[go: up one dir, main page]

EP3010909A1 - Phényl-2,3-benzodiasépine substituée - Google Patents

Phényl-2,3-benzodiasépine substituée

Info

Publication number
EP3010909A1
EP3010909A1 EP14730906.6A EP14730906A EP3010909A1 EP 3010909 A1 EP3010909 A1 EP 3010909A1 EP 14730906 A EP14730906 A EP 14730906A EP 3010909 A1 EP3010909 A1 EP 3010909A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
phenyl
amino
dihydro
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14730906.6A
Other languages
German (de)
English (en)
Inventor
Stephan Siegel
Stefan BÄURLE
Arwed Cleve
Bernard Haendler
Amaury Ernesto FERNÁNDEZ-MONTALVÁN
Ursula MÖNNING
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Priority to EP14730906.6A priority Critical patent/EP3010909A1/fr
Publication of EP3010909A1 publication Critical patent/EP3010909A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to BET protein-inhibiting, in particular BRD4-inhibitory substituted phenyl-2,3-benzodiazepines, pharmaceutical agents containing the
  • This invention relates to the use of BET protein inhibitors in benign hyperplasia, atherosclerotic diseases, sepsis, autoimmune diseases, vascular diseases, viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.
  • the human BET family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and BRDT) containing two related bromodomains and one extra-terminal domain (Wu and Chiang, J. Biol. Chem., 2007 , 282: 13141-13145).
  • the bromodomains are protein regions that recognize acetylated lysine residues. Such acetylated lysines are often found at the N-terminal end of histones (eg, histone 3 or histone 4) and are features of open chromatin structure and active gene transcription (Kuo and Allis, Bioessays, 1998, 20: 615). 626).
  • the various acetylation patterns recognized by BET proteins in histones have been well studied (Umehara et al., J. Biol. Chem., 2010, 285: 7610-7618;
  • bromodomains can recognize additional acetylated proteins.
  • BRD4 binds to RelA, resulting in the stimulation of NF- ⁇ B and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell Biol., 2009, 29: 1375-1387; Zhang et al., J. Biol Chem., 2012, 287: 28840-28851; Zou et al., Oncogene, 2013, doi: 10.1038 / onc.2013.179).
  • 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). Mechanistically, BET proteins play an important role in cell growth and in the cell cycle. Biol. Cell, 2009, 20: 4899-4909, Yang et al., Mol. Cell. Biol., 2008,
  • BRD4 is important for the post-mitotic reactivation of gene transcription (Zhao et al., Nat Cell Biol., 2011, 13: 1295-1304). It has been shown that BRD4 is essential for transcription elongation and recruitment of the elongation complex P-TEFb, which consists of CDK9 and cyclin Tl, resulting in the activation of RNA polymerase II (Yang et al., Mol. Cell, 2005, 19 : 535-545, Schröder et al., J. Biol. Chem., 2012, 287: 1090-1099). Consequently, the expression of genes involved in cell proliferation, such as c- Myc and Aurora B (You et al., Mol. Cell Biol., 2009, 29: 5094-5103; Zuber et al., Nature, 2011, 478: 524-528). BRD2 and BRD3 bind to transcribed genes in hyperacetylated
  • RNA polymerase II 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).
  • BRD2 and BRD4 knockout mice die prematurely during embryogenesis (Gyuris et al., Biochim Biophys Acta, 2009, 1789: 413-421, Houzelstein et al., Mol. Cell Biol., 2002, 22: 3794-3802 ).
  • Heterozygous BRD4 mice have various growth defects attributable to reduced cell proliferation (Houzelstein et al., Mol. Cell. Biol., 2002, 22: 3794-3802).
  • BET proteins play an important role in various tumor types.
  • the fusion between the BET proteins BRD3 or BRD4 and NUT results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet, Cytogenet., 2010, 203: 16 -20).
  • the fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 2011, 286: 27663-27675, Grayson et al., 2013, doi: 10-1038 / onc.2013.126).
  • 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. Amphfication 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
  • 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. Viral., 2012 , 86: 348-357; McBride and Jang, Viruses, 2013, 5: 1374-1394).
  • the herpesvirus which is responsible for the Sarcoma is responsible, interacts with various BET proteins, what for
  • 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
  • HDL Lipoproteins
  • ApoAl Lipoproteins
  • Elevated HDL levels are associated with a decreased risk of atherosclerosis (Chapman et al., Eur. Heart J., 2011, 32: 1345-1361).
  • the first published BRD4 inhibitors are phenyl-thieno-triazolo-l, 4-diazepine (4-phenyl-6-thieno [3,2-l [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).
  • the replacement of the thieno by a benzo moiety also leads to active inhibitors (J. Med. Chem. 201 1, 54, 3827-3838, E. Nicodeme et al., Nature 2010, 468, 119).
  • WO2012 / 075383 (Constellation Pharmaceuticals) describes 6-substituted-4 / f-isoxazolo [5,4-öf] [2] benzazepines and 4 / f-isoxazolo [3,4-öf] [2] benzazepines, including compounds disclosed in U.S. Pat Position 6 optionally substituted phenyl, as BRD4 inhibitors and also analogs with alternative heterocyclic fusion partners instead of the benzo moiety, eg thieno or Pyridoazepine.
  • BRD4 inhibitors is 7-isoxazoloquinolines and related quinolone derivatives (WO2011 / 054843, Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967, GlaxoSmithKline).
  • the novel compounds are novel substituted phenyl-2,3-benzodiazepines (1-phenyl-4,5-dihydro-3 / i-2,3-benzodiazepines) which, inter alia, on the benzodiazepine backbone do not fuse with a second heterocyclic moiety, especially one Isoxazole or triazole, and surprisingly still BET, in particular BRD4 -nnhibitors are.
  • the compounds of the invention differ from known 2,3-benzodiazepines described as AMPA receptor antagonists.
  • US Pat. Nos. 5,536,832 / EP 0492485, US Pat. No. 5,639,751, US Pat. No. 5,459,137 disclose substituted 1-phenyl-2,3-benzodiazepines which compulsorily have a methylenedioxy bridge fused to the benzodiazepine benzo portion.
  • 2,3-benzodiazepines are generally described as AMPA antagonists, without, however, disclosing specific example compounds.
  • the example compounds disclosed in WO 1997/028135 (Schering AG), WO 2001/098280 (Annovis, Inc.) and EP 0802195 / US 5,807,851 (EGIS Gyogysergyar, Rt) have nitro or -NH 2 groups on the 1-phenyl group but not substituted amino groups or acylamines; the generic claimed ether, amino and amide substituents also differ from the corresponding substituents in the compounds of the invention.
  • the compounds according to the invention furthermore differ from the known psychopharmacological l-phenyl-2,3-benzodiazepine derivatives which are inhibitors of the adenosine transporter and of the MT2 receptor (WO2008 / 124075, Teva Pharmaceutical Industries, Inc).
  • the example compounds disclosed there are substituted on the 1-phenyl group inter alia by NH 2 - acetamido, methoxy or nitro groups, but not by the ether, amide or substituted amino groups, as they have the compounds of the invention.
  • the generically claimed amino and amide substituents also differ from the corresponding substituents in the compounds of the invention.
