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WO2017063959A1 - Dérivés de la benzodiazépine n-sulfoximinophényl-substitués utilisés comme inhibiteurs de protéines bet - Google Patents

Dérivés de la benzodiazépine n-sulfoximinophényl-substitués utilisés comme inhibiteurs de protéines bet Download PDF

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Publication number
WO2017063959A1
WO2017063959A1 PCT/EP2016/074095 EP2016074095W WO2017063959A1 WO 2017063959 A1 WO2017063959 A1 WO 2017063959A1 EP 2016074095 W EP2016074095 W EP 2016074095W WO 2017063959 A1 WO2017063959 A1 WO 2017063959A1
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Prior art keywords
alkyl
alkoxy
unsubstituted
ring atoms
phenyl
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English (en)
Inventor
Stephan Siegel
Bernard Haendler
Antonius Ter Laak
Amaury Ernesto FERNANDEZ-MONTALVAN
Detlef STÖCKIGT
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Bayer Pharma AG
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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

Definitions

  • the present invention relates to bromodomain protein-inhibiting, in particular BET protein-inhibiting and preferably BRD4-inhibitory N-sulfoximinophenyl-substituted benzodiazepine derivatives, pharmaceutical compositions containing the compounds of the invention and their prophylactic and therapeutic use in hyperproliferative
  • this invention relates to the use of BET protein inhibitors in viral infections, in HIV-associated kidney diseases, in neurodegenerative diseases, in fibroses, in inflammatory diseases, in atherosclerotic erotic diseases, in heart failure, in muscular dystrophies, such as in fazioskapulohumeral muscular dystrophy , and male fertility control.
  • the bromodomain protein belonging to the bromodomain protein family has four members (BRD2, BRD3, BRD4 and HR DT), the two related bromodomains ([BRD4 (1)] and [BRD4 (2) ] and an extra-terminal domain (Gallenkamp et al., Chem. Med. Chem., 2014, 9: 438-464; Filippakopoulos and Knapp, Nature Reviews, 2014, 13: 337-356; Haendler et al, Epigenomics, 2015 , 7: 487-501).
  • the bromodomains are protein regions that recognize acetylated lysine residues.
  • acetylated lysines are often found at the N-terminal end of histones (eg, histone H3 or histone H4) and are features of open chromatin structure and active gene transcription (Kuo and Allis, Bioessays, 1998, 20: 615). 626).
  • histones eg, histone H3 or histone H4
  • the various acylation 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, doi / 10.1074 / jbc.Ml 12.359505).
  • the extra-terminal domain of BRD2, BRD3 and BRD4 interacts with several proteins that have a role in chromatin modulation and regulation of gene expression (Rahman et al., Mol. Cell Biol., 2011, 31: 2641-2652).
  • BET proteins play an important role in cell growth and cell cycle. Biol. Cell, 2009, 20: 4899-4909; Yang et al., Mol. Cell. Biol., 2008, 28: 967-976). BRD4 is important for the post-mitotic reactivation of gene transcription (Zhao et al., Nat Cell Biol., 2011, 13: 1295-1304). It has been shown that BRD4 is essential for the transcription elongation and recruitment of the elongation complex P-TEFb CDK9 and cyclin Tl exists, resulting in the activation of RNA polymerase! I (Yang et al., Mol. Cell, 2005, 19: 535-545; Schröder et al., J. Biol.
  • RNA polymerase 11 Chromatin amplify and promote transcription by RNA polymerase 11 (LeRoy et al., Mol. Cell, 2008, 30: 51-60).
  • BRD4 binds to promoter regions of several genes activated in the Gl phase, such as cyclin D 1 and D2 (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040-9048).
  • c-Myc expression an essential factor in cell proliferation, following BRD4 inhibition has been demonstrated (Dawson et al., Nature, 201 1, 478: 529-533; Delmore et al., Cell, 201 1, 146: 1-14; Mertz et al., Proc, Natl. Acad. Sci. USA, 2011, 108: 16669-16674).
  • BRD2 and BRD4 knockout mice die prematurely during embryogenesis (Gyuris et al., Biochim Biophys Acta, 2009, 1789: 413-421, Houzelstein et al., Mol. Cell Biol., 2002, 22: 3794-3802 ).
  • Heterozygous BRD4 mice have various growth defects attributable to reduced cell proliferation (Houzelstein et al., Mol. Cell. Biol., 2002, 22: 3794-3802).
  • BRDT has an essential function in spermatogenesis (Berkovits and Wolgemuth, Curr., Top. Dev. Biol., 2013, 102: 293-326).
  • BET proteins play an important role in various types of tumors.
  • the fusion between the BET proteins BRD3 or BRD4 and NUT a protein normally only expressed in the testes, results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet., Cytogenet, 2010, 203: 16- 20).
  • the fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 201 1, 286: 27663-27675).
  • the growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073).
  • BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, doi: 10.1038). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo. Amplification of the DNA region containing the BRD4 gene was detected in primary breast tumors (Kadota et al., Cancer Res, 2009, 69: 7357-7365). Also for BRD2 there is data related to a role in tumors.
  • a transgenic mouse BRD2 selective in B cells highly express B-cell lymphomas and leukemias (Greenwall et al., Blood, 2005, 103: 1475-1484).
  • BET inhibitors used in various preclinical in vitro and in vivo tumor models suggest an essential role of BET proteins, especially BRD4, in hematological tumors such as AML, multiple myeloma, and lymphomas (Delmore et al., Cell, 201 1, 146: 904-91; Zuber et al., Nature, 2011, 478: 524-528; Merz et al., Proc, Natl.
  • prostate cancer Asangani et al., Nature, 2014, 510: 278-282
  • breast cancer Nagarajan et al., Cell Reports, 2014, 8: 460-469, Shi et al. , Cancer Cell, 2014, 25: 210-225
  • ovarian cancer Baratta et al., Proc. Natl. Acad. Sei., 2015, 1 12: 232-237
  • liver cancer Zhang et al., Int. J. Immunopathol. Pharmacol., 2015, 28: 36-44
  • lung cancer Shiamura et al., Clin.
  • 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, 30: 1374-1394).
  • the herpesvirus responsible for the Kapos i sarcoma interacts with various BET proteins, what for the
  • BRD4 By binding to P-TEFb, BRD4 also plays an important role in H IV replication (Bisgrove et al., Proc Natl Acad., USA, 2007, 104: 13690-13595). A role of BRD4 in the control of the latency of H IV proviruses has also been demonstrated (Boehm et al., Cell Cycle, 2013, 1 2: 452-462). Human T-cell leukemia virus 1 (HTLV-1) is also controlled by BRD4 via the NF- ⁇ B pathway (Wu et al., J. Biol.
  • BET proteins are also involved in inflammatory processes.
  • BRD2 hypomorphic mice show reduced infiltration 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 infiltration.
  • Macrophages prevent a BRD4 inhibitor expression of inflammatory genes, such as for example, IL-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1179-1123).
  • BET proteins are also involved in the pathogenesis of fibrosis.
  • the inhibition of BET leads to reduced migration and proliferation of pulmonary fibroblasts obtained from patients suffering from idiopathic pulmonary fibrosis.
  • Reduction in fibrosis has also been demonstrated in a bleomycin-induced lung fibrosis mouse model after treatment with a BET inhibitor (Tang et al., Mol. Pharmacol., 2013, 83: 283-293; Tang et al., Am Pathol., 2013, 183: 470-479).
