DE102017005089A1 - Substituted 3,4-dihydroquinoxaline-2 (1H) -one - Google Patents

Abstract

The present invention relates to BET protein-inhibiting, in particular BRD4-inhibitory substituted 3,4-dihydroquinoxaline-2 (1H) -ones of the general formula I in which R1, R2, R3, R4, R4, R5 and R6 have the meanings given in the description , Intermediates for the preparation of the compounds according to the invention, pharmaceutical agents containing the compounds according to the invention and their prophylactic and therapeutic use in hyper-proliferative diseases, in particular in tumor diseases. Furthermore, this invention relates to the use of BET protein inhibitors in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.

Description

The present invention relates to BET protein-inhibiting, in particular BRD4-inhibitory 3,4-dihydroquinoxaline-2 (1H) -ones, intermediates for the preparation of the compounds of the invention, pharmaceutical compositions containing the compounds of the invention and their prophylactic and therapeutic use in hyper-proliferative diseases, especially in tumor diseases. Furthermore, this invention relates to the use of BET protein inhibitors in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.

The human BET family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and BRDT) that contain two related bromodomains and one extra-terminal domain ( Wu and Chiang, J. Biol. Chem., 2007, 282: 13141-13145 ). The bromodomains are protein regions that recognize acetylated lysine residues. Such acetylated lysines are often found at the N-terminal end of histones (eg histone H3 or histone H4) and are features of open chromatin structure and active gene transcription ( Kuo and Allis, Bioessays, 1998, 20: 615-626 ). In addition, bromodomains can recognize additional acetylated proteins. For example, BRD4 binds to RelA, resulting in the stimulation of NF-κB and transcriptional activity of inflammatory genes ( Huang et al., Mol. Cell. Biol., 2009, 29: 1375-1387 ). BRD4 also binds to cyclin T1 and forms an active complex important for transcription elongation ( Schröder et al., J. Biol. Chem., 2012, 287: 1090-1099 ). 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 Cellular Biol., 2011, 31: 2641-2652 ).

Mechanistically, BET proteins play an important role in cell growth and cell cycle. They are associated with mitotic chromosomes, suggesting a role in epigenetic memory ( Dey et al., Mol. Biol. Cell, 2009, 20: 4899-4909 ; Yang et al., Mol. Cell. Biol., 2008, 28: 967-976 ). A role of BRD4 in the post-mitotic reactivation of gene transcription has been investigated ( Zhao et al., Nat. Cell. Biol., 2011, 13: 1295-1304 ). BRD4 is essential for transcription elongation and recruits the elongation complex P-TEFb, which consists of CDK9 and cyclin T1, which leads to the activation of RNA polymerase II ( Yang et al., Mol. Cell, 2005, 19: 535-545 ; Schröder et al., J. Biol. Chem., 2012, 287: 1090-1099 ). Thus, the expression of genes involved in cell proliferation, such as c-myc, cyclin D1 and aurora B ( You et al., Mol. Cell. Biol., 2009, 29: 5094-5103 ; Zuber et al., Nature, 2011, doi: 10.1038 ). BRD2 is involved in the regulation of target genes of the androgen receptor ( Draker et al., PLOS Genetics, 2012, 8, e1003047 ). BRD2 and BRD3 bind to transcribed genes in hyperacetylated chromatin regions and promote transcription by RNA polymerase II ( LeRoy et al., Mol. Cell, 2008, 30: 51-60 ).

The knockdown of BRD4 or the inhibition of the interaction with acetylated histones in different cell lines leads to a G1 arrest ( Mochizuki et al., J. Biol. Chem., 2008, 283: 9040-9048 ; Mertz et al., Proc. Natl. Acad. Sci. USA, 2011, 108: 16669-16674 ). It has also been shown that BRD4 binds to promoter regions of several genes that are activated in the G1 phase, such as cyclin D1 and D2 (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040-9048 ). In addition, an inhibition of the expression of c-Myc, an essential factor in cell proliferation, after 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. Sci. USA, 2011, 108: 16669-16674 ). Inhibition of the expression of androgen-regulated genes and binding of BRD2 to corresponding regulatory regions has also been demonstrated ( Draker et al., PLOS Genetics, 2012, 8, e1003047 ).

BRD2 and BRD4 knockout mice die early 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 due to reduced cell proliferation ( Cell, Biol., 2002, 22: 3794-3802 ). BET proteins play an important role in various tumor types. The fusion between the BET proteins BRD3 or BRD4 and NUT, a protein that is normally expressed only in the testes, leads to 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 ). Screening for therapeutic targets in an acute myeloid leukemia cell line (AML) showed that BRD4 plays an important role in this tumor ( Zuber et al., Nature, 2011, 478, 524-528 ). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML Xenografts in vivo. Further trials with a BRD4 inhibitor show that BRD4 plays a role in various hematological tumors, such as multiple myeloma ( Delmore et al., Cell, 2011, 146, 904-917 ) and Burkitt's Lymphoma ( Mertz et al., Proc. Natl. Acad. Sci. USA, 2011, 108, 16669-16674 ). BRD4 also plays an important role in solid tumors, such as lung cancer ( Lockwood et al., Proc. Natl. Acad. Sci. USA, 2012, 109, 19408-19413 ). Increased expression of BRD4 was found in multiple myeloma, and amplification of the BRD4 gene was also found in patients with multiple myeloma ( Delmore et al., Cell, 2011, 146, 904-917 ). Amplification of the DNA region containing the BRD4 gene was detected in primary breast tumors (K adota et al., Cancer Res, 2009, 69: 7357-7365 ). Also for BRD2 there is data related to a role in tumors. A transgenic mouse that selectively expresses BRD2 in B cells develops B-cell lymphomas and leukemias ( Greenwald et al., Blood, 2004, 103: 1475-1484 ).

BET proteins are also involved in viral infections. BRD4 binds to the E2 protein of various papillomaviruses and is important for the survival of viruses in latently infected cells ( Wu et al., Genes Dev., 2006, 20: 2383-2396 ; Vosa et al., J. Virol., 2006, 80: 8909-8919 ). Also, the herpesvirus responsible for Kaposi's sarcoma interacts with various BET proteins, which is important for disease resistance ( Viejo-Borbolla et al., J. Virol., 2005, 79: 13618-13629 ; You et al., J. Virol., 2006, 80: 8909-8919 ). By binding to P-TEFb, BRD4 also plays an important role in the replication of HIV-1 ( Bisgrove et al., Proc. Natl Acad. Sci. USA, 2007, 104: 13690-13695 ). Treatment with a BRD4 inhibitor stimulates the dormant, untreatable reservoir of HIV-1 virus in T cells ( Banerjee et al., J. Leukoc. Biol., 2012, 92, 1147-1154 ). This reactivation could allow for new treatment options for AIDS treatment ( Zinchenko et al., J. Leukoc. Biol., 2012, 92, 1127-1129 ). A critical role of BRD4 in DNA replication of polyomaviruses has also been reported ( Wang et al., PLoS Pathog., 2012, 8, doi: 10.1371 ).

BET proteins are also involved in inflammatory processes. BRD2-hypomorphic mice show a reduced inflammation in adipose tissue ( Wang et al., Biochem. J., 2009, 425: 71-83 ). The infiltration of macrophages in white adipose tissue is reduced in BRD2-deficient mice ( Wang et al., Biochem. J., 2009, 425: 71-83 ). It has also been shown that BRD4 regulates a number of genes involved in inflammation. In LPS-stimulated macrophages, a BRD4 inhibitor prevents the expression of inflammatory genes, such as IL-1 or IL-6 ( Nicodeme et al., Nature, 2010, 468: 1119-1123 ).

BET proteins are also involved in the regulation of the ApoA1 gene ( Mirguet et al., Bioorg. Med. Chem. Lett., 2012, 22: 2963-2967 ). The corresponding protein is part of the higher density lipoprotein (HDL), which plays an important role in atherosclerosis ( Smith, Arterioscler. Thromb. Vasc. Biol., 2010, 30: 151-155 ). By stimulating ApoA1 expression, BET protein inhibitors may increase the levels of cholesterol HDL and thus be potentially useful for the treatment of atherosclerosis ( Mirguet el al., Bioorg. Med. Chem. Lett., 2012, 22: 2963-2967 ).

The BRDT BET protein plays an essential role in spermatogenesis by regulating the expression of several genes important during and after meiosis ( Shang et al., Development, 2007, 134: 3507-3515 ; Matzuk et al., Cell, 2012, 150: 673-684 ). Furthermore, BRDT is involved in the post-meiotic organization of chromatin ( Dhar et al., J. Biol. Chem., 2012, 287: 6387-6405 ). In vivo experiments in the mouse show that treatment with a BET inhibitor, which also inhibits BRDT, leads to a decrease in sperm production and infertility ( Matzuk et al., Cell, 2012, 150: 673-684 ).

All these studies show that the BET proteins play an essential role in various pathologies and also in male fertility. It would therefore be desirable to find potent and selective inhibitors that prevent the interaction between the BET proteins and acetylated proteins, particularly acetylated histone H4 peptides. These new inhibitors should also have suitable pharmacokinetic properties that allow in vivo, ie in the patient, to inhibit these interactions.

It has now been found that substituted dihydropyridopyrazinones have the desired properties, i. H. show a BET protein-inhibitory, in particular a BRD4 protein-inhibitory activity. The compounds according to the invention thus represent valuable active ingredients for prophylactic and therapeutic use in hyper-proliferative diseases, in particular in tumor diseases. Furthermore, the compounds according to the invention can be used in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control come.

State of the art

The nomenclature used in the consideration of the prior art (derived from the nomenclature software ACD Name batch, version 12.01, from Advanced Chemical Development, Inc.) is illustrated by the following figures:

With regard to the chemical structure, only very few types of BRD4 inhibitors have been described so far ( Chun-Wa Chung et al., Progress in Medicinal Chemistry 2012, 51, 1-55 ). The first published BRD4 inhibitors were diazepines. So z. Phenyl-thienotriazolo-1,4-diazepines (4-phenyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-α] [1,4] diazepines) WO2009 / 084693 (Mitsubishi Tanabe Pharma Corporation) and as compound JQ1 in WO2011 / 143669 (Dana Farber Cancer Institute). The replacement of the thieno by a benzo unit also leads to active inhibitors ( J. Med. Chem. 2011, 54, 3827-3838; E. Nicodeme et al., Nature 2010, 468, 1119 ). Other 4-phenyl-6H-thieno [3,2]] [1,2,4] triazolo [4,3-α] [1,4] diazepines and related compounds with alternative rings as the fusion partner instead of the benzo moiety become generic claimed or explicitly described in WO2012 / 075456 (Constellation Pharmaceuticals).

Azepines as BRD4 inhibitors are recently described in the WO2012 / 075383 (Constellation Pharmaceuticals). This application relates to 6-substituted-4H-isoxazolo [5,4-d] [2] benzazepines and 4H-isoxazolo [3,4-d] [2] benzazepines, including those compounds which have optionally substituted phenyl at position 6 and also analogs with alternative heterocyclic fusion partners instead of the benzo moiety, such as. B. thieno or Pyridoazepine. Another structural class of BRD4 inhibitors is described as 7-isoxazoloquinolines and related quinolone derivatives ( Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967 ). In WO2011 / 054845 (GlaxoSmithKline), other benzodiazepines are described as BRD4 inhibitors.

WO 2014/026997 . WO 2014/128067 . WO 2014/202578 . WO2015 / 121226 . WO2015 / 121230 . WO2015 / 121227 and WO2015 / 121268 disclose 1-phenyl and 1-heteroaryl-4,5-dihydro-3H-2,3-benzodiazepines as inhibitors of BET proteins, in particular of BRD4, inter alia for the treatment of hyperproliferative diseases. Of the compounds disclosed in these applications, the compounds of the present invention differ by the benzodiazepine skeleton.

WO2015 / 104653 (Aurigene Discovery Technologies) describes bicyclic heterocycles as bromodomain inhibitors. In this application, inter alia quinoxaline-2 (1H) -ones are described, which are substituted in the 6-position with heteroaromatic groups.

WO 2015/193228 and WO 193/193229 disclose 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -ones and WO 2015/193217 and WO 2015/193219 disclose 3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -ones as inhibitors of BET proteins, in particular BRD4, inter alia for the treatment of hyperproliferative disorders. The 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -ones are in the 7-position and the 3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -ones are substituted in the 6-position with an aromatic amino or ether group, while the compounds of the present invention are substituted on the one hand in the corresponding position directly and not via an N or O atom linked to an aromatic group and on the other another have a bicyclic skeleton.

Due to these essential structural differences, it was not to be expected that the compounds claimed here would also be BRD4-inhibitory. It is therefore surprising that the compounds according to the invention have a good inhibitory effect despite these structural differences.

Some writings contain structurally similar, but to completely different mechanisms of action and partly also other indications directed connections. Dihydropyridopyrazinones and related bicyclic systems are described in a number of patent applications.

WO 2010/085570 (Takeda Pharmaceutical Company) describes inhibitors of poly-ADP-ribose polymerase (PARP) derived from a series of bicyclic and tricyclic scaffolds, and 3,4-dihydropyrido [2,3-b] pyrazine-2 (1H ) -one derivatives, as a medicament for the treatment of various diseases. The example compounds disclosed therein differ from the compounds according to the invention for example by the type and position of the substitution on the pyrido part of the dihydropyridopyrazinone skeleton.

WO 2006/005510 (Boehringer Ingelheim) describes 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives as inhibitors of PLK-1 for the treatment of hyperproliferative diseases.

WO 2008/117061 (Sterix Ltd) describes a number of bicyclic chemotypes as inhibitors of steroid sulfatase, inter alia, for use in inhibiting the growth of tumors.

US 2006/0019961 (PE Mahaney et al.) Describes substituted 3,4-dihydroquinoxaline-2 (1H) -one derivatives as modulators of the estrogen receptor for the treatment of various inflammatory, cardiovascular and autoimmune diseases.