  • W094 / 26718 and EP0703222A1 are substituted 3-amino-2,3-dihydro-1 / il-benzazepin-2-ones or the corresponding 2-thiones and analogs in which the benzo unit by alternative substituted monocyclic systems and in which the 2-ketone or the 2-thione together with the substituted nitrogen atom of the azepine ring can form a heterocycle, 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.
  • diseases of the CNS such as anxiety and depression, and of Diseases of the pancreas and gastrointestinal ulcers described.
  • Ligands of the gastrin and the cholecystokinin receptor are described in WO2006 / 051312 (James Black Foundation). They also include substituted 3,5-dihydro-4 / i-2,3-benzodiazepin-4-ones derived from the compounds of the invention mainly by the obligatory oxo group in position 4 and by a mandatory carbonyl group-containing alkyl chain in position 5 differ.
  • the compounds according to the invention inhibit the interaction between BET proteins, in particular BRD4 and an acetylated histone 4 peptide, and inhibit the growth of cancer cells. They thus represent new valuable and effective compounds for the therapy of human and animal diseases, in particular of
  • X is an oxygen or sulfur atom
  • R la is -OR 6 or -NR 7 R 8 ,
  • c are independently hydrogen, halogen, hydroxy, cyano, nitro or a GC 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxy-C 6 -alkyl, halo-6 GC - Alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl radical or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • R is a G-C3-alkyl or trifluoromethyl or a C3 or C t -cycloalkyl radical
  • R 3 is C 1 -C 3 -alkyl, G-C 3 -alkoxy, amino or C 1 -C 3 -alkylamino,
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino,
  • C 3 -C 10 -cycloalkyl- which may optionally be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-ci- C6-alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy -, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • monocyclic heteroaryl having 5 or 6 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, Ci-Ce-alkoxy-Ci-COE alkyl, hydroxy-Ci-COE-alkyl, Ci-COE-alkylamino, amino-Ci-COE-alkyl, CI-C ⁇ - alkylamino-Ci-COE-alkyl -, halogen-Ci-Cö-alkyl, halogeno-Ci-Cö-alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or
  • monocyclic heterocyclyl having 3 to 8 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, cyano, oxo, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, Ci-Cö-alkylamino, amino-Ci-Cö-alkyl, Ci-Ce-alkylamino-Ci-Cö-alkyl, hydroxy-Ci-Ce-alkyl , Halogen-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or
  • phenyl which may be monosubstituted or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, carboxy, CI-C ⁇ - alkyl, Ci-Cö-alkoxy, Ci-Ce-alkoxy -Ci-Cö-alkyl, Ci-Cö-alkylamino, amino-Ci-Cö-alkyl, Ci-Cö-alkylaminocarbonyl, Ci-Cö-alkylaminosulfonyl, CI-C ⁇ - alkylamino-Ci-Cö-alkyl , Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • a monocyclic heterocyclyl radical having 3 to 8 ring atoms which may optionally be monosubstituted by oxo, Ci-C 3 alkyl, C 1 -C 3 - alkylcarbonyl, Ci-C t-alkoxycarbonyl, phenyl-Ci-C 3 -alkyl- or Cs-Ccycloalkyl-, or
  • aryl or heteroaryl radical is a mono- or bicyclic aryl or heteroaryl radical, where the radicals mentioned may optionally be monosubstituted or disubstituted by identical or different substituents with halogen, hydroxyl, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -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, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl , C 1 -C 3 -alkylcarbonylamino, C 1 -C 3 -alkylsulfonylamino, C 1 -C 3 -alkylcarbonyl, C 1 -C 3 -alkylsulf
  • phenyl radical contained therein may be optionally substituted once or twice, identically or differently, by halogen, hydroxy, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, Ci-C 3 alkoxy, C 1 -C 3 - alkylamino, amino-Ci-C 3 alkyl, Ci-C 3 alkylaminocarbonyl, C 1 -C 3 - alkylaminosulfonyl, Ci-C3 alkylcarbonylamino -, C 1 -C 3 - alkylsulfonylamino, Ci-C3-alkylcarbonyl, Ci-C 3 alkylsulfonyl or trifluoromethoxy,
  • methylene group contained therein may optionally be substituted by one hydroxy group or by one or two C 1 -C 3 -alkyl groups,
  • 2 -Heterobicycloalkylrest is a monocyclic heterocyclyl radical having 3 to 8 ring atoms, a bridged Coe-C heterocycloalkyl, a Cs-C -Heterospirocycloalkylrest or a Ce-Ci, where the radicals mentioned may optionally be mono- or disubstituted by identical or different and be substituted can be reacted with oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, phenyl-C 1 -C 3 -alkyl or C 3 -C 7 -cycloalkyl-,
  • aryl or heteroaryl radical is a mono- or bicyclic aryl or heteroaryl radical, where the radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with halogen, hydroxyl, cyano, C 1 -C 3 -alkyl, fluoroC 1 -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-, C 1 -C 4 -alkyl, C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl, C 1 -C 3 -alkylcarbonylamino, C 1 -C 3 -alkylsulfonylamino, C 1 -C 3 -alkylcarbonyl, C 1 -C 3 -al
  • monocyclic heterocyclyl radical having 3 to 8 ring atoms, which may optionally be monosubstituted by oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkyl,
  • a monocyclic heterocyclyl radical having 3 to 8 ring atoms for a monocyclic heterocyclyl radical having 3 to 8 ring atoms, a bridged Cö-C-Heterocycloalkylrest, a Cs-C-Heterospirocycloalkylrest or a
  • C6-Ci 2 is -Heterobicycloalkylrest, wherein said radicals are optionally may be mono- or disubstituted by identical or different substituted with oxo, C 1 -C3- alkyl, Ci-C3-alkylcarbonyl, Ci-C t-alkoxycarbonyl , Phenyl-C 1 -C 3 -alkyl or C 3 -C -cycloalkyl-,
  • aryl or heteroaryl radical is a mono- or bicyclic aryl or heteroaryl radical, where the radicals mentioned may optionally be monosubstituted or disubstituted by identical or different substituents with halogen, hydroxyl, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -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, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl, C 1 -C 3 -alkylcarbonylamino -, Ci-C3-alkylsulfonylamino, Ci-C3-alkylcarbonyl, Ci-C3-alkylsulfonyl or trifluorome
  • Ci-Cö-alkyl- which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen, hydroxy, carboxy, cyano, Ci-Cö-alkoxy, -NR 9 R 10 , phenyl, a monocyclic heteroaryl with 5 or 6 ring atoms, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • the monocyclic heterocyclyl radical may in turn optionally be monosubstituted or disubstituted, identically or differently, with oxo, C 1 -C 3 -alkyl-, C 1 -C 3 -alkylcarbonyl-, C 1 -C 4 -alkoxycarbonyl-, phenyl-C 1 -C 3 -alkyl or C3-C7 cycloalkyl,
  • C3-Cio-Cycloalkyl- which may optionally be monosubstituted or polysubstituted by identical or different substituents with fluorine, hydroxyl, oxo, cyano, Ci-C 3 alkyl, Ci- C 3 alkoxy- or -NR 9th R 10 ,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identically or differently, with halogen, hydroxy, cyano, C 1 -C 3 -alkyl, fluoro-G-C 1 -alkyl, hydroxy-C 1 -Cs-alkyl, Ci-Cs-alkoxy
  • hyperproliferative diseases tumors and as BET protein inhibitors in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.
  • the invention is based on the following definitions:
  • Alkyl is a linear or branched, saturated, monovalent hydrocarbon radical having generally 1 to 6 carbon atoms (Ci-Ce alkyl), preferably 1 to 4 (Ci-C 4 alkyl), 2 to 4 (C 2 - C 4 Alkyl) or 1 to 3 carbon atoms (C 1 -C 3 -alkyl).
  • Particularly preferred is a methyl, ethyl, propyl, isopropyl or tert-butyl radical.
  • Cycloalkyl is a mono- or bicyclic, saturated, monovalent