  • Apolipoprotein AI (ApoAl) is a major component of high density
  • HDL Lipoproteins
  • ApoAl Lipoproteins
  • Elevated HDL levels are associated with a decreased risk of atherosclerosis (Chapman et al., Eur. Heart J. 201 1, 32: 1 345-1361).
  • Increased expression of BRD4 was observed during cardiac hypertrophy and attributed to the regulation of atrial natriuretic factor expression (Spiltoir et al., J. Mol. Cell. Cardiol., 2013, 63: 175-179). Accordingly, BRD4 could also play an important role in heart failure.
  • BET proteins play an essential role in various pathologies and also in male fertility. It is therefore desirable to find potent and selective inhibitors which prevent the interaction between the BET proteins, for example BRD2, BRD3, BRD4 and BRDT, and acetylated proteins, especially acetylated histone H4 peptides.
  • BRD2, BRD3, BRD4 and BRDT acetylated proteins, especially acetylated histone H4 peptides.
  • 1-Aryl-4,5-dihydro-3-2,3-benzodiazepines have long been known, inter alia, as modulators or antagonists of excitatory amino acid receptors, for example the AMPA receptor, and are among others as potential therapeutics for diseases described central nervous origin.
  • WO 2001/098280 discloses 1-phenyl-4,5-dihydro-3: 2-2,3-benzodiazepines as antagonists of the non-NMDA ionotropic excitatory amino acid (EAA) receptor.
  • EAA excitatory amino acid
  • EP 0 492 485, US 5,519,019, US 5,536,832, US 5,639,751 and US 5,459,137 disclose N-acyl-2,3-benzodiazepines as excitatory amino acid receptor antagonists derived from the compounds of the present invention, inter alia, by U.S. Patent Nos. 4,640,731; distinguish obligate methylenedioxy group at C-7 and C-8 of the B enzodiazepine scaffold.
  • the compounds according to the invention furthermore differ, inter alia, by the substitution on the phenyl ring linked to Cl of the benzodiazepine skeleton by other known 2,3-benzodiazepines, such as the numerous published AMPA antagonists (see, for example, WO 1997/28135 (Schering AG), EP 0802195, US 5,807,851, HU 0097000688, WO 2002/050044 and WO 2007/077469 (Egis Gyogyszergyar)), as well as antagonists of the MT2 receptors and inhibitors of the adenosine transporter (WO 2008/124075, Teva Pharmaceuticals).
  • AMPA antagonists see, for example, WO 1997/28135 (Schering AG), EP 0802195, US 5,807,851, HU 0097000688, WO 2002/050044 and WO 2007/077469 (Egis Gyogyszergyar)
  • WO 1997/034878 and US 5,891,871 disclose 3,5-dihydro-4H-2,3-benzodiazepin-4-ones derived from the compounds of the present invention inter alia by the oxo substitution at C 4 of the benzodiazepine scaffold, as antagonists or positive modulators of the AMPA receptor.
  • Ligands of the gastrin and the cholecystokinin receptor are described in WO2006 / 051312 (James Black Foundation). They also include substituted 3,5-dihydro-4 // - 2,3-bcnzodiazcpin-4-ones, which of the novel compounds, inter alia, by the obligatory oxo group in position 4 and by a mandatory, containing a carbonyl group
  • WO 2008/121877 discloses cyclic and acyclic hydrazone derivatives as inhibitors of the functional transmembrane conductance regulatory polypeptide in cystic fibrosis (CFTR), inter alia, for the treatment of diarrhea and polycystic kidney disease (PKD).
  • CFTR cystic fibrosis
  • PPD polycystic kidney disease
  • B enzo diazep in derivatives are not disclosed by way of example.
  • WO 2014/026997 discloses 1-phenyl- and 1-heteroaryl-4,5-dihydro-3 / 7- 2,3-benzodiazepines as inhibitors of BET proteins, in particular of BRD4, inter alia for the treatment of hyperproliferative diseases.
  • the compounds of the present invention differ by substitution on the phenyl or heteroaryl ring attached to C-1 of the benzodiazepine skeleton.
  • the compounds according to the invention inhibit the interaction between BET proteins, in particular BRD4, and an acetylated histone H4 peptide.
  • BET proteins in particular BRD4
  • an acetylated histone H4 peptide In particular, they inhibit the growth of cancer or tumor cells and can also be used in viral infections, in HIV-associated neon diseases, in neurodegenerative diseases
  • R is G-C3-alkyl, trifluoromethyl or C3-Ct-cycloalkyl-, R is cyclopropyl, G-C3-alkyl, Ci-C3-alkoxy, amino, cyclopropylamino or
  • R 4 and W are independent of each other
  • C3-C10-o-cycloalkyl- or C4-C10-cycloalkenyl- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, carboxy, G-C6- Alkyl, G-C6-alkoxy,
  • phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, halogen, amino, hydroxy, cyano, nitro, carboxy, G-Ce-alkyl, G-Ce-alkoxy-, C 1-Ce-alkoxy-C 1 -Ce-alkyl,
  • C 1 -C 6 -alkylaminosulfonyl C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl-, Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkoxy,
  • Halogen-C i -Ce-alkyl, halo-C i -C, alkoxy, C i -C e -alkylsulfonyl, Cs-Cio-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms are independently
  • C 1 -C 6 -alkyl which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl, C 3 -C 8 -cycloalkyl, or by monocyclic heterocyclyl- with 4 up to 8 ring atoms,
  • phenyl in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl-, C 1 -C 4 -alkoxy, halogeno-C 1 -C 4 -alkyl or halogeno-C 1 -C 4 -alkoxy-, and
  • monocyclic heterocyclyl having 4 to 8 ring atoms in addition to the mentioned sulfur atom may contain one or two further heteroatoms and which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, G-C3-alkyl, fluoro-C 1 -C 3 -alkyl-, C 3 -C 6 -cycloalkyl-, cyclopropylmethyl-, C 1 -C 3 -alkylcarbonyl- or C 1 -C 4 -alkoxycarbonyl-, independently of one another for hydrogen or for unsubstituted or once or twice, identical or different with hydroxy, oxo or G -C3 Alkoxy-substituted C 1 -C 3 -alkyl-, or fluoro-C 1 -C 3 -alkyl- stand, or
  • Inhibitors for a variety of prophylactic and therapeutic uses are suitable in hyperproliferative diseases, especially in cancer or
  • Tumor diseases as well as in viral infections, in HIV-associated kidney diseases, in neurodegenerative diseases, in fibroses, in inflammatory diseases, in atherosclerotic erotic diseases, in heart failure, in muscular dystrophies, such as in fazioskapulohumeral muscular dystrophy, and in male fertility control.
