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WO2016062688A1 - Dérivés de 1-phényl-4,5-dihydro-3h-2,3-benzodiazépines - Google Patents

Dérivés de 1-phényl-4,5-dihydro-3h-2,3-benzodiazépines Download PDF

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Publication number
WO2016062688A1
WO2016062688A1 PCT/EP2015/074214 EP2015074214W WO2016062688A1 WO 2016062688 A1 WO2016062688 A1 WO 2016062688A1 EP 2015074214 W EP2015074214 W EP 2015074214W WO 2016062688 A1 WO2016062688 A1 WO 2016062688A1
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Prior art keywords
phenyl
dihydro
dimethyl
dimethoxy
carboxamide
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German (de)
English (en)
Inventor
Stephan Siegel
Arwed Cleve
Bernard Haendler
Knut Eis
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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
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/02—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to bromodomain protein-inhibiting, in particular BET protein-inhibiting and preferably BRD4-inhibitory carboxamides, pharmaceutical compositions containing the compounds of the invention and their prophylactic and therapeutic use in hyperproliferative diseases, especially in cancer or tumor diseases. Furthermore, this invention relates to the use of BET protein inhibitors in benign hyperplasia, atherosclerotic diseases, sepsis,
  • Kidney diseases neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases, heart failure, muscular dystrophies such as fazioskapulohumeral muscular dystrophy and male fertility control.
  • the bromodomain protein family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4, and BRDT) that share 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).
  • 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
  • histone H4 histone H4
  • 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, resulting in activation of RNA polymerase II (Yang et al., Mol. Cell, 2005, 19: 535-545; Schröder et al., J. Biol.
  • RNA polymerase II Chromatin regions and promote transcription by RNA polymerase II (LeRoy et al., Mol. Cell, 2008, 30: 51-60).
  • BRD4 binds to promoter regions of several genes activated in the Gl phase, such as cyclin D1 and D2 (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040- 9048).
  • cyclin D1 and D2 activated in the Gl phase
  • inhibition of c-Myc expression, an essential factor in cell proliferation, following BRD4 inhibition has been demonstrated (Dawson et al., Nature, 2011, 478: 529-533, Delmore et al., Cell, 2011, 146: 1-14, Mertz et al., Proc Natl Acad., 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 tumor types.
  • the fusion between the BET proteins BRD3 or BRD4 and NUT a protein normally only expressed in the testes, results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet, Cytogenet., 2010, 203: 16 -20).
  • the fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 2011, 286: 27663-27675).
  • the growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073).
  • BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, doi: 10.1038). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo. Amplification of the DNA region containing the BRD4 gene was detected in primary breast tumors (Kadota et al., Cancer Res, 2009, 69: 7357-7365). Also for BRD2 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).
  • the anti-proliferative effects of BET inhibitors used in various preclinical in vitro and in vivo tumor models indicate an essential role of BET proteins, especially BRD4, in hematological tumors such as AML, multiple myeloma and lymphomas (Delmore et al., Cell, 2011, 146: 904-917; Zuber et al., Nature, 2011, 478: 524-528; Merz et al., Proc. Natl. Acad. Sci.
  • prostate cancer Asangani et al., Nature, 2014, 510: 278-282
  • breast cancer Nagarajan et al., Cell Reports, 2014, 8: 460-469; Shi et al., Cancer Cell, 2014, 25: 210 -225
  • lung cancer Shi ckwood et al., Proc. Natl. Acad. Be. USA, 2012, 109: 19408-19413
  • melanoma Gal et al., J. Invest.
  • BRD4 binds to the E2 protein of various papillomaviruses and is important for survival of the viruses in latently infected cells (Wu et al., Genes Dev., 2006, 20: 2383-2396; Vosa et al., J. Virol., 2012 , 86: 348-357; McBride and Jang, Viruses, 2013, 30: 1374-1394).
  • the herpesvirus responsible for Kaposi's sarcoma also interacts with various BET proteins
  • BRD4 By binding to P-TEFb, BRD4 also plays an important role in the replication of HIV (Bisgrove et al., Proc Natl Acad., USA, 2007, 104: 13690-13695). A role of BRD4 in the control of latency of HIV proviruses has also been shown (Boehm et al., Cell Cycle, 2013, 12: 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 inflammation in adipose tissue (Wang et al., Biochem J., 2009, 425: 71-83).
  • the infiltration of macrophages into white adipose tissue is also reduced in BRD2-deficient mice (Wang et al., Biochem J., 2009, 425: 71-83).
  • BRD4 regulates a number of genes involved in inflammation.
  • Macrophages prevent a BRD4 inhibitor from expression of inflammatory genes, such as IL-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1119-1123).
  • Apolipoprotein AI (ApoAl) is a major component of high density
  • HDL Lipoproteins
  • ApoAl Lipoproteins
  • Elevated HDL levels are associated with a decreased risk of atherosclerosis (Chapman et al., Eur. Heart J., 2011, 32: 1345-1361).
  • 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 that prevent the interaction between the BET proteins, for example BRD2, BRD3, BRD4 and BRDT, and acetylated proteins, especially acetylated histone H4 peptides.
  • L-aryl-4,5-dihydro-3i7-2,3-benzodiazepines have long been known, inter alia, as modulators or antagonists of excitatory amino acid receptors, for example the AMPA receptor, and are among others as potential therapeutics for diseases of central nervous origin described.
  • WO 2001/098280 discloses 1-phenyl-4,5-dihydro-3,2,3-benzodiazepines as antagonists of the non-NMDA ionotropic excitatory amino acid (EAA) receptor.
  • EAA excitatory amino acid
  • the compounds according to the invention furthermore differ, inter alia, by the substitution on the aromatics associated with Cl of the benzodiazepine skeleton of other known 2,3-benzodiazepines such as the numerous published AMPA antagonists (see, for example, WO 1997/28135 (Schering AG), US Pat. No. 5,807,851, HU 0097000688, WO
  • WO 1997/034878 and US 5,891,871 disclose 2,3-benzodiazepine-4-ones which differ from the compounds of the present invention by the oxo substitution at C-4 of the benzodiazepine skeleton Antagonists or positive modulators of the AMPA receptor.
  • Ligands of the gastrin and the cholecystokinin receptor are described in WO2006 / 051312 (James Black Foundation). They also include substituted 3,5-dihydro-4i7-2,3-benzodiazepin-4-ones, which differ from the compounds of the invention mainly by the obligatory oxo group in position 4 and by a mandatory, carbonyl group-containing alkyl chain in position 5.
  • WO 2014/026997 discloses 1-phenyl and 1-heteroaryl-4,5-dihydro-3,2,3-benzodiazepines as inhibitors of BET proteins, in particular of BRD4, inter alia for the treatment of hyperproliferative diseases. Of the disclosed in this application
  • Exemplary compounds differ from the compounds of the present invention by the substitution on the phenyl ring linked to C-1 of the benzodiazepine skeleton.