  • Hydrocarbon radical with usually 3 to 10 (C3-Cio-cycloalkyl), preferably 3 to 8
  • Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.
  • bicyclic cycloalkyl radicals are:
  • phenyl-Ci-C 3 alkyl a group is to be understood, which is composed of an optionally substituted phenyl group and a Ci-C 3 alkyl group, and on the C 1 -C 3 - alkyl group at 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 3 (C 1 -C 3 -alkoxy) carbon atoms. Examples and preferred are:
  • Alkoxyalkyl is an alkoxy-substituted alkyl radical.
  • C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl- means that the bond to the rest of the molecule takes place via the alkyl moiety.
  • Oxo may be attached to atoms of suitable valence, for example to a saturated carbon atom or to sulfur.
  • Alkylamino is 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 in each case 1 to 3 carbon atoms per
  • Examples include:
  • methylamino and N, N-dimethylamino are particularly preferred.
  • Examples include acetyl and propanoyl. Preference is acetyl.
  • Alkylcarbonylamino Alkylcarbonylamino:
  • Examples include:
  • Examples include:
  • Methylsulfonyl ethylsulfonyl, propylsulfonyl.
  • Preferred is methylsulfonyl.
  • Methylsulfonylamino Ethylsulfonylamino-, Propylsulfonylamino-.
  • Heteroatoms are oxygen, nitrogen or sulfur atoms.
  • aryl
  • An aryl radical or aryl means a monovalent, mono- or bicyclic, from
  • Carbon atoms existing aromatic ring system are naphthyl, biphenyl and phenyl.
  • Preference is phenyl.
  • a heteroaryl radical or heteroaryl radical denotes a monovalent, mono- or bicyclic aromatic ring system having at least one heteroatom.
  • heteroatoms can be
  • 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:
  • Heteroaryl radicals with 10 ring atoms include, for example, the rings:
  • Monocyclic heterocyclyl or a mocoyclic heterocyclyl group means a non-aromatic monocyclic ring system having at least one heteroatom or a
  • Hetero group As heteroatoms nitrogen atoms, oxygen atoms and / or Sulfur atoms occur.
  • a monocyclic heterocyclyl ring according to the present invention may have 3 to 8, preferably 4 to 7, more preferably 5 or 6 ring atoms.
  • monocychic heterocyclyl radicals having 3 ring atoms mention may be made of aziridinyl.
  • Exemplary and preferred for monocychsche Heterocyclylreste with 4 ring atoms are called: Azetidinyl-, Oxetanyl-.
  • Exemplary and preferred for monocychic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl.
  • 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.
  • C5-Ci 2 -Heterospirocycloalkyl- is understood to mean a fusion of two saturated ring systems that share a common atom, in which C5-C 12 indicating the number of ring members, with a replacement of 1-4 carbon atoms by heteroatoms such as defined above in any combination.
  • Examples are azaspiro [2.3] hexyl, azaspiro [3.3] heptyl,
  • C 6 -C 12 heterobicycloalkyl is meant a fusion of two saturated ring systems sharing in common two directly adjacent atoms in which C 6 -C 12 indicates the number of ring members, with a replacement of 1-4 carbon atoms by heteroatoms as defined above in any combination.
  • Examples are systems derived from bicyclo [2.2.0] hexyl, bicyclo [3.3.0] octyl, bicyclo [4.4.0] decyl, bicyclo [5.4.0] undecyl, bicyclic [3.2.0] heptyl, Bicyclo [4.2.0] octyl, bicyclo [5.2.0] nonyl, bicyclo [6.2.0] decyl,
  • Bridged C6-C heterocycloalkyl refers to a fusion of at least two saturated rings sharing two atoms not directly adjacent to each other, in which C6-C12 indicates the number of ring members, and in the 1-4 carbon atoms are replaced by heteroatoms as defined above in any combination. Examples are 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 3 -alkyl radicals.
  • Trifluoromethyl 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,5,5,5-pentafluoropentyl or
  • 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 3 -alkoxy radicals.
  • Hydroxyalkyl is an alkyl radical having at least one hydroxy substituent.
  • a hydroxy-C 1 -C 6 -alkyl radical is an alkyl radical having 1-6 carbon atoms and at least one hydroxy substituent.
  • Aminoalkyl is an alkyl radical having at least one amino substituent.
  • An amino-Ci-Cö-alkyl radical is an alkyl radical having 1-6 carbon atoms and at least one amino substituent.
  • Alkylaminoalkyl is an alkyl radical having at least one alkylamino substituent.
  • a C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl radical is an alkyl radical having 1-6 carbon atoms and at least one C 1 -C 6 -alkylamino substituent as defined above.
  • X is an oxygen atom
  • R la is -OR 6 or -NR 7 R 8 ,
  • R lb and R lc independently of one another represent hydrogen, halogen, hydroxyl, cyano, or a C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkyl or fluoro-C 1 -C 4 -alkyl 3 alkoxy radical
  • R 2 is methyl or ethyl, represents C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino or C 1 -C 3 -alkylamino, independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine,
  • C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulfonyl which may be mono- or polysubstituted, may be identical or different substituted with halogen, amino, hydroxy, carboxy, hydroxy-Ci-Cö-alkyl, Ci-Cö-alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, Ci-Cö-alkylamino or amino-C 1 -C 6 -alkyl-, a monocyclic heterocyclyl radical having 3 to 8 ring atoms or a monocyclic heteroaryl radical having 5 or 6 ring atoms, wherein said monocyclic heterocyclyl and heteroaryl radicals may in turn optionally be monosub
  • monocyclic heteroaryl having 5 or 6 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl-, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl-, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl- , Halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or
  • monocyclic heterocyclyl having 3 to 8 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, cyano, oxo, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl-, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl-, hydroxy-C 1 -C 6 -alkyl- , Halogen-C 6 -alkyl, halogen-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, for C 1 -C 8 -alkyl which is monosubstit
  • benzyl radical is a benzyl radical, it being possible for the phenyl radical contained therein to be optionally substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-, halogen, or C 1 -C 3 -alkoxy-,
  • monocyclic heterocyclyl radical having 4 to 7 ring atoms, which may optionally be monosubstituted by oxo, C 1 -C 3 -alkyl-, C 1 -C 3 -alkylcarbonyl, benzyl- or C 1 -C 4 -alkoxycarbonyl-,
  • R 12 is Ci-Cö-alkyl-, which may optionally be mono- or di-substituted by identical or different substituents with fluorine, hydroxy, Ci-C 3 -alkoxy- or -NR 9 R 10 , or
  • C3-C7-cycloalkyl- which may optionally be monosubstituted or polysubstituted by identical or different substituents, with fluorine, hydroxyl, oxo, cyano, C 1 -C 3 -alkyl-,
  • X is an oxygen atom
  • R l is -OR 6 or -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine,
  • R 1b represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • R 6 represents C 2 -C 4 -alkyl which is monosubstituted by C 1 -C 3 -alkylamino, or
  • phenyl radical which may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine, bromine, methoxy or ethoxy,
  • benzyl radical is a benzyl radical, it being possible for the phenyl radical contained therein to be optionally substituted once or twice, identically or differently, by methyl, ethyl, fluorine, chlorine, bromine, methoxy- or ethoxy-,
