EP2958922A1 - Pyrrolo-triazolodiazépines et pyrazolo-triazolodiazépines utilisées en tant qu'inhibiteurs de protéines bet pour traiter des maladies hyperprolifératives - Google Patents

Pyrrolo-triazolodiazépines et pyrazolo-triazolodiazépines utilisées en tant qu'inhibiteurs de protéines bet pour traiter des maladies hyperprolifératives

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Publication number
EP2958922A1
EP2958922A1 EP14704595.9A EP14704595A EP2958922A1 EP 2958922 A1 EP2958922 A1 EP 2958922A1 EP 14704595 A EP14704595 A EP 14704595A EP 2958922 A1 EP2958922 A1 EP 2958922A1
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Prior art keywords
alkyl
alkoxy
halogen
amino
ring atoms
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English (en)
Inventor
Norbert Schmees
Bernd Buchmann
Bernard Haendler
Roland Neuhaus
Pascale Lejeune
Martin Krüger
Amaury Ernesto FERNANDEZ-MONTALVÁN
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Bayer Pharma AG
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Bayer Pharma AG
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    • C07—ORGANIC CHEMISTRY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • 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
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    • 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
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    • 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
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    • 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
    • A—HUMAN NECESSITIES
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • PYRROLO- AND PYRAZOLO-TRIAZOLODIAZEPINE AS BET PROTEIN INHIBITORS FOR THE TREATMENT OF HYPER-PROLIFERATIVE DISEASES
  • the present invention relates to BET protein-inhibiting, in particular BRD2, BRD3 and BRD4-inhibitory bicyclo- and spiro-substituted pyrrolo and pyrazolo-diazepines, intermediates for the preparation of the compounds of the invention, pharmaceutical compositions containing the compounds of the invention and their prophylactic and therapeutic use in hyper-proliferative diseases, especially in tumor diseases. Furthermore, this invention relates to the use of BET protein inhibitors in benign hyperplasia, in
  • Atherosclerotic diseases sepsis, autoimmune diseases, vascular diseases, viral infections, neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases and male fertility control.
  • the human BET family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and BRDT) containing two related bromodomains and one extra-terminal domain (Wu and Chiang, J. Biol. Chem., 2007 , 282: 13141-13145).
  • the bromodomains are protein regions that recognize acetylated lysine residues. Such acetylated lysines are often found at the N-terminal end of histones (eg, histone H3 or histone H4) and are features of open chromatin structure and active gene transcription (Kuo and Allis, Bioessays, 1998, 20: 615). 626).
  • bromodomains can recognize additional acetylated proteins.
  • BRD4 binds to RelA, resulting in the stimulation of NF- ⁇ B and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell Biol., 2009, 29: 1375-1387; Zhang et al., J. Biol Chem., 2012, doi / 10.1074 / jbc.Ml 12.359505).
  • BRD2, BRD3 and BRD4 interacts with several proteins that have a role in chromatin modulation and regulation of gene expression (Rahman et al., Mol. Cell Biol., 2011, 31: 2641-2652).
  • BET proteins play an important role in cell growth and cell cycle. Biol. Cell, 2009, 20: 4899-4909; Yang et al., Mol. Cell. Biol., 2008, 28: 967-976). BRD4 is important for the post-mitotic reactivation of gene transcription (Zhao et al., Nat Cell Biol., 2011, 13: 1295-1304). It has been shown that BRD4 is essential for the
  • RNA polymerase II Transcription elongation and for the recruitment of the elongation complex P-TEFb, which consists of CDK9 and cyclin Tl, which leads to 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).
  • RNA polymerase II Yang et al., Mol. Cell, 2005, 19: 535-545; Schröder et al. J. Biol. Chem., 2012, 287: 1090-1099.
  • genes involved in cell proliferation is stimulated, 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 chromatin regions
  • 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.
  • 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 ).
  • 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).
  • BRD4 inhibitor The growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073). Screening for therapeutic targets in an acute myeloid leukemia cell line (AML) showed that BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, doi: 10.1038). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo. Amplification of the DNA region containing the BRD4 gene has been detected in primary breast tumors (Kadota et al., Cancer Res.
  • 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).
  • the herpesvirus responsible for Kaposi's sarcoma interacts with various BET proteins, which is important for disease resistance (Viejo-Borbolla et al., J. Viral., 2005, 79: 13618-13629; You et al , J. Viral., 2006, 80: 8909-8919).
  • BRD4 By binding to P-TEFb, BRD4 also plays an important role in the replication of HIV (Bisgrove et al., Proc Natl Acad., USA, 2007, 104: 13690-13695). BET proteins are also involved in inflammatory processes. BRD2-hypomorphic mice show reduced inflammation in adipose tissue (Wang et al., Biochem J., 2009, 425: 71-83). The infiltration of macrophages into white adipose tissue is also reduced in BRD2-deficient mice (Wang et al., Biochem J., 2009, 425: 71-83). It has also been shown that BRD4 regulates a number of genes involved in inflammation. In LPS-stimulated macrophages, a BRD4 inhibitor prevents the expression of inflammatory genes, such as IL-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1119-1123).
  • BET proteins also regulate the expression of the ApoAl gene, which plays an important role in
  • Apolipoprotein AI is a major component of high density lipoproteins (HDL) and increased expression of ApoAl results in elevated blood cholesterol levels (Degoma and Rader, Nat. Rev. Cardiol., 2011, 8: 266-277). Elevated HDL levels are associated with a decreased risk of atherosclerosis (Chapman et al., Eur. Heart J., 2011, 32: 1345-1361).
  • the first published BRD4 inhibitors are phenyl-thieno-triazolo-l, 4-diazepine (4-phenyl-6-thieno [3,2-] [l, 2,4] triazolo [4,3-a] [ l, 4] diazepines) as described in WO2009 / 084693 (Mitsubishi Tanabe Pharma Corporation) and with the compound JQ1 in WO2011 / 143669 (Dana Farber Cancer Institute). Replacement of the thieno by a benzo moiety also results in active inhibitors (J. Med. Chem., 2011, 54, 3827-3838, E. Nicodeme et al., Nature 2010, 468, 1119). This and another publication indicate that the 1,4-benzodiazepine or thieno-1,4-diazepine
  • Ring system fused pyrazole unit is actively involved in the binding of the target protein BRD4 (P. Filippakopoulos et al., Nature 2010, 468, 1067).
  • Other 4-phenyl-6 # -thieno [3,2- /] [l, 2,4] triazolo [4,3-a] [l, 4] diazepines and related compounds with alternative rings as the fusion partner instead of the benzo moiety are generically addressed or directly described in WO2012 / 075456 (Constellation Pharmaceuticals).
  • 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 pyridoazepines.
  • WO2013 / 184876 and WO2013 / 184878 (Constellation Pharmaceuticals) describe further benzoisoxazoloazepine derivatives as inhibitors of bromodomain-containing proteins.
  • BRD4 inhibitors is 7-isoxazoloquinolines and related quinoline derivatives (WO2011 / 054843, Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967, GlaxoSmithKline).