  • Fertility control can be used.
  • the compounds according to the invention inhibit the interaction between BET proteins, in particular BRD4, and an acetylated histone H4 peptide.
  • 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 kidney diseases, in neurodegenerative diseases
  • Ci-C3-alkyl in which "*" in each case the point of attachment to the rest of the molecule, is Ci-C3-alkyl, trifluoromethyl or Cs-C t-Cycloalkyl- stands, for cyclopropyl, Ci-C3-alkyl, Ci-C3 Alkoxy, amino, cyclopropylamino or Ci-C3-Alkylamino- stand independently
  • monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, carboxy, C 1 -C 6 -alkyl-, Coe-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkylamino, amino-G-Ce-alkyl, GC 6 - alkylamino-Ci-Ce-alkyl, hydroxy-Ci- Ce-alkyl, halo-Ci-Ce-alkyl,
  • monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl- , C 3 -C 6 -cycloalkyl, cyclopropylmethyl, Ci-C3-alkylcarbonyl or GC t-alkoxycarbonyl, for hydroxy, Ci-Cö-alkyl, Ci-Cö-alkoxy, halo-Ci-C3-alkyl , Hydroxy-G-
  • C 3 alkyl, GG alkoxy GG alkyl or C 3 -Cio cycloalkyl stands, or
  • Ci-C3-alkoxy- or Ci C3 alkyl represents GG alkyl, which is unsubstituted
  • C 1 -C 6 -alkyl which is monosubstituted, disubstituted or trisubstituted, identically or differently, by hydroxyl, oxo, fluorine, cyano, C 1 -C 4 -alkoxy, halogeno-C 1 -C 4 -alkyl, alkoxy, -NR 9 R 10 , Cs-Cs-cycloalkyl, C4-C8-cycloalkenyl, monocyclic heterocyclyl having 4 to 8 ring atoms, Cs-Cn-spirocycloalkyl, C5-C11 heterospirocycloalkyl, bridged C6-Ci2 Cycloalkyl, bridged C 6 -C 12 heterocycloalkyl, C 6 -C 12 bicycloalkyl, C 6 -C 12 heterobicycloalkyl, phenyl or monocyclic heteroaryl having 5 or 6 ring atoms,
  • Heterocyclyl having 4 to 8 ring atoms, Cs-Cn-spirocycloalkyl, C5-C11 heterospirocycloalkyl, bridged C6-C12 cycloalkyl, bridged C6-C12 heterocycloalkyl, C6-C12 bicycloalkyl, C0-Cn heterobicycloalkyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents, such as hydroxy, fluoro, oxo, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, Cyclopropylmethyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl or -NR 9 R 10 , and
  • phenyl and monocyclic heteroaryl having 5 or 6 ring atoms are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, trifluoromethyl, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy-,
  • C3-C8-cycloalkyl is C3-C8-cycloalkyl, C4-C8-cycloalkenyl, Cs-Cn-spirocycloalkyl, bridged C6-Ci2-cycloalkyl or C6-Ci2-bicycloalkyl- which are unsubstituted or mono- or disubstituted by identical or different are substituted with hydroxy, oxo, cyano, fluoro, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, trifluoromethyl or -NR 9 R 10 , or
  • phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, halogen, cyano, Ci-C4-alkyl, C2-C4-alkenyl, C2 C4-alkynyl, halo-Ci-C4-alkyl, Ci-C 4 alkoxy alkoxy, halo-Ci-C 4, C 4 alkylthio, Halogeno-C 1 -C 4 -alkylthio, -NR 9 R 10 , -C ( O) -NR 9 R 10 or monocyclic heterocyclyl having 4 to 8 ring atoms,
  • R 13 is hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxyl, oxo or Ci-C3-alkoxy-substituted Ci-C3-alkyl-, or fluoro-Ci-C3-alkyl-,
  • C 1 -C 3 -alkyl in which C 1 -C 3 -alkyl, in turn, is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, cyano, oxo,
  • Inhibitors are suitable for a variety of prophylactic and therapeutic uses, especially in hyperproliferative diseases, in cancer or
  • Tumor diseases and in viral infections, in HIV-associated kidney diseases, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases, in heart failure, in muscular dystrophies such as
  • 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, C 3 -C 6 -cycloalkyl, ci C 3 alkylcarbonyl or C 1 -C 4 alkoxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 4 -alkoxy, fluoroCG 3 -alkyl, hydroxy-C 1 -C 3 -alkyl or C 3 -C 7 -cycloalkyl-,
  • phenyl represents phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents, are substituted by halogen, GC 3 -alkoxy- or C 3 alkyl, is C t -C 6 alkyl, which is unsubstituted,
  • C 1 -C 6 -alkyl which is mono-, di- or trisubstituted by identical or different substituents with hydroxyl, oxo, fluorine, cyano, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkoxy- , -NR 9 R 10 , C 3 -C 8 -cycloalkyl, monocyclic heterocyclyl- having 4 to 8 ring atoms, phenyl or monocyclic heteroaryl- with 5 or 6 Ring atoms,
  • Cs-Cs-cycloalkyl and monocyclic heterocyclyl having 4 to 8 ring atoms in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, Ci-C3-alkyl, fluoro-Ci- C 3 alkyl -, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl or -NR 9 R 10 , and wherein phenyl and monocyclic heteroaryl having 5 or 6 ring atoms are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, trifluoromethyl, methyl or methoxy,
  • C3-C8-cycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, cyano, fluorine or Ci-C3-alkyl-, or
  • phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, halogen, cyano, Ci-C t-alkyl, fluoro-Ci-C3-alkyl , C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkoxy, C 1 -C 3 -alkylthio, fluoro-C 1 -C 3 -alkylthio, -NR 9 R 10 or -C ( O) - NR 9 R 10 , represents hydrogen, C 1 -C 3 -alkyl 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, methyl, ethyl, cyclopropyl, acetyl or ieri.