  • a monocyclic heterocyclyl radical having 4 to 7 ring atoms or a bridged C 0 -C 10 -heterocycloalkyl radical, where the radicals mentioned may optionally be monosubstituted by methyl, ethyl, acetyl or tert-butoxycarbonyl,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine, bromine, methoxy or ethoxy,
  • monocyclic heterocyclyl radical having 4 to 7 ring atoms, optionally may be monosubstituted by methyl, ethyl, acetyl or ieri-butoxycarbonyl, R 11 is C 1 -C 4 -alkyl which is monosubstituted with -NR 9 R 10 ,
  • ⁇ is a monocyclic heterocyclyl radical having 4 to 7 ring atoms or a bridged C 0 -C 10 -heterocycloalkyl radical, where the radicals mentioned may optionally be monosubstituted by methyl, ethyl, acetyl, benzyl or ieri-butoxycarbonyl,
  • radicals mentioned may optionally be monosubstituted or disubstituted by identical or different substituents, with methyl, ethyl, fluorine, chlorine or bromine, and
  • R 12 is C 1 -C 3 -alkyl-
  • C 3 -C 7 -cycloalkyl- which may optionally be mono- or polysubstituted by identical or different substituents with fluorine, hydroxyl, oxo, methyl, ethyl, methoxy, ethoxy, or A ⁇ N-dimethylamino-,
  • ⁇ is a monocyclic heterocyclyl radical having 4 to 7 ring atoms or a bridged C 0 -C 10 -heterocycloalkyl radical, where the radicals mentioned may optionally be monosubstituted by methyl, ethyl, acetyl, benzyl or ieri-butoxycarbonyl,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine or bromine, and also their polymorphs, enantiomers, Diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • X is an oxygen atom
  • R l is -OR 6 and is in the meta or jara position to the benzodiazepine
  • R 1b represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • R 6 represents C 1 -C 4 -alkyl which is monosubstituted with C 1 -C 3 -alkylamino
  • phenyl radical which may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine, bromine, methoxy- or ethoxy-,
  • benzyl radical is a benzyl radical, it being possible for the phenyl radical contained therein to be optionally substituted once or twice, identically or differently, by methyl, ethyl, fluorine, chlorine, bromine, methoxy- or ethoxy-,
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine
  • R lb is hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl stands,
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • R 8 is hydrogen or C 1 -C 3 -alkyl-
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl
  • R 11 is C 1 -C 4 -alkyl which is monosubstituted with -NR 9 R 10 ,
  • ⁇ is a monocyclic heterocyclyl radical having 4 to 7 ring atoms or a bridged C 0 -C 10 -heterocycloalkyl radical, where the radicals mentioned may optionally be monosubstituted by methyl, ethyl, acetyl, benzyl or ieri-butoxycarbonyl,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine or bromine, and also their polymorphs, enantiomers, Diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine
  • R 1b represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • R 8 is hydrogen or C 1 -C 3 -alkyl-
  • R 12 is C 1 -C 3 -alkyl-
  • C3-C7-cycloalkyl- which may optionally be mono- or polysubstituted by identical or different substituents with fluorine, hydroxyl, oxo, methyl, ethyl, methoxy, ethoxy, or A ⁇ N-dimethylamino-,
  • a monocyclic heterocyclyl radical having 4 to 7 ring atoms or a bridged C 0 -C 10 -heterocycloalkyl radical where the radicals mentioned may optionally be monosubstituted by methyl, ethyl, acetyl, benzyl or ieri-butoxycarbonyl,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine or bromine, and also their polymorphs, enantiomers, Diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine
  • R lb is hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl stands,
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • R 7 is C 2 -C 4 -alkyl or C 3 -C 7 -cycloalkyl which is monosubstituted by -NR 9 R 10 , or
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine, bromine,
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl
  • X is an oxygen atom
  • R l is -OR 6 or -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine,
  • R 1b is hydrogen or fluorine
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen, chlorine, methoxy or trifluoromethoxy
  • R 6 is A ⁇ N-dimethylaminoethyl
  • R 7 is A ⁇ N-dimethylaminoethyl or A 1 N-dimethylaminopropyl-,
  • R is hydrogen or methyl
  • R 11 is -CH 2 -NH (CH 3 ), -CH 2 -N (CH 3 ) 2 , methylpiperidinyl, methylpyrrolyl,
  • R 12 is methyl, trifluoromethyl, phenyl, benzyl, cyclopropyl, tetrahydropyran-4-yl or pyrid-3-yl-, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and Solvates of these salts.
  • X is an oxygen atom
  • R la is -OR 6 or -NR 7 R 8 , and is in the jara position to the benzodiazepine, R lb and Rlc are hydrogen,
  • R 2 is methyl
  • R 3 is methylamino, is hydrogen or methoxy
  • monocyclic heterocyclyl radical having 4 to 7 ring atoms which may optionally be monosubstituted by methyl, acetyl or ieri-butoxycarbonyl, is C 1 -C 2 -alkyl which is monosubstituted by -NR 9 R 10 ,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, Ethyl, fluorine, chlorine or bromine,
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • R la is -OR 6 , and is in jara position to benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R 6 is C 1 -C 4 -alkyl which is monosubstituted or C 1 -C 3 -alkylamino-substituted, or a monocyclic heterocyclyl radical having 6 ring atoms, which may optionally be monosubstituted by methyl,
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the jara position to the benzodiazepine, R lb and Rlc are hydrogen,
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R is hydrogen
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl-
  • R 12 is C 1 -C 5 -alkyl, fluorine-C 1 -C 3 -alkyl or C 3 -C 7 -cycloalkyl-,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine or bromine,
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the jara position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is hydrogen or methoxy
  • R 5 is methoxy- or trifluoromethoxy-
  • R 7 is C 2 -C 4 -alkyl or C 3 -C 7 -cycloalkyl which is monosubstituted by -NR 9 R 10 , or
  • radicals for a monocyclic heterocyclyl radical having 6 ring atoms or for Azabicyclo [2.2.2] oct-3-yl-, wherein said radicals may optionally be monosubstituted with methyl, acetyl or ieri-butoxycarbonyl, or
  • R 8 is hydrogen or methyl
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl
  • a monocyclic heterocyclyl radical having 4 to 7 ring isomers which may optionally be monosubstituted with methyl, acetyl or ieri-butoxycarbonyl, and their polymorphs, tautomers, solvates, physiologically acceptable Salts and solvates of these salts,
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R la is -OR 6 or -NR 7 R 8 , and is in the jara position to the benzodiazepine, R lb and Rlc are hydrogen,
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is hydrogen or methoxy
  • R 5 is methoxy or trifluoromethoxy
  • R 6 for a residue is selected
  • R 12 represents methyl, trifluoromethyl, phenyl, benzyl, cyclopropyl, tetrahydropyran-4-yl or pyrid-3-yl, and their polymorphs, tautomers, solvates, physiologically tolerated salts and solvates of these salts,