  • Pyridinones and pyridazinones (WO 2013/185284, WO 2013/188381; Abbott Laboratories) and isoindolones (WO 2013/155695, WO 2013/158952; Abbott Laboratories) are inhibitors of binding of bromodomains of BET proteins to N-acetylated lysine. Residues containing proteins described.
  • Receptors are described in WO2006 / 051312 (James Black Foundation). They also include substituted 3,5-dihydro-4 / i-2,3-benzodiazepin-4-ones which are different from the compounds according to the invention Compounds differ mainly by the obligatory oxo group in position 4 and by a mandatory carbonyl group-containing alkyl chain in position 5. Finally, substituted 3,5-dihydro-4 / i-2,3-benzodiazepin-4-ones are also described as AMPA antagonists in WO97 / 34878 (Cocensys Inc.). Despite a very broad generic claim regarding the possible substitution patterns on the benzodiazepine skeleton, the embodiments are limited to a narrow range.
  • DE3435973 describes 6-aryl-triazolo-diazepines which carry an annulated pyrrole ring with N in position 2.
  • the compounds are used in the treatment of pathological conditions and diseases involving acetylglyceryl-ester phosphorylcholine (PAF).
  • PAF acetylglyceryl-ester phosphorylcholine
  • these compounds have no side chain in position 4. Only substitution with a methyl group has been described on a diazepinone system with a pyrazole annulation (J. Med. Chem. 24, (1981), p982ff, DeWald et al.).
  • the compounds according to the invention are novel pyrrolo and pyrazolo-diazepines which are based on
  • Diazepingerüst a bicyclo or spiro group having surprisingly BET protein inhibitory, in particular BRD2, BRD3 and BRD4 inhibitory activity, and inhibit the interaction between BRD4 inhibitors and an acetylated histone H4 peptide and inhibit the growth of cancer cells .
  • BET protein inhibitory in particular BRD2, BRD3 and BRD4 inhibitory activity
  • BRD4 inhibitors an acetylated histone H4 peptide and inhibit the growth of cancer cells
  • the compounds of the invention inhibit the interaction between 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.
  • X is a carbon or a nitrogen atom
  • n and m are independently 0 or 1
  • R 1 , R 4 and R 5 are identical or different from each other for hydrogen, hydroxy, cyano, nitro, amino,
  • R 2 represents hydrogen or represents Ci-COE-alkyl, aminocarbonyl, Ci-COE-alkylcarbonyl, CI-C ⁇ -
  • C3-Cio-Cycloalkyl- which is optionally mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, Ci-Cö-alkyl, CI-C ⁇ - alkoxy, Ci-C6-alkoxy-Ci -C6-alkyl, Ci-Cö-alkylamino, amino-Ci-Cö-alkyl, Ci-C6-alkylamino-Ci-C6-alkyl, halogen-Ci-Cö-alkyl, halogen-Ci-Cö-alkoxy or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • Ci-Cö-alkyl is phenyl, which is optionally monosubstituted or polysubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, nitro, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy Ci-Cö-alkyl, Ci-Cö-alkylamino, amino-Ci-Cö-alkyl, Ci-Cö-alkylaminocarbonyl, Ci-Cö-alkylcarbonyl, Ci-Cö-alkylamino-sulfonyl, Ci-Cö- Alkylsulfonyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, halogeno-C 1 -C 6
  • Phenylsulfonyl- or Ci-C6-Alkylaminosulfonyl- which are optionally mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, hydroxy-G-Ce-alkyl, Ci-C 6 -alkoxy, Ci -C 6 -alkoxy-C 1 -C 6 -alkyl, GG-alkylamino or amino-GG-alkyl, when X is a carbon atom, or
  • Phenylsulfonyl or GG-alkylaminosulfonyl- which are optionally mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, hydroxy-G-Ce-alkyl, GC 6 -alkoxy, Ci-C 6 - Alkoxy-Ci-C 6 alkyl, GG-alkylamino or amino-GG-alkyl when X is a nitrogen atom, or
  • heteroaromatic or heterocyclic ring having 5 to 7 ring atoms, which is optionally monosubstituted or polysubstituted by identical or different halogen, amino, hydroxy, cyano, nitro, carboxy, GC 6 alkyl -, GC 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, G-G-alkylamino, amino-GG-alkyl, GG-alkylaminocarbonyl, GG-alkyl-aminosulfonyl, GG Alkylcarbonyl, GG-alkylsulphonyl, GG-alkylamino-G-G-alkyl, hydroxy-G-Ce-alkyl, halogeno-GC 6 -alkyl, halogeno-GG-alkoxy, C 3 -C 10 -cycloalkyl- or a monocycl
  • a spirocycloalkyl or heterospirocycloalkyl radical of 7 to 12 ring atoms a bridged cycloalkyl radical or a bridged heterocycloalkyl radical of 7 to 12 ring atoms, where the radicals mentioned here are optionally mono- or polysubstituted by identical or different substituents with halogen, cyano, nitro , Hydroxy, amino, oxo, carboxy, GG alkyl, GG alkoxy, GG alkoxy GG alkyl, hydroxy GG alkyl, GG alkylamino, amino GG alkyl, GG alkylamino -GG-alkyl, halogen-GG-alkyl, halogen-GG-alkoxy, G-Go-cycloalkyl, phenyl, halophenyl, phenyl-GG-alkyl, phenyl-GC 6 -alkoxy, pyridinyl- , -
  • phenyl monocyclic heterocyclyl having 3 to 8 ring atoms or monocyclic heteroaryl- with 5 or 6 Ring atoms in which phenyl, heteroaryl and heterocyclyl are optionally monosubstituted or disubstituted by halogen, C 1 -C 3 -alkoxy or C 1 -C 3 -alkyl, R 9 is C 1 -C 6 -alkyl-,
  • X is a carbon or a nitrogen atom
  • n and m are independently 0 or 1
  • R 1 , R 4 and R 5 are identical or different from each other for hydrogen, hydroxy, cyano, nitro, amino,
  • Ci-Cö-alkylsulfonyl- which are optionally mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, hydroxy-C
  • Ci-Cö-alkyl Ci-Cö-alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, Ci-Cö-alkylamino, amino Ci-Cö-alkyl, monocyclic heterocyclyl having 3 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, in which the said monocyclic heterocyclyl and heteroaryl radicals are in turn optionally monosubstituted by C 1 -C 3 -alkyl,
  • Y represents a spirocycloalkyl or heterospirocycloalkyl radical of 7 to 12 ring atoms, a bridged cycloalkyl radical or a bridged heterocycloalkyl radical of 7 to 12 ring atoms, where the radicals mentioned here are optionally mono- or polysubstituted identically or differently with halogen, cyano, Hydroxyl, amino, oxo, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, , Amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogen-
  • R is hydrogen, Ci-C 3 alkyl, cyclopropyl, or D1-C 1 -C 3 6 and R 7 independently of one another - alkylamino-Ci-C3-alkyl are,