  • -butoxycarbonyl for C 3 alkyl or C 1 -C 4 alkoxy, is C 4 -C 6 alkyl which is unsubstituted
  • C 1 -C 6 -alkyl which is mono-, di- or trisubstituted by identical or different substituents with hydroxyl, oxo, fluorine, cyano, C 1 -C 3 -alkoxy, -NR 9 R 10 , C 3 -C 6 Cycloalkyl, monocyclic heterocyclyl having 4 to 6 ring atoms, phenyl or monocyclic heteroaryl having 5 or 6 ring atoms,
  • C 3 -C 6 -cycloalkyl- and monocyclic heterocyclyl having 4 to 6 ring atoms are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo or C 1 -C 3 -alkyl-, and in which phenyl- and monocyclic heteroaryl- with 5 or 6 ring atoms unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy,
  • phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, halogen, cyano, methyl, ethyl, trifluoromethyl, methoxy, Ethoxy, trifluoromethoxy, -NR 9 R 10 or -C ( O) -NR 9 R 10 ,
  • R is hydrogen, methyl or ethyl
  • R 3 is methylamino
  • Imidazolidinyl-, tetrahydrofuryl and tetrahydropyranyl- in turn are unsubstituted or mono- or di-substituted by identical or different substituents with oxo or methyl, and
  • phenyl, imidazolyl, furyl, pyrazolyl and pyridinyl are unsubstituted or monosubstituted or disubstituted by identical or different substituents with methyl,
  • phenyl, pyrazolyl, isoxazolyl or pyridinyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, methyl, methoxy or -C ( 0) -NH 2 , for Is hydrogen or methyl,
  • R 2 is methyl
  • R 3 is methylamino
  • R 4 is methoxy
  • R 5 is methoxy
  • R 7 is hydrogen, for a group
  • R is hydrogen or methyl
  • (+) - 1- (4- ⁇ [2- (Dimethylamino) ethyl] (methyl) carbamoyl ⁇ phenyl) -7,8-dimethoxy- / V, 4-dimethyl-4,5-dihydro-3i7-2,3 benzodiazepine-3-carboxamide; (4R) -7,8-dimethoxy- / V, 4-dimethyl- 1- [4- (phenylcarbamoyl) -phenyl] -4,5-dihydro-3ii-2,3-benzodiazepine-3-carboxamide;
  • (+) - 7,8-Dimethoxy-N 4-dimethyl-1 - ⁇ 4- [(4-methylpentan-2-yl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide; (4R) -1- (4- ⁇ [2- (Dimethylamino) ethyl] (methyl) carbamoyl ⁇ phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide;
  • (4R) -7,8-dimethoxy-N 4-dimethyl-1- (4- ⁇ [2- (morpholin-4-yl) ethyl] carbamoyl ⁇ phenyl) -4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide
  • (4R) -7,8-dimethoxy-N 4-dimethyl-1 - ⁇ 4 - [(pyridin-2-ylmethyl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine-3 carboxamide;
  • (+) - 1- (4- ⁇ [1- (Dimethylamino) propan-2-yl] carbamoyl ⁇ phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide;
  • (4R) -7,8-dimethoxy-N 4-dimethyl-1 - ⁇ 4 - [(3-methylpyridin-4-yl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;
  • (+) - 7,8-dimethoxy-N 4-dimethyl-1 - ⁇ 4 - [(1,1-trifluoropropan-2-yl) carbamoyl] -phenyl ⁇ -4,5-dihydro-3H-2, 3-benzodiazepine-3-carboxamide;
  • (4R) -7,8-dimethoxy-N 4-dimethyl-1- (4- ⁇ [(1-methyl-1H-pyrazol-3-yl) -methyl] carbamoyl-jphenyl) -4,5-dihydro-3H- 2,3-benzodiazepin-3-carboxamide;
  • (4R) -7,8-dimethoxy-N 4-dimethyl-1- (4- ⁇ [(2R) -3-methylbutan-2-yl] carbamoyl ⁇ phenyl) -4,5-dihydro-3H-2, 3-benzodiazepine-3-carboxamide
  • (4R) -7,8-Dimethoxy-N 4-dimethyl-1 - ⁇ 4 - [(2-methylpyridin-3-yl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;
  • (+) - 7,8-Dimethoxy-N 4-dimethyl-1 - (4- ⁇ [2- (piperidin-1-yl) ethyl] carbamoyl ⁇ phenyl) -4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide; (+) - 7,8-dimethoxy-1- ⁇ 4 - [(2-methoxyethyl) carbamoyl] phenyl ⁇ -N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;
  • (+) - 7,8-dimethoxy-N 4-dimethyl-1 - ⁇ 4- [(4-methylphenyl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; 1- (4- ⁇ [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] carbonyl ⁇ phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide; 1- (4- ⁇ [(2S) -2-hydroxypropyl] carbamoyl ⁇ phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;
  • (+) - 7,8-dimethoxy-N 4-dimethyl-1- [4- (pyridin-4-ylcarbamoyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (+) - 7,8-Dimethoxy-N, 4-dimethyl-1 - ⁇ 4 - [(pyridin-2-ylmethyl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine-3 carboxamide; 1- (4- ⁇ [(2R) -l-hydroxy-3-methylbutan-2-yl] carbamoyl ⁇ phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2, 3-benzodiazepine-3-carboxamide; (+) - 1 - ⁇ 4- [(4-carbamoylphenyl) carbamoyl] phenyl ⁇ -7,8
  • (+) - 7,8-Dimethoxy-N 4-dimethyl-1 - ⁇ 4- [(pyridin-4-ylmethyl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine-3 carboxamide; (+) - 7,8-dimethoxy-N, 4-dimethyl-1- [4- (pyridin-2-ylcarbamoyl) -pheriyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;
  • (+) - 7,8-Dimethoxy-N 4-dimethyl-1- (4- ⁇ [2- (2-oxo-imidazolidin-1-yl) -ethyl] -carbamoyl ⁇ -phenyl) -4,5-dihydro-3H-2 , 3-benzodiazepin-3-carboxamide; 1 - (4- ⁇ [(2R) -1-Hydroxybutan-2-yl] carbamoyl ⁇ phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine -3-carboxamide;
  • (+) - 7,8-Dimethoxy-N 4-dimethyl-1 - ⁇ 4- [(3-methylpyridin-4-yl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide; 1- (4- ⁇ [(3R) -4-hydroxy-3-methylbutyl] carbamoyl ⁇ phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;
  • (+) - 7,8-Dimethoxy-N 4-dimethyl-1 - (4- ⁇ [2- (1H-pyrazol-1-yl) -ethyl] -carbamoyl ⁇ -phenyl) -4,5-dihydro-3H- 2,3-benzodiazepin-3-carboxamide; (+) - 1- (4- ⁇ [4- (hydroxymethyl) piperidin-1-yl] carbonyl ⁇ phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide;
  • (+) - 7,8-Dimethoxy-N 4-dimethyl-1- (4- ⁇ [(1-methyl-1H-pyrazol-5-yl) methyl] carbamoyl ⁇ phenyl) -4,5-dihydro-3H -2,3-benzodiazepine-3-carboxamide; 7,8-dimethoxy-N, 4-dimethyl-1- (4- ⁇ [(2R) -3-methylbutan-2-yl] carbamoyl ⁇ phenyl) -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;
  • (+) - 7,8-Dimethoxy-N 4-dimethyl-1 - ⁇ 4 - [(2-methylpyridin-3-yl) carbamoyl] phenyl ⁇ -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;
  • ( ⁇ ) -7,8-Dimethoxy-N 4-dimethyl-1- (4- ⁇ [(1-methyl-1H-pyrazol-4-yl) methyl] carbamoyl ⁇ phenyl) -4,5-dihydro-3H -2,3-benzodiazepine-3-carboxamide;
  • R preferably represents a group
  • R is particularly preferably a group
  • R very particularly preferably represents a group
  • R 7 is hydrogen, and wherein "*" represents the point of attachment to the remainder of the molecule.