  • Preference is given to those compounds of the general formula (I) in which, for a group, e
  • R 2 is methyl
  • R 3 is cyclopropyl, Ci-C3-alkyl, cyclopropylamino or
  • R 4 and R 5 are independently
  • C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulphonyl which are unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, amino, hydroxy, carboxy, C 1 -C 3 alkyl, hydroxy-C 3 alkyl, Ci-C 3 alkoxy, C i -C 3 alkoxy-C i -C 3 alkyl, C i -C 3 alkylamino , Amino-C i -C 3 -alkyl-,
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, carboxy, C 1 -C 3 -alkyl-, C 3 -alkoxy, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl-,
  • Fluoro-C i -C 3 alkoxy or C i -C 3 alkylsulfonyl- stand independently of one another
  • phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkyl or fluoro-C 1 -C 3 -alkoxy,
  • Ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C 3 alkyl or Ci-C4-alkoxycarbonyl, or
  • phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or mono- or disubstituted by identical or different substituents with halogen, cyano, Ci-C 3 alkyl, GC 3 alkoxy, trifluoromethyl or
  • monocyclic heterocyclyl having 4 to 8 ring atoms, which may contain one or two further heteroatoms in addition to said sulfur atom, and which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl, independently of one another for hydrogen, G-C 3 Alkyl, acetyl, propionyl or fluoro-C 1 -C 3 -alkyl,
  • monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, cyano, C 1 -C 3 -alkyl- , Cs-Ce-cycloalkyl, C 1 -C 3 -alkylcarbonyl- or
  • C 1 -C 4 -alkoxycarbonyl for hydroxy, C 1 -C 3 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 3 -alkyl,
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and W are independent of each other
  • R 8 and R 9 are independently
  • R 8 and R 9 together with the sulfur atom to which they are attached, for
  • monocyclic heterocyclyl having 4 to 7 ring atoms, which in addition to the sulfur atom mentioned may contain a further heteroatom and which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo or methyl,
  • R 10 is hydrogen, methyl or ethyl
  • R 12 is hydroxy, G-C3-alkyl or G-C4-alkoxy
  • R 13 is G-Cs-alkyl-, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their Razemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R 2 is ( ⁇ -configured, and their mixtures of stereoisomers in which predominate those stereoisomers in which the center of asymmetry represented by the carbon atom bound to R (S) - is configured.
  • R 2 is methyl
  • R 3 is C 1 -C 3 -alkylamino
  • R 4 and W independently of one another are C 1 -C 3 -alkoxy
  • R ' is hydrogen or fluorine
  • R 8 and R 9 are independently
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl, methoxy or
  • R- stands for methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R ' is hydrogen
  • R 8 and R 9 are independently
  • R 8 and R 9 together with the sulfur atom to which they are attached, stand for monocyclic heterocyclyl having 5 to 6 ring atoms, which may contain, in addition to the sulfur atom mentioned, another oxygen atom,
  • R 10 is hydrogen
  • R 13 is methyl, as well as their polymorphs, tautomers, solvates, physiologically tolerated salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R is ( ⁇ -configured, and their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetry center (5) represented by the carbon atom bound to R is configured.
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • (4S) -7,8-dimethoxy-N 4-dimethyl-l- ⁇ 4 - [(4-oxido-l, 4- -oxathian 4-4-ylidene) amino] phenyl ⁇ -4,5-dihydro- 3H-2,3-benzodiazepine-3-carboxamide
  • (4S) -7,8-dimethoxy-N 4-dimethyl-1- (4 - ⁇ [(S) - (S) -methyl (oxido) -phenyl-, 6 -sulfanylidene] -amino ⁇ -phenyl) -4, 5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;
  • (4S) -1- (3 - ⁇ [(2-Fluo-phenyl) (methyl) -oxido- ⁇ 6 -sulfanylidene] -amino ⁇ -phenyl) -7,8-dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide;
  • R 1 particularly preferably represents a group
  • R 1 particularly preferably represents a group
  • R 1 particularly preferably represents a group
  • R 1 particularly preferably represents a group
  • R 1 is more preferably a group
  • R is preferably methyl or ethyl.
  • R 3 is preferably cyclopropyl, C 1 -C 8 -alkyl, cyclopropylamino or C 1 -C 3 -alkylamino.
  • R 3 particularly preferably represents C 1 -C 3 -alkylamino.
  • R ' is very particularly preferably methylamino.
  • R 4 and R 5 are each independently preferably
  • G-Ce-alkyl, G-Ce-alkoxy, Ci-Ce-alkylamino, phenylamino, Ci-C6-alkylcarbonylamino, Ci-C6-alkylaminocarbonyl or Ci-Ce-alkylaminosulfonyl, which is unsubstituted are mono-, di- or trisubstituted by the same or different substituents are substituted by halogen, amino, hydroxy, carboxy, GC 3 alkyl, hydroxy Ci-C 3 alkyl, Ci-C 3 alkoxy, C C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino, amino-C 1 -C 3 -alkyl, -C (OO) -NR 10 R ", -C ( 0) -R 12 or monocyclic
  • R 4 and R 5 independently of one another are particularly preferably
  • R is particularly preferably hydrogen, hydroxyl, cyano, fluorine, chlorine or bromine,
  • R 4 is particularly preferably C 1 -C 3 -alkoxy and W is particularly preferably hydrogen, hydroxyl, cyano, fluorine, chlorine or bromine,
  • Ci-Cs-alkoxy, C1-C3-alkylamino or -C ( O) -R 12 .
  • R 5 particularly preferably represents C 1 -C 3 -alkoxy.
  • R 4 and R 5 furthermore, independently of one another, particularly preferably represent C 1 -C 3 -alkyl, C 3 -C 3 -alkoxy or C 1 -C 3 -alkylamino.
  • R 4 and R 5 are independently further particularly preferably represents GC 3 alkoxy.
  • R 4 and R 5 very particularly preferably each represent methoxy.
  • R 6 preferably represents alkyl 3 represents hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or represents C, Ci-C 3 alkoxy, C 1 -C 3 alkoxy-C 1 -C 3 alkyl, fluoro-Ci-C 3 alkyl, fluoro-C 1 -C 3 alkoxy or C 3 alkylsulfonyl.
  • R ' is preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or methyl, methoxy, methoxymethyl, methoxyethyl, difluoromethyl,
  • Trifluoromethyl, trifluoromethoxy or methylsulfonyl Trifluoromethyl, trifluoromethoxy or methylsulfonyl.
  • R is preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or methylsulfonyl.
  • R ' is preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl or methoxy.
  • R 6 particularly preferably represents hydrogen, fluorine or methoxy.
  • R " is more preferably hydrogen or fluorine.
  • R ' is more preferably fluorine.
  • R 6 is very particularly preferably hydrogen.
  • R 8 and R 9 independently of one another are preferably C 1 -C 4 -alkyl, which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy- or phenyl-, in which phenyl itself is unsubstituted is mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl, C 1 -C 6 -alkoxy, fluoro-C 1 -C 3 -alkyl or fluoro-ci C 3 alkoxy,
  • R 8 and R 9 together with the sulfur atom to which they are attached, are monocyclic heterocyclyl- having 4 to 8 ring atoms, which in addition to the abovementioned sulfur atom may contain one or two further heteroatoms and which is unsubstituted or mono- or di-twice, is identical or different substituted with hydroxy, oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl-.
  • R 8 and R ' are, independently of one another, preferably C 1 -C 6
  • Alkyl which is unsubstituted or monosubstituted by cyano, Ci-C3-alkoxy- or phenyl-, wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C 1 C 3 alkyl, C 1 -C 8 alkoxy, fluoro C 1 -C 3 alkyl or fluoro C 1 -C 3 alkoxy,
  • R 8 and R ' are preferably taken together with the sulfur atom to which they are attached, for monocyclic heterocyclyl having 4 to 8 ring atoms, which may contain one or two further heteroatoms in addition to said sulfur atom and unsubstituted is monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl-.
  • R 8 and R 9 together with the sulfur atom to which they are attached are monocyclic heterocyclyl having 4 to 7 ring atoms, which in addition to said sulfur atom may contain another heteroatom and which is unsubstituted or mono- or di-twice, same or is variously substituted with oxo or methyl.
  • R 8 and R 9 are particularly preferably together with the
  • Ring atoms which may contain a further heteroatom in addition to said sulfur atom and which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo or methyl.