WO 2006/050054 . WO 2007/134169 and US 2009/0264384 (Nuada LLC) describe a number of bicyclic chemotypes as inhibitors of tumor necrosis factor alpha (TNF-α) as well as various isoforms of phosphodiesterase for the treatment of, among others, inflammatory diseases.

WO 2012/088314 (Agios Pharmaceuticals) discloses a series of bicyclic chemotypes as modulators of pyruvate kinase M2.

WO 2003/020722 and WO 2004/076454 (Boehringer Ingelheim) disclose 7,8-dihydropteridine-6 (5H) -ones as inhibitors of specific cell cycle kinases for the treatment of hyperproliferative diseases.

WO 2006/018182 (Boehringer Ingelheim) describes pharmaceutical preparations of 7,8-dihydropteridine-6 (5H) -ones in combination, inter alia, with various cytostatics for the treatment of tumor diseases.

WO 2006/018185 (Boehringer Ingelheim) describes the use of 7,8-dihydropteridine-6 (5H) -ones for the therapy of various tumor diseases.

WO 2011/101369 (Boehringer Ingelheim), WO 2011/113293 (Jiangsu Hengrui Medicine), WO 2009/141575 (Chroma Therapeutics) WO 2009/071480 (Nerviano Medical Sciences), as well WO 2006/021378 . WO 2006/021379 and WO 2006/021548 (also Boehringer Ingelheim) disclose further 7,8-dihydropteridine-6 (5H) -one derivatives as inhibitors of PLK-1 for the treatment of hyperproliferative disorders.

US 6,369,057 describes various quinoxaline and quinoxalinone derivatives as antiviral agents; EP 0657166 and EP 728481 describe combinations of such compounds with nucleosides or protease inhibitors with antiviral activity.

WO 2007/022638 (Methylgene Inc.) generally disclose HDAC inhibitors of several chemotypes, however, the structures of the exemplified compounds disclosed differ significantly from the compounds of the present invention.

WO 1999/050254 (Pfizer) describes a number of bicyclic chemotypes as inhibitors of serine proteases for antithrombotic therapy, but these compounds differ significantly by the nature and position of the substituents of the inventive compounds.

Some of C-6 having an aromatic amino group, the phenyl group of which in turn is substituted with a para-terminal amide group, substituted 3,4-dihydroquinoxaline-2 (1H) -one derivatives (corresponding to 2-oxo-1,2,3,4 Tetrahydroquinoxaline derivatives) are indexed by Chemical Abstracts as "Chemical Library" substances without literature reference [see 4 - {[(3R) -4-cyclopentyl-3-ethyl-1-methyl-2-oxo-1,2,3 , 4-tetrahydroquinoxalin-6-yl] amino} -3-methoxy-N- [2-methyl-1- (pyrrolidin-1-yl) -propan-2-yl] -benzamide, CAS Registry-No. 1026451-60-4, N- (1-Benzylpiperidin-4-yl) -4 - {[(3R) -4-cyclopentyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline 6-yl] amino} -3-methoxybenzamide, CAS registry no. 1026961-36-3, 4 - {[(3R) -4-cyclohexyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl] amino} -N- [1- (dimethylamino) -2-methylpropan-2-yl] -3-methoxybenzamide, CAS Registry-No. 1025882-57-8]. A therapeutic application is not yet described for these compounds.

Nevertheless, there is still a great need for selectively effective compounds for the prophylaxis and treatment of diseases, in particular hyperproliferative diseases, and especially of tumor diseases.

in der
R¹ für eine Gruppe -C(=O)NR⁷R⁸, -S(=O)₂NR⁷R⁸, -NR⁹S(=O)₂R¹⁰, -S(=O)₂R¹⁰ oder Cyano steht,
R² für Wasserstoff, Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Halogenalkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkoxy oder Phenoxy steht, worin Phenoxy gegebenenfalls ein-, zwei- oder dreifach, gleich oder verschieden substituiert sein kann mit Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkyl oder C₁-C₄-Halogenalkoxy,
R³ für Methyl oder Ethyl steht,
R⁴ und R⁵ unabhängig voneinander für Wasserstoff oder C₁-C₃-Alkyl stehen,
oder
R⁴ und R⁵ gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, eine Cyclopropylgruppe oder Cyclobutylgruppe bilden,
R⁶ für C₁-C₃-Alkyl steht, das gegebenenfalls einfach substituiert sein kann mit C₂-C₃-Alkoxy, C₃-C₆-Cycloalkyl-, Phenyl oder 4- bis 8-gliedrigem Heterocycloalkyl,
worin C₃-C₆-Cycloalkyl und 4- bis 8-gliedriges Heterocycloalkyl gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit Halogen oder C₁-C₃-Alkyl,
und
worin Phenyl gegebenenfalls ein-, zwei- oder dreifach, gleich oder verschieden substituiert sein kann mit Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkyl oder C₁-C₄-Halogenalkoxy,
oder
für C₃-C₆-Cycloalkyl oder 4- bis 8-gliedriges Heterocycloalkyl steht, die gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit C₁-C₃-Alkyl, C₁-C₃-Halogenalkyl oder -C(=O)OR¹¹,
und
worin 4- bis 8-gliedriges Heterocycloalkyl mit dem Rest des Moleküls über ein Kohlenstoffatom des 4- bis 8-gliedrigen Heterocycloalkyls verbunden ist,
R⁷ und R⁸ unabhängig voneinander für Wasserstoff, C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl stehen,
worin das C₁-C₄-Alkyl mit C₃-C₆-Cycloalkyl substituiert sein kann, oder
R⁷ und R⁸ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, für 4- bis 8-gliedriges Heterocycloalkyl oder C₅-C₁₁-Heterospirocycloalkyl stehen, die gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit Halogen oder C₁-C₃-Alkyl,
R⁹ für Wasserstoff steht,
R¹⁰ für C₁-C₄-Alkyl, C₃-C₆-Cycloalkyl, C₁-C₄-Halogenalkyl oder 4- bis 8-gliedriges Heterocycloalkyl steht,
worin C₃-C₆-Cycloalkyl gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein kann mit Halogen,
und
worin 4- bis 8-gliedriges Heterocycloalkyl mit dem Rest des Moleküls über ein Kohlenstoffatom des 4- bis 8-gliedrigen Heterocycloalkyls verbunden ist,
oder
R⁹ und R¹⁰ gegebenenfalls so miteinander verbunden sind, dass sie gemeinsam für eine Gruppe *-(CH₂)₂-*, *-(CH₂)₃-* oder *-(CH₂)₄-* stehen, worin ”*” die Anknüpfungspunkte an den Rest des Moleküls bedeuten,
R¹¹ für C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl steht,
sowie deren Diastereomere, Racemate, Polymorphe und physiologisch verträglichen Salze, überraschenderweise die Interaktion zwischen BRD4 und einem acetylierten Histon 4-Peptid inhibieren und somit das Wachstum von Krebs- und Tumorzellen hemmen.It has now been found that compounds of the general formula (I)

in the
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -NR ⁹ S (= O) ₂ R ¹⁰ , -S (= O) ₂ R ¹⁰ or Cyano stands,
R ^{2 is} hydrogen, halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy or phenoxy, in which phenoxy optionally may be mono- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
R ^{3 is} methyl or ethyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or C ₁ -C ₃ -alkyl,
or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group or cyclobutyl group,
R ^{6 is} C ₁ -C ₃ -alkyl which may optionally be monosubstituted by C ₂ -C ₃ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl or 4 to 8-membered heterocycloalkyl,
in which C ₃ -C ₆ -cycloalkyl and 4- to 8-membered heterocycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
and
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
is C ₃ -C ₆ -cycloalkyl or 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen, C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl,
wherein the C ₁ -C ₄ alkyl may be substituted by C ₃ -C ₆ cycloalkyl, or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, are 4- to 8-membered heterocycloalkyl or C ₅ -C ₁₁ -heterospirocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl or 4- to 8-membered heterocycloalkyl,
in which C ₃ -C ₆ -cycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
or
R ⁹ and R ^{10 are} optionally joined together such that they together represent a group * - (CH ₂ ) ₂ - *, * - (CH ₂ ) ₃ - * or * - (CH ₂ ) ₄ - *, in which * "Signify the points of attachment to the rest of the molecule,
R ^{11 is} C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl,
and their diastereomers, racemates, polymorphs and physiologically acceptable salts, surprisingly inhibit the interaction between BRD4 and an acetylated histone 4-peptide and thus inhibit the growth of cancer and tumor cells.

Preference is given to those compounds of the general formula (I) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -NR ⁹ S (= O) ₂ R ¹⁰ or -S (= O) ₂ R ¹⁰ .
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or C ₁ -C ₃ -alkyl,
or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group,
R ^{6 is} C ₁ -C ₃ -alkyl, which may optionally be monosubstituted with phenyl,
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
represents 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₄ -alkyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, represent 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} C ₁ -C ₄ -alkyl,
R ^{11 is} C ₁ -C ₄ -alkyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Very particular preference is given to those compounds of the general formula (I) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ or -NR ⁹ S (= O) ₂ R ¹⁰ ,
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or methyl,
R ^{6 is} methyl, which may be monosubstituted with phenyl,
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
represents 6-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein the 6-membered heterocycloalkyl is linked to the remainder of the molecule via a carbon atom of the 6-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen or methyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, represent 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} methyl,
R ^{11 is} tert-butyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Very particular preference is given to those compounds of the general formula (I) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ or -NR ⁹ S (= O) ₂ R ¹⁰ ,
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ^{4 is} methyl,
R ^{5 is} hydrogen,
R ^{6 is} benzyl, piperidin-4-yl or 1- (tert-butoxycarbonyl) piperidin-4-yl,
R ⁷ and R ⁸ independently of one another represent hydrogen or methyl,
or
R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent morpholin-4-yl,
R ^{9 is} hydrogen,
R ^{10 is} methyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

in der
R¹ für eine Gruppe -C(=O)NR⁷R⁸, -S(=O)₂NR⁷R⁸, -NR⁹S(=O)₂R¹⁰, -S(=O)₂R¹⁰ oder oder Cyano steht,
R² für Wasserstoff, Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Halogenalkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkoxy oder Phenoxy steht,
worin Phenoxy gegebenenfalls ein-, zwei- oder dreifach, gleich oder verschieden substituiert sein kann mit Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkyl oder C₁-C₄-Halogenalkoxy,
R³ für Methyl oder Ethyl steht,
R⁴ und R⁵ unabhängig voneinander für Wasserstoff oder C₁-C₃-Alkyl stehen,
oder
R⁴ und R⁵ gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, eine Cyclopropylgruppe oder Cyclobutylgruppe bilden,
R⁶ für C₁-C₃-Alkyl steht, das gegebenenfalls einfach substituiert sein kann mit C₂-C₃-Alkoxy, C₃-C₆-Cycloalkyl-, Phenyl oder 4- bis 8-gliedrigem Heterocycloalkyl,
worin C₃-C₆-Cycloalkyl und 4- bis 8-gliedriges Heterocycloalkyl gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit Halogen oder C₁-C₃-Alkyl,
und
worin Phenyl gegebenenfalls ein-, zwei- oder dreifach, gleich oder verschieden substituiert sein kann mit Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkyl oder C₁-C₄-Halogenalkoxy,
oder
für C₃-C₆-Cycloalkyl oder 4- bis 8-gliedriges Heterocycloalkyl steht, die gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit C₁-C₃-Alkyl, C₁-C₃-Halogenalkyl oder -C(=O)OR¹¹,
und
worin 4- bis 8-gliedriges Heterocycloalkyl mit dem Rest des Moleküls über ein Kohlenstoffatom des 4- bis 8-gliedrigen Heterocycloalkyls verbunden ist,
R⁷ und R⁸ unabhängig voneinander für Wasserstoff, C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl stehen,
worin das C₁-C₄-Alkyl mit C₃-C₆-Cycloalkyl substituiert sein kann,
oder
R⁷ und R⁸ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, für 4- bis 8-gliedriges Heterocycloalkyl oder C₅-C₁₁-Heterospirocycloalkyl stehen, die gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit Halogen oder C₁-C₃-Alkyl,
R⁹ für Wasserstoff steht,
R¹⁰ für C₁-C₄-Alkyl, C₃-C₆-Cycloalkyl, C₁-C₄-Halogenalkyl oder 4- bis 8-gliedriges Heterocycloalkyl steht,
worin C₃-C₆-Cycloalkyl gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein kann mit Halogen,
und
worin 4- bis 8-gliedriges Heterocycloalkyl mit dem Rest des Moleküls über ein Kohlenstoffatom des 4- bis 8-gliedrigen Heterocycloalkyls verbunden ist,
oder
R⁹ und R¹⁰ gegebenenfalls so miteinander verbunden sind, dass sie gemeinsam für eine Gruppe *-(CH₂)₂-*, *-(CH₂)₃-* oder *-(CH₂)₄-* stehen, worin ”*” die Anknüpfungspunkte an den Rest des Moleküls bedeuten,
R¹¹ für C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl steht,
sowie deren Diastereomere, Racemate, Polymorphe und physiologisch verträglichen Salze.Preference is given to compounds of the general formula (Ia)