  • R 2 is preferably methyl or ethyl. In the general formula (I), R 2 is preferably methyl.
  • R 3 is preferably cyclopropyl, C 1 -C 3 -alkyl,
  • R 3 is particularly preferably C 1 -C 3 -alkylamino.
  • R 3 very particularly preferably represents methylamino.
  • R 4 and R 5 are each independently preferably
  • R 4 particularly preferably represents C 1 -C 3 -alkoxy and R 5 particularly preferably represents hydrogen, cyano, fluorine, chlorine or bromine,
  • R 4 particularly preferably represents hydrogen, cyano, fluorine, chlorine or bromine,
  • R 5 particularly preferably represents C 1 -C 3 -alkoxy.
  • R 4 and R 5 independently of one another are particularly preferably C 1 -C 3 -alkoxy.
  • R 4 and R 5 very particularly preferably each represent methoxy.
  • R 7 preferably represents hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or represents C 3 alkyl, Ci-C 3 alkoxy, Ci-C 3 alkoxy-Ci C 3 alkyl, fluoro-C 1 -C 3 -alkyl or fluoro-C 1 -C 3 -alkoxy.
  • R 7 is preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or methyl, methoxy, methoxymethyl, methoxyethyl, difluoromethyl,
  • R 7 is preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl or methoxy.
  • R 7 particularly preferably represents hydrogen, fluorine or chlorine.
  • R 7 is very particularly preferably hydrogen.
  • R 9 and R 10 are independently of each other preferably
  • Hydrogen C 1 -C 3 -alkyl, acetyl, propionyl or fluoro-C 1 -C 3 -alkyl, or together with the nitrogen atom to which they are bonded, for monocyclic heterocyclyl having 4 to 8 ring atoms, the is unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, oxo, cyano, C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 3 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl -.
  • R 9 and R 10 are independently of each other preferably
  • R 9 and R 10 are preferably, together with the nitrogen atom to they are bonded, for 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, C 3 -C 6 -cycloalkyl, Ci-C3-alkylcarbonyl or Ci-C t-alkoxycarbonyl-.
  • R 9 and R 10 independently of one another particularly preferably represent hydrogen, methyl, ethyl or acetyl, or together with the nitrogen atom to which they are attached, monocyclic heterocyclyl having 4 to 8 Ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluoro, oxo, methyl, ethyl, cyclopropyl, acetyl or ieri.-butoxycarbonyl.
  • R 9 and R 10 independently of one another particularly preferably represent hydrogen, methyl, ethyl or acetyl.
  • R 9 and R 10 are particularly preferably together with the nitrogen atom to which they are attached, for monocyclic heterocyclyl of 4 to 8
  • Ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluoro, oxo, methyl, ethyl, cyclopropyl, acetyl or ieri.-butoxycarbonyl.
  • R 11 is preferably C 1 -C 3 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl or C 3 -C 7 -cycloalkyl-,
  • R 11 is particularly preferably Ci-C3-alkyl or Ci-C / t-alkoxy.
  • R 12 is preferably C 4 -C 6 -alkyl which is unsubstituted, or
  • C 1 -C 6 -alkyl which is mono-, di- or trisubstituted by identical or different substituents with hydroxyl, oxo, fluorine, cyano, GC 3 -alkoxy, fluoro-C 1 -C 3 -alkoxy, -NR 9 R 10 , C 3 -C 8 cycloalkyl, monocyclic heterocyclyl having 4 to 8 ring atoms, phenyl or monocyclic heteroaryl having 5 or 6 ring atoms,
  • Cs-Cs-cycloalkyl and monocyclic heterocyclyl having 4 to 8 ring atoms in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 - Alkyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4- Alkoxycarbonyl or -NR 9 R 10 , and
  • phenyl and monocyclic heteroaryl having 5 or 6 ring atoms are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, trifluoromethyl, methyl or methoxy,
  • R 12 particularly preferably represents C t-Ce-alkyl which is unsubstituted
  • C 1 -C 6 -alkyl which is mono-, di- or trisubstituted by identical or different substituents with hydroxyl, oxo, fluorine, cyano, C 1 -C 3 -alkoxy-, -NR 9 R 10 , C 3 -C 6 Cycloalkyl, monocyclic
  • C 3 -C 6 -cycloalkyl and monocyclic heterocyclyl having 4 to 6 ring atoms in turn are unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, oxo or Ci-C 3 alkyl, and
  • phenyl and monocyclic heteroaryl having 5 or 6 ring atoms are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy,
  • phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different hydroxy, halogen, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy -, NR 9 R 10 or
  • R 12 is particularly preferably C t -C 6 -alkyl which is unsubstituted, or
  • C 1 -C 6 -alkyl which is mono-, di- or trisubstituted by identical or different substituents with hydroxyl, oxo, fluorine, cyano, C 1 -C 3 -alkoxy-, -NR 9 R 10 , Cs-C 6 -cycloalkyl monocyclic heterocyclyl having 4 to 6 ring atoms, phenyl or monocyclic heteroaryl having 5 or 6 ring atoms,
  • Cs-Cö-cycloalkyl and monocyclic heterocyclyl having 4 to 6 ring atoms are unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, oxo or Ci-C3-alkyl-, and
  • phenyl and monocyclic heteroaryl having 5 or 6 ring atoms are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy.
  • R 12 particularly preferably represents C 5 -C 6 -cycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl or ethyl,
  • R 12 particularly preferably represents phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, halogen, cyano, Methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, -NR 9 R 10 or
  • R 12 is very particularly preferably C t -C 6 -alkyl-, which is unsubstituted
  • C 1 -C 6 -alkyl which is mono-, di- or trisubstituted by identical or different substituents with hydroxyl, fluorine, cyano, methoxy, dimethylamino, acetylamino, cyclopropyl, pyrrolidinyl, piperidinyl, morpholinyl , Imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, imidazolyl, furyl, pyrazolyl or pyridinyl,
  • Tetrahydrofuryl- and Tetrahydropyranyl- are in turn unsubstituted or mono- or disubstituted by identical or different substituents with oxo or methyl, and wherein phenyl, imidazolyl, furyl, pyrazolyl and pyridinyl are unsubstituted or once or twice, the same or differently substituted with methyl,
  • phenyl, pyrazolyl, isoxazolyl or pyridinyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, methyl, methoxy or
  • R 12 is very particularly preferably C t -C 6 -alkyl-, which is unsubstituted
  • C 1 -C 6 -alkyl which is mono-, di- or trisubstituted by identical or different substituents with hydroxyl, fluorine, cyano, methoxy, dimethylamino, acetylamino, cyclopropyl, pyrrolidinyl, piperidinyl, morpholinyl , Imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, imidazolyl, furyl, pyrazolyl or pyridinyl,
  • cyclopropyl, pyrrolidinyl, piperidinyl, morpholinyl, imidazolidinyl, Tetrahydrofuryl- and Tetrahydropyranyl- are in turn unsubstituted or mono- or disubstituted by identical or different substituents with oxo or methyl, and wherein phenyl, imidazolyl, furyl, pyrazolyl and pyridinyl are unsubstituted or once or twice, the same or differently substituted with methyl.