  • R 8 is hydroxy, C 1 -C 6 -alkyl, G-C 1 -alkoxy, halogen-C 1 -C 3 -alkyl-, hydroxy-C 1 -C 3 -
  • X is a carbon or a nitrogen atom
  • n and m are independently 0 or 1
  • R 1 , R 4 and R 5 are identical or different from each other for hydrogen, hydroxy, cyano,
  • C 1 -C 6 -alkyl is hydrogen or C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, phenylsulfonyl or C 1 -C 6 -alkylsulfonyl, which are optionally mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxyl or carboxy, or
  • C3-Cio-Cycloalkyl- which is optionally mono- or polysubstituted by identical or different substituents with halogen, Ci-Cö-alkyl or Ci-Cö-alkoxy, or
  • phenyl which is optionally mono- or polysubstituted by identical or different substituents with halogen, hydroxy, cyano, carboxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, halo-Ci-Cö-alkyl, halogen -C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl or a monocyclic heterocyclyl radical having 3 to 8 ring atoms,
  • C 1 -C 6 -alkyl is hydrogen or C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, phenylsulfonyl or C 1 -C 6 -alkylsulfonyl, which are optionally mono- or polysubstituted, identically or differently, by halogen, amino, hydroxyl, carboxy, Hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, G-C 1 -C 6 -alkylamino or amino-C 1 -C 6 -alkyl-, when X is represents a carbon atom,
  • C 1 -C 6 -alkyl is hydrogen or C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, phenylsulfonyl or C 1 -C 6 -alkylsulfonyl, which are optionally mono- or polysubstituted, identically or differently, by halogen, amino, hydroxyl, carboxy, Hydroxy-Ce-Ce, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkylamino or amino-Ci-Cö-alkyl, when X is a nitrogen atom stands,
  • R 6 and R 7 independently of one another represent hydrogen, C 1 -C 3 -alkyl, cyclopropyl or C 1 -C 3 -alkylamino-C 1 -C 3 -alkyl-,
  • R 8 is hydroxy, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy, halogeno-C 1 -C 3 -alkyl-, hydroxy-C 1 -C 3 -
  • R 9 is C 1 -C 6 -alkyl-
  • X is a carbon or a nitrogen atom
  • n and m are independently 0 or 1
  • R 1 , R 4 and R 5 are the same or different from each other for hydrogen, cyano, halogen or for
  • R 2 is hydrogen or C 1 -C 6 -alkyl, which is optionally mono- or polysubstituted by halogen,
  • phenyl which is optionally mono- or polysubstituted by identical or different substituents with halogen, cyano, Ci-Cö-alkyl, Ci-Cö-alkoxy, halo-Ci-Cö-alkyl or halogen-Ci-Cö alkoxy,
  • R 3 is hydrogen or C 1 -C 6 -alkyl- which is optionally mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, C 1 -C 6 -alkoxy or C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl when X is a carbon atom, or
  • R 3 is hydrogen or C 1 -C 6 -alkyl, which is optionally monosubstituted or polysubstituted, identically or differently, by halogen or C 1 -C 6 -alkoxy, if X is a nitrogen atom,
  • R 2 and R 3 together with the ring atoms N and X can form another heteroaromatic or heterocyclic ring having 5 to 7 ring atoms, which is optionally mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, cyano, Ci-Cö Alkyl, C 1 -C 6 -alkoxy, halogen-C 1 -C 6 -alkyl or halogen-C 1 -C 6 -alkoxy,
  • Y represents a spirocycloalkyl or heterospirocycloalkyl radical of 7 to 12 ring atoms, a bridged cycloalkyl radical or a bridged heterocycloalkyl radical of 7 to 12 ring atoms, where the radicals mentioned here are optionally mono- or polysubstituted identically or differently with halogen, cyano, oxo, hydroxy, Ci-C 3 alkyl, Ci-C 3 alkoxy, halogen-C 3 alkyl, halogen Ci-C 3 alkoxy, C 3 -C 7 -
  • R 6 and R 7 are independently hydrogen, GC 3 alkyl, cyclopropyl, or di-GC 3 - alkylamino-Ci-C 3 are alkyl,
  • R 8 for hydroxy, GC 6 -alkyl, C 1 -C 3 -alkoxy, halogen-C 1 -C 3 -alkyl, hydroxy-GC 3 -
  • R 9 is C 1 -C 6 -alkyl-
  • X is a carbon or a nitrogen atom
  • n and m are independently 0 or 1
  • R 1 , R 4 and R 5 are the same or different and represent hydrogen or halogen
  • R 2 is hydrogen or GC 3 alkyl
  • R 3 is hydrogen or GC 3 alkyl when X is a carbon atom
  • R 3 is hydrogen or GC 3 alkyl when X is nitrogen
  • R 6 and R 7 independently of one another represent hydrogen or C 1 -C 3 -alkyl
  • R 8 is hydroxy, GC 6 alkyl, Ci-C 3 alkoxy, halo-Ci-C 3 alkyl, phenyl or monocyclic heterocyclyl having 3 to 8 ring atoms, wherein phenyl and heterocyclyl optionally - or doubly substituted with halogen, C 1 -C 3 -alkoxy or C 1 -C 3 -alkyl,
  • R 9 is Ci-Cs-alkyl-
  • X is a carbon or a nitrogen atom
  • n and m are independently 0 or 1
  • R 1 is hydrogen or halogen
  • R 2 is hydrogen or C 1 -C 3 -alkyl
  • R 3 is hydrogen or C 1 -C 3 -alkyl when X is a carbon atom, or
  • R 3 is hydrogen or C 1 -C 3 -alkyl, when X is a nitrogen atom,
  • R 4 and R 5 are hydrogen
  • R 8 is hydroxy, C 1 -C 6 -alkyl or halogeno-C 1 -C 3 -alkyl
  • X is a carbon or a nitrogen atom
  • n and m are independently 0 or 1
  • R 1 is hydrogen, fluorine, chlorine or bromine
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl when X is a carbon atom
  • R 4 and R 5 are hydrogen
  • Y represents a spirocycloalkyl or heterospirocycloalkyl radical of 7 to 11 ring atoms, a bridged cycloalkyl radical or a bridged heterocycloalkyl radical of 7 to 8 ring atoms, where the radicals mentioned here are optionally mono- or polysubstituted identically or differently with oxo, fluorine, Chlorine, bromine,
  • R 8 is hydroxy, C 1 -C 6 -alkyl or halogeno-C 1 -C 3 -alkyl
  • X is a carbon or nitrogen atom
  • n and m are independently 0 or 1
  • R 1 is hydrogen or chlorine
  • R 2 is hydrogen or methyl
  • R 3 is methyl when X is a carbon atom
  • R 3 is hydrogen or methyl when X is a nitrogen atom
  • R 4 and R 5 are hydrogen
  • R 8 is hydroxy, GC 6 -alkyl or halo-C 1 -C 3 -alkyl-,
  • X is a carbon or nitrogen atom
  • n and m are independently 0 or 1
  • R 1 is hydrogen or chlorine
  • R 2 is hydrogen or methyl
  • R 3 is methyl when X is a carbon atom
  • R 3 is hydrogen or methyl when X is a nitrogen atom
  • R 4 and R 5 are hydrogen
  • X may represent a carbon or nitrogen atom.