  • R 8 and R ' are particularly preferably together with the
  • Ring atoms which in addition to the sulfur atom mentioned may contain another heteroatom and which is unsubstituted or monosubstituted by oxo or methyl.
  • R 8 and R 9 are gememsam with the sulfur atom to which they are attached, for monocyclic Heterocyclyl- with 5 to 6 ring atoms, which may contain in addition to said sulfur atom, another oxygen atom.
  • R 8 and R 9 very particularly preferably together with the sulfur atom to which they are bonded, are monocyclic heterocyclyl of 5 to 6
  • R 10 and R 11 are each independently preferably
  • R 10 and R 11 are taken together with the nitrogen atom to which they are attached, for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, oxo, cyano, C C 1 -C 3 alkyl,
  • R 10 and R 11 are each independently preferably
  • R 10 and R 11 are preferably together with the nitrogen atom to which they are bonded, for monocyclic heterocyclyl having 4 to 8 ring atoms, the is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluoro, oxo, cyano, G-C3-alkyl, G-Ce-cycloalkyl, C i -C3 -alkylcarbonyl or C 1 -IVA-alkoxycarbonyl-.
  • R 10 and R H independently of each other are preferably
  • R ! O is particularly preferably hydrogen, methyl or ethyl.
  • R 10 and R H independently of one another, are particularly preferably hydrogen or methyl.
  • R 10 is particularly preferably hydrogen or methyl.
  • R 10 and R 11 are more preferably hydrogen.
  • R 10 is particularly preferably hydrogen.
  • R 12 is preferably hydroxy, GC 3 alkyl, Ci-Ct-alkoxy, fluoro-Ci-C 3 alkyl, hydroxy-Ci-C 3 alkyl, Ci-C 3 -alkoxy-C 1 -C 3 -alkyl or C 3 -C 7 -cycloalkyl, or for phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or a - or doubly, the same or different, are substituted with halogen, GC 3 -alkoxy or GC 3 -alkyl-.
  • R 12 is preferably hydroxy, GC 3 -alkyl, G-C 4 -alkoxy, fluoro-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl or C 1 - C 3 -alkoxy-C 1 -C 3 -alkyl-.
  • R 12 is preferably C 3 -C 7 -cycloalkyl-
  • R 12 is particularly preferably hydroxy, GC 3 -alkyl or C 1 -C 4 -alkoxy.
  • R 13 is preferably GC 3 alkyl or benzyl.
  • R is particularly preferably C 1 -C 3 -alkyl-.
  • R 13 is very particularly preferably methyl.
  • R 2 is more preferably methyl
  • R 3 is methylamino
  • R 4 is C 1 -C 3 -alkoxy
  • R 5 is C 1 -C 3 -alkoxy.
  • R 2 is methyl
  • R 3 is
  • B enzo diazep in scaffold represented stereocenter preferably either racemic or predominantly or at least 95% in the ( ⁇ configuration, in general formula (I) this is due to the carbon atom of R ' attached to R "
  • B enzodiazepine framework represented stereocenter particularly preferably predominantly or completely in the ( ⁇ configuration.
  • B enzodiazepine framework represented stereocentre most preferably predominantly in the (S) configuration.
  • B enzodiazepine scaffold more preferably represented at least 95% stereocenter in the ( ⁇ configuration.
  • Alkyl represents a linear or branched, saturated, monovalent hydrocarbon radical having generally 1 to 6 (C 1 -C 4 -alkyl), preferably 1 to 4 (C 1 -C 4 -alkyl), and particularly preferably 1 to 3 carbon atoms (G-Cs-alkyl).
  • Particularly preferred is a methyl, ethyl, propyl, isopropyl or feri-butyl radical.
  • 3-en-1-yl or buta-1, 3-dienyl residue Preferred are ethenyl and allyl.
  • Cycloalkyl- stands for a monocyclic, saturated, monovalent hydrocarbon radical with generally 3 to 10 (C 3 -C 10 -cycloalkyl), preferably 3 to 8 carbon atoms
  • Cs-Cs-cycloalkyl or 3 to 6 carbon atoms (Cs-Ce-cycloalkyl).
  • C4-C6-cycloalkenyl, C4-C8-cycloalkenyl, C4-C 1 o-cycloalkenyl, or Cs-Cg-cycloalkenyl- is a monocyclic, mono- or polyunsaturated, non-aromatic, composed exclusively of carbon atoms Ring system with 4 to 6 atoms, 4 to 8 atoms, 4 to 10 atoms, or 5 to 8 atoms to understand. Examples are cyclobutene-1-yl, cyclopentene-1-yl, cyclohexene-2-yl, cyclohexene-1-yl and cycloocta-2,5-dienyl.
  • Phenylalkyl-phenyl-C 1 -C 3 -alkyl- is a group which is composed of an optionally substituted phenyl radical and a C 1 -C 3 -alkyl group, and which via the C 1 -C 3 -alkyl group to the radical of the molecule is bound.
  • the alkyl radical here has the meanings given above under alkyl.
  • benzyl examples which may be mentioned are benzyl, phenethyl, phenylpropyl, benzyl being preferred.
  • Alkoxy- represents a linear or branched, saturated alkyl ether radical of the formula -O-alkyl having generally 1 to 6 (C 1 -C 6 -alkoxy), preferably 1 to 4 (C 1 -C 4 -alkoxy), and particularly preferably 1 to 3 (C 1 -C 3 alkoxy) carbon atoms.
  • Alkoxyalkyl- stands for an alkoxy-substituted alkyl radical, for example C 1 -C 6 -alkoxy-G-Ce-alkyl or C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl.
  • C 1 -Cö-alkoxy-C 1 -Cö-alkyl- means that the alkoxyalkyl group is bonded via the alkyl moiety to the remainder of the molecule.
  • Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to sulfur.
  • Alkylamino stands for an amino radical having one or two (independently selected) alkyl substituents with generally 1 to 6 (C 1 -C 6 -alkylamino), preferably 1 to 3 carbon atoms (C 1 -C 3 -alkylamino).
  • (C 1 -C 3) -alkylamino stands for example for a monoalkylamino radical having 1 to 3 carbon atoms or for a dialkylamino radical having in each case 1 to 3 carbon atoms per
  • Examples include:
  • Phenylamino-phenylamino- stands for a radical Ph-NH- or for a radical Ph-N (C i -C 3 -alkyl) -.
  • Examples include:
  • N-phenylamino N-methyl-N-phenylamino and N-ethyl-N-phenylamino. Preference is given to ⁇ -phenylamino.
  • Preference is given to C 1 -C 3 -alkylsulfonyl, particularly preferably methylsulfonyl and ethylsulfonyl.
  • Methylaminosulfonyl ethylaminosulfonyl, dimethylaminosulfonyl.
  • Heteroatoms are oxygen, nitrogen or sulfur atoms.
  • Monocyclic heteroaryl means a monovalent, monocyclic, aromatic
  • Ring system with at least one heteroatom As heteroatoms, it is possible for stoichi atoms, oxygen atoms, or sulfur atoms to occur.
  • the bond valency may be at any aromatic carbon atom or at a nitrogen atom.
  • a monocyclic heteroaryl group according to the present invention has 5 or 6 ring atoms.
  • heteroaryl radicals having 5 ring atoms include the rings:
  • Heteroaryl radicals having 6 ring atoms include, for example, the rings:
  • Monocyclic heterocyclyl means a saturated or mono- or polyunsaturated but not aromatic monocyclic ring system having at least one heteroatom.