  • R 12 very particularly preferably represents C 3 -C 6 -cycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano or methyl,
  • phenyl, pyrazolyl, isoxazolyl or pyridinyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, methyl, methoxy or
  • R 12 very particularly preferably represents C 3 -C 6 -cycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano or methyl,
  • R 12 is very particularly preferably C 3 -C 6 -cycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano or methyl.
  • R 12 is very particularly preferably tetrahydropyranyl, or piperidinyl, which is unsubstituted or monosubstituted by methyl.
  • R 12 is most preferably a group
  • R 12 is most preferably a group
  • R 13 is preferably hydrogen, C 1 -C 3 -alkyl or fluoro-C 1 -C 3 -alkyl-.
  • R 13 particularly preferably represents hydrogen, methyl or ethyl. In the general formula (I), R 13 very particularly preferably represents hydrogen or methyl.
  • R 12 and R 13 are particularly preferably taken together with the nitrogen atom to which they are attached, for monocyclic heterocyclyl of 4 to 7
  • Ring atoms or bridged C0-Cio-heterocycloalkyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, methyl, ethyl,
  • R 12 and R 13 very particularly preferably together with the Nitrogen atom to which they are attached, for pyrrolidinyl, piperidinyl, piperazinyl,
  • Morpholinyl, thiomorpholinyl, azepinyl or 2,5-diazabicyclo [2.2.1] heptyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, methyl, hydroxymethyl or -C ( 0 ) -NH2.
  • R 12 and R 13 are most preferably in common with the
  • R 12 is very particularly preferably C t -C 6 -alkyl-, which is unsubstituted
  • C 1 -C 6 -alkyl which is mono-, di- or trisubstituted by identical or different substituents with hydroxyl, fluorine, cyano, methoxy, dimethylamino, acetylamino, cyclopropyl, pyrrolidinyl, piperidinyl, morpholinyl , Imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, imidazolyl, furyl, pyrazolyl or pyridinyl,
  • Tetrahydrofuryl- and Tetrahydropyranyl- are in turn unsubstituted or mono- or disubstituted by identical or different substituents with oxo or methyl, and wherein phenyl, imidazolyl, furyl, pyrazolyl and pyridinyl are unsubstituted or once or twice, the same or differently substituted with methyl,
  • phenyl, pyrazolyl, isoxazolyl or pyridinyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, methyl, methoxy or
  • R 13 very particularly preferably represents hydrogen or methyl
  • R 12 is very particularly preferably C t -C 6 -alkyl-, which is unsubstituted
  • Tetrahydrofuryl- and Tetrahydropyranyl- are in turn unsubstituted or mono- or disubstituted by identical or different substituents with oxo or methyl, and wherein phenyl, imidazolyl, furyl, pyrazolyl and pyridinyl are unsubstituted or once or twice, the same or differently substituted with methyl,
  • R 13 very particularly preferably represents hydrogen or methyl
  • R very particularly preferably represents C 3 -C 6 -cycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano or methyl,
  • phenyl, pyrazolyl, isoxazolyl or pyridinyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, methyl, methoxy or
  • R 13 very particularly preferably represents hydrogen or methyl
  • Benzodiazepine skeleton represented stereocenter preferably either racemic or predominantly or completely in the ( ⁇ configuration before.
  • Benzodiazepine skeleton represented preferred stereocenter stereocenter before.
  • Benzodiazepine skeleton represented stereocenter particularly preferably predominantly or completely in the ( ⁇ configuration before.
  • Benzodiazepine skeleton represented stereocentre most preferably predominantly in the (S) configuration.
  • Alkyl stands for a linear or branched, saturated, monovalent hydrocarbon radical with generally 1 to 6 (C 1 -C 6 -alkyl), preferably 1 to 4 (C 1 -C 4 -alkyl), and particularly preferably 1 to 3 carbon atoms (C 1 -C 3 -alkyl).
  • Particularly preferred is a methyl, ethyl, propyl, isopropyl or ieri-butyl radical.
  • Cycloalkyl- stands for a monocyclic, saturated, monovalent hydrocarbon radical having generally 3 to 10 (C 3 -C 10 -cycloalkyl) atoms, preferably 3 to 7 carbon atoms
  • Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.
  • C 1 -C 6 -cycloalkenyl, C 1 -C 5 -cycloalkenyl, C 1 -C 10 -cycloalkenyl or C 5 -C 8 -cycloalkenyl is a monocyclic, mono- or polyunsaturated, non-aromatic aromatic ring system with 4 to 6, 4 to 8 atoms, or 5 to 8 atoms to understand. Examples are cyclobuten-1-yl, cyclopenten-1-yl, cyclohexene-2-yl, cyclohexene-1-yl and cycloocta-2,5-dienyl.
  • 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 Ci-Cö-alkoxy-Ce-Ce-alkyl or Ci-Cs-alkoxy-Ci-Cs-alkyl.
  • Ci-C6-alkoxy-Ci-C6-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 to form a carbonyl group Preferably, the bond to carbon to form a carbonyl group, and the
  • 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 represents, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms each
  • Examples include:
  • Phenylamino- represents a radical Ph-NH- or a radical Ph-N (Ci-C3-alkyl) -. Examples include:
  • Phenylamino methylphenylamino and ethyl-phenylamino. Preference is given to N-phenylamino.
  • Alkylthio is a linear or branched, saturated radical of the formula -S-alkyl having generally 1 to 4 (C 1 -C 4 -alkylthio), preferably 1 to 3 (C 1 -C 3 -alkylthio) carbon atoms. Examples and preferred are:
  • a C 1 -C 3 -alkylcarbonyl radical is to be understood as meaning a C 1 -C 3 -alkyl-C (0O) group. Preference is given to acetyl or propanoyl.
  • Methylaminosulfonyl ethylaminosulfonyl, dimethylaminosulfonyl.
  • Heteroatoms are oxygen, nitrogen or sulfur atoms.
  • Heteroaryl means in the context of the present invention, a monovalent monocyclic aromatic ring system consisting of 5 or 6 ring atoms having at least one heteroatom. As heteroatoms nitrogen atoms, oxygen atoms or sulfur atoms can occur. The bond valency may be at any aromatic carbon atom or at a nitrogen atom.
  • 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 monounsaturated or polyunsaturated but non-aromatic monocyclic ring system having at least one heteroatom.
  • Heteroatoms can be nitrogen atoms, oxygen atoms or sulfur atoms.