in the
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -NR ⁹ S (= O) ₂ R ¹⁰ , -S (= O) ₂ R ¹⁰ or or cyano stands,
R ^{2 is} hydrogen, halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy or phenoxy,
wherein phenoxy may optionally be mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
R ^{3 is} methyl or ethyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or C ₁ -C ₃ -alkyl,
or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group or cyclobutyl group,
R ^{6 is} C ₁ -C ₃ -alkyl which may optionally be monosubstituted by C ₂ -C ₃ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl or 4 to 8-membered heterocycloalkyl,
in which C ₃ -C ₆ -cycloalkyl and 4- to 8-membered heterocycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
and
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
is C ₃ -C ₆ -cycloalkyl or 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen, C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl,
wherein the C ₁ -C ₄ -alkyl may be substituted by C ₃ -C ₆ -cycloalkyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, are 4- to 8-membered heterocycloalkyl or C ₅ -C ₁₁ -heterospirocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl or 4- to 8-membered heterocycloalkyl,
in which C ₃ -C ₆ -cycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
or
R ⁹ and R ^{10 are} optionally joined together such that they together represent a group * - (CH ₂ ) ₂ - *, * - (CH ₂ ) ₃ - * or * - (CH ₂ ) ₄ - *, in which * "Signify the points of attachment to the rest of the molecule,
R ^{11 is} C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Preference is given to those compounds of the general formula (Ia) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -NR ⁹ S (= O) ₂ R ¹⁰ or -S (= O) ₂ R ¹⁰ .
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or C ₁ -C ₃ -alkyl,
or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group,
R ^{6 is} C ₁ -C ₃ -alkyl, which may optionally be monosubstituted with phenyl,
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
represents 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₄ -alkyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, represent 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} C ₁ -C ₄ -alkyl,
R ^{11 is} C ₁ -C ₄ -alkyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Very particular preference is given to those compounds of the general formula (Ia) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ or -NR ⁹ S (= O) ₂ R ¹⁰ ,
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or methyl,
R ^{6 is} methyl, which may be monosubstituted with phenyl,
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
represents 6-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein the 6-membered heterocycloalkyl is linked to the remainder of the molecule via a carbon atom of the 6-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen or methyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, represent 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} methyl,
R ^{11 is} tert-butyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Very particular preference is given to compounds of the general formula (Ia) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ or -NR ⁹ S (= O) ₂ R ¹⁰ ,
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ^{4 is} methyl,
R ^{5 is} hydrogen,
R ^{6 is} benzyl, piperidin-4-yl or 1- (tert-butoxycarbonyl) piperidin-4-yl,
R ⁷ and R ⁸ independently of one another represent hydrogen or methyl,
or
R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent morpholin-4-yl,
R ^{9 is} hydrogen,
R ^{10 is} methyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

in der
R¹ für eine Gruppe -C(=O)NR⁷R⁸, -S(=O)₂NR⁷R⁸, -NR⁹S(=O)₂R¹⁰, -S(=O)₂R¹⁰ oder Cyano steht,
R² für Wasserstoff, Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Halogenalkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkoxy oder Phenoxy steht,
worin Phenoxy gegebenenfalls ein-, zwei- oder dreifach, gleich oder verschieden substituiert sein kann mit Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkyl oder C₁-C₄-Halogenalkoxy,
R³ für Methyl oder Ethyl steht,
R⁴ und R⁵ unabhängig voneinander für Wasserstoff oder C₁-C₃-Alkyl stehen,
oder
R⁴ und R⁵ gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, eine Cyclopropylgruppe oder Cyclobutylgruppe bilden,
R⁶ für C₁-C₃-Alkyl steht, das gegebenenfalls einfach substituiert sein kann mit C₂-C₃-Alkoxy, C₃-C₆-Cycloalkyl-, Phenyl oder 4- bis 8-gliedrigem Heterocycloalkyl,
worin C₃-C₆-Cycloalkyl und 4- bis 8-gliedriges Heterocycloalkyl gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit Halogen oder C₁-C₃-Alkyl,
und
worin Phenyl gegebenenfalls ein-, zwei- oder dreifach, gleich oder verschieden substituiert sein kann mit Halogen, Cyano, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Halogenalkyl oder C₁-C₄-Halogenalkoxy,
oder
für C₃-C₆-Cycloalkyl oder 4- bis 8-gliedriges Heterocycloalkyl steht, die gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit C₁-C₃-Alkyl, C₁-C₃-Halogenalkyl oder -C(=O)OR¹¹,
und
worin 4- bis 8-gliedriges Heterocycloalkyl mit dem Rest des Moleküls über ein Kohlenstoffatom des 4- bis 8-gliedrigen Heterocycloalkyls verbunden ist,
R⁷ und R⁸ unabhängig voneinander für Wasserstoff, C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl stehen,
worin das C₁-C₄-Alkyl mit C₃-C₆-Cycloalkyl substituiert sein kann,
oder
R⁷ und R⁸ gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, für 4- bis 8-gliedriges Heterocycloalkyl oder C₅-C₁₁-Heterospirocycloalkyl stehen, die gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein können mit Halogen oder C₁-C₃-Alkyl,
R⁹ für Wasserstoff steht,
R¹⁰ für C₁-C₄-Alkyl, C₃-C₆-Cycloalkyl, C₁-C₄-Halogenalkyl oder 4- bis 8-gliedriges Heterocycloalkyl steht,
worin C₃-C₆-Cycloalkyl gegebenenfalls ein- oder zweifach, gleich oder verschieden substituiert sein kann mit Halogen,
und
worin 4- bis 8-gliedriges Heterocycloalkyl mit dem Rest des Moleküls über ein Kohlenstoffatom des 4- bis 8-gliedrigen Heterocycloalkyls verbunden ist,
oder
R⁹ und R¹⁰ gegebenenfalls so miteinander verbunden sind, dass sie gemeinsam für eine Gruppe *-(CH₂)₂-*, *-(CH₂)₃-* oder *-(CH₂)₄-* stehen, worin ”*” die Anknüpfungspunkte an den Rest des Moleküls bedeuten,
R¹¹ für C₁-C₄-Alkyl oder C₃-C₆-Cycloalkyl steht,
sowie deren Diastereomere, Racemate, Polymorphe und physiologisch verträglichen Salze.Preference is given to compounds of the general formula (Ib)

in the
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -NR ⁹ S (= O) ₂ R ¹⁰ , -S (= O) ₂ R ¹⁰ or Cyano stands,
R ^{2 is} hydrogen, halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy or phenoxy,
wherein phenoxy may optionally be mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
R ^{3 is} methyl or ethyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or C ₁ -C ₃ -alkyl,
or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group or cyclobutyl group,
R ^{6 is} C ₁ -C ₃ -alkyl which may optionally be monosubstituted by C ₂ -C ₃ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl or 4 to 8-membered heterocycloalkyl,
in which C ₃ -C ₆ -cycloalkyl and 4- to 8-membered heterocycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
and
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
is C ₃ -C ₆ -cycloalkyl or 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen, C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl,
wherein the C ₁ -C ₄ -alkyl may be substituted by C ₃ -C ₆ -cycloalkyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, are 4- to 8-membered heterocycloalkyl or C ₅ -C ₁₁ -heterospirocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl or 4- to 8-membered heterocycloalkyl,
in which C ₃ -C ₆ -cycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
or
R ⁹ and R ^{10 are} optionally joined together such that they together represent a group * - (CH ₂ ) ₂ - *, * - (CH ₂ ) ₃ - * or * - (CH ₂ ) ₄ - *, in which * "Signify the points of attachment to the rest of the molecule,
R ^{11 is} C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Preference is given to those compounds of the general formula (Ib) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -NR ⁹ S (= O) ₂ R ¹⁰ or -S (= O) ₂ R ¹⁰ .
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or C ₁ -C ₃ -alkyl,
or
R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group,
R ^{6 is} C ₁ -C ₃ -alkyl, which may optionally be monosubstituted with phenyl,
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
represents 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₄ -alkyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, represent 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} C ₁ -C ₄ -alkyl,
R ^{11 is} C ₁ -C ₄ -alkyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Very particular preference is given to those compounds of the general formula (Ib) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ or -NR ⁹ S (= O) ₂ R ¹⁰ ,
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ⁴ and R ⁵ independently of one another represent hydrogen or methyl,
R ^{6 is} methyl, which may be monosubstituted with phenyl,
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
represents 6-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
and
wherein the 6-membered heterocycloalkyl is linked to the remainder of the molecule via a carbon atom of the 6-membered heterocycloalkyl,
R ⁷ and R ⁸ independently of one another represent hydrogen or methyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, represent 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
R ^{9 is} hydrogen,
R ^{10 is} methyl,
R ^{11 is} tert-butyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Very particular preference is given to compounds of the general formula (Ib) in which
R ^{1 is} a group -C (= O) NR ⁷ R ⁸ or -NR ⁹ S (= O) ₂ R ¹⁰ ,
R ^{2 is} hydrogen,
R ^{3 is} methyl,
R ^{4 is} methyl,
R ^{5 is} hydrogen,
R ^{6 is} benzyl, piperidin-4-yl or 1- (tert-butoxycarbonyl) piperidin-4-yl,
R ⁷ and R ⁸ independently of one another represent hydrogen or methyl,
or
R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent morpholin-4-yl,
R ^{9 is} hydrogen,
R ^{10 is} methyl,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Preference is given to compounds of the general formula (I) in which R ^{1 is} a group -C (OO) NR ⁷ R ⁸ , -S (OO) ₂ NR ⁷ R ⁸ , -NR ⁹ S (OO) ₂ R ¹⁰ , -S (= O) ₂ R ¹⁰ or cyano.

Preference is given to compounds of the general formula (I) in which R ^{1 is} a group -C (OO) NR ⁷ R ⁸ , -S (OO) ₂ NR ⁷ R ⁸ , -NR ⁹ S (OO) ₂ R ¹⁰ or -S (= O) ₂ R ¹⁰ .

Preference is given to compounds of the general formula (I) in which R ^{1 is} a group -C (OO) NR ⁷ R ⁸ or -NR ⁹ S (OO) ₂ R ¹⁰ .

Preference is given to compounds of the general formula (I) in which R ^{1 is} a -C (= O) NR ⁷ R ^{8 group} .

Preference is given to compounds of the general formula (I) in which R ^{1 represents} a group -NR ⁹ S (= O) ₂ R ¹⁰ .

Preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ Halogenoalkoxy or phenoxy, in which phenoxy may optionally be mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - Haloalkyl or C ₁ -C ₄ haloalkoxy.

Preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen.

Preference is given to compounds of the general formula (I) in which R ^{3 is} methyl or ethyl.

Preference is given to compounds of the general formula (I) in which R ^{3 is} methyl.

Preference is given to compounds of the general formula (I) in which R ⁴ and R ^5, independently of one another, are hydrogen or C ₁ -C ₃ -alkyl,
or
in which R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group or cyclobutyl group.

Preference is given to compounds of the general formula (I) in which R ⁴ and R ^5, independently of one another, are hydrogen or C ₁ -C ₃ -alkyl,
or
in which R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl group.

Preference is given to compounds of the general formula (I) in which R ⁴ and R ⁵ independently of one another are hydrogen or methyl.

Preference is given to compounds of the general formula (I) in which R ^{4 is} methyl.

Preference is given to compounds of the general formula (I) in which R ^{5 is} hydrogen.

Preference is given to compounds of the general formula (I) in which R ^{4 is} methyl and R ^{5 is} hydrogen.

Preference is given to compounds of the general formula (I) in which R ^{6 is} C ₁ -C ₃ -alkyl which may optionally be monosubstituted by C ₂ -C ₃ -alkoxy, C ₃ -C ₆ -cycloalkyl-, phenyl or 4- to 8-membered heterocycloalkyl,
in which C ₃ -C ₆ -cycloalkyl and 4- to 8-membered heterocycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl,
and
wherein phenyl optionally mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
is C ₃ -C ₆ -cycloalkyl or 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ ,
wherein 4- to 8-membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl.

Preference is given to compounds of the general formula (I) in which R ^{6 is} C ₁ -C ₃ -alkyl which may optionally be monosubstituted by phenyl, in which phenyl may optionally be mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
represents 4- to 8-membered heterocycloalkyl, which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or -C (= O) OR ¹¹ , wherein 4- to 8-membered heterocycloalkyl is bonded to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl.

Preference is given to compounds of the general formula (I) in which R ^{6 is} methyl which may optionally be monosubstituted by phenyl, in which phenyl may optionally be mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy,
or
represents 6-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (OO) OR ¹¹ , in which the membered heterocycloalkyl is linked to the rest of the molecule via a carbon atom of the 6-membered heterocycloalkyl.

Preference is given to compounds of the general formula (I) in which R ^{6 is} benzyl, piperidin-4-yl or 1- (tert-butoxycarbonyl) piperidin-4-yl.

Preference is given to compounds of the general formula (I) in which R ^{6 is} benzyl.

Preference is given to compounds of the general formula (I) in which R ^{6 is} piperidin-4-yl.

Preference is given to compounds of the general formula (I) in which R ^{6 is} 1- (tert-butoxycarbonyl) piperidin-4-yl.

Preference is given to compounds of the general formula (I) in which R ⁷ and R ⁸ independently of one another are hydrogen, C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl, in which the C ₁ -C ₄ -alkyl is substituted by C ₃ -C ₆ -cycloalkyl may be substituted,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, are 4- to 8-membered heterocycloalkyl or C ₅ -C ₁₁ -heterospirocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl.

Preference is given to compounds of the general formula (I) in which R ⁷ and R ^8, independently of one another, are hydrogen or C ₁ -C ₄ -alkyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, are 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl.

Preference is given to compounds of the general formula (I) in which R ⁷ and R ^8, independently of one another, are hydrogen or methyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, are 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl.

Preference is given to compounds of the general formula (I) in which R ⁷ and R ^8, independently of one another, are hydrogen or methyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, represent morpholin-4-yl.

Preference is given to compounds of the general formula (I) in which R ⁷ and R ^8, independently of one another, are hydrogen or methyl.

Compounds of general formula (I), in which ⁷ and R ^8, R together with the nitrogen atom to which they are attached represent 4- to 8-membered heterocycloalkyl, which is optionally mono- or disubstituted, preferred are be the same or different substituents may be halogen or C ₁ -C ₃ alkyl.

Preference is given to compounds of the general formula (I) in which R ⁷ and R ⁸ together with the nitrogen atom to which they are attached are morpholin-4-yl.

Preference is given to compounds of the general formula (I) in which R ^{9 is} hydrogen and R ^{10 is} C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl or 4 to 8 is a membered heterocycloalkyl,
in which C ₃ -C ₆ -cycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen,
and wherein 4- to 8-membered heterocycloalkyl is linked to the remainder of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl,
or
R ⁹ and R ^{10 are} optionally joined together such that they together represent a group * - (CH ₂ ) ₂ - *, * - (CH ₂ ) ₃ - * or * - (CH ₂ ) ₄ - *, in which * "Signify the points of attachment to the rest of the molecule.