  • m and n independently of one another can stand for 0 or 1.
  • R 1 , R 4 and R 5 may be the same or different and represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, halogen or optionally mono- or polysubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 1 -C 8 -alkyl, -Alkylamino- or amino-C 1 -C 6 -alkyl-, substituted 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- , Ci-Cö-alkylcarbonyl,
  • R 1 , R 4 and R 5 identical or different from one another, represent hydrogen, cyano, halogen or optionally C 1-10 -alkyl substituted with halogen mono- or polysubstituted or Ci-Cö alkoxy stand.
  • R 1 , R 4 and R 5 are hydrogen or halogen.
  • R 4 and R 5 are hydrogen.
  • C3-Cio-cycloalkyl- which may optionally be mono- or polysubstituted by identical or different substituents with halogen, Ci-Cö-alkyl or Ci-Cö-alkoxy,
  • R 2 is hydrogen or methyl.
  • R 3 is hydrogen or C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, phenylsulfonyl or C 1 -C 6 -alkylsulfonyl, where the radicals mentioned are optionally - or polysubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, hydroxy-Ci-Cö-alkyl, CI-C ⁇ - alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, Ci -Cö-alkylamino and / or amino-Ci-Cö-alkyl-, and in which X is a carbon atom.
  • R 3 is hydrogen or C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, phenylsulfonyl or C 1 -C 6 -alkylsulfonyl, where the radicals mentioned are optionally - or polysubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, hydroxy-Ci-Cö-alkyl, CI-C ⁇ - alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, Ci -Cö-alkylamino and / or amino-Ci-Cö-alkyl-, and in which X is a nitrogen atom.
  • R 3 is hydrogen or C 1 -C 3 -alkyl-, and in which X is a carbon atom.
  • R 3 is hydrogen or C 1 -C 3 -alkyl-, and in which X is a nitrogen atom.
  • R 6 and R 7 are independently hydrogen, Ci-C 3 alkyl, cyclopropyl, or di-Ci-C 3 alkyl-amino-Ci-C 3 Alkyl stand.
  • R 6 and R 7 independently of one another are hydrogen or C 1 -C 3 -alkyl.
  • R 8 is hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogeno-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 Alkyl, GC 3 - alkoxy-Ci-C 3 alkyl, Cs-Cs-cycloalkyl, phenyl, monocyclic heterocyclyl having 3 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, wherein phenyl, Heteroaryl and heterocyclyl optionally mono- or disubstituted by halogen, Ci-C 3 alkoxy or Ci-C 3 alkyl.
  • R 8 is hydroxy, CI-C ⁇ - alkyl, Ci-C 3 alkoxy, halogen-C 3 alkyl, phenyl or monocyclic heterocyclyl with 3 to 8 ring atoms, in which phenyl and heterocyclyl may optionally be monosubstituted or disubstituted by halogen, Ci-C 3 alkoxy or Ci-C 3 alkyl.
  • inventive compounds are present.
  • the circle should represent both as a possible position of the double bonds, as shown here:
  • Alkyl is a linear or branched, saturated, monovalent hydrocarbon radical having generally 1 to 6 (C 1 -C 6 -alkyl), preferably 1 to 4 (C 1 -C 4 -alkyl), and particularly preferably 1 to 3 carbon atoms (C 1 -C 4 -alkyl) C3 alkyl).
  • Particularly preferred is a methyl, ethyl, propyl, isopropyl or ieri-butyl radical.
  • Cycloalkyl is a monodic, saturated, monovalent hydrocarbon radical having generally 3 to 10 (C 3 -Cio-cycloalkyl), preferably 3 to 8
  • Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.
  • Alkoxy is a linear or branched, saturated alkyl ether radical of the formula -O-alkyl having usually 1 to 6 (C I -C ⁇ - alkoxy), preferably 1 to 4 (Ci-C t-alkoxy), and particularly preferably 1 to 3 (C 1 -C 3 -alkoxy) carbon atoms.
  • Alkoxyalkyl is an alkoxy-substituted alkyl radical, for example Ci-Ce-alkoxy-Ci-Cö-alkyl or Ci-Cs-alkoxy-Ci-Cs-alkyl.
  • Ci-Ce-alkoxy-Ci-Cö-alkyl- means that the alkoxyalkyl group is bonded via the alkyl moiety to the rest of the molecule.
  • Oxo may be attached to atoms of suitable valence, for example to a saturated carbon atom or to sulfur.
  • the bond to carbon is to form a carbonyl group or bond to sulfur to form a sulfinyl or sulfonyl group.
  • 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 is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent. Examples include:
  • Examples include acetyl and propanoyl.
  • Methylsulfonyl ethylsulfonyl, propylsulfonyl.
  • Methylaminosulfonyl ethylaminosulfonyl, dimethylaminosulfonyl.
  • phenyl-Ci-Cö-alkyl- is meant a group which is composed of a
  • alkyl radical here has the meanings given above under alkyl.
  • benzyl examples which may be mentioned are benzyl, phenethyl, phenylpropyl, phenylpentyl, benzyl being preferred.
  • phenyl-Ci-Cö-alkoxy- is to understand a group which is composed of an optionally substituted phenyl radical and a Ci-Cö-alkoxy group, and bound via the Ci-Cö-alkoxy group to the rest of the molecule is.
  • the alkoxy radical here has the meanings given above under alkoxy.
  • benzoxy examples which may be mentioned are benzoxy, phenethoxy, phenylpropyloxy, phenylpentyloxy, benzoxy being preferred.
  • Examples include phenylsulfonyl, o- or p-toluylsulfonyl, m-chlorophenylsulfonyl. heteroatoms
  • Heteroatoms are oxygen, nitrogen or sulfur atoms.
  • Heteroaryl means a monovalent, aromatic ring system with 1, 2 or 3 heteroatoms. As heteroatoms nitrogen atoms, oxygen atoms and / or sulfur atoms may occur.
  • the binding valency can be attached to any aromatic carbon atom or to a
  • 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:
  • Monocyclic heterocyclyl means a non-aromatic monocyclic ring system having 1, 2 or 3 heteroatoms. As heteroatoms nitrogen atoms, oxygen atoms and / or
  • a monocyclic heterocyclyl ring according to the present invention may have 3 to 8, preferably 4 to 7, particularly preferably 5 or 6 ring atoms.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 4 ring atoms are: azetidinyl, oxetanyl.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 5 ring atoms are: pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, dioxolanyl and tetrahydrofuranyl.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 7 ring atoms are: azepanyl, oxepanyl, 1,3-diazepanyl, 1,4-diazepanyl.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 8 ring atoms are: oxocanyl, azocanyl.