  • a monocyclic heterocyclyl ring according to the present invention may have 4 to 8, preferably 4 to 6, particularly preferably 5 or 6 ring atoms.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 4 ring atoms are: azetidinyl, oxetanyl.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl.
  • azepanyl By way of example and with preference for monocyclic heterocyclyl radicals having 7 ring atoms, mention may be made of azepanyl, oxepanyl, 1,3-diazepanyl, 1,4-diazepanyl-.
  • Exemplary and preferred for monocyclic heterocyclyl radicals having 8 ring atoms are: oxocanyl, azocanyl.
  • monocyclic heterocyclyl radicals preference is given to 4 to 6-membered, saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S.
  • Cs-Cn-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.
  • Carbon atoms through heteroatoms as defined above in any combination is to be understood as meaning a fusion of two saturated ring systems sharing in common two directly neighboring atoms. Examples are bicyclo [2.2.0] hexyl, bicyclo [3.3.0] octyl,
  • bridged ring system such as C6-Ci2 bridged Coe-Cn-cycloalkyl or bridged C6-Ci2 heterocycloalkyl is understood to mean a fusion of at least two saturated rings which share two atoms which are not directly adjacent to each other.
  • bridged carbocycle bridged cycloalkyl
  • bridged heterocycle bridged Heterocycloalkyl-
  • Examples are bicyclo [2.2.1] heptyl, azabicyclo [2.2.1] heptyl, oxazabicyclo [2.2.1] heptyl, thiazabicyclo [2.2.1] heptyl,
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl represents an alkyl radical having at least one halogen substituent.
  • a halo-Ci-Cö-alkyl radical is an alkyl radical having 1-6 carbon atoms and at least one halogen substituent. If several halogen substituents are present, they may also be different. Preference is given to fluorine-Ci-Cö-alkyl and fluoro-Ci-C t-alkyl, particularly preferred are fluorine-Ci-Cs-alkyl radicals.
  • Trifluoromethyl 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,5,5,5-pentafluoropentyl or
  • perfluorinated alkyl radicals such as trifluoromethyl or Pentafluorethyl-.
  • 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 halogen substituents are present, they may also be different. Preference is given to fluorine-C 1 -C 6 -alkoxy, fluorine-C 1 -C 4 -alkoxy radicals, particular preference to fluorine-C 1 -C 3 -alkoxy radicals.
  • Haloalkylthio is an alkylthio radical having at least one halogen substituent.
  • a halo-C 1 -C 4 -alkylthio radical is an alkylthio radical having 1-4 carbon atoms and at least one halogen substituent. If several halogen substituents are present, they may also be different. Preference is given to fluorine-C 1 -C 3 -alkylthio radicals. Examples and also preferred are:
  • Hydroxyalkyl- hydroxyalkyl- represents an alkyl radical having at least one hydroxy substituent.
  • a hydroxy-C 1 -C 6 -alkyl radical is an alkyl radical consisting of 1-6 carbon atoms and at least one hydroxy substituent. Preference is given to hydroxy-C 1 -C 3 -alkyl radicals, particularly preferably hydroxymethyl- and 2-hydroxyethyl-. aminoalkyl
  • Aminoalkyl- stands for an alkyl radical having at least one amino substituent.
  • amino-Ci-Cö-alkyl radical is an alkyl radical consisting of 1-6 carbon atoms and at least one amino substituent. Preference is given to amino-C 1 -C 3 -alkyl radicals, particularly preferably aminomethyl- and 2-aminoethyl-.
  • Alkylaminoalkyl- represents an alkyl radical substituted with 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.
  • alkylaminoalkyl- examples include -Dimefhylaminoefhyl-, A ⁇ -Dimethylaminomethyl-, N, N-diethylaminoethyl, / V, / V-dimethylaminopropyl, / V-methylaminoethyl, -Methylaminomethyl-.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. But are also included salts that are not suitable for pharmaceutical applications but for example for the isolation or purification of the Compounds according to the invention can be used.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of
  • Hydrochloric hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds of the invention further include base addition salts of, for example, alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, or ammonium salts derived from ammonia or organic amines containing from 1 to 16 carbon atoms, such as Example methylamine, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine,
  • alkali metals such as sodium or potassium
  • alkaline earth metals such as calcium or magnesium
  • ammonium salts derived from ammonia or organic amines containing from 1 to 16 carbon atoms such as Example methylamine, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanol
  • arginine lysine, ethylenediamine, / V-methylpiperidine, methylglucamine, dimethylglucamine, ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol,
  • 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 etches 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 Tetramethylammonium, tetraethylammonium, 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 can, depending on their structure in
  • the compounds according to the invention have an asymmetric center on the carbon atom to which R 2 is bonded (C-4). They can therefore be present as pure enantiomers, racemates, but also as diastereomers or mixtures thereof, if one or more of the substituents described in the formula (I) another
  • Asymmetrieelement contains, for example, a chiral carbon atom.
  • the present invention therefore also encompasses diastereomers and their respective mixtures. From the mixtures mentioned, the pure enantiomers and diastereomers can be isolated in a known manner; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on chiral or achiral phase. As a rule, 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 2 is (-configured.)
  • Another subject of the present invention are stereoisomeric mixtures of the (45) -configured compounds of the invention with their (4R) Isomers, in particular the corresponding racemates, of the further diastereomeric and enantiomeric mixtures in which the (45) -form predominates If the compounds according to the invention can occur in tautomeric forms, 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 here to mean a compound in which at least one atom within the compound according to the invention is bound to another atom of the same atomic number, but with is replaced by a different atomic mass than the usual or predominantly occurring in nature atomic mass.
  • 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), U C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C, 82 Br, 123 1, 124 L 129 I and 131 L
  • Certain isotopic variants of a compound of the invention, such as in particular those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or the distribution of active ingredient in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • 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
  • 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 application which release the compounds according to the invention rapidly and modified, and which contain the compounds according to the invention in crystalline, amorphized or may contain dissolved form such as tablets (uncoated or coated tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), rapidly disintegrating in the oral cavity tablets or films / wafers, films / lyophilisates, capsules (for example, hard or soft gelatin 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., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and
  • Infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Other routes of administration are suitable, for example Inhalation medicines (i.a.
  • Ophthalmic preparations vaginal capsules, aqueous suspensions (lotions, shake 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 are pharmaceutical 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 humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts to change the osmotic pressure or buffers are used.
  • Remington's Pharmaceutical Science 15th ed. Mack Publishing Company, East Pennsylvania (1980).
  • the pharmaceutical formulations can be any suitable pharmaceutical formulations.
  • auxiliaries may be, for example, salts, saccharides (mono-, di-, tri-, oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils,
  • Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • the present invention relates to the compounds of the invention.
  • They can be used for the prophylaxis and treatment of human diseases, in particular tumors.