Preference is given to compounds of the general formula (I) in which R ^{9 is} hydrogen.

Preference is given to compounds of the general formula (I) in which R ^{10 is} C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C ₁ -C ₄ -haloalkyl, in which C ₃ -C ₆ -cycloalkyl is optionally one - or may be di-substituted, the same or different, with halogen.

Preference is given to compounds of the general formula (I) in which R ⁹ and R ¹⁰ are bonded together in such a way that they together represent a group * - (CH ₂ ) ₂ - *, * - (CH ₂ ) ₃ - * or * - (CH ₂ ) ₄ - *, where "*" represents the points of attachment to the rest of the molecule.

Preference is given to compounds of the general formula (I) in which R ^{10 is} C ₁ -C ₄ -alkyl.

Preference is given to compounds of the general formula (I) in which R ^{10 is} methyl.

Preference is given to compounds of the general formula (I) in which R ^{11 is} C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl.

Preference is given to compounds of the general formula (I) in which R ^{11 is} C ₁ -C ₄ -alkyl.

Preference is given to compounds of the general formula (I) in which R ^{11 is} tert-butyl.

The radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced, irrespective of the particular combinations of radicals indicated, by any definitions of radicals of other combinations.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

Very particular preference is given to the following compounds of general formula (I):
N- {3 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] phenyl} methanesulfonamide
N- {2 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] phenyl} methanesulfonamide
2 - [-4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl (3R)] benzamide,
2 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] -N, N-dimethylbenzamide,
3 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] -N-methylbenzamide,
(3R) -4-benzyl-1,3-dimethyl-6- [3- (morpholin-4-ylcarbonyl) phenyl] -3,4-dihydro-2 (1H-one,
3 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] -N, N-dimethylbenzamide,
3 - [-4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl (3R)] benzamide,
tert-butyl 4 - [(2R) -2,4-dimethyl-7- {3 - [(methylsulfonyl) amino] phenyl} -3-oxo-3,4-dihydro-1 (2H) -yl] piperidine 1-carboxylate,
tert-butyl 4 - [(2R) -7- (2-carbamoylphenyl) -2,4-dimethyl-3-oxo-3,4-dihydro-1 (2H) -yl] piperidine-1-carboxylate,
tert-butyl 4 - [(2 R) -7- [2- (dimethylcarbamoyl) phenyl] -2,4-dimethyl-3-oxo-3,4-dihydro-1 (2H) -yl] piperidine-1-carboxylate .
tert -Butyl 4 - [(2R) -2,4-dimethyl-7- [3- (morpholin-4-ylcarbony1) phenyl] -3-oxo-3,4-dihydroquinoxaline-1 (2H) -yl] piperidine-1-carboxylate,
tert-butyl 4 - [(2R) -2,4-dimethyl-7- {2 - [(methylsulfonyl) amino] phenyl} -3-oxo-3,4-dihydro-1 (2H) -yl] piperidine 1-carboxylate,
tert-butyl 4 - [(2R) -7- (3-carbamoylphenyl) -2,4-dimethyl-3-oxo-3,4-dihydro-1 (2H) -yl] piperidine-1-carboxylate,
N- {3 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] -phenyl} -methanesulfonamide,
(3R) -1,3-dimethyl-6- [3- (morpholin-4-ylcarbonyl) phenyl] -4- (piperidin-4-yl) -3,4-dihydro-2 (1H) -one,
N- {2 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] -phenyl} -methanesulfonamide,
2 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] -N, N-dimethylbenzamide,
2 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] benzamide, and
3 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] benzamide,
as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

definitions:

The term "substituted" means that one or more hydrogens on the designated atom or group are replaced by a selection from the group indicated, provided that the normal valence of the designated atom has not been exceeded under the present circumstances becomes. Combinations of substituents and / or variables are permissible.

If radicals are substituted in the compounds according to the invention, the radicals can, unless stated otherwise, be monosubstituted or polysubstituted. Within the scope of the present invention, the meanings of all residues that occur multiple times are independent of each other. Substitution by one, two or three identical or different substituents is preferred. Substitution by a substituent is particularly preferred.

The terms mentioned in the present text preferably have the following meaning: The term "halogen atom" denotes a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

The term "C ₁ -C ₄ -alkyl" denotes a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3 or 4 carbon atoms, e.g. As a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group. The group has in particular 1, 2 or 3 carbon atoms ("C ₁ -C ₃ -alkyl"), z. As a methyl, ethyl, propyl or isopropyl group.

The term "C ₁ -C ₄ haloalkyl" refers to a straight or branched chain saturated monovalent hydrocarbon group in which the term "C ₁ -C ₄ alkyl" is as defined above and in which one or more of the hydrogen atoms are represented by the same or different Halogen atoms are replaced. The halogen atom is in particular fluorine. The C ₁ -C ₄ -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1 , 3-difluoropropane-2-yl.

The term "C ₁ -C ₄ -alkoxy" denotes a straight-chain or branched saturated monovalent group of the formula (C ₁ -C ₄ -alkyl) -O-, in which the term "C ₁ -C ₄ -alkyl" as defined above is, for. As a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy group.

The term "C ₁ -C ₄ haloalkoxy" refers to a straight-chain or branched saturated monovalent C ₁ -C ₄ alkoxy group as defined above in which one or more of the hydrogen atoms is replaced by identical or different halogen atoms. The halogen atom is in particular fluorine. The C ₁ -C ₄ -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

The term "C ₃ -C ₆ cycloalkyl" refers to a saturated monovalent hydrocarbon ring having 3, 4, 5 or 6 carbon atoms ("C ₃ -C ₆ cycloalkyl"). The C ₃ -C ₆ cycloalkyl group is to Example, a monocyclic hydrocarbon ring, z. As a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "4- to 8-membered heterocycloalkyl" refers to a monocyclic saturated heterocycle having a total of 4 to 8 ring atoms and containing one or two identical or different ring heteroatoms from the group consisting of N, O and S.

The heterocycloalkyl group may be, but is not limited to, for example, a 4-membered ring such as azetidinyl, oxetanyl or thietanyl; or a 5-membered ring such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl; or a 6-membered ring such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, or a 7-membered ring such as azepanyl, 1, 4-diazepanyl or 1,4-oxazepanyl.

The term "heterospirocycloalkyl" refers to a bicyclic saturated heterocycle having a total of 5, 6, 7, 8, 9, 10 or 11 ring atoms in which the two rings share a common ring carbon atom, wherein the "heterospirocycloalkyl" is one or two of the same contains various ring heteroatoms from the group N, O and S; the heterospirocycloalkyl group may be attached to the remainder of the molecule via any of the carbon atoms except the spiro carbon atom or, if present, a nitrogen atom.

The heterospirocycloalkyl group is, for example, azaspiro [2.3] hexyl, azaspiro [3.3] heptyl, oxaazaspiro [3.3] heptyl, thiaazaspiro [3.3] heptyl, oxaspiro [3.3] heptyl, oxazaspiro [5.3] nonyl, oxazaspiro [4.3] octyl , Oxazaspiro [5.5] undecyl, diazaspiro [3.3] heptyl, thiazaspiro [3.3] heptyl, thiazaspiro [4.3] octyl, azaspiro [5.5] undecyl or any of the other homologous frameworks such as spiro [3.4] -, spiro [4.4] -, spiro [2.4] -, spiro [2.5] -, spiro [2.6] -, spiro [3.5] -, spiro [3.6] -, spiro [4.5] - and spiro [4.6] -.

The term "C ₁ -C ₄ " as used in this text, e.g. In connection with the definition of "C ₁ -C ₄ -alkyl", "C ₁ -C ₄ -haloalkyl", "C ₁ -C ₄ -alkoxy" or "C ₁ -C ₄ -haloalkoxy", to a An alkyl group having a limited number of carbon atoms of 1 to 4, ie, 1, 2, 3 or 4 carbon atoms.

Furthermore, the term "C ₃ -C ₆ " as used herein, e.g. In the definition of "C ₃ -C ₆ cycloalkyl ^" , to a cycloalkyl group having a limited number of carbon atoms of 3 to 6, ie 3, 4, 5 or 6 carbon atoms.

If a range of values is listed, it should encompass each individual value and sub-ranges within the range.

"C ₁ -C ₄ " is for example C ₁ , C ₂ , C ₃ C ₄ , C ₁ -C ₄ , C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₄ , C ₂ -C ₃ and C ₃ -C ₄ .

For example, "C ₁ -C ₃ " is intended to include C ₁ , C ₂ , C ₃ , C ₁ -C ₃ , C ₁ -C _2, and C ₂ -C ₃ .

For example, "C ₃ -C ₆ " is understood to mean C ₃ , C ₄ , C ₅ , C ₆ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₆ , C ₄ -C ₅ and C ₅ -C ₆ .

For example, "C ₄ -C ₈ " is intended to mean C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₄ -C ₈ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₈ , C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -C ₈ , C ₆ -C ₇ and C ₇ -C ₈ .

For example, "C ₅ -C ₁₁ " is C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₅ -C ₁₁ , C ₅ -C ₁₀ , C ₅ -C ₉ , C ₅ -C ₈ , C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -C ₁₁ , C ₆ -C ₁₀ , C ₆ -C ₉ , C ₆ -C ₈ , C ₆ -C ₇ , C ₇ -C ₁₁ , C ₇ -C ₁₀ , C ₇ -C ₉ , C ₇ -C ₈ , C ₈ -C ₁₁ , C ₈ -C ₁₀ , C ₈ -C ₉ , C ₉ -C ₁₁ , C ₉ -C ₁₀ and C ₁₁ -C ₁₁ include.

Compounds of the invention are the compounds of the general formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas below and their salts, solvates and solvates of the salts of the general formula (I) and of the general formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of the general formula (I), mentioned below, are not already salts, solvates and solvates of the salts.

Also to be considered as encompassed by the present invention is the use of the salts of the compounds of the invention.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, eg. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

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.

The present invention also relates to medicaments comprising the compounds according to the invention together with at least one or more further active compounds, in particular for the prophylaxis and / or therapy of tumor diseases.

Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

Depending on their structure, the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers. The compounds according to the invention can have an asymmetric center on the carbon atom to which the substituents R ⁴ and R ^{5 are} bonded (C-3 or C-2, depending on the R ⁶ group). They may 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) contains a further asymmetric element, for example a chiral carbon atom. The present invention therefore also encompasses diastereomers and their respective mixtures. From such mixtures, the pure stereoisomers 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 enantiomers according to the invention inhibit the target proteins differently and have different activity in the cancer cell lines investigated. The more active enantiomer is preferred, which is often that at which the center of asymmetry represented by the carbon atom attached to R ⁴ and R ^{5 is} (R) -configured.

Another object of the present invention are enantiomeric mixtures of the (3R) - or (2R) -configured compounds according to the invention with their (3S) - or (2S) -enantiomers, in particular the corresponding racemates and mixtures of enantiomers in which the (3R) - or (2R) form predominates.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

The compounds of the general formula (I) can be present as isotopic variants. The invention therefore comprises one or more isotopic variants of the compounds of the general formula (I), in particular deuterium-containing compounds of the general formula (I). The term "isotopic variant" of a compound or reagent is defined as a compound having an unnatural portion of one or more of the isotopes of which such a compound is constructed.

The term "isotopic variant of the compound of general formula (I)" is defined as a compound of general formula (I) having an unnatural portion of one or more of the isotopes constituting such a compound.

By the term "unnatural fraction" is meant a proportion of such an isotope that is higher than its natural abundance. The natural abundances of isotopes to be used in this context are found in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70 (1), 217-235, 1998 ,

Examples of such isotopes are stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹¹ 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 Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I.

With regard to the treatment and / or prophylaxis of the disorders specified here, the isotopic variant (s) of the compounds of the general formula (I) preferably contain deuterium ("deuterium-containing compounds of the general formula (I)"). Isotopic variants of the compounds of general formula (I) incorporating one or more radioactive isotopes such as ³ H or ¹⁴ C are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred for their ease of installation and detectability. In a compound of the general formula (I), positron emitting isotopes such as ¹⁸ F or ¹¹ C can be incorporated. These isotopic variants of the compounds of general formula (I) are suitable for use in in vivo imaging applications. Deuterium-containing and ¹³ C-containing compounds of the general formula (I) can be used in the course of preclinical or clinical studies in mass spectrometry analyzes.

Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to those skilled in the art, such as those described in the Schemes and / or Examples described herein, by replacing a reagent with an isotopic variant of the reagent, preferably a deuterium-containing reagent , Depending on the desired deuteration sites, in some cases deuterium may be incorporated from D ₂ O either directly into the compounds or into reagents that may be used for the synthesis of such compounds. A useful reagent for incorporating deuterium into molecules is also deuterium gas. A rapid route to the incorporation of deuterium is the catalytic deuteration of olefinic bonds and acetylenic bonds. For the direct exchange of hydrogen to deuterium in functional hydrocarbons, metal catalysts (ie Pd, Pt and Rh) in the presence of deuterium gas may also be used. Various deuterated reagents and building blocks are commercially available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

The term "deuterium-containing compound of the general formula (I)" is defined as a compound of the general formula (I) in which one or more hydrogen atoms are replaced by one or more deuterium atoms and in which the frequency of deuterium in each deuterated position of the compound of the general formula (I) is higher than the natural frequency of deuterium, which is about 0.015%. In particular, in a deuterium-containing compound of the general formula (I), the abundance of deuterium in each deuterated position of the compound of the general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70%. or 80%, preferably higher than 90%, 95%, 96% or 97%, still more preferably higher than 98% or 99% in this position or these positions. It is understood that the frequency of deuterium in each deuterated position is independent of the frequency of deuterium in other deuterated positions.