  • Heteroatoms can occur as sto ffatoms, oxygen atoms or sulfur atoms.
  • a monocyclic heterocyclyl ring according to the present invention may have 4 to 8, preferably 4 to 7, more preferably 5 or 6 ring atoms.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 4 ring atoms are: azetidinyl, oxetanyl.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 5 ring atoms are: pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, dioxolanyl, thiazolidinyl,
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl, oxathianyl 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.
  • monocyclic heterocyclyl radicals preference is given to 4 to 7-membered, saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl represents an alkyl radical having at least one halogen substituent.
  • a halo-C 1 -C 6 -alkyl radical is an alkyl radical having 1-6 carbon atoms and at least one
  • Halogen substituents If several halogen substituents are present, they may also be different. Preference is given to fluoro-C 1 -C 6 -acyl and fluoro-C 1 -C 4 -alkyl radicals, particular preference to fluorine-C 1 -C 3 -alkyl radicals.
  • Haloalkoxy stands for an alkoxy radical with at least one halogen substituent.
  • a halo-C 1 -C 6 alkoxy radical is an alkoxy radical having 1-6 carbon atoms and at least one halogen substituent. If several halo substituents are included, they may also be different. Preference is given to fluoro-C 1 -C 6 -alkoxy, fluoro-C 1 -C 4 -alkoxy radicals, particular preference being given to fluoro-C 1 -C 3 -alkoxy radicals.
  • Hydroxyalkyl represents an alkyl radical having at least one hydroxy substituent.
  • a hydroxy-C 1 -C 6 -alkyl radical is an alkyl radical consisting of 1-6 carbon atom and at least one hydroxy substituent. Preference is given to hydroxy-C 1 -C 3 -alkyl radicals, particular preference to hydroxymethyl- and 2-hydroxyethyl-.
  • Aminoalkyl- stands for an alkyl radical having at least one amino substituent.
  • amino-Ci-Ce-alkyl radical is an alkyl radical consisting of 1-6 carbon atoms and at least one amino substituent. Preference is given to amino-C i -C 3 -alkyl radicals, particular preference is given to aminomethyl- and 2-aminoethyl-.
  • 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-.
  • C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl- means that the alkylaminoalkyl group is bonded via the alkyl part to the remainder of the molecule.
  • alkylaminoalkyl are N, N-dimethylaminoethyl, N, N-dimethylaminomethyl, N, N-diethylaminoethyl, N, N-dimethylaminopropyl, N-methylaminoethyl, N-methylaminomethyl.
  • leaving group refers to an atom or group of atoms that is displaced in a chemical reaction as a stable species with entrainment of the bonding electrons.
  • leaving groups are halogen, in particular fluorine, chlorine, bromine or Iodine, (methylsulfonyl) oxy, [(trifluoromethyl) sulfonyl] oxy, [(nonafluorobutyl) sulfonyl] oxy, (phenylsulfonyl) oxy, [(4-methylphenyl) sulfonyl] oxy,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of this invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of
  • Hydrochloric hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds of the invention further include base addition salts of, for example, alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, or ammonium salts derived from ammonia or organic amines containing from 1 to 16 carbon atoms, such as for example, methylamine, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, NM ethylpiperidine, NM ethylglucamine, dimethylglucamine, ethylglucamine, 1 , 6-hexadiamine, glucosamine, sarcosine, serinol,
  • alkali metals such as sodium
  • the compounds according to the invention can form base addition salts with quaternary ammonium ions, which are obtained, for example, by quaternization of corresponding amines with agents such as lower alkyl halides, for example methyl, ethyl, propyl and butyl chlorides, bromides and iodides, dialkyl sulfates such as dimethyl , Diethyl dibutyl and diamyl sulfate, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, or arylalkyl halides such as benzyl bromide or phenethyl bromide. Examples of such quaternary ammonium ions are examples of such quaternary ammonium ions.
  • Tetramethylammonium T etraethylammonium, tetra (.propropyl) ammonium, tetra (n-butyl) ammonium, and benzyltrimethylammonium.
  • Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs can be present either as a single polymorph or as a mixture of several polymorphs in all concentration ranges.
  • compositions containing the compounds of the invention and at least one or more other active ingredients, in particular for
  • Solvent molecules form a complex. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds according to the invention have an asymmetric center on the carbon atom to which R 2 is bonded (C-4). They can therefore be present as pure enantiomers, racemates, but also as diastereomers or mixtures thereof, if one or more of the substituents described in the formula (I) another
  • Asymmetrieelement contains, for example, a dural carbon or sulfur atom.
  • the present invention therefore also encompasses diastereomers and their respective mixtures. From the mixtures mentioned, the pure enantiomers and diastereomers can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on chiral or achiral phase.
  • the stereoisomers according to the invention inhibit the target to different degrees and are active in different ways in the cancer cell lines investigated. The more active stereoisomer is preferred, which is often the one in which the center of asymmetry represented by the carbon atom attached to R is (-configured.
  • Another object of the present invention are stereoisomeric mixtures of (45) - configured compounds of the invention with their (4i?) - isomers, in particular the corresponding racemates, the other diastereomer and Enantiomerengemische in which outweighs the (45) form.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds 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), ⁇ (tritium), "C , !
  • isotopes such as deuterium
  • isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by corresponding isotopic modifications of the respective reagents and / or Starting compounds are used.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • the compounds according to the invention can act systemically and locally.
  • it may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds of the invention can be used in suitable forms.
  • Administration forms are administered.
  • Forms of administration which deliver the compounds according to the invention rapidly and modified, and which may contain the compounds according to the invention in crystalline, amorphized or dissolved form, such as e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed dissolving or insoluble
  • Oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, pellets, powders,
  • Emulsions, suspensions, aerosols or solutions Emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and
  • fusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines i.a.
  • Eye preparations vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, scattering powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • adjuvants include, among others.
  • Carriers e.g., microcrystalline cellulose, lactose, mannitol
  • solvents e.g., liquid polyethylene glycols
  • emulsifiers e.g., emulsifiers and dispersing or wetting agents
  • binders e.g., polyvinylpyrrolidone
  • synthetic and natural polymers e.g., albumin
  • stabilizers e.g.
  • Antioxidants such as ascorbic acid
  • dyes e.g., inorganic pigments such as iron oxides
  • flavor and / or odoriferous agents e.g., ascorbic acid
  • dyes e.g., inorganic pigments such as iron oxides
  • flavor and / or odoriferous agents e.g., ascorbic acid
  • dyes e.g., inorganic pigments such as iron oxides
  • compositions containing the compounds of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
  • excipients for example, vehicles, fillers, disintegrants,
  • Binders fillers, lubricants, adsorbents and diluents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents,
  • auxiliaries may be, for example, salts, saccharides (mono-, di-, tri-, oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils,
  • Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • the present invention relates to the compounds of the invention.
  • the compounds of the invention can be used for the prophylaxis and treatment of human diseases, in particular tumors.
  • the compounds of the invention can be used in particular to the
  • the compounds according to the invention are particularly suitable for the prophylaxis and therapy of hypersoluble diseases such as, for example
  • BPH benign prostatic hyperplasia
  • tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland are treatable Bone and connective tissue and metastases of these tumors.