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R la is -OR 6 , and is in the para position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R 6 for a residue is selected H, where "*" denotes in each case the point of attachment to the remainder of the molecule, as well as their polymorphs, tautomers, solvates, physiologically tolerated salts and solvates of these salts, with the proviso that the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in para-position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R ⁇ is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R s is hydrogen
  • R 11 for a residue is selected
  • R 12 is methyl, trifluoromethyl, phenyl, benzyl, cyclopropyl, tetrahydropyran-4-yl or pyrid-3-yl, where "*" denotes in each case the point of attachment to the remainder of the molecule, as well as their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts,
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the jara position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is hydrogen or methoxy
  • R 5 is methoxy- or trifluoromethoxy
  • R 7 for a remainder is chosen
  • R 8 is hydrogen or methyl, where "*" in each case denotes the point of attachment to the remainder of the molecule, and also their polymorphs, tautomers, solvates, physiologically tolerated salts and solvates of these salts,
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen or sulfur atom
  • R la is -OR 6 or -NR 7 R 8 ,
  • R lb and R lc are each independently hydrogen, halogen, hydroxy, cyano, nitro or a GC 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxy-C 6 alkyl, halogen -GC 6 - Alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl radical or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • R 2 is a C 1 -C 3 -alkyl or trifluoromethyl or a C 3 or C 4 -cycloalkyl radical
  • R 3 is C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, amino-, or C 1 -C 3 -alkylamino-,
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino,
  • C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulfonyl, which optionally has one or more times, may be identical or different substituted with halogen, amino, hydroxy, carboxy, hydroxy-Ci-Cö-alkyl, Ci-Cö-alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, Ci-Cö-alkylamino , Amino-Ci-Cö-alkyl, a monocyclic heterocyclyl radical having 3 to 8 ring atoms or a monocyclic heteroaryl radical having 5 or 6 ring atoms, wherein said monocyclic heterocyclyl and
  • Heteroaryl radicals may in turn optionally be monosubstituted with C 1 -C 3 -alkyl,
  • C 3 -C 10 -cycloalkyl- which may optionally be monosubstituted or polysubstituted, identically or differently, by halogen, amino, hydroxyl, C 1 -C 6 -alkyl-,
  • monocyclic heteroaryl having 5 or 6 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, Ci-Ce-alkoxy-Ci-COE alkyl, hydroxy-Ci-COE-alkyl, Ci-COE-alkylamino, amino-Ci-COE-alkyl, CI-C ⁇ - alkylamino-Ci-alkyl COE , Halogeno-Ci-Cö-alkyl, halogeno-Ci-Cö-alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or
  • monocyclic heterocyclyl having 3 to 8 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, cyano, oxo, carboxy, Ci-Cö-alkyl, Ci-Cö-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,
  • phenyl which may optionally be monosubstituted or polysubstituted by identical or different substituents, is halogen, amino, hydroxy, cyano, nitro, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy Ci-C6-alkyl, Ci-COE-alkylamino, amino-Ci- Coe-alkyl, Ci-COE-alkylaminocarbonyl, Ci-COE-alkylaminosulfonyl, Cl-C ⁇ - alkylamino-Ci-COE-alkyl , Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • Ci-C3-alkyl optionally monosubstituted with oxo, Ci-C3-alkyl, C 1 -C3-alkylcarbonyl, Ci-C t-alkoxycarbonyl, phenyl-Ci-C3-alkyl or Cs-CvCycloalkyl-, or
  • aryl or heteroaryl radical is a mono- or bicyclic aryl or heteroaryl radical, where the radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with halogen, hydroxyl, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -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, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl , C 1 -C 3 -alkylcarbonylamino, C 1 -C 3 -alkylsulfonylamino, C 1 -C 3 -alkylcarbonyl, C 1 -C 3 -alkylsulfony
  • 2 -Heterobicycloalkylrest is a monocyclic heterocyclyl radical having 3 to 8 ring atoms, a bridged Coe-C heterocycloalkyl, a Cs-C -Heterospirocycloalkylrest or a Ce-Ci, where the radicals mentioned may optionally be mono- or disubstituted by identical or different and be substituted can be reacted with oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, phenyl-C 1 -C 3 -alkyl or C 3 -C 7 -cycloalkyl-,
  • aryl or heteroaryl radical is a mono- or bicyclic aryl or heteroaryl radical, where the radicals mentioned are optionally one or two times, identical or different, may be substituted by halogen, hydroxyl, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, amino-C 1 -C 4 -alkyl, C 3 -alkyl, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl, C 1 -C 3 -alkylcarbonylamino, C 1 -C 3 -alkylsulfonylamino, C 1 -C 3 -alkylcarbonyl, C 1 -C 3 -alkylsulfon
  • monocyclic heterocyclyl radical having 3 to 8 ring atoms, which may optionally be monosubstituted by oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkyl,
  • 2 -Heterobicycloalkylrest is a monocyclic heterocyclyl radical having 3 to 8 ring atoms, a bridged Coe-C heterocycloalkyl, a Cs-C -Heterospirocycloalkylrest or a Ce-Ci, where the radicals mentioned may optionally be mono- or disubstituted by identical or different and be substituted can be reacted with oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, phenyl-C 1 -C 3 -alkyl or C 3 -C 7 -cycloalkyl-,
  • aryl or heteroaryl radical is a mono- or bicyclic aryl or heteroaryl radical, where the radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with halogen, hydroxyl, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -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, C 1 -C 3 -alkylaminocarbonyl, C 1 -C 3 -alkylaminosulfonyl , C 1 -C 3 -alkylcarbonylamino, C 1 -C 3 -alkylsulfonylamino, C 1 -C 3 -alkylcarbonyl, C 1 -C 3 -alkylsulfony
  • CI-C ⁇ - alkyl- which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen, hydroxy, carboxy, cyano, Ci-Cö-alkoxy, - NR 10 R n , phenyl, a monocyclic heteroaryl having 5 or 6 ring atoms, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, wherein
  • Phenyl and the monocyclic heteroaryl radical having 5 or 6 ring atoms may in turn be optionally mono- to trisubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl, trifluoromethyl, C 1 -C 3 -alkoxy- or trifluoromethoxy-,
  • the monocyclic heterocyclyl radical may in turn optionally be monosubstituted or disubstituted, identically or differently, with oxo, C 1 -C 3 -alkyl-, C 1 -C 3 -alkylcarbonyl-, C 1 -C 4 -alkoxycarbonyl-, phenyl-C 1 -C 3 -alkyl or Cs-Cv-cycloalkyl-,
  • C3-Cio-Cycloalkyl- which may optionally be monosubstituted or polysubstituted by identical or different substituents with fluorine, hydroxyl, oxo, cyano, Ci-C 3 alkyl, Ci-C 3 alkoxy or -NR 10th R n,
  • radicals mentioned may optionally be monosubstituted or disubstituted by identical or different substituents with halogen, hydroxy, cyano, C 1 -C 3 -alkyl, fluoro-G-Cs-alkyl, hydroxy-Ci -Cs-alkyl, C1-C3-
  • R la is -OR 6 or -NR 7 R 8 ,
  • R lb and R lc independently of one another represent hydrogen, halogen, hydroxy, cyano, or a Ci
  • C 3 -alkyl, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkyl or fluoro-C 1 -C 3 -alkoxy radical represents methyl or ethyl