  • the compounds of the invention can be used in particular to the
  • the compounds according to the invention are particularly suitable for the prophylaxis and therapy of hyper-proliferative diseases such as
  • BPH benign prostatic hyperplasia
  • tumors for example, 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, the bones as well as the 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 bronchial carcinomas such as squamous cell carcinoma
  • Adenocarcinoma large cell carcinoma
  • tumors of the brain are treatable
  • tumors of the male reproductive organs are treatable: prostate cancers,
  • tumors of the female reproductive organs are treatable:
  • tumors of the gastrointestinal tract are treatable:
  • Gastrointestinal stromal tumors As tumors of the urogenital tract, for example, 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:
  • 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 carcinoma breast cancer, especially of hormone receptor negative, Hormone receptor-positive or BRCA-associated breast carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma and colorectal
  • the compounds according to the invention can be used particularly advantageously for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as, for example, endometriosis, leiomyoma and benign prostatic hyperplasia.
  • the compounds according to the invention are also suitable for the fertility control of the man.
  • the compounds according to the invention are also suitable for the prophylaxis and therapy of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.
  • the compounds according to the invention are also suitable for the prophylaxis and therapy of inflammatory or autoimmune diseases such as, for example:
  • Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatoses, especially Boeck's disease
  • Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic or proliferative processes all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms in degenerative joint disease
  • Vasculitides Panarterilitis nodosa, temporal artery, erythema nodosum
  • Dermatological disorders associated with inflammatory, allergic and / or proliferative processes atopic dermatitis; Psoriasis; Pityriasis rubra pilaris; erythematous diseases induced by different noxae, e.g.
  • Kidney diseases associated with inflammatory, allergic and / or proliferative processes nephrotic syndrome; all nephritis
  • Liver diseases associated with inflammatory, allergic or proliferative processes acute liver cell decay; acute hepatitis of different causes, e.g. viral, toxic, drug-induced; Chronic aggressive and / or chronic intermittent hepatitis
  • Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, e.g.
  • Proctological diseases associated with inflammatory, allergic and / or proliferative processes analgesic; fissures; Hemorrhoids; idiopathic proctitis Eye diseases associated with inflammatory, allergic or proliferative processes: allergic keratitis, uveitis, ulceris; conjunctivitis; blepharitis; Neuritis nervi optici; Chlorioditis; Opthalmia sympathica
  • Neurological diseases associated with inflammatory, allergic or proliferative processes brain edema, especially tumor-related cerebral edema; Multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, eg BNS cramps
  • Blood disorders associated with inflammatory, allergic or proliferative processes acquired hemolytic anemia; idiopathic thrombocytopenia
  • Tumor diseases associated with inflammatory, allergic and / or proliferative processes acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in mammary, bronchial and
  • Severe states of shock e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • Emesis associated with inflammatory, allergic or proliferative processes e.g. in combination with a 5-HT3 antagonist in cytostatic vomiting - pain of inflammatory genesis, e.g. lumbago
  • the compounds according to the invention are also suitable for the treatment of viral
  • Diseases such as infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses, including HIV-associated kidney disease.
  • the compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, periferous vascular diseases, cardiovascular diseases, angina, ischemia, stroke, heart failure, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.
  • 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, Alzheimers disease and Parkinson's disease.
  • Another object of the present application are the compounds of the invention for use as medicaments, in particular for the prophylaxis and therapy of
  • the present invention further relates to the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Hormone receptor-positive or BRCA-associated breast carcinoma pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma and colorectal
  • the present invention further relates to the compounds according to the invention for the prophylaxis and therapy of leukemias, in particular acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas,
  • 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 therapy of
  • the present application further relates to 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 carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma,
  • 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 carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma,
  • 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 therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular
  • Estrogen receptor-alpha negative breast carcinoma melanoma or multiple myeloma.
  • Another object of the present application is the use of the compounds of the invention for the prophylaxis and therapy of tumor diseases.
  • the present application further relates to the use of the compounds according to the invention for the prophylaxis and 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,
  • 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 carcinoma pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma and colorectal
  • 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 myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, breast cancers, in particular estrogen receptor-alpha-negative breast carcinomas, melanomas or multiple myelomas.
  • leukemias in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, breast cancers, in particular estrogen receptor-alpha-negative breast carcinomas, melanomas or multiple myelomas.
  • 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 cancer especially androgen receptor-positive prostate cancer
  • Hormone receptor-positive or BRCA-associated breast carcinoma pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma and colorectal Carcinomas.
  • 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 myeloid leukemias,
  • Prostate cancer especially androgen receptor-positive prostate cancer
  • 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 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.
  • Another object of the present invention are therefore pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the prophylaxis and therapy of the aforementioned diseases.
  • the compounds according to the invention can be used with known anti-hyperproliferative, cytostatic or cytotoxic substances which are used to treat
  • Angiogenesis show positive effects.
  • the compounds according to the invention can also be combined with recombinant proteins.
  • the compounds of the invention may also be used in combination with antihormones and steroidal metabolic enzyme inhibitors which are particularly suitable because of their favorable side effect profile.
  • the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.
  • Transformations include reactions that introduce a functional group that allows further conversion of substituents.
  • Suitable protecting groups as well as methods for their introduction and removal are known to those skilled in the art (see, for example, T.W. Greene and P.G.M. Wuts in: Protective Groups in Organic Synthesis, 4th Edition, Wiley 2006).
  • the combination of two or more reaction steps without intermediate workup in a manner known in the art is possible (for example, in so-called “one-pot” reactions).
  • Metal carbonyl complexes are used, e.g. Dicobaltoctacarbonyl (see
  • a methodical alternative to the introduction of Carboxygmppe in compounds of the formula (IIIa) or (FFLB) consists in the familiar to those skilled metalation of halogenated precursors, such as the bromophenyl benzodiazepines of the formula (IIa) or (IIb), to form organolithium or organolithium compounds followed by reaction with carbon dioxide (see, for example, Bioorganic and Medicinal Chemistry, 1999, 7, 1597-1610).
  • benzoic acid derivatives of the formula (IIIa) or (IIIb) can then be coupled with amines of the formula R 12 R 13 NH, in which R 12 and R 13 are defined as for the general formula (I), to form carboxamides of the formula (I) ,
  • R 12 and R 13 are defined as for the general formula (I)
  • carboxamides of the formula (I) for this purpose, a variety of methods are available to the person skilled in the art (see, for example, "Compendium of Organic Synthetic Methods", Volume I-VI
  • T3P propanephosphonic acid anhydride
  • a base preferably triethylamine or N-ethyl- / V-isopropyl-2-amine
  • COMU ⁇ [(Z) - (1-cyano-2-ethoxy-2-] oxoethylidene) amino] oxy ⁇ - / V, / V-dimethylmorpholin-4-ylmethaneiminium hexafluorophosphate
  • Scheme 1 Preparation of the compounds of the general formula (I) from bromophenyl precursors of the formulas (IIa) or (IIb).
  • Percentage yield data (in% of Th) may be purity-adjusted.
