WO2017005711A1 - Phosphorous-and sulfur-substituted benzodiazepine derivatives - Google Patents

Abstract

The invention relates to bromodomain-protein-inhibiting, in particular BET-protein-inhibiting, and preferably BRD4-inhibiting phosphorous- and sulfur-substituted benzodiazepine derivatives of the general formula (I), in which R¹, R², R³, R⁴, and R⁵ have the meanings as specified in the description, to pharmaceutical agents containing the compounds according to the invention, and to the prophylactic and therapeutic use thereof in hyper-proliferative diseases, in particular in tumor diseases. The invention further relates to the use of BET protein inhibitors in benign hyperplasias, atherosclerotic diseases, sepsis, autoimmune diseases, vascular disorders, viral infections, HIV-associated kidney diseases, neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases, cardiac insufficiency, muscular dystrophies such as, for example, facioscapulohumeral muscular dystrophy, and in male fertility control.

Description

 Phosphorus and Sulfur-substituted Bcnzodiazcpin Dcrivatc

The present invention relates to bromodomain protein inhibitor cells, in particular to BET protein-inhibiting and preferably BRD4-inhibitory phosphorus- and sulfur-substituted benzodiazepine derivatives, to pharmaceutical agents containing the compounds according to the invention and to their prophylactic and therapeutic use in hyperproliferative

Diseases, especially in cancer or tumor diseases. Furthermore, this invention relates to the use of BET protein inhibitors in benign hyperplasia, atherosclerotic diseases, sepsis, autoimmune diseases, vascular diseases, viral infections, in HIV-associated kidney diseases, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic erotic diseases, in heart failure Muscular dystrophies such as fazioskapulohumeral muscular dystrophy and in male fertility control. The bromodomain protein belonging to the bromodomain protein family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and HR DT), the two related bromodomains ([BRD4 (1)] and [BRD4 (2) ] and an extra-terminal domain (Gallenkamp et al., Chem. Med. Chem., 2014, 9: 438-464; Filippakopoulos and Knapp, Nature Reviews, 2014, 13: 337-356; Haendler et al, Epigenomics, 2015 , 7: 487-501). The bromodomains are protein regions that recognize acylated 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). The various acylation patterns recognized by BET proteins in histones have been well studied (Umehara et al., J. Biol. Chem., 2010, 285: 7610-761 8;

Filippakopoulos et al., Cell, 2012, 149: 214-231). In addition, bromodomains can recognize additional acetylated proteins. For example, BRD4 binds to RelA, resulting in the stimulation of NF-B and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell. Biol., 2009, 29: 1375-1387; Zhang et al., J. Biol Chem., 2012, doi / 10.1074 / jbc.Ml 12.359505). The extra-terminal domain of BRD2, BRD3 and BRD4 interacts with several proteins that have a role in chromatin modulation and regulation of gene expression (Rahman et al., Mol. Cell Biol., 2011, 31: 2641-2652).

Mechanistically, BET proteins play an important role in cell growth and cell cycle. Biol. Cell, 2009, 20: 4899-4909; Yang et al., Mol. Cell. Biol., 2008, 28: 967-976). BRD4 is important for the post-mitotic reactivation of gene transcription (Zhao et al., Nat Cell Biol., 2011, 13: 1295-1304). It has been shown that BRD4 is essential for the "

Transcription elongation and recruitment of the elongation complex P-TEFb, which consists of CD 9 and cyclin Tl, which leads to the activation of RNA polymerase 11 (Yang et al., Mol. Cell, 2005, 19: 535-545; Schröder et al. , J. Bio]. Chem., 2012, 287: 1090-1099). Thus, the expression of genes involved in cell proliferation is stimulated, such as c-myc and aurora B (You et al., Mol. Cell. Biol., 2009, 29: 5094-5103; Zuber et al. Nature, 2011, 478: 524-528). BRD2 and BRD3 bind to transcribed genes in hyperacetylated

Chromatin amplify and promote transcription by RNA polymerase 11 (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 lead to an Gl residue and to cell death by apoptosis (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 activated in the Gl phase, such as cyclin D1 and D2 (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040 -9048). In addition, inhibition of c-Myc expression, an essential factor in cell proliferation, following BRD4 inhibition was 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 to 16674).