  • C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulfonyl, which optionally has one or more times, may be identical or different substituted with halogen, amino, hydroxy, carboxy, hydroxy-Ci-Cö-alkyl, Ci-Cö-alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, Ci-Cö-alkylamino or amino-C 1 -C 6 -alkyl-, a monocyclic heterocyclyl radical having 3 to 8 ring atoms or a monocyclic heteroaryl radical having 5 or 6 ring atoms, wherein said monocyclic heterocyclyl and heteroaryl radicals may in turn optionally be monosubstituted
  • monocyclic heteroaryl having 5 or 6 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, Ci-C6-alkoxy-Ci-C6 alkyl, hydroxy-Ci-COE-alkyl, Ci-COE-alkylamino, amino-Ci-COE-alkyl, C I -C ⁇ - alkylamino-Ci-COE Alkyl, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, or
  • monocyclic heterocyclyl having 3 to 8 ring atoms which may be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, cyano, oxo, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl-, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl-, halo-Ci-C 6 -alkyl, halo-C 6 alkoxy, C 3 -C 10 - cycloalkyl, or a monocychschen heterocyclyl radical having 3 to 8 ring atoms, simply by C 3 alkylamino substituted C 2 -C 6 -alky
  • Ci-C3-alkyl optionally monosubstituted by oxo, Ci-C3-alkyl, C1-C3-alkylcarbonyl, Ci-C t-alkoxycarbonyl, benyzl or Cs-CvCycloalkyl-, or
  • monocyclic heterocyclyl radical having 4 to 7 ring atoms, which may optionally be monosubstituted by oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, benzyl or C 1 -C 4 -alkoxycarbonyl-,
  • R 12 is C 1 -C 6 -alkyl- which may optionally be monosubstituted or disubstituted by identical or different substituents with fluorine, hydroxyl, C 1 -C 3 -alkoxy- or -NR 10 R n , and also their polymorphs, enantiomers, diastereomers, Razemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • C 2 -C 4 -alkyl which is monosubstituted by C 1 -C 3 -alkylamino, or represents a monocyclic heterocyclyl radical having 4 to 7 ring atoms, which may optionally be monosubstituted by methyl, ethyl, acetyl or ieri-butoxycarbonyl , or
  • phenyl radical which may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine, bromine, methoxy- or ethoxy-,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine, bromine, methoxy or ethoxy,
  • Ring atoms is substituted C 1 -C 3 -alkyl or fluoro-C 1 -C 3 -alkyl, where the said phenyl and heteroaryl radicals may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, Chlorine or bromine, R 8 is hydrogen or C 1 -C 3 -alkyl-,
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl-
  • R 11 is simply with -NR 9
  • R 10 represents substituted GC 4 -alkyl
  • ⁇ is a monocyclic heterocyclyl radical having 4 to 7 ring atoms or a bridged C 0 -C 10 -heterocycloalkyl radical, where the radicals mentioned may optionally be monosubstituted by methyl, ethyl, acetyl, benzyl or ieri-butoxycarbonyl,
  • radicals mentioned may optionally be monosubstituted or disubstituted by identical or different substituents, with methyl, ethyl, fluorine, chlorine or bromine, and
  • R 12 is C 1 -C 3 -alkyl-
  • X is an oxygen atom
  • R l is -OR 6 and is in the meta or jara position to the benzodiazepine
  • R 1b represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • R 6 represents C 1 -C 4 -alkyl which is monosubstituted by C 1 -C 3 -alkylamino, or a monocyclic heterocyclyl radical having 4 to 7 ring atoms, which may optionally be monosubstituted by methyl, ethyl, acetyl or ferric Butoxycarbonyl, or
  • phenyl radical which may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine, bromine, methoxy- or ethoxy-,
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine
  • R 1b represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 8 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • Ci-Cs-alkoxy fluoro-Ci-C 3 -alkoxy
  • R 8 is hydrogen or C 1 -C 3 -alkyl-
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl
  • R 11 is C 1 -C 4 -alkyl which is monosubstituted with -NR 9 R 10 ,
  • ⁇ is a monocyclic heterocyclyl radical having 4 to 7 ring atoms or a bridged C 0 -C 10 -heterocycloalkyl radical, where the radicals mentioned may optionally be monosubstituted by methyl, ethyl, acetyl, benzyl or ieri-butoxycarbonyl,
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine or bromine, and also their polymorphs, enantiomers, Diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine
  • R 1b represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • R 8 is hydrogen or C 1 -C 3 -alkyl-
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl
  • R 12 is C 1 -C 3 -alkyl-, as well as their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine
  • R 1b represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and R 5 independently of one another represent hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine,
  • R 7 is C 2 -C 4 -alkyl or C 3 -C 7 -cycloalkyl which is monosubstituted by -NR 9 R 10 , or
  • radicals mentioned may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, chlorine, bromine,
  • Ring atoms is substituted C 1 -C 3 -alkyl or fluoro-C 1 -C 3 -alkyl, where the said phenyl and heteroaryl radicals may optionally be monosubstituted or disubstituted, identical or different, with methyl, ethyl, fluorine, Chlorine or bromine, R 8 is hydrogen or C 1 -C 3 -alkyl-, and
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl-
  • X is an oxygen atom
  • R l is -OR 6 or -NR 7 R 8 , and is in the meta or jara position to the benzodiazepine,
  • R 1b is hydrogen or fluorine
  • R lc is hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 and R 5 independently of one another represent hydrogen, chlorine, methoxy or trifluoromethoxy
  • R 6 is A ⁇ N-dimethylaminoethyl
  • R 7 is A ⁇ N-dimethylaminoethyl or A 1 N-dimethylaminopropyl-,
  • R l is -OR 6 or -NR 7 R 8 and is in the jara position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is hydrogen or methoxy
  • R 5 is methoxy or trifluoromethoxy
  • R 6 stands for C 1 -C 3 -alkylamino-substituted C 2 -C 4 -alkyl, or for a monocyclic heterocyclyl radical having 6 ring atoms, which may be simple may be substituted with methyl,
  • R 7 is C 2 -C 4 -alkyl or C 3 -C 7 -cycloalkyl which is monosubstituted by -NR 9 R 10 , or
  • R 8 is hydrogen or methyl
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl-
  • R 12 is C 1 -C 3 -alkyl
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R la is -OR 6 , and is in jara position to benzodiazepine, R lb and Rlc are hydrogen,
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R 6 stands for C 1 -C 4 -alkylamino-substituted C 2 -C 4 -alkyl, or for a monocyclic heterocyclyl radical with 6 ring atoms, which may optionally be monosubstituted by methyl, and
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl-
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the jara position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R 8 is hydrogen
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl-
  • R 12 is C 1 -C 3 -alkyl
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in the jara position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is hydrogen or methoxy
  • R 5 is methoxy- or trifluoromethoxy-
  • R 7 is C 2 -C 4 -alkyl or C 3 -C 7 -cycloalkyl which is monosubstituted by -NR 9 R 10 , or
  • R 8 is hydrogen or methyl
  • R 9 and R 10 independently of one another represent hydrogen or C 1 -C 3 -alkyl-
