represents monocyclic heteroaryl with 5 ring atoms, which is unsubstituted or monosubstituted or disubstituted with Ci-C3-alkyl
  • R 7 is very particularly preferably phenyl, which is unsubstituted or monosubstituted with halogen.
  • R 7 is very particularly preferably cyclopropylsulfonyl or
  • imidazolyl which is unsubstituted or monosubstituted with methyl
  • phenyl which is unsubstituted or monosubstituted with fluorine.
  • R 7 is very particularly preferably cyclopropylsulfonyl or methylsulfonyl.
  • R 7 is very particularly preferably phenylsulfonyl.
  • R 7 very particularly preferably represents imidazolyl which is unsubstituted or monosubstituted by methyl.
  • R 7 very particularly preferably represents phenyl which is unsubstituted or monosubstituted by fluorine.
  • R 7 very particularly preferably represents imidazolyl which is unsubstituted or monosubstituted by methyl
  • phenyl which is unsubstituted or monosubstituted with fluorine.
  • R 7 is more preferably cyclopropylsulfonyl or
  • R 7 is most 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 3 -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 particularly preferably represents C 1 -C 3 -alkyl-, trifluoromethyl-, C 3 -C 6 -cycloalkyl-,
  • R 11 is particularly preferably Ci-C3-alkyl, trifluoromethyl, Cs-Ce-cycloalkyl-.
  • R 11 is particularly preferably phenyl or monocyclic heterocyclyl having 4 to 6 ring atoms.
  • Benzodiazepine skeleton represented stereocenter preferably either racemic or predominantly or completely in the ( ⁇ configuration before.
  • Benzodiazepine skeleton represented preferred stereocenter stereocenter before. In the general formula (I), this is due to the carbon atom of R 2 bonded to R 2
  • Benzodiazepine skeleton represented stereocenter particularly preferably predominantly or completely in the ( ⁇ configuration before.
  • Benzodiazepine skeleton represented stereocentre most preferably predominantly in the (S) configuration.
  • 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 -alkyl) C 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
  • C3-C6-alkynyl is preferred
  • 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-C 1 -C 6 -alkyl is meant a group which is composed of an optionally substituted phenyl radical and a C 1 -C 6 -alkyl group and which are bonded via the C 1 -C 6 -alkyl group to the rest of the molecule is.
  • 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.
  • Phenoxy- represents a radical of the formula -O-phenyl.
  • Alkoxy alkyl is an alkoxy-substituted alkyl radical, for example Ci-Cö-alkoxy-Ce-Ce-alkyl or Ci-Cs-alkoxy-Ci-Cs-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:
  • Phenylamirio 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 (Ci-Cs-alkylfhio) carbon atoms.
  • Methylsulfonyl ethylsulfonyl, propylsulfonyl.
  • Hydrocarbon radical having usually 3 to 6 carbon atoms is (C3-C6-Cycloalkylsulfo- nyl-).
  • Phenylthio is a radical of the formula -S-phenyl. phenylsulfinyl
  • Methylaminosulfonyl ethylaminosulfonyl, dimethylaminosulfonyl.
  • Heteroatoms are oxygen, nitrogen or sulfur atoms.
  • Aryl means a monovalent, mono- or bicyclic aromatic ring system consisting of carbon atoms. 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 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 has two immediately adjacent ring atoms each to form an aliphatic cyclic radical with 4 to 7 ring atoms is condensed, which may optionally contain one or two heteroatoms, which may be the same or different.
  • heteroatoms nitrogen atoms, oxygen atoms or sulfur atoms can occur.
  • Partially saturated bicyclic aryl radicals include, for example, the groups:
  • Partially saturated bicyclic heteroaryl radicals include, for example, the groups:
  • 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.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl.
  • azepanyl By way of example and with preference for monocyclic heterocyclyl radicals having 7 ring atoms, mention may be made of azepanyl, oxepanyl, 1,3-diazepanyl, 1,4-diazepanyl-.