  • Preferred monocyclic heterocyclyl radicals are 4 to 7-membered, saturated
  • C5-C11 -spirocycloalkyl- or Cs-Cn-heterospirocycloalkyl- with a replacement of 1-4 carbon atoms by heteroatoms as defined above in any combination is meant a fusion of two saturated ring systems sharing a common atom.
  • Examples are spiro [2.2] pentyl, spiro [2.3] hexyl, azaspiro [2.3] hexyl, spiro [3.3] heptyl,
  • bridged ring system such as C6-Ci2 cycloalkyl or bridged C-Coe bridged Ce- 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, diazabicyclo [2.2.1] heptyl,
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is an alkyl radical having at least one halogen substituent.
  • a halo-C 1 -C 6 -alkyl radical is an alkyl radical having 1-6 carbon atoms and at least one
  • Halogen substituents If several halogen substituents are present, they may also be different.
  • Trifluoromethyl 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,5,5,5-pentafluoropentyl or 3,3,4,4,5,5,5-
  • perfluorinated alkyl radicals such as trifluoromethyl or pentafluoroethyl.
  • Haloalkoxy is an alkoxy radical having at least one halogen substituent.
  • Halogen substituents If several halogen substituents are present, they may also be different. Preference is given to fluoroalkoxy 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.
  • 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-alkylaminoalkyl for example di-C 1 -C 3 -alkylamino-C 1 -C 3 -alkyl-, means that the abovementioned alkylamino moiety necessarily contains two alkyl groups, which may be identical or different.
  • alkylaminoalkyl examples include A ⁇ N-dimethylaminoethyl, A ⁇ N-dimethylaminomethyl, N, N-diethylaminoethyl, ⁇ .V-dimethylaminopropyl, N-methylaminoethyl, N-methylaminomethyl.
  • radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced, irrespective of the particular combinations of radicals indicated, by any definitions of radicals of other combinations.
  • Salts which are preferred in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic,
  • 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, N-methylpiperidine, N-methylglucamine, dimethylglucamine, ethylglucamine, 1.6 Hexadiamine, glucosamine, sarcosine, serinol,
  • alkali metals such as sodium or potassium
  • alkaline earth metals such as
  • 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
  • Examples of such quaternary ammonium ions are tetramethylammonium, tetraethylammonium, tetra (w-propyl) ammonium, tetra (w-butyl) ammonium, 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.
  • compositions containing the compounds of the invention and at least one or more other active ingredients are pharmaceutical compositions containing the compounds of the invention and at least one or more other active ingredients, in particular for the prophylaxis and / or therapy of tumor diseases.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers.
  • Diastereomers or mixtures thereof are present when one or more of the substituents described in formula (I) contains another asymmetric element, for example a chiral carbon atom.
  • the present invention therefore also encompasses enantiomers and diastereomers and their respective mixtures. From such mixtures, the pure enantiomers and diastereomers can be isolated in a known manner; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on chiral or achiral phase.
  • the enantiomers 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 enantiomer is preferred, which is often the 4S enantiomer.
  • 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 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, M S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 1, 124 1, 129 I and 131 I.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • the compounds according to the invention can act systemically and / or 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.
  • Administration forms are administered.
  • Parenteral administration can be done by bypassing a resorption step (e.g.
  • intravenously, intraarterially, intracardially, intraspinally or intralumbarally) or with the involvement of resorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and
  • Infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations,
  • Vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds of the invention can be converted into the mentioned application forms become. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include carriers (for example, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid
  • compositions containing the compounds of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
  • excipients examples include excipients, fillers, disintegrants, binders, humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants,
  • Preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers are used. Reference may be made to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).
  • the pharmaceutical formulations can be any suitable pharmaceutical formulations.
  • auxiliaries for the purposes of the invention may be, for example, salts, saccharides (mono-, di-, tri-, oligo-, and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.
  • the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.
  • the present invention relates to the compounds of the invention.
  • the compounds of the invention can be used for the prophylaxis and treatment of human diseases, in particular tumors.
  • the compounds of the invention can be used in particular to the
  • the compounds of the invention are particularly suitable for the prophylaxis and / or treatment 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.
  • tumors of the male reproductive organs are treatable:
  • 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 Intraocular melanomas
  • 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:
  • AIDS-associated lymphomas Treatable as leukemias for example:
  • the compounds according to the invention can be used for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas,
  • breast cancer in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinoma, pancreatic carcinoma, renal cell carcinoma,
  • 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 / or therapy of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.
  • the compounds according to the invention are also suitable for the prophylaxis and / or 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, before all toxic pulmonary edema; Sarcoidoses and granulomatoses, in particular Boeck's disease Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes: all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms of degenerative joint disease (arthrosis); traumatic arthritis; Collagenosis of any genesis, eg systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Still's syndrome, Felty syndrome
  • Vascular damage vacular damage (vasculature): Panarteritis nodosa, temporal arteritis, erythema nodosum
  • Dermatological disorders associated with inflammatory, allergic and / or proliferative processes atopic dermatitis; Psoriasis; Pityriasis rubra pilaris; erythematous diseases induced by different noxae, e.g.
  • Liver diseases associated with inflammatory, allergic and / or proliferative processes acute liver cell decay; acute hepatitis of different causes, e.g. viral, toxic, drug-induced; 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 and / or proliferative processes: allergic keratitis, uveitis, ulceris; conjunctivitis; blepharitis; Neuritis nervi optici; Chlorioditis; Opthalmia sympathica
  • Neurological diseases associated with inflammatory, allergic and / or proliferative processes brain edema, especially tumor-related cerebral edema; Multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, e.g. BNS cramps
  • Blood disorders associated with inflammatory, allergic and / or proliferative processes acquired hemolytic anemia; idiopathic thrombocytopenia
  • Tumor diseases associated with inflammatory, allergic and / or proliferative processes acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in mammary, bronchial and
  • Severe states of shock e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • Adrenal insufficiency e.g. congenital hypopituitarism
  • acquired secondary adrenal insufficiency e.g. postinfectious, tumors, etc
  • Emesis associated with inflammatory, allergic and / or proliferative processes e.g. in combination with a 5-HT3 antagonist in cytostatic vomiting - pain of inflammatory genesis, e.g. lumbago
  • Diseases such as infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.
  • the compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, periferous vascular diseases, cardiovascular diseases, angina, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.
  • the compounds of the invention are also useful in the treatment of neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. These diseases are well characterized in humans but also exist in others
  • Another object of the present application are the compounds of the invention for use as medicaments, in particular for the prophylaxis and / or therapy of
  • 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 cancers, in particular androgen receptor-positive prostate carcinomas,
  • Hormone receptor-positive or BRCA-associated breast cancers pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal carcinomas.
  • a further subject of the present application are the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • Another object of the invention is the use of the compounds of the invention for the manufacture of a medicament.
  • Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of
  • a further subject of the present application is the use of the compounds according to the invention for the production of a medicament for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular of
  • Hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinomas pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung cancers, endometrial carcinomas and colorectal carcinomas.
  • Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of leukemias, especially acute myeloid leukemias, prostate cancer, especially androgen receptor-positive prostate cancer, breast cancer, in particular estrogen receptor-negative alpha breast carcinomas, melanomas or multiple myelomas.
  • Another object of the present application is the use of the compounds of the invention for the prophylaxis and / or therapy of tumor diseases.
  • the present application further relates to the use of 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, cervical carcinomas, breast cancers, in particular of hormone receptor negative,
  • Hormone receptor-positive or BRCA-associated breast cancers pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal carcinomas.
  • a further subject matter of the present application is the use of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • a further subject of the present application are pharmaceutical formulations in the form of tablets containing one of 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, cervical carcinomas,
  • breast cancer in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinoma, pancreatic carcinoma, renal cell carcinoma,
  • Another object of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of leukemias, especially acute myeloid leukemias, prostate cancer, especially androgen receptor-positive prostate cancer, breast cancer, especially estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • leukemias especially acute myeloid leukemias, prostate cancer, especially androgen receptor-positive prostate cancer, breast cancer, especially estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • Another object of the invention is the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.
  • Another object of the invention is the use of the compounds of the invention for the treatment of benign hyperplasia, inflammatory diseases, autoimmune
  • the compounds according to the invention can be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancers.
  • the combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.
  • Daunorubicin DaunoXome, Decadron, Decadron Phosphate, Decitabine, Degarelix, Delestrogen, Denileukin Diftitox, Depomedrol, Deslorelin, Dexrazoxane, Diethylstilbestrol, Diflucan, 2 ', 2'-Difluorodeoxycytidine, DN-101, Docetaxel, Doxifluridine, Doxorubicin (adriamycin), dronabinol, dSLIM, Dutasteride, DW-166HC, Edotecarin, Efl Ornithine, Eligard, Elitek, Ellence, Emend,
  • Enzalutamide Epirubicin, Epoetin-alfa, Epogen, Epothilone and its derivatives, Eptaplatin, Ergamisol, Erlotinib, Erythro-hydroxynonyladenine, Estrace, Estradiol, Estramustine sodium phosphate,
  • Pazopanib pediapred, pegaspargase, pegasys, pemetrexed, pentostatin, N-phosphonoacetyl-L-aspartate, picibanil, pilocarpine hydrochloride, pirarubicin, plerixafor, plicamycin, PN-401, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, Procarbitol, Procrit, QS-21, Quazepam, R-1589, Raloxifene, Raltitrexed, Ranpirnas, RDEA119, Rebif, Regorafenib, 13-cis Retinoic Acid, Rhenium 186 Etidronate, Rituximab, Roferon A, Romidepsin, Romurtide, Ruxolitinib, Salagen, Salinomycin, Sandostatin, Sargramostim, Satraplatin, Semaxatinib, Se
  • the compounds of the invention may also be treated with biological therapeutics such as antibodies (eg, aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, ofatumumab, panitumumab, pertuzumab, rituximab, tositumumab, trastuzumab ) and recombinant proteins.
  • biological therapeutics such as antibodies (eg, aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, of
  • the compounds of the invention may also be used in combination with others, against the
  • Angiogenesis-targeted therapies such as bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib or thalidomide. Combinations with antihormones and steroidal metabolic enzyme inhibitors are because of their favorable
  • the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention. Preparation of the compounds of the invention
  • R 1 , R 2 , R 3 , R 4 and R 5 and n and m here have the meanings given under the general formula I.
  • the execution of the reaction sequence a) and b) for ring closure of the pyrrole is a sequence known to the skilled person (II Farmaco, Ediette Scientifica (1984), 39, p 538ff, Tarzia et al.).
  • LG is to be understood as a leaving group, which, as described here, for example, a halogen or a boronic acid may be.
  • 4-aminopyrazolo-benzophenones can be prepared according to a reaction sequence shown in Scheme 2.
  • R 1 , R 2 , R 3 , R 4 and R 5 and n and m here have the meanings given under the general formula I.
  • R 2 is halogen, K 2 C0 3 , DMF;
  • ArR R 4 R 5 , AlCl 3 ;
  • Fe Fe, NH 4 Cl, water, EtOH
  • alkyl halides or alkyl sulfates in step a) alkyl substituents R 2 according to general formula (I) can be introduced by methods known to those skilled in the art.
  • acyl halides or acyl anhydrides or aryl and alkylsulfonyl chlorides By reaction with acyl halides or acyl anhydrides or aryl and alkylsulfonyl chlorides, acyl or aryl or alkylsulfonyl substituents can be introduced as R 2 according to general formula (I) by methods known to the person skilled in the art.
  • Aryl and heteroaryl radicals as R 2 can be converted by reaction with the corresponding aryl or heteroaryl halides and a transition metal catalyst of palladium or copper (J. Am. Chem. Soc.
  • LG is to be understood as a leaving group, which, as described here, for example, a halogen or a boronic acid may be.
  • step a) The pyrazoles Pyr A and Pyr B generated in Scheme 2, step a) are separated according to
  • R 1 , R 2 , R 3 , R 4 and R 5 and n and m have the meanings given under the general formula I.
  • R 1 , R 2 , R 3 , R 4 , R 5 and X and n and m have the meanings given under the general formula I.
  • the circle means a presence of possible double bond isomers in the case of X is nitrogen, as shown here:
  • a strong acid such as trifluoroacetic acid or hydrochloric acid is used.
  • R 1 , R 2 , R 3 , R 4 , R 5 and X and n and m have the meanings given under the general formula I.
  • the circle means a presence of possible double bond isomers in the case of X is nitrogen, as shown here:
  • R 1 , R 2 , R 3 , R 4 , R 5 and X and n and m have the meanings given under the general formula I.
  • the circle means a presence of possible double bond isomers in the case of X is nitrogen, as shown here:
  • alkyl groups are methyl, ethyl or longer homologous esters.
  • Reactions can be preferably carried out using alkali hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide in aqueous alcoholic solutions.
  • alkali hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide in aqueous alcoholic solutions.
  • Branched alkyl groups such as tert-butyl esters can preferably be hydrolyzed under acidic conditions.
  • a variety of methods are known to those skilled in the art. By way of example only the use of e.g. HCl in organic solvents or pure or diluted
  • the amides of the general formula (I) according to the invention are thus prepared by reacting the carboxylic acids, for example with the amines generally available commercially, with additional activation by a method which is generally known to the person skilled in the art. As possible methods its here mentioned the use of HATU, HBTU, PyBOB or T3P with addition of a suitable base. Conversion of the carboxylic acids to their amides is generally described in reference books such as Compendium of Organic Synthetic Methods, Volume I-VI (Wiley Interscience) or The Practice of Peptides
  • R 1 , R 2 , R 3 , R 4 , R 5 and X and n and m have the meanings given under the general formula I.