  • hematological tumors are treatable
  • treatable as breast tumors are:
  • 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:
  • Treatable as tumors of the female reproductive organs for example: endometrial carcinomas
  • tumors of the gastrointestinal tract are treatable:
  • tumors of the urogenital tract are treatable:
  • tumors of the eye are treatable:
  • Intraocular melanomas For example, tumors of the liver are treatable:
  • tumors of the skin are treatable:
  • tumors of the head and neck are treatable:
  • Carcinomas of the midline structures (such as NMC, CA French, Annu Rev. Pathol., 2012, 7: 247-265)
  • sarcomas are treatable:
  • lymphomas are treatable: Non-Hodgkin's lymphoma
  • 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 cancer especially androgen receptor-positive prostate cancer
  • Cervical carcinomas breast cancers, in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinomas, pancreatic carcinomas, neuronal carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal carcinomas.
  • the compounds according to the invention can be used particularly advantageously for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as fibrosis, endometriosis, leiomyoma and benign prostatic hyperplasia.
  • the compounds according to the invention are preferably suitable for the prophylaxis and / or therapy of idiopathic pulmonary fibrosis.
  • the compounds according to the invention are also suitable for the fertility control of the male.
  • the compounds according to the invention are also suitable for the prophylaxis and therapy of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.
  • the compounds according to the invention are also suitable for the prophylaxis and therapy of inflammatory or autoimmune diseases such as, for example:
  • Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of
  • Pulmonary edema especially toxic pulmonary edema
  • Sarcoidoses and granulomatoses especially Boeck's disease
  • Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic or proliferative processes all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic
  • Panarteritis nodosa 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.
  • Kidney diseases associated with inflammatory, allergic and / or proliferative processes nephrotic syndrome; all nephritis
  • proliferative processes regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, e.g.
  • Proctological diseases associated with inflammatory, allergic and / or proliferative processes analgesic; fissures; Hemorrhoids; idiopathic proctitis - eye diseases associated with inflammatory, allergic or proliferative processes: allergic keratitis, uveitis, ulceris; conjunctivitis; blepharitis; Neuritis nervi optici; Chlorioditis; Opthalmia sympathica
  • Neurological diseases associated with inflammatory, allergic or proliferative processes brain edema, especially tumor-related brain edema; Multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, e.g. BNS-seizures
  • Tumor diseases associated with inflammatory, allergic and / or proliferative processes acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in mammary, bronchial and prostate carcinoma
  • the compounds according to the invention are also suitable for the treatment of viral
  • the compounds according to the invention are also suitable for the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, peripheral vascular diseases, cardiovascular diseases, angina, pectoris, ischaemia, stroke, cardiac insufficiency, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity,
  • the compounds according to the invention are also suitable for the treatment of
  • Muscular dystrophies such as fazioskapulohumeral muscular dystrophy.
  • the compounds according to the invention are also suitable for the treatment of
  • neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease.
  • Another object of the present invention are the compounds of the invention for use as medicaments, in particular for the prophylaxis and / or therapy of
  • the present invention furthermore relates to the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and acute T cell leukemias, B cell lymphomas, for example diffuse large B cell lymphomas, multiple myelomas, prostate carcinomas , especially androgen receptor-positive prostate carcinomas, renal cell carcinomas, melanomas and other skin tumors,
  • leukemias in particular acute myeloid leukemias and acute T cell leukemias
  • B cell lymphomas for example diffuse large B cell lymphomas, multiple myelomas, prostate carcinomas , especially androgen receptor-positive prostate carcinomas, renal cell carcinomas, melanomas and other skin tumors,
  • Lung carcinomas for example non-small cell lung carcinomas, colon carcinomas, for example colorectal carcinomas, carcinomas, uterine carcinomas, Squamous cell carcinoma, ovarian adenocarcinoma, rhabdomyosarcoma and choriocarcinoma.
  • the present invention furthermore relates to the compounds according to the invention for the prophylaxis and / or therapy of acute myeloid leukemias, T cell leukemias, diffuse large B cell lymphomas, multiple myelomas, androgen receptor-positive prostate carcinomas, melanomas, squamous cell carcinomas and rhabdomyosarcomas.
  • 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 invention is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases.
  • Another object of the present invention 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 and acute T-cell leukemias, B-cell lymphomas, such as diffuse large B-cell Lymphomas, multiple myelomas, prostate cancers, especially androgen receptor-positive prostate cancers,
  • Renal cell carcinoma, melanoma and other skin tumors lung carcinoma, for example non-small cell lung carcinoma, colon carcinoma, for example colorectal
  • Ovarian adenocarcinomas, rhabdomyosarcomas and choriocarcinomas Another object of the present invention is the use of the compounds according to the invention for the manufacture of a medicament for the prophylaxis and / or treatment of acute myeloid leukemias, T cell leukemias, diffuse large B cell lymphomas, multiple myelomas, androgen receptor positive prostate carcinomas, melanomas .
  • Another object of the present invention is the use of the compounds of the invention for the prophylaxis and / or therapy of tumor diseases.
  • Another object of the present invention is the use of the compounds of the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and acute T cell leukemias, B cell lymphomas, for example diffuse large B-cell lymphomas, multiple myelomas, prostate cancers, especially androgen receptor-positive prostate carcinomas, renal cell carcinomas, melanomas and other skin tumors, lung carcinomas such as non-small cells
  • leukemias in particular acute myeloid leukemias and acute T cell leukemias
  • B cell lymphomas for example diffuse large B-cell lymphomas, multiple myelomas, prostate cancers, especially androgen receptor-positive prostate carcinomas, renal cell carcinomas, melanomas and other skin tumors, lung carcinomas such as non-small cells
  • Bronchial carcinomas such as colorectal carcinomas
  • the present invention furthermore relates to the use of the compounds according to the invention for the prophylaxis and / or therapy of acute myeloid leukemias, T cell leukemias, diffuse large B cell lymphomas, multiple myelomas, androgen receptor positive prostate carcinomas, melanomas, squamous cell carcinomas and rhabdomyosarcomas ,
  • Another object of the present invention is a method for the prophylaxis and / or therapy of tumor diseases, comprising the administration of a compound according to the invention according to the general formula (I).
  • a further subject matter of the present invention is a method for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and acute T cell leukemias, B cell lymphomas, for example diffuse large cell B cell lymphomas, multiple myelomas, prostate carcinomas, especially androgen receptor-positive
  • Prostate carcinoma, renal cell carcinoma, melanoma and other skin tumors Prostate carcinoma, renal cell carcinoma, melanoma and other skin tumors
  • Lung carcinomas for example non-small cell lung carcinomas, colon carcinomas, for example colorectal carcinomas, carcinomas, uterine carcinomas,
  • Squamous cell carcinoma, ovarian adenocarcinoma, rhabdomyosarcoma and choriocarcinoma comprising administering a compound of the invention according to the general formula (I).
  • Another object of the present invention is a method for the prophylaxis and / or therapy of acute myeloid leukemias, T cell leukemias, diffuse large B-cell lymphomas, multiple myelomas, androgen receptor-positive prostate carcinomas, melanomas, squamous cell carcinomas and rhabdomyosarcomas comprising Administration of a compound of the invention corresponding to the general formula (I).
  • Another object of the present invention are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and acute T- Cell leukemias, B cell lymphomas, such as diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, especially androgen receptor-positive
  • Prostate carcinoma, renal cell carcinoma, melanoma and other skin tumors Prostate carcinoma, renal cell carcinoma, melanoma and other skin tumors
  • Lung carcinomas for example non-small cell lung carcinomas, colon carcinomas, for example colorectal carcinomas, bladder carcinomas, uterine carcinomas,
  • Another object of the present invention are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of acute myeloid leukemias, T-cell leukemias, diffuse large B-cell lymphoma, multiple myeloma, androgen receptor-positive prostate cancer , Melanoma, squamous cell carcinoma and Rhabdomyo sarcoma.