  • 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 bicyclo [2.2.0] hexyl, bicyclo [3.3.0] octyl,
  • Bicyclo [6.3.0] undecyl and bicyclo [5.4.0] undecyl including heteroatom modified variants such as e.g. Azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl, diazabicyclo [4.3.0] nonyl, oxazabicyclo [4.3.0] nonyl, thiazabicyclo [4.3.0] nonyl or azabicyclo [4.4.0 ] decyl and radicals derived from other possible combinations as defined.
  • C ⁇ -CIO-Heterobicycloalkyl- is preferred.
  • bridged ring system such as C6-Ci2 bridged C6-Ci 2 cycloalkyl or bridged C6-Ci2 heterocycloalkyl is understood to mean a fusion of at least two saturated rings which share two atoms which are not directly adjacent to each other .
  • bridged carbocycle bridged cycloalkyl
  • bridged heterocycle bridged Heterocycloalkyl-
  • 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. Examples and also preferred are:
  • Hydroxyalkyl is an alkyl radical having at least one hydroxy substituent.
  • a hydroxy-C 1 -C 6 -alkyl radical is an alkyl radical consisting of 1-6 carbon atoms and at least one hydroxy substituent.
  • Aminoalkyl is an alkyl radical having at least one amino substituent.
  • amino-Ci-Cö-alkyl radical is an alkyl radical consisting of 1-6 carbon atoms and at least one amino substituent. alkylaminoalkyl
  • Alkylaminoalkyl- represents an alkyl radical substituted by alkylamino as defined above, for example C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl or C 1 -C 3 -alkylamino-C 1 -C 3 -alkyl-.
  • Ci-Ce-alkylamino-Ci-Cö-alkyl- means that the alkylaminoalkyl group is bonded 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), 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 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 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 quanitization of corresponding amines with etches such as lower alkyl halides, for example methyl, ethyl, propyl and
  • 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
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds according to the invention 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) another
  • Asymmetrieelement contains, 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 the one in which the center of asymmetry represented by the carbon atom bound to R 2 is (-configured.
  • Another object of the present invention are stereoisomeric mixtures of (45) - configured compounds of the invention with their (4R) 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 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), U 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 such as, in particular, those in which one or more radioactive isotopes are incorporated, 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; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • iso- Topical variants of the compounds according to the invention can be prepared by the methods known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • the compounds according to the invention can act systemically and locally.
  • it may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds of the invention can be used in suitable forms.
  • Administration forms are administered.
  • 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
  • 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.
  • Inhalation medicines i.a.
  • 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.
  • excipients include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers, and dispersing or wetting agents (e.g.
  • 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 reacting the active substance (s) with those in the field of galenics
  • excipients for example, vehicles, fillers, disintegrants,
  • Binders humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents,
  • the pharmaceutical formulations can be any suitable pharmaceutical formulations.
  • auxiliaries may be, for example, salts, saccharides (mono-, di-, oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • the present invention relates to the compounds of the invention.
  • They can be used for the prophylaxis and treatment of human diseases, in particular tumors.
  • the compounds of the invention can be used in particular to the
  • the compounds of the invention are particularly suitable for the prophylaxis and therapy of hyper-proliferative diseases such as
  • BPH benign prostatic hyperplasia
  • tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland are treatable Bone and connective tissue and metastases of these tumors.
  • hematological tumors are treatable
  • treatable as breast tumors are:
  • 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.
  • the tumors of the male reproductive organs are treatable: prostate carcinomas,
  • Penis cancer For example, tumors of the female reproductive organs are treatable:
  • tumors of the gastrointestinal tract are treatable:
  • Gastrointestinal stromal tumors For example, 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:
  • Treatable as leukemias for example: Acute myeloid leukemias
  • 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 carcinomas pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, 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 are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as, for example, endometriosis, leiomyoma and benign prostatic hyperplasia.
  • the compounds according to the invention are also suitable for the fertility control of the man.