  • the circle means a presence of possible double bond isomers in the case of X is nitrogen, as shown here:
  • alkylmagnesium or alkyllithium reagents are generally known to the person skilled in the art and can be carried out starting from corresponding alkyl halides such as iodides, bromides or chlorides with, for example, the elemental metal, eg magnesium or lithium, or else by reaction with a correspondingly reactive magnesium or lithium Alkyl reagent such as di-iso-propylmagnesium or butyllithium.
  • NMR signals are given with their respective recognizable multiplicity or their combinations.
  • S singlet
  • d doublet
  • t triplet
  • q quartet
  • qi quintet
  • m multiplet
  • b broad signal.
  • the mother liquor which contained still further product, was purified by chromatography on silica gel, whereby an additional 3.2 g of the desired ieri-butyl- Ar - [4- (4-chlorobenzoyl) -l, 5-dimethyl-1/1-pyrrole-3 -yl] carbamate.
  • the mixture was then stirred at 120 ° C. for 2 h and then at 25 ° C. for 16 h.
  • the reaction mixture was diluted with 250 ml of ethyl acetate and extracted with 150 ml of water. After phase separation, the aqueous phase was extracted three times with 150 ml of ethyl acetate.
  • the combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo.
  • the crude product thus obtained was purified by chromatography on silica gel (hexane / ethyl acetate gradient). This gave 14.7 g of (4-chlorophenyl) (1-methyl-4-nitro-1H-pyrazol-3-yl) ketone.
  • the compounds mentioned in the preceding examples represent valuable selected intermediate compounds (intermediates) which are preferably used in the preparation of the compounds according to the invention.
  • the present invention thus also relates to intermediate compounds of the general formulas Ia and Ib
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, n and m are the meanings given in the general formula I and R 10 in the general formula Ib is hydrogen, and their sodium, potassium , Lithium or cesium salts.
  • the present invention particularly relates to the following intermediates
  • reaction mixture was diluted with ethyl acetate and the organic phase was washed with water.
  • the aqueous phase was extracted after phase separation twice with 25 ml of ethyl acetate.
  • the combined organic phases were washed once with saturated
  • Nortropinone hydrochloride (CAS 25602-68-0) in 0.97 ml of DMF was stirred at RT overnight. Of the The mixture was added to saturated sodium chloride solution / water, extracted three times with dichloromethane, washed twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by chromatography on silica gel (dichloromethane / methanol gradient).
  • the resulting crude product was purified by RP-HPLC chromatography (XBridge C18 5 ⁇ 100x30 mm, eluent water / acetonitrile gradient, 0.1% formic acid as an additive, flow rate: 50 ml / min).
  • the obtained substance was dissolved in dichloromethane and extracted with sodium hydrogen sulfate solution and saturated sodium chloride solution. The solution was dried with sodium sulfate and concentrated in vacuo. 23 mg of (-) - 2 - [(4) -6- (4-chloro) -yl, 7,8-trimethyl-4,8-dihydropyrrolo [3,4- [l, 2,4] were obtained.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the Ac-H4 peptide may be derived from e.g. Biosyntan (Berlin, Germany).
  • Microtiter plate (Greiner Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany). The assay was started by adding 2 ⁇ of a 2.5-fold concentrated BRD4 solution (usually 10 nM final concentration in the 5 ⁇ of the reaction volume) in aqueous assay buffer [50 mM HEPES pH 7.5, 50 mM
  • Fluorescence emission at 620 nm and 665 nm after excitation at 330-350 nm in a TR-FRET meter e.g. a Rubystar or Pherastar (both from BMG Lab Technologies, Offenburg,
  • Readings of a set of controls typically 32 data points containing all reagents. Instead of test substances, 50 ⁇ l of DMSO (100%) were used. 100% inhibition was the mean of the measurements from a set of controls (typically 32 data points) containing all reagents except BRD4.
  • the ability of the substances to inhibit cell proliferation was determined.
  • Cell viability was determined using the alamarBlue® reagent (Invitrogen) in a Victor X3 Multilabel Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelength was 590 nM.
  • MOLM-13 cells (DSMZ, ACC 554) were added to a concentration of 4000 cells
  • ⁇ growth medium (RPMI1640, 10% FCS) seeded on 96 well microtiter plates.
  • the B 16F10 cells (ATCC, CRL-6475) were seeded to 96-500 microtiter plates at a concentration of 300-500 cells / well in ⁇ growth medium (DMEM with phenol red, 10% FCS).
  • the MOLP-8 cells (DSMZ, ACC 569) were seeded to a concentration of 4000 cells / well in ⁇ growth medium (RPMI1640, 20% FCS) on 96 well microtiter plates.
  • the LAPC-4 cells (ATCC, PTA-1441 TM) were seeded to a concentration of 4000 cells of AVELL in ⁇ growth medium (RPMI1640, 2mM L-glutamine, 10% cFCS) on 96 well microtiter plates. One day later, the LAPC-4 cells were treated with 1 nM methyltrienolone and various drug dilutions.
  • the MDA-MB-231 cells (DSMZ, ACC 732) were secreted to a concentration of 4000 cells seeded in ⁇ growth medium (DMEM / Ham's F12 medium, 10% FCS) on 96 well microtiter plates.
  • the fluorescence values were determined (Cl values).
  • the plates were then treated with various dilutions of the substance (1E-5M, 3E-6M, 1E-6M, 3E-7M, 1E-7M, 3E-8M, 1E-8M) and 96 (MOLM-13 , B16F10, MDA-MB-431 cells), 120 (MOLP-8 cells) or 168 (LAPC-4 cells) for hours at 37 ° C.
  • the fluorescence values were determined (CO values).
  • the Cl values were subtracted from the CO values and the results compared between cells that were different
  • MOLM-13 DSMZ Acute myeloid leukemia
  • Table 2 shows the results from the BRD4 (BDI) binding assay.
  • the table shows the results from various cell proliferation assays.
  • HBM human liver microsomes
  • the incubations were carried out with 2.4 ml HLM solution (0.5 mg / ml protein content), 30 ⁇ of the
  • Test compound final concentration 1 ⁇
  • Samples are taken at 6 times (2 to 60 minutes), precipitated with the same volume of methanol, and the recovery of the test substances used in the supernatant is determined by means of LC-MS / MS analysis. From the resulting half-life of the substance degradation, the so-called intrinsic clearance of the substance was calculated in the liver microsome approach. With the help of various physiological parameters according to the well-stirred model, a (metabolic) in vivo clearance with respect to phase I reactions was predicted.

Abstract

L'invention concerne des pyrrolo-diazépines et des pyrazolo-diazépines à substitution bicyclo et spiro inhibant les protéines BET et inhibant en particulier BRD2, BRD3 et BRD4, lesdits composés étant représentés par la formule générale I dans laquelle X, Y, n, m, R1, R2, R3, R4 et R5 sont tels que décrits dans la description. Cette invention concerne en outre des produits intermédiaires pour générer lesdits composés ainsi que leur utilisation prophylactique et thérapeutique dans le cas de maladies hyperprolifératives, en particulier en cas de maladies tumorales. Cette invention concerne en outre l'utilisation desdits composés en tant qu'inhibiteurs de protéines BET dans des hyperplasies bénignes, maladies athérosclérotiques, septicémies, maladies auto-immunes, angiopathies, infections virales, maladies neurodégénératives, maladies inflammatoires et pour influer sur la fertilité masculine.