By the selective incorporation of one or more deuterium atoms in a compound of the general formula (I), the physico-chemical properties (such as acidity [ CL Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490 ], Basicity [ CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641 ], Lipophilicity [ B. Tests et al., Int. J. Pharm., 1984, 19 (3), 271 ]) and / or the metabolism profile of the molecule are changed and changes in the ratio of parent compound to metabolites or the amounts of metabolites formed are caused. Such changes may result in certain therapeutic benefits and may therefore be preferred in certain circumstances. There have been reports of decreased metabolic rates and metabolism switching, where the ratio of metabolites changes ( AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102 ). These changes in exposure to parent compound and metabolites can have important consequences with regard to pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases, deuterium replacement reduces or eliminates the formation of an undesirable or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410 ; Efavirenz: AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102 ). In other cases, the main effect of deuteration is to reduce the rate of systemic clearance. This increases the biological half-life of the compound. To the potential clinical Advantages include the ability to maintain a similar systemic exposure with reduced peak levels and elevated trough levels. Depending on the pharmacokinetics / pharmacodynamics relationship of the particular compound, this could lead to fewer side effects and increased efficacy. Examples of this deuterium effect are ML-337 ( CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208 ) and odanacatib (K. Kassahun et al., WO2012 / 112363 ). Other cases have also been reported in which decreased rates of metabolism result in an increase in drug exposure without altering the rate of systemic clearance (eg. Rofecoxib: F. Schneider et al., Medic. Forsch./Drug. Res., 2006, 56, 295 ; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993 ). Deuterated drugs that exhibit this effect may have reduced dosage requirements (eg, lower doses or lower doses to achieve the desired effect) and / or lower metabolite loads.

A compound of general formula (I) may have several potential sites of metabolism. To optimize the above-described effects on physico-chemical properties and metabolism profile, deuterium-containing compounds of general formula (I) having a particular pattern of one or more deuterium-hydrogen exchanges may be chosen. In particular, the deuterium atom (s) of the deuterium-containing compound (s) of general formula (I) is / are attached to a carbon atom and / or are in the positions of the compound of general formula (I) which are sites of attack of metabolizing enzymes such as B. cytochrome P ₄₅₀ is.

In another embodiment, the present invention relates to a deuterium-containing compound of the general formula (I) having 1, 2, 3 or 4 deuterium atoms, in particular having 1, 2 or 3 deuterium atoms.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.

For these routes of administration, the compounds according to the invention can be administered in suitable administration forms.

Suitable for oral administration are all application forms known per se to the person skilled in the art, which can rapidly deliver the compounds according to the invention. The compounds according to the invention may in this case be present in crystalline, amorphous or dissolved form, for example in tablets (non-coated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), in the oral cavity rapidly disintegrating tablets , in films / wafers, in films / lyophilisates, in capsules (for example hard or soft gelatin capsules), in dragees, in granules, in pellets, in powders, in emulsions, in suspensions, in aerosols or in solutions.

Parenteral administration can be done bypassing a resorption step (for example intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration are suitable as application forms u. a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration, for example, inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions, sprays are suitable; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or 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 manner known to those skilled in the art by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include u. a. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.

Another object of the present 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 to the person skilled in the art by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.

As auxiliaries, for example, vehicles, fillers, disintegrants, binders, humectants, lubricants, adsorbents and agents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts to change the osmotic pressure or buffer be used. It is up Remington's Pharmaceutical Science, 15th ed Mack Publishing Company, East Pennsylvania (1980) to point.

The pharmaceutical formulations may be in solid form, for example as tablets, dragees, pills, suppositories, capsules, transdermal systems or in semi-solid form, for example as ointments, creams, gels, suppositories, emulsions or in liquid form, for example as solutions, Tinctures, suspensions or emulsions are present.

Auxiliaries for the purposes of the invention may be, for example, salts, saccharides (mono-, di-, tri-, oligo-, and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.

For oral or oral administration, in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question. For parenteral administration in particular suspensions, emulsions and above all solutions in question.

The compounds according to the invention are suitable for the prophylaxis and / or therapy of hyperproliferative diseases such as, for example, psoriasis, keloids and other skin-related hyperplasias, and for the prophylaxis and / or therapy of benign prostate hyperplasia (BPH), solid tumors and hematological tumors.

As solid tumors according to the invention, 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, are treatable Bone and connective tissue and metastases of these tumors.

For example, as a hematological tumor, multiple myelomas, lymphomas or leukemias are treatable.

Breast tumors, for example, are treatable breast cancers with positive hormone receptor status, breast cancers with negative hormone receptor status, Her-2 positive breast cancers, hormone receptor and Her-2 negative breast cancers, BRCA-associated breast cancers, and inflammatory breast cancer.

Non-small cell lung carcinomas and small cell bronchial carcinomas, for example, are treatable as tumors of the respiratory tract.

For example, tumors of the brain are treatable by gliomas, glioblastomas, astrocytomas, meningiomas and medulloblastomas.

For example, tumors of the male reproductive organs are treatable prostate carcinomas, malignant epididymal tumors, malignant testicular tumors and penile carcinomas.

For example, endometrial carcinomas, cervical carcinomas, ovarian carcinomas, vaginal carcinomas and vulvar cancers are treatable as tumors of the female reproductive organs.

Treatable tumors of the gastrointestinal tract include, for example, treatable colorectal carcinomas, anal carcinomas, gastric carcinomas, pancreatic carcinomas, esophageal carcinomas, gall bladder carcinomas, small bowel carcinomas, salivary gland carcinomas, neuroendocrine tumors, and gastrointestinal stromal tumors.

For example, tumors of the urogenital tract are treatable by bladder carcinomas, renal cell carcinomas, and carcinomas of the renal pelvis and the urinary tract.

For example, retinoblastomas and intraocular melanomas are treatable as tumors of the eye

Treatable hepatocellular carcinomas and cholangiocellular carcinomas, for example, are tumors of the liver.

For example, treatable tumors of the skin are malignant melanomas, basaliomas, spinaliomas, Kaposi's sarcomas and Merkel cell carcinomas.

For example, tumors of the head and neck are treatable with laryngeal carcinomas and carcinomas of the pharynx and oral cavity.

For example, soft-tissue sarcomas and osteosarcomas are treatable as sarcomas.

For example, non-Hodgkin's lymphomas, Hodgkin's lymphomas, cutaneous lymphomas, central nervous system lymphomas and AIDS-associated lymphomas are treatable as lymphomas.

Treatable as leukemias, for example, are acute myeloid leukemias, chronic myeloid leukemias, acute lymphatic leukemias, chronic lymphocytic leukemias and hair cell leukemias.

Advantageously, the compounds according to the invention can be used for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular of hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinomas, pancreatic carcinomas, Renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma and colorectal carcinoma.

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 cancers, in particular androgen receptor-positive prostate carcinomas, breast cancers, in particular estrogen receptor-alpha-negative breast carcinomas, melanomas or multiple myelomas.

The compounds according to the invention are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as, for example, endometriosis, lineage myoma and benign prostatic hyperplasia.

The compounds according to the invention are also suitable for the prophylaxis and / or therapy of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.

• – Lungenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: chronisch obstruktive Lungenerkrankungen jeglicher Genese, vor allem Asthma bronchiale; Bronchitis unterschiedlicher Genese; alle Formen der restriktiven Lungenerkrankungen, vor allem allergische Alveolitis; alle Formen des Lungenödems, vor allem toxisches Lungenödem; Sarkoidosen und Granulomatosen, insbesondere Morbus Boeck.
• – Rheumatische Erkrankungen/Autoimmunerkrankungen/Gelenkerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: alle Formen rheumatischer Erkrankungen, insbesondere rheumatoide Arthritis, akutes rheumatisches Fieber, Polymyalgia rheumatica; reaktive Arthritis; entzündliche Weichteilerkrankungen sonstiger Genese; arthritische Symptome bei degenerativen Gelenkerkankungen (Arthrosen); traumatische Arthritiden; Kollagenosen jeglicher Genese, beispielsweise systemischer Lupus erythematodes, Sklerodermie, Polymyositis, Dermatomyositis, Sjögren-Syndrom, Still-Syndrom, Felty-Syndrom,
• – Allergien, die mit entzündlichen und/oder proliferativen Prozessen einhergehen: alle Formen allergischer Reaktionen, beispielsweise Quincke Ödem, Heuschnupfen, Insektenstich, allergische Reaktionen auf Arzneimittel, Blutderivate, Kontrastmittel etc., anaphylaktischer Schock, Urtikaria, Kontaktdermatitis,
• – Gefäßentzündugen (Vaskulitiden): Panarterilitis nodosa, Arterilitis temporalis, Erythema nodosum,
• – Dermatologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: atopische Dermatitis; Psoriasis; Pityriasis rubra pilaris; erythematöse Erkrankungen, ausgelöst durch unterschiedliche Noxen, z. B. Strahlen, Chemikalien, Verbrennungen etc.; bullöse Dermatosen; Erkrankungen des lichenoiden Formenkreises; Pruritus; seborrhoisches Ekzem; Rosacea; Pemphigus vulgaris; Erythema exsudativum multiforme; Balanitis; Vulvitis; Haarausfall wie Alopecia areata; kutane T-Zell Lymphome.
• – Nierenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: nephrotisches Syndrom; alle Nephritiden.
• – Lebererkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: akuter Leberzellzerfall; akute Hepatitis unterschiedlicher Genese, beispielsweise viral, toxisch, arzneimittelinduziert; chronisch aggressive und/oder chronisch intermittierende Hepatitis.
• – Gastrointestinale Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: regionale Enteritis (Morbus Crohn); Colitis ulcerosa; Gastritis; Refluxoesophagitis; Gastroenteritiden anderer Genese, beispielsweise glutensensitive Enteropathie (einheimische Sprue).
• – Proktologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: Analekzem; Fissuren; Hämorrhoiden; idiopatische Proktitis.
• – Augenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: allergische Keratitis, Uveitis, Iritis; Konjuktivitis; Blepharitis; Neuritis nervi optici; Chlorioditis; Opthalmia sympathica.
• – Erkrankungen des Hals-Nasen-Ohren-Bereiches, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: allergische Rhinitis, Heuschnupfen; Otitis externa, beispielsweise bedingt durch Kontaktexem, Infektion etc.; Otitis media.
• – Neurologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: Hirnödem, vor allem Tumor-bedingtes Hirnödem; multiple Sklerose; akute Encephalomyelitis; Meningitis; verschiedene Formen von Krampfanfällen, beispielsweise BNS-Krämpfe.
• – Bluterkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: erworbene hämolytische Anämie; idiopathische Thrombozytopenie.
• – Tumorerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: akute lymphatische Leukämie; maligne Lymphome; Lymphogranulomatosen; Lymphosarkome; ausgedehnte Metastasierungen, vor allem bei Mamma-, Bronchial- und Prostatakarzinomen.
• – Endokrine Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: endokrine Orbitopathie; thyreotoxische Krise; Thyreoditis de Quervain; Hashimoto Thyreoditis; Morbus Basedow. Organ- und Gewebstransplantationen, Graft-versus-Host disease.
• – Schwere Schockzuständen, beispielsweise anaphylaktischer Schock, systemic inflammatory response syndrome (SIRS).
• – Substitutionstherapie bei: angeborene primäre Nebenniereninsuffizienz, z. B. kongenitales adrenogenitales Syndrom; erworbene primäre Nebenniereninsuffizienz, z. B. Morbus Addison, autoimmune Adrenalitis, beispielsweise postinfektiös, Tumoren, Metastasen, etc; angeborene sekundäre Nebenniereninsuffizienz, beispielsweise kongenitaler Hypopituitarismus; erworbene sekundäre Nebenniereninsuffizenz, beispielsweise postinfektiös, Tumoren, etc.
• – Emesis, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen, beispielsweise in Kombination mit einem 5-HT3-Antagonisten bei Zytostatika-bedingten Erbrechen.
• – Schmerzen bei entzündlicher Genese, z. B. Lumbago.

The compounds according to the invention are also suitable for the prophylaxis and / or therapy of inflammatory or autoimmune diseases such as, for example:

• - lung 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 and / or proliferative processes: all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms of degenerative joint disease (arthrosis); traumatic arthritis; Collagenosis of any genesis, for example systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren's syndrome, still syndrome, Felty syndrome,
• Allergies associated with inflammatory and / or proliferative processes: all forms of allergic reactions, for example Quincke's edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis,
• Vascular inflammatory disease (vasculitis): Panarteritis nodosa, temporal arteritis, erythema nodosum,
• Dermatological disorders associated with inflammatory, allergic and / or proliferative processes: atopic dermatitis; Psoriasis; Pityriasis rubra pilaris; Erythematous diseases, triggered by different Noxen, z. B. blasting, chemicals, burns etc .; bullous dermatoses; Diseases of the lichenoid type; pruritus; seborrheic eczema; rosacea; Pemphigus vulgaris; Erythema exudative multiforme; balanitis; vulvitis; Hair loss such as alopecia areata; cutaneous T-cell lymphomas.
• Kidney diseases associated with inflammatory, allergic and / or proliferative processes: nephrotic syndrome; all nephritis.
• - liver diseases associated with inflammatory, allergic and / or proliferative processes: acute liver cell decay; acute hepatitis of various causes, such as 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, for example, gluten-sensitive enteropathy (native sprue).
• - Proctological diseases associated with inflammatory, allergic and / or proliferative processes: analgesic; fissures; Hemorrhoids; idiopathic proctitis.
• O eye diseases associated with inflammatory, allergic and / or proliferative processes: allergic keratitis, uveitis, iritis; conjunctivitis; blepharitis; Neuritis nervi optici; Chlorioditis; Opthalmia sympathica.
• - diseases of the ear, nose and throat, which are associated with inflammatory, allergic and / or proliferative processes: allergic rhinitis, hay fever; Otitis externa, for example due to contact xem, infection, etc .; Otitis media.
• - Neurological diseases associated with inflammatory, allergic and / or proliferative processes: brain edema, especially tumor-related cerebral edema; multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, such as BNS cramps.
• - blood disorders associated with inflammatory, allergic and / or proliferative processes: acquired hemolytic anemia; idiopathic thrombocytopenia.
• - tumors associated with inflammatory, allergic and / or proliferative processes: acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in mammary, bronchial and prostate cancers.
• Endocrine disorders associated with inflammatory, allergic and / or proliferative processes: endocrine orbitopathy; thyrotoxic crisis; Thyreoditis de Quervain; Hashimoto's thyroiditis; Graves' disease. Organ and tissue transplants, graft-versus-host disease.
• - Severe states of shock, such as anaphylactic shock, systemic inflammatory response syndrome (SIRS).
• - Substitution therapy in: congenital primary adrenal insufficiency, eg. Congenital adrenogenital syndrome; acquired primary adrenal insufficiency, e.g. Addison's disease, autoimmune adrenalitis, for example, postinfectious, tumors, metastases, etc .; congenital secondary adrenal insufficiency, such as congenital hypopituitarism; acquired secondary adrenal insufficiency, for example, postinfectious, tumors, etc.
• - Emesis associated with inflammatory, allergic and / or proliferative processes, for example in combination with a 5-HT3 antagonist in cytostatic vomiting.
• - Pain in inflammatory genesis, z. Eg lumbago.