  • 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 diseases, sepsis, viral infections, vascular diseases and neurodegenerative conditions
  • the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • a further subject of the present invention are therefore medicaments comprising a compound according to the invention and one or more further active compounds, in particular for the prophylaxis and therapy of the abovementioned disorders.
  • the compounds according to the invention can be used with known anti-hyperproliferative, cytostatic or cytotoxic substances which are used for the treatment of
  • pharmacologically active substances which are suitable for a combination are mentioned by way of example, without this enumeration being conclusive: 1311-chTNT, abarelix, abiraterone, aclarubicin, aflibercept, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide , bisantrene, bleomycin, bortezomib, bosutinib, brentuximab, buserelin, busulfan, cabazitaxel, cabozantinib-s-malate, calcium foliate
  • the compounds according to the invention can also be combined with recombinant proteins.
  • the compounds according to the invention can also be used in combination with antihormones and steroidal metabolic enzyme inhibitors, which are particularly suitable because of their favorable side effect profile.
  • Synthesis route are produced. It describes the preparation of compounds of the formulas (Ia) and (Ib) which are part of the general formula (I).
  • Diastereomer mixtures can be separated into the pure stereoisomers by the separation methods familiar to the person skilled in the art, for example preparative HPLC on a chiral stationary phase.
  • the synthesis of compounds of general formula (I) can proceed from B enzodiazepinderivaten of formula (IIa) or (IIb), in which R ⁇ R ", R 4 , R ⁇ R 'and R are defined as for the general formula (I), and in which LG is a leaving group, for example chlorine, bromine, iodine or trifluoromethylsulfonyloxy, preferably bromine.
  • Trifluoromethylsulfonyloxy preferably bromine
  • the said reaction of compounds of the formula (IIa) or (IIb) with sulfoximines of the formula (III) is carried out, for example, in the presence of a
  • Palladium species preferably tris (dibenzylideneacetone) dipalladium (0), and a ligand, preferably 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl (RuPhos) or (R) - (+) - (l, l' - binaphthalene-2, 2'-diyl) bis (diphenylphosphine) ((R) - (+) - BINAP), as well as in the presence of a base, preferably sodium tert-butylate, in an organic solvent such as, for example
  • T etrahydrofuran or dioxane at a temperature in the range of 40 ° C to 150 ° C, preferably 50 ° C to 100 ° C, optionally using a microwave reactor.
  • Sulfoximines of the formula (III) are known to the person skilled in the art, commercially available in many cases and described in the literature (for a review see, for example, U. Lücking et al., Angewandte Chemie, International Edition 2013, 52 (36), 9399-9408).
  • Scheme 1 Preparation of sulfones of the formulas (Ia) or (Ib) from B enzodiazepine derivatives of the formulas (IIa) or (IIb).
  • Percentage yield data (in% of Th) may be purity-adjusted.
  • Method 1 Instrument: Agilent UHPLCMS 1290 Tof; Column: Acquity UPLC BEH C18 1.7 ⁇ , 50x2.1mm; Eluent A: water + 0.05% by volume of formic acid (99%), eluent B: acetonitrile + 0.05% by volume of formic acid (99%); Gradient: 0-1.7 min 2-90% B, 1.7-2.0 min 90% B; Flow 1.2 ml / min; Temperature: 60 ° C; DAD scan: 190-390 nm.
  • preparative RP-HPLC refers to a purification on commercial preparative H [. ( ' Plants using commercially available "reversed phase” materials as the stationary phase.) As mobile phase are gradients of water and acetonitrile,
  • Method A Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3 ⁇ 100x4.6mm; Eluent A: hexane + 0.1% by volume diethylamine (99%); Eluent B: ethanol; isocratic: 80% A + 20% B; Flow 1.0 ml / min; Temperature: 25 ° C; DAD @ 254 nm
  • ⁇ -NMR signals are given with their respective recognizable multiplicity or their combinations.
  • s singlet
  • d doublet
  • t triplet
  • q quartet
  • qi quintet
  • sp septet
  • m multiplet
  • br broad signal.
  • the chemical shifts of the signals ( ⁇ ) are given in ppm (parts per million).
  • Substance names of intermediates and example substances were generated with the program 'ACD / Name' of the company ACD LABS, and adjusted if necessary. in some cases, common names of commercially available reagents were used instead of those generated by the 'ACD / Name' program.
  • Example 1A 3.38 g of Example 1A were prepared starting from 8.1 g (18.17 mmol) of racemic ( ⁇ ) -l- (3-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide, whose synthesis is described in WO 2014026997, by enantiomer separation by HPLC on a dural phase under the following conditions.
  • Example 2A are isolated.
  • Example 2A (4R) - (3-Bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide
  • Tris (dibenzylideneacetone) dipalladium (0) (CAS [51364-51 -3]) and finally 31 mg (324 ⁇ ) of sodium tert-butoxide added.
  • the mixture was degassed again, saturated with argon and then stirred at 60 ° C for 2 hours. After cooling, the mixture was added with 2M aqueous hydrochloric acid and adjusted to pH4. The solvent was removed on a rotary evaporator and the residue was purified by preparative RP-HPLC. 24 mg (21% of theory) of the desired product were obtained as a solid.
  • Protein-Protein W echsehvirkungsassay binding assay BRD4 / acetylated peptide H4
  • Assay buffer [50 mM HEPES pH 7.5, 50 mM sodium chloride (NaCl), 0.25 mM (II APS and 0.05% serum albumin (BSA)] to the substances in the assay plate followed by a 10 minute incubation step at 22 ° C for pre-equilibration of putative complexes between BRD4 (1) and the substances followed by 3 ⁇ of a 1.67-fold concentrated solution (in the assay buffer) consisting of Ac-H4 peptide (83.5 nM) and TR-FR ET detection reagents [ 16.7 nM anti-6His XL665 and 3.34 nM streptavidin cryptate (both from Cisbio Bioassays, Codolet, France) and 668 mM potassium fluoride (KF)] were added. The mixture was then incubated in the dark for one hour at 22 ° C and then for at least 3 hours and at most overnight at 4 ° C. The formation of BRD4 (1) / Ac-H4
  • the data obtained (ratio) were normalized with 0% inhibition equal to the mean of the measurements of a set of controls (typically 32 data points) containing all reagents. Instead of test substances, 50 ⁇ l DM SO (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 (1).
  • the assay typically involved 11 different concentra tions of each substance (0.1 nM, 0.33 ⁇ , 1.1 iiM, 3.8 nM, 13 nM, 44 nM, 0.15 ⁇ , 0.51 ⁇ , 1.7 ⁇ , 5.9 ⁇ and 20 ⁇ ) as duplicates on the same microtiter Plate measured.
  • 100-fold concentrated solutions in DM SO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Grein er Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany). The test was started by the addition of 2 ⁇ of a 2.5-fold concentrated BRD4 (2) solution (usually 100 nM final concentration in the 5 ⁇ of the reaction volume) in aqueous
  • the maturity of the substances was determined to inhibit cell proliferation.
  • Cell viability was determined using the alamarBlue® reagent (In vi trogen) 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 exposed to a concentration of 4000 cells / well in ⁇ growth medium (RPMI1640 and stable glutamine, 10% FCS) at 96well
  • MOLP-8 cells (DSMZ, ACC 569) were added to 96well at a concentration of 4000 cells / well in ⁇ ⁇ growth medium (RPMI1640 and stable glutamine, 20% FCS)
  • HBL-1 cells (Ref Y. Nozawa et al., Tohoku J. Exp. Med. (1988) 156: 319-330) were added to a concentration of 1000 cells / well in 30 ⁇ l growth medium (RPMI1640 and stable glutamine, 10% FCS) seeded on 384well microtiter plates.