  • the compounds according to the invention are also suitable for the prophylaxis and 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 Granulomatoses, in particular, Boeck's disease
  • Rheumatic disorders / autoimmune disorders / 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
  • Vasculitides Panarterilitis nodosa, temporal artery, erythema nodosum
  • Dermatological disorders associated with inflammatory, allergic and / or proliferative processes atopic dermatitis; Psoriasis; Pityriasis rubra pilaris;
  • erythematous diseases induced by different noxae e.g. Blasting, chemicals, burns etc .
  • bullous dermatoses Diseases of the lichenoid type; pruritus; Seborrheic dermatitis; rosacea; Pemphigus vulgaris; Erythema exudative multiforme; balanitis; vulvitis; Hair loss such as alopecia areata; cutaneous T-cell lymphoma
  • Kidney diseases associated with inflammatory, allergic and / or proliferative processes nephrotic syndrome; all nephritis
  • Liver diseases associated with inflammatory, allergic or proliferative processes acute liver cell decay; acute hepatitis of different causes, e.g. viral, toxic, drug-induced; Chronic aggressive and / or chronic intermittent hepatitis
  • Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, e.g. native sprue
  • 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
  • Neurological diseases associated with inflammatory, allergic or proliferative processes brain edema, especially tumor-related cerebral edema; Multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, e.g. BNS-seizures
  • Blood disorders associated with inflammatory, allergic or proliferative processes acquired hemolytic anemia; idiopathic thrombocytopenia
  • Tumor diseases associated with inflammatory, allergic and / or proliferative processes acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in mammary, bronchial and
  • Endocrine disorders associated with inflammatory, allergic or proliferative processes endocrine orbitopathy; thyrotoxic crisis; Thyreoditis de Quervain; Hashimoto's thyroiditis; Graves' disease
  • Severe states of shock e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • Emesis associated with inflammatory, allergic or proliferative processes e.g. in combination with a 5-HT3 antagonist in cytostatic vomiting - pain of inflammatory genesis, e.g. lumbago
  • the compounds according to the invention are also suitable for the treatment of viral
  • Diseases such as infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.
  • the compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, periferous vascular diseases, cardiovascular diseases, angina, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.
  • the compounds according to the invention are also suitable for the treatment of
  • neurodegenerative diseases such as multiple sclerosis, Alzheimers disease and Parkinson's disease. These diseases are well characterized in humans but also exist in other mammals.
  • Another object of the present application are the compounds of the invention for use as medicaments, in particular for the prophylaxis and therapy of
  • the present invention further relates to the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Hormone receptor-positive or BRCA-associated breast carcinoma pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma and colorectal
  • the present invention further relates to the compounds according to the invention for the prophylaxis and therapy of leukemias, in particular acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas,

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  • Organic Chemistry (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne des 2,3-benzodiazépines substituées en position 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 et R6 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/EP2015/052709 2014-02-14 2015-02-10 2,3-benzodiazépines substituées en position 9 WO2015121230A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués
CN117717892A (zh) * 2024-02-08 2024-03-19 四川益能康生环保科技有限公司 一种用于吸收二氧化硫的复合型脱硫剂及其制备工艺

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2008124075A1 (fr) * 2007-04-02 2008-10-16 Teva Pharmaceutical Industries Ltd. Nouveaux dérivés de 2,3-benzodiazépine et leur utilisation en tant qu'agents antipsychotiques
WO2011054553A1 (fr) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Inhibiteur de bromodomaine de benzodiazépine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008124075A1 (fr) * 2007-04-02 2008-10-16 Teva Pharmaceutical Industries Ltd. Nouveaux dérivés de 2,3-benzodiazépine et leur utilisation en tant qu'agents antipsychotiques
WO2011054553A1 (fr) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Inhibiteur de bromodomaine de benzodiazépine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués
CN117717892A (zh) * 2024-02-08 2024-03-19 四川益能康生环保科技有限公司 一种用于吸收二氧化硫的复合型脱硫剂及其制备工艺
CN117717892B (zh) * 2024-02-08 2024-04-30 四川益能康生环保科技有限公司 一种用于吸收二氧化硫的复合型脱硫剂及其制备工艺

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