The compounds according to the invention are also suitable for the treatment of viral diseases, such as, for example, infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.

The compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, peripheral vascular disorders, cardiovascular disorders, angina, pectoris, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.

The compounds according to the invention are also suitable for the treatment of neurodegenerative diseases such as, for example, multiple sclerosis, Alzheimer's disease and Parkinson's disease.

These diseases are well characterized in humans but also exist in other mammals.

Another object of the present invention relates to the use of the compounds of the invention as medicaments, in particular for the prophylaxis and / or therapy of tumor diseases.

A further subject matter of the present invention relates to the use of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular of hormone receptor-negative, hormone receptor-positive or BRCA- associated mammary carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma and colorectal carcinoma.

Another object of the present invention relates to the use of the compounds of the invention for the prophylaxis and / or therapy of leukemias, especially acute myeloid leukemias, prostate cancer, especially androgen receptor-positive prostate cancer, breast cancer, in particular estrogen receptor-negative breast cancer, melanoma or multiple myeloma.

Another object of the present invention relates to the use of the compounds of the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias.

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 relates to the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases.

A further subject matter of the present application 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 cancers, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal carcinomas.

Another object of the present invention relates to the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or treatment of leukemias, in particular acute myeloid leukemias, prostate cancer, in particular androgen receptor-positive prostate cancer, breast cancer, in particular estrogen receptor-negative alpha breast carcinoma, melanoma or multiple myelomas.

Another object of the present invention relates to the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias.

Another object of the present invention relates to the use of the compounds of the invention for the prophylaxis and / or therapy of tumor diseases.

Another object of the present invention relates to the use of the compounds of the invention for the prophylaxis and / or therapy of leukemias, especially acute myeloid Leukemia, prostate cancer, especially androgen receptor-positive prostate cancer, cervical cancer, breast cancer, especially hormone receptor-negative, hormone receptor-positive or BRCA-associated breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung cancer, endometrial carcinoma and colorectal carcinoma ,

Another object of the present invention relates to the use of the compounds of the invention for the prophylaxis and / or therapy of leukemias, especially acute myeloid leukemias, prostate cancer, especially androgen receptor-positive prostate cancer, breast cancer, in particular estrogen receptor-negative breast cancer, melanoma or multiple myeloma.

Another object of the present invention relates to the use of the compounds of the invention for the prophylaxis and / or therapy of leukemias.

A further subject of the present invention relates to 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 cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular of hormone receptor negative, Hormone receptor-positive or BRCA-associated breast cancers, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung cancers, endometrial carcinomas and colorectal cancers.

Another object of the present invention relates to pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of leukemias, especially acute myeloid leukemias, prostate cancer, especially androgen receptor-positive prostate cancer, breast cancer, especially estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.

Another object of the present invention relates to 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.

Another object of the invention relates to the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.

Another object of the invention relates to 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 diseases.

The compounds according to the invention can be used alone or as needed in combination with one or more further 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 / or therapy of the aforementioned diseases.

For example, the compounds of the invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic chemical and biological substances for the treatment of cancers. The combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.

As suitable combination active ingredients may be mentioned by way of example, without this enumeration being conclusive:
131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl-5-aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, Anetumab Ravtansine, Angiotensin II, Antithrombin III, Aprepitant, Arcitumomab, Arglabin, Arsenic Trioxide, Asparaginase, Axitinib, Azacitidine, Belotecan, Bendamustine, Besilesomab, Belinostat, Bevacizumab, Bexarotene, Bicalutamide, Bisantrene, Bleomycin, Blinatumomab, Bortezomib, Buserelin, Bosutinib, Brentuximab Vedotin, busulfan, cabazitaxel, cabozantinib, calcitonin, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, Cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, Crisantaspase, crizotinib, cyclopho sphamid, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin-diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + Estrone, dronabinol, edrecolomab, elliptinium acetate, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin-alfa, epoetin-beta, epoetin-zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estrustine, etoposide, ethinyl estradiol, everolimus, exemestane, fadrozole, Fentanyl, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, Fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoterate meglumine salt, gadoversetamide, gadoxetate disodium salt (Gd-EOB-DTPA disodium salt), gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxime, goserelin, granisetron, granulocyte colony stimulating factor (G- CSF), granulocyte macrophage colony stimulating factor (GM-CSF), histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan, ibutinib, idarubicin, ifosfamide, imatinib, imiquimod, improversulfan, indisetron, incadronic acid, ingenolmebutate , Interferon-alpha, Interferon-beta, Interferon-gamma, Iobitridol, Iobenguane (123I), Iomeprol, Ipilimumab, Irinotecan, Itraconazole, Ixabepilone, Ixazomib, Lanreotide, Lansoprazole, Lansoprazole, Lapatinib, Lasocholine, Lenalidomide, Lenvatinib, Lenograstim, Lentinan, Letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lipegfilgrastim, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, M edroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, Mopidamole, morphine hydrochloride, morphine sulphate, nabilone, nabiximoles, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant / palonosetron, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrin, nivolumab, Obinutuzumab, octreotide, ofatumumab, olaparib, omacetaxine mepesuccinate, omeprazole, ondansetron, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronate, Panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, pemb rolizumab, peg-interferon-alfa-2b, pemetrexed, pentostatin, peplomycin, perflubutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, Porfimer Sodium, Pralatrexate, Prednimustine, Prednisone, Procarbazine, Procodazole, Propranolol, Quinagolide, Rabeprazole, Racotumomab, Radium-223 chloride, Radotinib, Raloxifene, Raltitrexed, Ramosetron, Ramucirumab, Ranimustin, Rasburicase, Razoxan, Refametinib, Regorafenib, Risedronic Acid, Rhenium-186 Etidronate, Rituximab, Rolapitant, Romidepsin, Romurtide, Roniciclib, Samarium (153Sm) Lexidronam, Satumomab, Secretin, Siltuximab, Sipuleucel-T, Sizofiran, Sobuzoxan, Sodium glycididazole, Sonidegib, Sorafenib, Stanozolol, Streptozocin, Sunitinib, Talaporfin, Talimogen Laherparepvec, Tamibaroten, Tamoxifen, Tapentadol, Tasonermin, Teceleukin, Technetium (99mTc) Nofetumomab Merpentan, 99mTc-HYNIC [Ty r3] octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, toositumomab, trabectedin, trametinib, tramadol, Trastuzumab, Treosulfan, Tretinoin, Trifluridine + Tipiracil, Trametinib, Trilostane, Triptorelin, Trofosfamide, Thrombopoietin, Ubenimex, Valrubicin, Vandetanib, Vapreotide, Valatinib, Vemurafenib, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vismodegib, Vorinostat, Yttrium-90- Glass microspheres, Zinostatin, Zinostatin Stimalamer, Zoledronic Acid, Zorubicin.

In particular, the compounds of the invention with antibodies such. , Aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, ofatumumab, panitumumab, pertuzumab, rituximab, tositumumab or trastuzumab, as well as recombinant proteins.

In particular, the compounds of the invention in combination with anti-angiogenic therapies such as. Bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib, lenalidomide or thalidomide are used.

Combinations with antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.

Combinations with inhibitors of P-TEFb and / or CDK9 are also particularly suitable because of the possible synergistic effects.

• • eine verbesserte Wirksamkeit bei der Verlangsamung des Wachstums eines Tumors, bei der Reduktion seiner Größe oder sogar bei seiner völligen Eliminierung im Vergleich zu einer Behandlung mit einem einzelnen Wirkstoff;
• • die Möglichkeit, die verwendeten Chemotherapeutika in geringerer Dosierung als bei der Monotherapie einzusetzen;
• • die Möglichkeit einer verträglicheren Therapie mit weniger Nebeneffekten im Vergleich zur Einzelgabe;
• • die Möglichkeit zur Behandlung eines breiteren Spektrums von Tumorerkrankungen;
• • das Erreichen einer höheren Ansprechrate auf die Therapie;
• • eine längere Überlebenszeit der Patienten im Vergleich zur heutigen Standardtherapie.

In general, the following objectives can be pursued with the combination of the compounds according to the invention with other cytostatic or cytotoxic agents:

• • improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to treatment with a single drug;
• • the possibility of using the chemotherapeutic agents used in lower doses than in monotherapy;
• • the possibility of a more tolerable therapy with fewer side effects compared to a single dose;
• • the ability to treat a wider range of tumors;
• • achieving a higher response rate to therapy;
• • longer patient survival compared to today's standard therapy.

In addition, the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.

Preparation of the compounds according to the invention:

NMR signals are given with their respective recognizable multiplicity or their combinations. Where s = singlet, d = doublet, t = triplet, q = quartet, qi = quintet, sp = septet, m = multiplet, b = broad signal. For example, signals with combined multiplicity are given as dd = doublet of doublet.

In the present description mean: Example example (+) - BINAP (R) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (±) -BINAP 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (racemic) Boc tert-butoxycarbonyl CDCl ₃ deuterochloroform CHAPS Dimethyl 3- {[3- (4- {5,9,16-trihydroxy-2,15-dimethyltetracyclo- [8.7.0.0 ^2.7 .0 ^11.15 ] heptadecan-14-yl} pentanamido) propyl] azaniumyl} propane 1-sulfonate DAD Diode array detector dba dibenzylideneacetone DMF N, N-dimethylformamide DMSO-d6 deuterated dimethyl sulfoxide DMSO dimethyl sulfoxide HPLC High Performance Liquid Chromatography LCMS Liquid chromatography coupled with mass spectrometry min minutes RP-HPLC Reversed Phase High Performance Liquid Chromatography RT room temperature RuPhos 2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide THF tetrahydrofuran Xanthphos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene XPhos 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl

General description of the preparation of the compounds of general formula I according to the invention

The compounds of the formula (I) according to the invention can be prepared by synthetic routes, which are described below. The substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{10 of} the formulas contained in the schemes are defined as for the general formula (I).

Schema 1: Herstellung von Verbindungen der allgemeinen Formel (I)

Scheme 1: Preparation of compounds of general formula (I)

As shown in Scheme 1, compounds of general structure (II) can be reacted with compounds of general structure (III) with the aid of a suitable catalyst. In this case, X is typically a group which can be activated with a transition metal catalyst, and then subsequently react with the bromide of the compounds (II) to give compounds of the general formula (I). Examples of such leaving groups are the boronic acids and their derivatives known in the literature, such as boronic acid alkyl esters or boron trifluoride groups. With the help of a suitable transition metal as a catalyst, such. As palladium, the components react in a well-known to the expert Suzuki reaction. This requires the use of a base such as, for example, an alkali metal carbonate, for example potassium carbonate, an alkali metal phosphate, for example trisodium phosphate, or else an alkali metal salt of an aliphatic alcohol of the formula C ₁ -C ₄ -alkyl-OH, for example sodium tert-butylate. As a palladium ligand system is here z. Dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (complex with dichloromethane, CAS 95464-05-4); Alternatively, palladium (II) acetate or palladium (dba) complexes such as Pd ₂ (dba) ₃ (CAS Nos. 51364-51-3 and 52409-22-0) may also be used, for example, in combination with ligands such as (+) - BINAP, xanthphos, XPhos or RuPhos (cf. US2006 / 009457 A1 ). In recent years, catalysts have also been described which form a preformed complex of palladium, ligands and an aminobiphenyl unit ( Angew. Chem. Int. Ed., 47, (2008), p. 6338 f. ; J. Am. Che. Soc., 132, (2010), p. 14073 f. ). These complexes may also be useful in the practice of some examples.

Alternatively, intermediates can be used in which X z. B. is a halogen, especially bromine. In this case, according to one described in the literature ( Molander et al., J. Org. Chem., 77, (2012), p. 8678 ff. ) Regulation a boronic acid intermediate palladium-catalyzed prepared and then immediately further reacted with compounds of general formula (II) to the compounds of general formula (I) according to the invention.

Depending on the base used, in the preparation of the compounds of the general formula (I) according to the invention on the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, racemization or epimerization may occur to varying degrees. To obtain the pure enantiomers or epimers of the compounds of the general formula (I) according to the invention, these stereoisomer mixtures can be separated by HPLC methods known to the person skilled in the art on chromatography columns with a chiral stationary phase.

The preparation of compounds of the general formula (II) has been described (eg in WO2014095775 ). These compounds serve as starting material for the preparation of the compounds of the formula (I) according to the invention. In addition to the synthetic sequences discussed below, according to the general knowledge of those skilled in organic chemistry, further synthetic routes for the synthesis of compounds of general formula (I) according to the invention can be followed.