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R la is -OR 6 or -NR 7 R 8 , and is in the jara position to the benzodiazepine, R lb and Rlc are hydrogen,
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is hydrogen or methoxy
  • R 5 is methoxy or trifluoromethoxy
  • R 6 for a residue is selected
  • R 8 is hydrogen or methyl
  • R 11 for a residue is selected or
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R l is -OR 6 , and is in the / wa position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R 6 for a residue is selected
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in para-position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy, stands for methoxy
  • R is methyl
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • X is an oxygen atom
  • R l is -NR 7 R 8 , and is in ara position to the benzodiazepine
  • R lb and Rlc are hydrogen
  • R 2 is methyl
  • R 3 is methylamino, is hydrogen or methoxy, is methoxy- or trifluoromethoxy, a radical is selected from
  • R is hydrogen or methyl
  • the stereogenic center represented by the carbon atom of the benzodiazepine skeleton attached to R 2 is either racemic or predominantly or fully in the (3) configuration.
  • (4S) -7,8-Dimethoxy-.V 4-dimethyl-1 - ⁇ 4- [(1-methylpiperidin-4-yl) -amino] -phenyl ⁇ -4,5-dihydro-3 / i-2,3 benzodiazepine-3-carboxamide
  • - (4R) -7, 8-dimethoxy-N 4-dimethyl-1 - ⁇ 4- [(1-methylpiperidin-4-yl) -amino] -phenyl ⁇ -4,5-dihydro- 3 / i-2,3-benzodiazepin-3-carboxamide
  • (+) - 1- (4- ⁇ [2- (dimethylamino) ethyl] amino ⁇ phenyl) -7,8-dimethoxy- Ar , 4-dimethyl-4,5- dihydro-3 / i-2,3-benzodiazepin-3-carboxamide,
  • (4S) -7,8-dimethoxy-.V 4-dimethyl-1 - ⁇ 4- [methyl (1-methylpiperidin-4-yl) amino] phenyl ⁇ -4,5-dihydro-3 / i-2, 3-benzodiazepine-3-carboxamide, - (+) - ieri-butyl-4 - [ ⁇ 4- [7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3 / i- 2,3-benzodiazepin-1-yl] phenyl ⁇ methylamino] -piperidine-1-carboxy-lat.
  • (+) - 7,8-Dimethoxy- Ar 4-dimethyl-1- (4- ⁇ [ira-Al-4- (4-methylpiperazin-1-yl) cyclohexyl] amino ⁇ phenyl) -4,5- dihydro-3 / i-2,3-benzodiazepin-3-carboxamide,
  • (+) - 7,8-Dimethoxy- Ar 4-dimethyl-1- ⁇ 3- [methyl (pyridin-3-yl) -amino] -phenyl ⁇ -4,5-dihydro-3 / i-2,3- benzodiazepine-3-carboxamide, - ( ⁇ ) -7,8-dimethoxy-.V, 4-dimethyl-1 - ⁇ 3- [(1-methylpiperidin-4-yl) -amino] -phenyl ⁇ -4,5-dihydro- 3 / i-2,3-benzodiazepin-3-carboxamide,
  • (+) - 1- (3- ⁇ [3 - (dimethylamino) propyl] methylamino ⁇ -4-fluorophenyl) -7,8-dimethoxy-A r, 4- dimethyl-4,5-dihydro-3 / i-2 , 3-benzodiazepine-3-carboxamide,
  • (+) - 1- (4- ⁇ [(dimethylamino) acetyl] amino ⁇ phenyl) -7,8-dimethoxy- Ar , 4-dimethyl-4,5-dihydro-3 / i-2,3-benzodiazepine 3-carboxamide,
  • (+) - 1- (4- ⁇ [(1-Benzylpiperidin-4-yl) carbonyl] amino ⁇ phenyl) -7,8-dimethoxy / Y, 4-dimethyl-4,5-dihydro-3 / i 2,3-benzodiazepin-3-carboxamide,
  • (4S) -7,8-dimethoxy / Y 4-dimethyl-1 - ⁇ 4- [(1-methylpiperidin-4-yl) oxy] phenyl ⁇ -4,5-dihydro-3 / i-2,3 benzodiazepine-3-carboxamide, - (+) - 1- ⁇ 4- [2- (dimethylamino) ethoxy] phenyl ⁇ -7,8-dimethoxy / Y, 4-dimethyl-4,5-dihydro-3 / i -
  • (+) - 7,8-Dimethoxy- / Y 4-dimethyl-1- (4-phenoxyphenyl) -4,5-dihydro-3 / i-2,3-benzodiazepine-3-carboxamide, - (+) - 1- [4- (4-fluorophenoxy) phenyl] -7,8-dimethoxy- / Y, 4-dimethyl-4,5-dihydro-3 / i-2,3-benzodiazepine-3-carboxamide,
  • X may represent an oxygen or sulfur atom.
  • X is preferably an oxygen atom.
  • R la may represent -OR 6 or -NR 7 R. 8
  • R 1 is preferably -OR 6 .
  • R 1 is preferably -NR 7 R 8 .
  • R 1b preferably represents hydrogen, halogen, hydroxyl, cyano, or a C 1 -C 8 -alkyl, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkyl or fluorine C 1 -C 3 -alkoxy radical.
  • R 1b is particularly preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or trifluoromethyl.
  • R 1b is particularly preferably hydrogen, fluorine, chlorine, bromine or cyano.
  • R 1b is particularly preferably hydrogen, fluorine, methyl, methoxy or trifluoromethyl.
  • R 1b is particularly preferably hydrogen, fluorine or chlorine.
  • R 1b is most preferably hydrogen or fluorine.
  • R 1b is most preferably hydrogen. In the general formula (I), R 1b is most preferably fluorine.
  • R lc is preferably hydrogen, halogen, hydroxy, cyano, or a Ci-C 3 alkyl, Ci-C 3 alkoxy, fluoro-Ci-C 3 alkyl or fluorine -Ci-C 3 alkoxy radical.
  • R lc is more preferably hydrogen.
  • R 2 may be a C 1 -C 3 -alkyl or trifluoromethyl or a C 3 or C 4 -cycloalkyl radical.
  • R 2 is preferably methyl or ethyl.
  • R 2 is particularly preferably methyl.
  • R 3 may be C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino or C 1 -C 3 -alkylamino-.
  • R 3 is particularly preferably C 1 -C 3 -alkylamino.
  • R 3 is particularly preferably Ci-C2-alkylamino.
  • R 3 very particularly preferably represents methylamino.
  • R 4 and R 5 may independently of one another represent hydrogen, hydroxyl, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine,
  • Ci-COE-alkyl, Ci-COE-alkoxy, Ci-COE-alkylamino, Ci-COE-alkylcarbonylamino, CI-C ⁇ - alkylaminocarbonyl or C-Coe-alkylaminosulfonyl which is optionally substituted one or more times , identical or different, may be substituted by halogen, amino, hydroxy, carboxy, hydroxy-Ci-Cö-alkyl, Ci-Cö-alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, Ci-Cö-alkylamino -, amino-Ci-Cö-alkyl, a monocyclic heterocyclyl radical having 3 to 8 ring atoms or a monocyclic heteroaryl radical having 5 or 6 ring atoms, wherein said monocyclic heterocyclyl and heteroaryl radicals in turn may optionally be monosubstituted with Ci-C 3 alkyl .
  • C 3 -C 10 -cycloalkyl- which may optionally be monosubstituted or polysubstituted by identical or different substituents with halogen, amino, hydroxyl, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkoxy-ci- C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • monocyclic heteroaryl having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, nitro, Carboxy, GG-alkyl, GG-alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-GG-alkyl, GG-alkylamino, amino-GG-alkyl, GG-alkylamino GG-alkyl, halogen-GG-alkyl, halogen-GG-alkoxy, C3-Cio-cycloalkyl, or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Neurology (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
  • Transplantation (AREA)
  • Virology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne une phényl-2,3-benzodiazépine substituée inhibitrice de la protéine BET, en particulier, inhibitrice de BRD4, de formule générale (I), dans laquelle X, R1a, R1b, R1c, R2, R3, R4 et R5 qui ont les significations indiquées dans la description, décrivent des agents pharmaceutiques contenant les composés selon l'invention et leur utilisation prophylactique et thérapeutique dans les maladies hyper-prolifératives, en particulier dans les maladies tumorales. En outre, l'invention concerne l'utilisation d'inhibiteurs de la protéine BET dans des hyperplasies bénignes, des maladies athéroscléreuses, une septicémie, des maladies auto-immunes, des maladies vasculaires, des infections virales, dans des maladies neurodégénératives, dans des maladies inflammatoires, dans des maladies athéroscléreuses et dans le contrôle de la fertilité masculine.
EP14730906.6A 2013-06-17 2014-06-17 Phényl-2,3-benzodiasépine substituée Withdrawn EP3010909A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP14730906.6A EP3010909A1 (fr) 2013-06-17 2014-06-17 Phényl-2,3-benzodiasépine substituée