  • Method 2 Instrument: Waters Acquity Platform ZQ4000; Column: Waters BEHC 18, 50 mm x 2.1 mm, 1.7 ⁇ ; Eluent A: water / 0.05% AS, eluent B: ACN / 0.05% AS; Gradient: 0.0 min 98% A ⁇ 0.2 min: 98% A ⁇ 1.7 min: 10% A ⁇ 1.9 min: 10% A ⁇ 2 min: 98% A ⁇ 2.5 min: 98 % A; Flow: 1.3 ml / min; Column temperature: 60 ° C; UV detection: 200-400 nm.
  • Method 3 UPLC-SQD-HCOOH; Instrument: Waters Acquity UPLC-MS SQD; Column: Acquity UPLC BEH C18 1,7 50x2,1mm; Eluent A: water + 0.1% by volume formic acid (99%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 ml / min; Temperature: 60 ° C; Injection: 2 ⁇ ; DAD scan: 210-400 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).
  • preparative RP-HPLC denotes purification on commercially available preparative HPLC plants using commercially available reversed phase materials as the stationary phase mobile phase are gradients of water and acetonitrile, optionally with the addition of small amounts of formic acid, trifluoroacetic acid or ammonia as additives used.
  • the mixture was filtered, washed with ethyl acetate, and the organic phase was washed three times with saturated aqueous sodium chloride solution, dried with sodium sulphate and the solvent was removed on a rotary evaporator. The residue was purified by chromatography. 466 mg (10% of theory) of the product were obtained as a dark solid.
  • Example 1.1A was prepared starting from (4R) -1- (4-bromophenyl) -7,8-dimethoxy- / V, 4-dimethyl-4,5-dihydro-3i7-2,3-benzodiazepine-3-carboxamide, which is analogous to that in WO2014128067
  • Example 1A can be prepared analogously synthesized according to the production voucher indicated for the preparation of Example 1A.
  • Example 1.2A was prepared starting from (+) - 4- [7,8-dimethoxy-4-methyl-3-
  • Example 1.2A 4 - [(4 L S ') - 7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3ii-2,3-benzodiazepin-1-yl] benzoic acid
  • Example 1.2A From Example 1, Example 1.2A and the corresponding commercially available amines were prepared analogously to Example 1: CAS number name
  • Example 1A The compounds in the following table were prepared in analogy to the preparation of Example 6 either from the racemic carboxylic acid (+) - 4- [7,8-dimethoxy-4-methyl-3- [(methylamino) carbonyl] -4,5-dihydro -3ii-2,3-benzodiazepin-1-yl] benzoic acid (Example 1A) or from 4 - [(4R) -7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3ii 2,3-benzodiazepin-1-yl] benzoic acid (Example 1.1A).
  • (+) - 4- [7,8-dimethoxy-4-methyl-3 - [(methylamino) carbolyl] -4,5-dihydro-3i-2 were dissolved in 10 ml of THF, 3-benzodiazepin-l-yl] benzoic acid (example 1A) provided 79.8 mg (0.4 mmol) of the commercially available ieri-butyl (l l S, 4 l S) -2,5-diazabicyclo [2.2.1] heptane 2-carboxylate (CAS [113451-59-5]) and 175 ⁇ / V ethyl / V-isopropylpropan-2-amine (1.0 mmol).
  • Example 1A Analogously to Example 1, from Example 1A and the corresponding commercially available amines were:
  • Protein-protein interaction assay binding assay BRD4 / acetylated peptide H4
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the Ac-H4 peptide may be derived from e.g. Biosyntan (Berlin, Germany).
  • Assay buffer [50 mM HEPES pH 7.5, 50 mM sodium chloride (NaCl), 0.25 mM CHAPS and 0.05% serum albumin (BSA)] to the substances in the assay plate. This was followed by a 10 minute incubation step at 22 ° C for the pre-equilibration of putative complexes between BRD4 (1) and the substances.
  • 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 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 (1).
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the recombinant BRD4 (2) protein produced in house by Filippakopoulos et al., Cell, 2012, 149: 214-231 was expressed in E. coli and purified by (Ni-NTA) affinity and (Sephadex G-75) size exclusion chromatography.
  • the Ac-H4 peptide may be derived from e.g. Biosyntan (Berlin, Germany).
  • Assay buffer [50 mM HEPES pH 7.5, 50 mM sodium chloride (NaCl); 50 mM potassium fluoride (KF); 0.25 mM CHAPS and 0.05% serum albumin (BSA)] to the substances in the test plate. This was followed by a 10 minute incubation step at 22 ° C for the pre-equilibration of putative

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Abstract

L'invention concerne des carboxamides inhibant les protéines à bromodomaine, en particulier les protéines BET, de préférence la BRD4, de formule générale (I), dans laquelle R2, R3, R3, R4 et R5 sont tels que définis dans la description. L'invention concerne également des substances pharmaceutiques contenant les composés selon l'invention ainsi que leur utilisation prophylactique et thérapeutique dans le cas de maladies hyperprolifératives, en particulier dans le cas de maladies tumorales. De plus, l'utilisation d'inhibiteurs des protéines BET est décrite dans les hyperplasies bénignes, les maladies athérosclérotiques, la septicémie, les maladies auto-immunes, les maladies vasculaires, les infections virales, les maladies rénales associées au VIH, les maladies neurodégénératives, les maladies inflammatoires, les maladies athérosclérotiques, l'insuffisance cardiaque, les dystrophies musculaires, comme par exemple la dystrophie musculaire fascio-scapulo-humérale et dans les contrôles de la fertilité masculine.
PCT/EP2015/074214 2014-10-23 2015-10-20 Dérivés de 1-phényl-4,5-dihydro-3h-2,3-benzodiazépines Ceased WO2016062688A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5519019A (en) * 1990-12-21 1996-05-21 Gyogyszerkutato Intezet N-acyl-2,3-benzoidazepine derivatives, pharmaceutical compositions containing them and process for preparing same
US5807851A (en) * 1996-04-04 1998-09-15 Egis Gyogyszergyar Rt. 2,3-Benzodiazepine Derivatives as non-competitive AMPA
WO2001098280A2 (fr) * 2000-06-16 2001-12-27 Annovis, Inc. Antagonistes 5h-2,3-benzodiazepine de recepteurs d'acide amine excitateurs
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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5519019A (en) * 1990-12-21 1996-05-21 Gyogyszerkutato Intezet N-acyl-2,3-benzoidazepine derivatives, pharmaceutical compositions containing them and process for preparing same
US5807851A (en) * 1996-04-04 1998-09-15 Egis Gyogyszergyar Rt. 2,3-Benzodiazepine Derivatives as non-competitive AMPA
WO2001098280A2 (fr) * 2000-06-16 2001-12-27 Annovis, Inc. Antagonistes 5h-2,3-benzodiazepine de recepteurs d'acide amine excitateurs
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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021152113A1 (fr) 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Dérivés de 2,3-benzodiazépines substitués

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