Some compounds of the general formula (III) which lead to the compounds of the formula (I) according to the invention are commercially available. Other compounds of general formula (III) wherein R ^{1 is} -S (= O) ₂ NR ⁷ R ⁸ or -S (= O) ₂ R ¹⁰ and X is bromo are e.g. B. prepared by general synthetic routes as described in Scheme 2.

Synthesis path A can be followed, for example, to prepare bromides (x = Br) of the general formula (III-a) in which R ^{1 is} -S (= O) ₂ NR ⁷ R ⁸ . Synthesis path B can be used, for example, for the preparation of bromides (X = Br) of the general formula (III-b) in which R ^{1 is} -S (= O) ₂ R ¹⁰ .

Schema 2: Herstellung von Verbindungen der allgemeinen Formel (III-a) und (III-b).

Scheme 2: Preparation of compounds of general formula (III-a) and (III-b).

Sulfonyl halides of the general formula (IV) are commercially available (synthesis route Scheme 2, A). The reaction with a suitable amine of the general formula (V), wherein R ⁷ and R ^{8 are} defined as for the general formula (I), under conditions known in the art in a suitable solvent such. For example, THF or dichloromethane usually in the presence of a suitable base such. As triethylamine, N, N-di-iso-propylethylamine or pyridine, thereby leading to intermediates of general formula (III-a). Likewise, compounds of the general formula (VI) whose synthesis is described (eg in WO2015004075 . WO2015193217 . WO2015193217 ), are converted into the corresponding bromides of the general formula (III-b) under conditions known to those skilled Sandmeyer reaction (synthesis route Scheme 2, B).

The present invention likewise provides for the use of the intermediates of the general formula (II) in which R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings given in the general formula (I) for preparing the compounds of the general formula according to the invention (I).

The present invention likewise relates to the use of the intermediates of the general formula (III) in which R ¹ and R ^{2 have} the meanings given in the general formula (I) and X for boronic acid (B (OH) ₂ ) and their in the Literature known derivatives such as boronic acid alkyl ester, Br or BF ₃ , for the preparation of the compounds of general formula (I) according to the invention.

embodiments

The following examples illustrate the preparation of the compounds of the invention without limiting the invention to these examples.

First, the preparation of the intermediates will be described, which are finally preferably used for the preparation of the compounds of the invention.

IUPAC names were created using the nomenclature software ACD Name batch, version 12.01, from Advanced Chemical Development, Inc., and adapted as needed, for example, to the German-language nomenclature. Intermediate 1: tert -Butyl 4 - [(2R) -7-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-1 (2H) -yl] -piperidine-1-carboxylate

A solution of 3.0 g (12.44 mmol) of (3R) -6-bromo-3-methyl-3,4-dihydroquinoxaline-2 (1H) -one (preparation described in WO2014095775 , Intermediate 2), 7.44 g (37.33 mmol) of tert-butyl-4-oxopiperidine-1-carboxylate, 1.83 g (37.33 mmol) of phenylsilane and 3.78 g (12.44 mmol) of dibutyltin dichloride in 100 ml of THF was stirred at RT for 72 hours. The solution was completely concentrated in vacuo and purified by chromatography on silica gel. After repeated purification by RP-HPLC, 2.40 g of the desired product could be obtained as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d6): δ = 0.96 (d, 3H), 1.40 (s, 9H), 1.45-1.64 (m, 3H), 1.88 (d, 1H), 2.70-3.00 (m , 2H), 3.61-3.72 (m, 1H), 3.90 (q, 1H), 4.00 (t, 2H), 6.73 (d, 1H), 6.88 (dd, 1H), 7.06 (d, 1H), 10.42 ( s, 1H). Intermediate 2: tert -Butyl 4 - [(2R) -7-bromo-2,4-dimethyl-3-oxo-3,4-dihydroquinoxaline-1 (2H) -yl] piperidine-1-carboxylate

A solution of 2.4 g (5.6 mmol) of intermediate 1 in 40 ml of DMF at 0 ° C was added in portions with 366 mg (8.4 mmol) of sodium hydride (60% in white oil) and then added 1.19 g (8.4 mmol) of methyl iodide. After the addition was stirred at 0 ° C for one hour. The reaction mixture was treated with half-concentrated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were washed with aqueous sodium bicarbonate solution. After removal of the solvent, the crude product was purified by chromatography on silica gel. After removal of DMF residues by lyophilization, 2.47 g of the desired product were obtained as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.13 (d, 3H), 1.49 (s, 9H), 1.58-1.76 (m, 3H), 2.00 (dd, 1H), 2.72-2.89 (m, 2H), 3.36 (s, 3H), 3.48-3.58 (m, 1H), 4.11 (q, 1H), 4.21 (d, 1H), 4.29 (d, 1H), 6.84 (d, 1H), 7.02-7.10 (m, 2H). Example 1: N- {3 - [(3R) -4-Benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline-6-yl] -phenyl} -methanesulfonamide

Beispiel 9: tert-Butyl-4-[(2R)-2,4-dimethyl-7-{3-[(methylsulfonyl)amino]phenyl}-3-oxo-3,4-dihydrochinoxalin-1(2H)-yl]piperidin-1-carboxylat

100 mg of (3R) -4-benzyl-6-bromo-1,3-dimethyl-3,4-dihydroquinoxaline-2 (1H) -one (preparation described in WO2014095775 , Intermediate 4) were initially charged in a mixture of 2.5 ml of 1,4-dioxane, 2.4 ml of DMF and 0.8 ml of water and 158 mg of {3 - [(methylsulfonyl) amino] phenyl} boric acid (CAS 148355-75-3), 66 Potassium carbonate and 36 mg of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (complex with dichloromethane, CAS 95464-05-4) were added. The mixture was irradiated for 50 minutes at 130 ° C in the microwave. The reaction mixture was filtered and impregnated by means of. Purified RP-HPLC. 24 mg of the desired product were obtained as a solid.
¹ H-NMR (400 MHz, CDCl _3): δ = 1.18 (d, 3H), 3:04 (s, 3H), 3:46 (s, 3H), 4:08 (q, 1H), 4.23 (d, 1H), 4.66 (d, 1H), 6.66 (s, br, 1H), 6.91 (d, 1H), 7.04 (d, 1H), 7.10 (dd, 1H), 7.19 (d, 1H), 7.29-7.51 (m, 8H ). Table 1: Analogously to Example 1, from (3R) -4-benzyl-6-bromo-1,3-dimethyl-3,4-dihydroquinoxaline-2 (1H) -one (preparation described in WO2014095775 , Intermediate 4) and the corresponding commercially available Boronsäurederivaten the following example compounds prepared:

Example 9: tert -Butyl 4 - [(2R) -2,4-dimethyl-7- {3 - [(methylsulfonyl) amino] phenyl} -3-oxo-3,4-dihydroquinoxaline-1 (2H) -yl ] -piperidine-1-carboxylate

Beispiel 15: N-{3-[(3R)-1,3-Dimethyl-2-oxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydrochinoxalin-6-yl]-phenyl}methansulfonamid

100 mg of tert-butyl 4 - [(2R) -7-bromo-2,4-dimethyl-3-oxo-3,4-dihydrochnoxalin-1 (2H) -yl] piperidine-1-carboxylate (intermediate 2) in a mixture of 2 ml of 1,4-dioxane, 1.9 ml of DMF and 0.6 ml of water and 123 mg of {3 - [(methylsulfonyl) amino] phenyl} boric acid (CAS 148355-75-3), 51 mg of potassium carbonate and 28 mg Dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (complex with dichloromethane, CAS 95464-05-4) was added. The mixture was irradiated for 3 hours at 130 ° C in the microwave and then heated at 100 ° C for a further 16 hours. The reaction mixture was filtered and purified by preparative RP-HPLC. 40 mg of the desired product were obtained as a solid.
¹ H-NMR (400 MHz, DMSO-d6): δ = 0.97 (d, 3H), 1.40 (s, 9H), 1.49-1.63 (m, 3H), 1.92-2.00 (m, 1H), 2.70-2.97 (m, 2H), 3.01 (s, 3H), 3.29 (s, 3H), 3.68-3.79 (m, 1H), 3.93-4.07 (m, 2H), 4.08 (q, 1H), 7.09-7.22 (m , 4H), 7.36-7.42 (m, 2H), 7.44 (s, br, 1H), 9.76 (s, br, 1H). TABLE 2 Analogously to Example 9, the following example compounds were prepared from Intermediate 2 and the corresponding commercially available boronic acid derivatives:

Example 15: N- {3 - [(3R) -1,3-Dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] -phenyl} methanesulfonamide

Tert-Butyl 4 - [(2R) -2,4-dimethyl-7- {3 - [(methylsulfonyl) amino] phenyl} -3-oxo-3,4-dihydroquinoxaline 25 mg (47 μmol) (2H ) -yl] piperidine-1-carboxylate (Example 9) were dissolved in 3 ml of dichloromethane and 0.5 ml of trifluoroacetic acid added. The mixture was allowed to stir at RT for 16 hours. All volatiles were removed on a rotary evaporator. The residue was treated with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. Removal of the solvent gave 20 mg of the desired product as a solid.
¹ H-NMR (400 MHz, DMSO-d6): δ = 1.01 (d, 3H), 1.55-1.71 (m, 3H), 1.92-2.00 (m, 1H), 2.57-2.75 (m, 2H), 3.03 (s, 3H), 3.04-3.14 (m, 2H), 3.31 (s, 3H), 3.61-3.72 (m, 1H), 4.08 (q, 1H), 7.10-7.22 (m, 4H), 7.38-7.43 (m, 2H), 7.43-7.47 (m, 1H). Table 3: Analogously to Example 15, the following example compounds were prepared from the example compounds 10, 11, 12, 13 and 14 by cleavage of the tert-butoxycarbonyl group:

Biological activity of the compounds according to the invention

Protein-protein interaction assay: binding assay BRD4 / acetylated peptide H4

1. Assay Description BRD4 Bromodomain 1 [BRD4 (1)]

To assess the BRD4 (1) binding potency of the substances described in this application, their ability to dose-dependently inhibit the interaction between BRD4 (1) and acetylated histone H4 was quantified.

For this purpose, a time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used, demonstrating the binding between N-terminal His6-tagged BRD4 (1) (amino acids 67-152) and a synthetic acetylated histone H4 (acylated histone H4). H4) peptide with sequence GRGK (Ac) GGK (Ac) GLGK (Ac) GGAK (Ac) RHGSGSK-biotin. That after Filippakopoulos et al., Cell, 2012, 149: 214-231 Recombinant BRD4 (1) protein produced in house was expressed in E. coli and purified by (Ni-NTA) affinity and (Sephadex G-75) size exclusion chromatography. The Ac-H4 peptide may be of z. B. Biosyntan (Berlin, Germany) are purchased.

In the assay, typically 11 different concentrations of each substance (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μM, 0.51 μM, 1.7 μM, 5.9 μM and 20 μM) were measured as duplicates on the same microtiter plate. For this, 100-fold concentrated solutions in DMSO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany). The assay was started by adding 2 μl of a 2.5-fold concentrated BRD4 (1) solution (usually 10 nM final concentration in the 5 μl of the reaction volume) in aqueous 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 test plate. This was followed by a 10 minute incubation step at 22 ° C for the pre-equilibration of putative complexes between BRD4 (Fig. 1 ) and the substances. Subsequently, 3 μl of a 1.67-fold concentrated solution (in the assay buffer) consisting of Ac-H4 peptide (83.5 nM) and TR-FRET detection reagents [16.7 nM anti-6His XL665 and 3.34 nM streptavidin Cryptate (both from Cisbio Bioassays, Codolet, France), such as 668 mM potassium fluoride (KF)].

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 complexes was determined by measuring the resonance energy transfer from the streptavidin-Eu cryptate to the anti-6His-XL665 antibody that is in the reaction. For this, the fluorescence emission at 620 nm and 665 nm after excitation at 330-350 nm in a TR-FRET meter, z. A Rubystar or Pherastar (both from BMG Lab Technologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of emission at 665 nm and at 622 nm (ratio) was taken as an indicator of the amount of BRD4 (1) / Ac-H4 complexes formed.

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 μl of DMSO (100%) were used. 100% inhibition was the mean of the readings from a set of controls (typically 32 data points) using all reagents except BRD4 ( 1 ) were included. The IC ₅₀ value was determined by regression analysis based on a 4-parameter equation (minimum, maximum, IC ₅₀ , Hill, Y = Max + (Min-Max) / (1 + (X / IC ₅₀ ) Hill).

2. Assay Description BRD4 Bromodomain 2 [BRD4 (2)]

To assess the BRD4 (2) binding potency of the substances described in this application, their ability to dose-dependently inhibit the interaction between BRD4 (2) and acetylated histone H4 was quantified.

For this purpose, a time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used, demonstrating the binding between N-terminal His6-tagged BRD4 (2) (amino acids 357-445) and a synthetic acetylated histone H4 (acylated histone H4). H4) peptide with sequence SGRGK (Ac) GGK (Ac) GLGK (Ac) GGAK (Ac) RHRKVLRDNGSGSK-biotin. That after Filippakopoulos et al., Cell, 2012, 149: 214-231 Recombinant BRD4 (2) protein produced in house was expressed in E. coli and purified by (Ni-NTA) affinity and (Sephadex G-75) size exclusion chromatography. The Ac-H4 peptide may be of z. B. Biosyntan (Berlin, Germany) are purchased.

In the assay, typically 11 different concentrations of each substance (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μM, 0.51 μM, 1.7 μM, 5.9 μM and 20 μM) were measured as duplicates on the same microtiter plate. For this, 100-fold concentrated solutions in DMSO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany). The assay was started by adding 2 μl of a 2.5-fold concentrated BRD4 (2) solution (usually 100 nM final concentration in the 5 μl of the reaction volume) in aqueous 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 complexes between BRD4 (2) and the substances. Subsequently, 3 μl of a 1.67-fold concentrated solution (in the assay buffer) consisting of Ac-H4 peptide (83.5 nM) and TR-FRET detection reagents [83.5 nM anti-6His XL665 (Cisbio Bioassays, Codolet, France ) and 12, 52 nM streptavidin-Eu), (Perkin Elmer, # W1024)] in the assay buffer.