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP13172351 2013-06-17
PCT/EP2014/062674 WO2014202578A1 (fr) 2013-06-17 2014-06-17 Phényl-2,3-benzodiasépine substituée
EP14730906.6A EP3010909A1 (fr) 2013-06-17 2014-06-17 Phényl-2,3-benzodiasépine substituée

Publications (1)

Publication Number Publication Date
EP3010909A1 true EP3010909A1 (fr) 2016-04-27

Family

ID=48613529

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14730906.6A Withdrawn EP3010909A1 (fr) 2013-06-17 2014-06-17 Phényl-2,3-benzodiasépine substituée

Country Status (5)

Country Link
EP (1) EP3010909A1 (fr)
JP (1) JP2016521722A (fr)
CN (1) CN105492436A (fr)
CA (1) CA2915419A1 (fr)
WO (1) WO2014202578A1 (fr)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
WO2014080290A2 (fr) 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Amines cycliques servant d'inhibiteurs de bromodomaines
WO2014096965A2 (fr) 2012-12-21 2014-06-26 Rvx Therapeutics Inc. Nouveaux composés hétérocycliques en tant qu'inhibiteurs de bromodomaine
WO2014143768A1 (fr) 2013-03-15 2014-09-18 Incyte Corporation Hétérocycles tricycliques en tant qu'inhibiteurs de protéine bet
JP6461121B2 (ja) 2013-06-21 2019-01-30 ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． 新規の二環式ブロモドメイン阻害剤
WO2015004534A2 (fr) 2013-06-21 2015-01-15 Zenith Epigenetics Corp. Nouveaux composés hétérocycliques utilisés en tant qu'inhibiteurs de bromodomaine
ES2635560T3 (es) 2013-07-08 2017-10-04 Incyte Holdings Corporation Heterociclos tricíclicos como inhibidores de la proteína NET
CN105593224B (zh) 2013-07-31 2021-05-25 恒元生物医药科技(苏州)有限公司 作为溴结构域抑制剂的新型喹唑啉酮类化合物
WO2015081189A1 (fr) 2013-11-26 2015-06-04 Incyte Corporation Hétérocycles bicycliques servant d'inhibiteurs des protéines bet
US9399640B2 (en) 2013-11-26 2016-07-26 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
US9309246B2 (en) 2013-12-19 2016-04-12 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
ES2942723T3 (es) 2014-04-23 2023-06-06 Incyte Holdings Corp 1H-pirrolo[2,3-C]piridin-7(6H)-onas y pirazolo[3,4-C]piridin-7(6H)-onas como inhibidores de proteínas BET
ES2855225T3 (es) 2014-09-15 2021-09-23 Incyte Corp Heterociclos tricíclicos para su uso como inhibidores de proteínas BET
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
EP3227280B1 (fr) 2014-12-01 2019-04-24 Zenith Epigenetics Ltd. Pyridines substituées comme inhibiteurs de bromodomaine
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
CN107406438B (zh) 2014-12-17 2021-05-14 恒翼生物医药科技(上海)有限公司 溴结构域的抑制剂
GB201504694D0 (en) 2015-03-19 2015-05-06 Glaxosmithkline Ip Dev Ltd Covalent conjugates
WO2017005711A1 (fr) * 2015-07-09 2017-01-12 Bayer Pharma Aktiengesellschaft Dérivés de benzodiazépine substitués par du phosphore et du soufre
WO2017063959A1 (fr) * 2015-10-15 2017-04-20 Bayer Pharma Aktiengesellschaft Dérivés de la benzodiazépine n-sulfoximinophényl-substitués utilisés comme inhibiteurs de protéines bet
WO2017075377A1 (fr) 2015-10-29 2017-05-04 Incyte Corporation Forme solide amorphe d'un inhibiteur de protéine bet
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
KR20250163425A (ko) 2016-06-20 2025-11-20 인사이트 코포레이션 Bet 저해제의 결정질 고체 형태
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
CN111529533B (zh) * 2020-06-05 2021-06-11 南华大学附属第一医院 溴结构域蛋白4抑制剂jq1或其衍生物在制备治疗脓毒症肠屏障损伤药物中的应用
CN112076189B (zh) * 2020-09-23 2021-11-12 唐怡庭 一种酰胺化合物在制备治疗脓毒症药物中的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU225100B1 (hu) * 2000-12-21 2006-06-28 Egyt Gyogyszervegyeszeti Gyar 2,3-Benzodiazepinszármazékok, ilyen hatóanyagot tartalmazó gyógyászati készítmények és alkalmazásuk
TW200902024A (en) * 2007-04-02 2009-01-16 Teva Pharma Novel 2,3-benzodiazepine derivatives and their use as antipsychotic agents

Also Published As

Publication number Publication date
WO2014202578A1 (fr) 2014-12-24
CA2915419A1 (fr) 2014-12-24
CN105492436A (zh) 2016-04-13
JP2016521722A (ja) 2016-07-25

Similar Documents

Publication Publication Date Title
EP3010909A1 (fr) Phényl-2,3-benzodiasépine substituée
EP2885286B1 (fr) 2,3-benzodiazépines
EP3027614B1 (fr) Dihydropyrido[3,4-b]pyrazinones substituées comme double inhibiteurs de la protéines bet et polo-like kinases
EP2958922A1 (fr) Pyrrolo-triazolodiazépines et pyrazolo-triazolodiazépines utilisées en tant qu'inhibiteurs de protéines bet pour traiter des maladies hyperprolifératives
EP3019493B1 (fr) Dihydrochinoxalinone et dihydropyridopyrazinone modifiées inhibitrices de la protéine bet
EP2900672B1 (fr) 5-aryl-triazolo-azépines inhibitrice de la protéine bet
EP2958923A1 (fr) Pyrrolo-diazépines et pyrazolo-diazépines substituées en position 4
EP2958909A1 (fr) 2,3-benzodiazépines bicyclo- et spirocyclosubstituées
EP2935261A1 (fr) Dihydrochinoxalinones inhibitrices de protéine bet
EP2935260A1 (fr) Dihydropyridopyrazinones inhibitrices de protéine bet
EP3157919A1 (fr) 3,4-dihydropyrido[2,3-b]pyrazinones inhibitrices de protéine bet, à groupe éther ou amino aromatique meta-substitué
WO2015121230A1 (fr) 2,3-benzodiazépines substituées en position 9
WO2015121268A1 (fr) 1-phényl-3h-2,3-benzodiazépines et leur utilisation comme inhibiteurs de bromodomaine
WO2015121226A1 (fr) 2,3-benzodiazépines substituées en position 6
WO2015121227A1 (fr) 1-phényl-3h-2,3-benzodiazépines disubstituées en position 6,9 et leur utilisation comme inhibiteurs de bromodomaine
WO2017063959A1 (fr) Dérivés de la benzodiazépine n-sulfoximinophényl-substitués utilisés comme inhibiteurs de protéines bet
WO2015193228A1 (fr) 1,4-dihydropyrido[3,4-b]pyrazinones inhibitrices de protéine bet, à groupe éther ou amino aromatique para-substitué
WO2015193217A1 (fr) Dérivés de dihydropyrido[2,3-b]pyrazinone inhibant la protéine bet, à groupe éther ou amino aromatique para-substitué
WO2016062688A1 (fr) Dérivés de 1-phényl-4,5-dihydro-3h-2,3-benzodiazépines
WO2017144393A1 (fr) Dérivés de 5-(phényl)-1,2-dihydro-3h-3-benzazépine-3-carboxamide substitués en 2 utilisés en tant qu'inhibiteurs de brd4 pour le traitement du cancer
WO2015193229A1 (fr) 1,4-dihydropyrido[3,4-b]pyrazinones inhibitrices de protéine bet, à groupe éther ou amino aromatique meta-substitué

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20160118

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

INTG Intention to grant announced

Effective date: 20161109

18W Application withdrawn

Effective date: 20161107