EP14704595.9A 2013-02-22 2014-02-17 Pyrrolo-triazolodiazépines et pyrazolo-triazolodiazépines utilisées en tant qu'inhibiteurs de protéines bet pour traiter des maladies hyperprolifératives Withdrawn EP2958922A1 (fr)

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Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101857599B1 (ko) 2010-05-14 2018-05-14 다나-파버 캔서 인스티튜트 인크. 종양형성, 염증성 질환 및 다른 장애를 치료하기 위한 조성물 및 방법
WO2011143660A2 (fr) 2010-05-14 2011-11-17 Dana-Farber Cancer Institute, Inc. Compositions et méthodes de traitement de la leucémie
WO2014080291A2 (fr) 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Dérivés biaryle servant d'inhibiteurs de bromodomaines
US9073878B2 (en) 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
JP2016507496A (ja) 2012-12-21 2016-03-10 ゼニス・エピジェネティクス・コーポレイションＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｃｏｒｐ． ブロモドメイン阻害剤としての新規複素環式化合物
HUE049469T2 (hu) 2013-06-21 2020-09-28 Zenith Epigenetics Ltd Új biciklusos bromodomén inhibitorok
EP3010918B1 (fr) 2013-06-21 2018-08-15 Zenith Epigenetics Ltd. Nouveaux composés bicycliques substitués utilisés comme inhibiteurs de bromodomaines
KR20160038008A (ko) 2013-07-31 2016-04-06 제니쓰 에피제네틱스 코포레이션 브로모도메인 억제제로서 신규 퀴나졸리논
US11446309B2 (en) 2013-11-08 2022-09-20 Dana-Farber Cancer Institute, Inc. Combination therapy for cancer using bromodomain and extra-terminal (BET) protein inhibitors
US10925881B2 (en) 2014-02-28 2021-02-23 Tensha Therapeutics, Inc. Treatment of conditions associated with hyperinsulinaemia
CA3000633C (fr) 2014-10-14 2023-10-03 The Regents Of The University Of California Utilisation d'inhibiteurs de cdk9 et d'inhibiteurs de brd4 pour inhiber une inflammation
AU2015339511B2 (en) 2014-10-27 2020-05-14 Tensha Therapeutics, Inc. Bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
CA2966303A1 (fr) 2014-12-01 2016-06-09 Zenith Epigenetics Ltd. Pyridines substituees comme inhibiteurs de bromodomaine
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
JP2017538721A (ja) 2014-12-17 2017-12-28 ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． ブロモドメインの阻害剤
GB201504694D0 (en) 2015-03-19 2015-05-06 Glaxosmithkline Ip Dev Ltd Covalent conjugates
WO2017059319A2 (fr) * 2015-10-02 2017-04-06 Dana-Farber Cancer Institute, Inc. Polythérapie par inhibiteurs de bromodomaine et blocage de point de contrôle
CN107629057B (zh) * 2016-07-19 2020-03-27 上海勋和医药科技有限公司 Bet蛋白抑制剂及其应用
CN107216332B (zh) * 2017-06-29 2019-04-30 上海药明康德新药开发有限公司 叔丁基-7-羟甲基-7,8-二氢4h吡唑并二氮杂卓5(6h)甲酸基酯的合成方法
CN107879989B (zh) * 2017-11-29 2020-01-03 重庆市中药研究院 具有生物活性的3,4,5-取代苯并二氮卓2-酮类药物分子及其制备方法
CN107759607B (zh) * 2017-11-29 2019-08-23 上海万巷制药有限公司 具有抗肿瘤活性的三氮唑并二氮卓化合物及其制备方法
WO2020206608A1 (fr) * 2019-04-09 2020-10-15 Ranok Therapeutics (Hangzhou) Co., Ltd. Procédés et compositions pour la dégradation ciblée de protéines

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3657271A (en) 1970-06-22 1972-04-18 Abbott Lab 1 3-dimethyl-5-methylamino-8-phenylpyrazolo(4 3-e)(1 4)diazepine
US4508730A (en) 1982-09-08 1985-04-02 Gruppo Lepetit S.P.A. 1,7-Dihydro-pyrrolo[3,4-e][1,4]diazepin-2(3H)-one derivatives a process for preparing them and their use as anticonvulsant and anti-anxiety agents
DE3435973A1 (de) 1984-10-01 1986-04-10 Boehringer Ingelheim KG, 6507 Ingelheim Diazepine enthaltende pharmazeutische zusammensetzungen mit paf-antagonistischer wirkung
EP0703222A1 (fr) 1993-05-13 1996-03-27 Yoshitomi Pharmaceutical Industries, Ltd. Compose de 3-aminoazepine et son utilisation pharmaceutique
US5891871A (en) 1996-03-21 1999-04-06 Cocensys, Inc. Substituted 2,3-benzodiazepin-4-ones and the use thereof
GB0425196D0 (en) 2004-11-15 2004-12-15 Black James Foundation Gastrin and cholecystokinin receptor ligands
EP2239264A4 (fr) * 2007-12-28 2012-01-11 Mitsubishi Tanabe Pharma Corp Agent antitumoral
GB0919432D0 (en) 2009-11-05 2009-12-23 Glaxosmithkline Llc Use
KR101857599B1 (ko) * 2010-05-14 2018-05-14 다나-파버 캔서 인스티튜트 인크. 종양형성, 염증성 질환 및 다른 장애를 치료하기 위한 조성물 및 방법
EP2585465B1 (fr) * 2010-06-22 2014-11-12 GlaxoSmithKline LLC Composés de benzotriazolodiazépine inhibiteurs de bromodomaines
AR084070A1 (es) 2010-12-02 2013-04-17 Constellation Pharmaceuticals Inc Inhibidores del bromodominio y usos de los mismos
WO2012075456A1 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals Inhibiteurs de bromodomaines et leurs utilisations
EP2838881B1 (fr) 2012-04-20 2018-08-08 AbbVie Inc. Dérivés d'iso-indolone
TWI602820B (zh) 2012-06-06 2017-10-21 星宿藥物公司 溴域抑制劑及其用途
EP2864336B1 (fr) 2012-06-06 2016-11-23 Constellation Pharmaceuticals, Inc. Inhibiteurs de bromo-domaine de benzo[b]isoxazoloazépines et applications associées
BR112014031068A2 (pt) 2012-06-12 2017-06-27 Abbvie Inc derivados piridinona e piridazinona
CA2901805A1 (fr) * 2013-02-22 2014-08-28 Bayer Pharma Aktiengesellschaft Pyrrolo-diazepines et pyrazolo-diazepines substituees en position 4

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2014128070A1 *

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