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 (2) / Ac-H4 complexes was determined by measuring the resonance energy transfer from the streptavidin-Eu chelate to the anti-6His-XL665 antibody that is in the reaction. For this, the fluorescence emission at 620 nm and 665 nm after excitation at 330-350 nm in a TR-FRET meter, z. A Rubystar or Pherastar (both from BMG Lab Technologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of emission at 665 nm and at 622 nm (ratio) was taken as an indicator of the amount of BRD4 (2) / Ac-H4 complexes formed.

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 μl 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 (2). The determination of the IC ₅₀ value was carried out by regression analysis based on a 4-parameter equation (minimum, maximum, IC ₅₀ , Hill, Y = Max + (Min-Max) / (1 + (X / IC ₅₀ ) Hill)).

3. Cell assay

Cell proliferation assays

3.1 Proliferation Assay [MOLM-13 (1)]

In accordance with the invention, the ability of the substances to inhibit the proliferation of the MOLM-13 cell line (German Collection of Microorganisms and Cell Cultures, ACC 554; Acute Myeloid Leukemia) was determined. Cell viability was determined using the alamarBlue ^® reagent (Invitrogen) in a Victor X3 Multilabel Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelength was 590 nM. The MOLM-13 cells were seeded at a density of 4000 cells / well in 100 μl growth medium (RPMI 1640 with stable glutamine and 10% fetal calf serum) on 96 well microtiter plates. After an overnight incubation at 37 ° C., the fluorescence values were determined (CI values). Then the plates were treated with various dilutions of substance and incubated for 96 hours at 37 ° C. Subsequently, the fluorescence values were determined (CO values). For data analysis, 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.

3.2 Proliferation Assay [MOLM-13 (2)]

In accordance with the invention, the ability of the substances to inhibit the proliferation of the MOLM-13 cell line (German Collection of Microorganisms and Cell Cultures, ACC 554; Acute Myeloid Leukemia) was determined. Cell viability was determined by the CellTiter-Glo ^® Reagent (Promega) in a Victor multilabel X3 Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelength was 590 nM.

The MOLM-13 cells were seeded at a density of 1000 cells / well in 30 μl growth medium (RPMI 1640 with stable glutamine, 10% fetal calf serum, and 1% Pen-Strep solution (GE Healthcare)) on 386 well microtiter plates. After an overnight incubation at 37 ° C., the fluorescence values were determined (CI values). Then the plates were treated with various dilutions of substance and incubated for 72 hours at 37 ° C. Subsequently, the fluorescence values were determined (CO values). For data analysis, 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.

4. Results:

4.1 binding assay

Table 4 shows the results from the BRD4 binding assay BRD4 (1) and BRD4 (2). Table 4: example IC ₅₀ [BRD4 (1)] (mol / l) IC ₅₀ [BRD4 (2)] (mol / l) 1 1.03e-06 1.42E-07 2 2.82E-06 2.57E-07 3 8.65E-07 8.17E-08 4 1.33E-07 7.06E-08 5 9.05E-07 7.15E-08 6 7.90E-07 7.96E-08 7 8.41E-07 1.11E-07 8th 8.68E-07 6.24E-08 9 8.66E-07 4.48E-07 10 2.03E-06 1.79E-06 11 9.89E-07 3.57E-07 12 9.99E-07 6.83E-07 13 2.31E-06 1.90E-06 14 1.24E-06 8.31E-07 15 1.78E-07 1.39E-07 16 5.26E-07 6.40E-07 17 1.14E-06 2.25.E-06 18 5.13E-07 1.75E-06 19 1.75E-06 3.48E-06 20 8.82E-07 1.28E-06

4.2 Cell proliferation assays

The ability of the compounds of the invention to inhibit the proliferation of the MOLM-13 cell line was determined.

Table 5 shows the results from the cell proliferation assay MOLM-13 (1). Table 5: example IC ₅₀ [MOLM-13 (1)] (mol / l) 4 1.03e-6 15 1.14E-6 18 2.34E-6

Table 6:

Table 5 shows the results from the cell proliferation assay [MOLM-13 (2)]. example IC ₅₀ [MOLM-13 (2)] (mol / l) 1 1.09E-06 2 > 1.00E-05 3 5.22E-06 5 2.30E-06 6 3.85E-06 7 1.11E-06 8th 1.63E-06 9 1.21E-06 10 4.09E-06 11 4.77E-06> 1.00E-05 12 2.23E-06 13 5.09E-06 example IC ₅₀ [MOLM-13 (2)] (mol / l) 14 2.03E-05 17 5.14E-06 20 5.08E-06> 1.00E-05

This is followed by a sequence protocol according to WIPO St. 25. This can be downloaded from the official publication platform of the DPMA.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

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Claims (16)

Compounds of the general formula (I)

in the R ¹ for a group -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -NR ⁹ S (= O) ₂ R ¹⁰ , -S (= O) ₂ R ¹⁰ or or cyano, R ² is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ -haloalkoxy or phenoxy, wherein phenoxy may optionally be mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ haloalkoxy, R ^{3 is} methyl or ethyl, R ⁴ and R ^{5 are} independently hydrogen or C ₁ -C ₃ alkyl, or R ⁴ and R ⁵ together with the carbon atom to which they are attached, a cyclopropyl group or cyclobutyl group, R ^{6 is} C ₁ -C ₃ -alkyl which may optionally be monosubstituted with C ₂ -C ₃ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl or 4- to 8-membered heterocycloalkyl, wherein C ₃ -C ₆ -cycloalkyl and 4- to 8-membered heterocycloalkyl optionally mono- or diacetic h, which may be substituted, identically or differently, by halogen or C ₁ -C ₃ -alkyl, and in which phenyl may optionally be mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy, or represents C ₃ -C ₆ -cycloalkyl or 4- to 8-membered heterocycloalkyl, which may optionally have one or two, may be the same or different substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or -C (= O) OR ¹¹ , and wherein 4- to 8-membered heterocycloalkyl with the remainder of the molecule via a carbon atom of the R ⁷ and R ⁸ independently of one another are hydrogen, C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl, in which the C ₁ -C ₄ -alkyl is C ₃ - C ₆ -Cycloalkyl may be substituted, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, for 4- to 8-membered heterocycloalkyl or C ₅ -C ₁₁ -heterospirocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl, R ^{9 is} hydrogen, R ^{10 is} C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl or 4- to 8-membered heterocycloalkyl, wherein C ₃ -C ₆ -cycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with halogen, and wherein 4-8 heterocycloalkyl is joined to the rest of the molecule via a carbon atom of the 4- to 8-membered heterocycloalkyl, or R ⁹ and R ^{10 are} optionally linked together so that they together represent a group * - (CH ₂ ) ₂ - *, * - (CH ₂ ) ₃ - * or * - (CH ₂ ) ₄ - * wherein "*" is the point of attachment to the remainder of the molecule, R ^{11 is} C ₁ -C ₄ alkyl or C ₃ -C ₆ Cycloalkyl is, as well as their diastereomers, racemates, polymorphs and physiologically acceptable salts. Compounds of the general formula (I) according to Claim 1, in which R ^{1 represents} a group -C (OO) NR ⁷ R ⁸ , -S (OO) ₂ NR ⁷ R ⁸ , -NR ⁹ S (OO) ₂ R ¹⁰ or -S (= O) ₂ R ¹⁰ , R ^{2 is} hydrogen, R ^{3 is} methyl, R ⁴ and R ^{5 are} independently hydrogen or C ₁ -C ₃ alkyl, or R ⁴ and R ⁵ together with the carbon atom to which they are attached, a cyclopropyl group R ^{6 is} C ₁ -C ₃ alkyl, which may optionally be monosubstituted by phenyl, wherein phenyl may optionally be mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl or C ₁ -C ₄ haloalkoxy, or represents 4- to 8-membered heterocycloalkyl, which may optionally be monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or -C (= O) OR ¹¹ , and wherein 4- to 8-membered heterocycloalkyl with the remainder of the molecule via a carbon atom of the 4- to 8-membered one Heterocycloalkyls connected, R ⁷ and R ^{8 are} independently hydrogen or C ₁ -C ₄ alkyl, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached are 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ -alkyl, R ^{9 is} R ¹⁰ is hydrogen, R ^{10 is} C ₁ -C ₄ -alkyl, R ^{11 is} C ₁ -C ₄ -alkyl, and their diastereomers, racemates, polymorphs and physiologically tolerable salts. Compounds of general formula I, according to claims 1 to 2, in which R ¹ is a group -C (= O) NR ⁷ R ⁸ or -NR ⁹ S ⁽⁼ O) ₂ R ^10, R ² represents hydrogen, R ^{3 is} methyl, R ⁴ and R ^{5 are} independently hydrogen or methyl, R ^{6 is} methyl, which may be monosubstituted by phenyl, wherein phenyl may be optionally substituted once, twice or three times, identically or differently with halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy, or represents 6-membered heterocycloalkyl which may be on or may be mono-, di-or may be substituted by C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl or -C (= O) OR ¹¹ , and wherein the 6-membered heterocycloalkyl is substituted with the remainder of the molecule via a carbon atom of the 6-membered heterocycloalkyl, R ⁷ and R ^{8 are} independently hydrogen or methyl, or R ⁷ and R ⁸ together with de m nitrogen atom to which they are attached, are 4- to 8-membered heterocycloalkyl, which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen or C ₁ -C ₃ alkyl, R ^{9 is} hydrogen, R ^{10 is} methyl, R ^{11 is} tert-butyl, as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts. Compounds of general formula I, according to claims 1, 2 or 3, wherein R ^{1 is} a group -C (= O) NR ⁷ R ⁸ or -NR ⁹ S (= O) ₂ R ¹⁰ , R ^{2 is} hydrogen R ^{3 is} methyl, R ^{4 is} methyl, R ^{5 is} hydrogen, R ^{6 is} benzyl, piperidin-4-yl or 1- (tert-butoxycarbonyl) piperidin-4-yl, R ⁷ and R ⁸ independently of one another are hydrogen or methyl, or R ⁷ and R ^8, together with the nitrogen atom to which they are bonded, are morpholin-4-yl, R ^{9 is} hydrogen, R ^{10 is} methyl, and their diastereomers, racemates , Polymorphs and physiologically acceptable salts. Compounds of general formula I, according to claims 1 to 4, selected from the group consisting of: N- {3 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] phenyl} methanesulfonamide N- {2 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] phenyl} methanesulfonamide 2 - [-4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl (3R)] benzamide, 2 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] -N, N-dimethylbenzamide, 3 - [(3R) -4-Benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl] -N-methylbenzamide, (3R) -4-benzyl-1, 3-dimethyl-6- [3- (morpholin-4-ylcarbonyl) phenyl] -3,4-dihydro-2 (1H) -one, 3 - [(3R) -4-benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl] -N, N-dimethylbenzamide, 3 - [(3R) -4-Benzyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline-6-yl] -benzamide, tert-butyl-4 - [(2R) -2, 4-dimethyl-7- {3 - [(methylsulfonyl) amino] phenyl} -3-oxo-3,4-dihydro-1 (2H) -yl] piperidine-1-carboxylate, tert-butyl 4 - [(2R) -7- (2-carbamoylphenyl) -2,4-dimethyl-3-oxo-3,4-dihydro-1 (2H) -yl] piperidine-1-carboxylate, tert-butyl 4 - [(2 R) -7- [2- (dimethylcarbamoyl) phenyl] -2,4-dimethyl-3-oxo-3,4-dihydro-1 (2H) -yl] piperidine-1-carboxylate . tert-butyl 4 - [(2R) -2,4-dimethyl-7- [3- (morpholin-4-ylcarbonyl) phenyl] -3-oxo-3,4-dihydro-1 (2H) -yl] piperidine -1-carboxylate, tert-butyl 4 - [(2R) -2,4-dimethyl-7- {2 - [(methylsulfonyl) amino] phenyl) -3-oxo-3,4-dihydro-1 (2H) -yl] piperidine l-carboxylate, tert-butyl 4 - [(2R) -7- (3-carbamoylphenyl) -2,4-dimethyl-3-oxo-3,4-dihydro-1 (2H) -yl] piperidine-1-carboxylate, N- {3 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] phenyl} methanesulfonamide (3R) -1,3-dimethyl-6- [3- (morpholin-4-ylcarbonyl) phenyl] -4- (piperidin-4-yl) -3,4-dihydro-2 (1H) -one, N- {2 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] phenyl} methanesulfonamide 2 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] -N, N-dimethylbenzamide, 2 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] benzamide, and 3 - [(3R) -1,3-dimethyl-2-oxo-4- (piperidin-4-yl) -1,2,3,4-tetrahydroquinoxalin-6-yl] benzamide, as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts. Use of the compounds according to claims 1 to 5 as medicaments. Use according to claim 6, for the prophylaxis and / or therapy of tumor diseases. Use of the compounds according to claims 1 to 5 for the preparation of a medicament. Use of the compounds according to claims 1 to 5 for the preparation of a medicament for the prophylaxis and / or therapy of tumor diseases. Use of the compounds according to claims 1 to 5, for the prophylaxis and / or therapy of hyperproliferative diseases. Use of the compounds according to claims 1 to 5 for the prophylaxis and / or therapy of viral infections, neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases and in male fertility control. Use of the compounds according to claims 1 to 5 for the preparation of a medicament for the prophylaxis and / or therapy of viral infections, neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases and in male fertility control. Compounds according to claims 1 to 5 in combination with one or more further pharmacologically active substances. Compounds in combination according to claim 13, for the prophylaxis and / or therapy of hyperproliferative diseases. Compounds in combination according to claim 13, for the prophylaxis and / or therapy of tumor diseases. Compounds in combination according to claim 15, for the prophylaxis and / or therapy of viral infections, neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases and in male fertility control.