  • the CH L-1 cells (ATCC, CRL-9446) were seeded to a concentration of 1000 cells / well in 30 ⁇ l growth medium (D EM, 10% FCS) on 384 well microtiter plates.
  • the LNCaP cells (DSMZ, ACC-268) were seeded to a concentration of 1000 cells / well in 30 ⁇ l growth medium (RPMI1640 without phenol red, stable glutamine, 10% FCS) on 384 well microtiter plates.
  • the DU-145 cells (DSMZ, ACC 261) were seeded to a concentration of 1000 cells / well in 30 ⁇ l growth medium (DMEM / Ham 's F12, stable glutamine, 10% FCS) on 384 well microtiter plates.
  • DMEM / Ham 's F12 stable glutamine, 10% FCS
  • the J82 cells (ATCC, HTB-1) were seeded to a concentration of 500 cells / well in Ear ⁇ growth medium (MEM Earle 's medium, 10% FCS) on 384 well microtiter plates.
  • Ear ⁇ growth medium MEM Earle 's medium, 10% FCS
  • the CCRF-CEM cells (ATCC, CRM-CCL-1 19) were seeded to a concentration of 16,000 cells / well in ⁇ growth medium (DM E and stable glutamine, 10% FCS) on 96 well microtiter plates.
  • NCI-H292 cells ATCC, CRL-1848 were seeded to a concentration of 500 cells / well in 30 ⁇ l growth medium (RPMI1640, 10% FCS) on 384 well microtiter plates.
  • the NCI-H520 cells (ATCC, HTB-i 82) were seeded to a concentration of 2000 cells / well in 30 ⁇ l growth medium (RPMI1640, 10% FCS) on 384 well microtiter plates.
  • OVCAR-3 cells ATCC, HTB-I 6! Were seeded to 384well microtiter plates to a concentration of 3000 cells / well in 30 ⁇ l growth medium (RPMI1640, 20% FCS, 10 ⁇ g / ml insulin).
  • the RD cells (ATCC, CCL-136) were seeded to a concentration of 2000 cells / well in 30 ⁇ l growth medium (DM EM, 10% FCS) on 384 well microtiter plates.
  • the SK-MEL-3 cells (DSMZ, ACC-321 were added to 384well at a concentration of 1000 cells / well in 30 ⁇ l growth medium (McCoy's 5A and stable glutamine, 10% FCS)
  • JEG-3 cells (ATCC, HTB-36) were added to 384well at a concentration of 1000 cells / well in 30 ⁇ l growth medium (DMEM / Ham 's 12 and stable glutamine, 10% FCS)
  • the CI values were subtracted from the CO values and the results compared between cells treated with different dilutions of the substance or with buffer solution only.
  • the IC 50 values (substance concentration necessary for 50% inhibition of cell proliferation) were calculated therefrom.
  • the preceding protocol uses the cell lines of Table 1, which exemplify the indicated indications.
  • Table 3 shows the results from MOLM-13, MOLP-8, HBL-1 and CHL-1 proliferation assay.
  • Table 4 shows the results from the LA PC -4. LNCaP and DU-1 45 proliferation assay.
  • Table 5 shows the results from the 5637, J82, CCRF-CEM and MES-SA proliferation assay.
  • Table 6 shows the results from the NCI-H292, NCI-H520, OVCAR3 and RD proliferation assay.
  • Table 7 shows the results from the SK-MEL-3, SW403, Caki-2 and JEG-3 proliferation assay.

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Abstract

L'invention concerne des dérivés de la benzodiazépine n-sulfoximinophényl-substitués, inhibiteurs de protéines à bromodomaines, notamment inhibiteurs de protéines BET et de préférence inhibiteurs de BRD4, de la formule générale (I) dans laquelle R1, R2, R3, R4 et R5 qui ont les significations indiquées dans la description, des compositions pharmaceutiques contenant les composés de l'invention et leur utilisation prophylactique et thérapeutique dans le domaine des maladies hyperprolifératives, notamment des maladies tumorales. En outre, l'utilisation d'inhibiteurs de la protéine BET dans le domaine des infections virales, des troubles rénaux associés au VIH, des maladies neurodégénératives, des fibroses, des maladies inflammatoires, des maladies athérosclérotiques, de l'insuffisance cardiaque, des dystrophies musculaires, comme par exemple la dystrophie musculaire fascioscapulohumérale et le contrôle de la fertilité masculine est décrite.
PCT/EP2016/074095 2015-10-15 2016-10-07 Dérivés de la benzodiazépine n-sulfoximinophényl-substitués utilisés comme inhibiteurs de protéines bet Ceased WO2017063959A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
WO2020020288A1 (fr) * 2018-07-25 2020-01-30 正大天晴药业集团股份有限公司 Composé sulfoximine en tant qu'inhibiteur de protéine à bromodomaine et composition pharmaceutique et son utilisation médicale

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WO2014026997A1 (fr) * 2012-08-16 2014-02-20 Bayer Pharma Aktiengesellschaft 2,3-benzodiazépines
WO2014128067A1 (fr) * 2013-02-19 2014-08-28 Bayer Pharma Aktiengesellschaft 2,3-benzodiazépines bicyclo- et spirocyclosubstituées
WO2014202578A1 (fr) * 2013-06-17 2014-12-24 Bayer Pharma Aktiengesellschaft Phényl-2,3-benzodiasépine substituée

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Publication number Priority date Publication date Assignee Title
WO2014026997A1 (fr) * 2012-08-16 2014-02-20 Bayer Pharma Aktiengesellschaft 2,3-benzodiazépines
WO2014128067A1 (fr) * 2013-02-19 2014-08-28 Bayer Pharma Aktiengesellschaft 2,3-benzodiazépines bicyclo- et spirocyclosubstituées
WO2014202578A1 (fr) * 2013-06-17 2014-12-24 Bayer Pharma Aktiengesellschaft Phényl-2,3-benzodiasépine substituée

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US12122833B2 (en) 2016-05-11 2024-10-22 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
WO2020020288A1 (fr) * 2018-07-25 2020-01-30 正大天晴药业集团股份有限公司 Composé sulfoximine en tant qu'inhibiteur de protéine à bromodomaine et composition pharmaceutique et son utilisation médicale
CN112424200A (zh) * 2018-07-25 2021-02-26 正大天晴药业集团股份有限公司 作为溴区结构域蛋白抑制剂的亚氨基砜类化合物、药物组合物及其医药用途
JP2021533186A (ja) * 2018-07-25 2021-12-02 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. ブロモドメインタンパク質阻害薬としてのイミノスルホン化合物、医薬組成物及びその医薬用途
CN112424200B (zh) * 2018-07-25 2022-09-20 正大天晴药业集团股份有限公司 作为溴区结构域蛋白抑制剂的亚氨基砜类化合物、药物组合物及其医药用途
JP7511557B2 (ja) 2018-07-25 2024-07-05 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド ブロモドメインタンパク質阻害薬としてのイミノスルホン化合物、医薬組成物及びその医薬用途
US12030880B2 (en) 2018-07-25 2024-07-09 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Iminosulfanone compound as bromodomain protein inhibitor and pharmaceutical composition and medical use thereof

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