 BRD2 and BRD4 knockout mice die prematurely during embryogenesis (Gyuris et al., Biochim Biophys Acta, 2009, 1789: 413-421, Houzelstein et al., Mol. Cell Biol., 2002, 22: 3794-3802 ). Heterozygous BRD4 mice have various growth defects attributable to reduced cell proliferation (Houzelstein et al., Mol. Cell. Biol., 2002, 22: 3794-3802). BRDT has an essential function in spermatogenesis (Berkovits and Wolgemuth, Curr., Top. Dev. Biol., 2013, 102: 293-326).

BET proteins play an important role in various tumor types. The fusion between the BET proteins BRD3 or BRD4 and NUT, a protein normally only expressed in the testes, results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet, Cytogenet., 2010, 203: 16 -20). The fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 2011, 286: 27663-27675). The growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073). Screening for therapeutic targets in an acute myeloid leukemia cell line (AML) showed that BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, doi: 10.1038). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo. Amplification of the DNA region containing the BRD4 gene was detected in primary breast tumors (Kadota et al., Cancer Res, 2009, 69: 7357-7365). Also for "

BRD2 has data on a role in tumors. A transgenic mouse that selectively overexpressing BRD2 in B cells develops B-cell lymphomas and leukemias (Greenwall et al., Blood, 2005, 103: 1475-1484). The anti-proliferative effects of BET inhibitors used in various preclinical in vitro and in vivo tumor models suggest an essential role of BET proteins, especially BRD4, in hematological tumors such as AML, multiple myeloma, and lymphomas ( Delmore et al., Cell, 201 1, 146: 904-917; Zuber et al., Nature, 2011, 478: 524-528; Merz et al., Proc. Natl. Acad., USA, 201 1, 108 Dawson et al., Nature, 201 1, 478: 529-533, Chaidos et al., Blood, 2014, 123: 697-705, Ceribelli et al., Proc, Natl. Acad , 2014, 11 1: 1 1365-1 1370; Emadali et al., EMBO Mol. Med., 2013, 5: 1 180-

10 1195; Trabucco et al., Clin. Cancer Res., 2014, pii: clincanres.3346.2013) and also in sound

Tumors such as prostate cancer (Asangani et al., Nature, 2014, 510: 278-282), breast cancer (Nagarajan et al., Cell Reports, 2014, 8: 460-469; Shi et al., Cancer Cell, 2014; 25: 210-225), lung cancer (Shimamura et al., Clin. Cancer Res., 2013, 19: 6183-6192, Lockwood et al., Proc Natl Acad., USA, 2012, 109: 19408-19413 ), Melanoma (Gallagher et al., J. Invest. Dermatol.

1 5 2014, doi: 10.1038 / jid.2014.243), pancreatic cancer (Sahai et al., Mol. Cancer Ther., 2014, 13: 1907-1917), glioblastoma (Pastori et al., Epigenetics, 9: 61-620 ), Neuroblastoma (Wyce et al., PLOS One, 2013, 8: e72967), and medulloblastoma (Henssen et al., Oncotarget, 2013, 4: 2080-2095). BET proteins are also involved in viral infections. BRD4 binds to the E2 protein of various papillomaviruses and is important for survival of the viruses in latently infected O cells (Wu et al., Genes Dev., 2006, 20: 2383-2396, Vosa et al., J. Viral. 2012, 86: 348-357;

 McBride and Jang, Viruses, 2013, 30: 1374-1394). The herpesvirus responsible for Kaposi's sarcoma also interacts with various BET proteins

 Disease resistance is important (Viejo-Borbolla et al., J. Viral., 2005, 79: 13618-13629; You et al., J. Viral., 2006, 80: 8909-8919). By binding to P-TEFb, BRD4 also plays an important role in the replication of HIV (Bisgrove et al., Proc, Natl Acad., USA, 2007, 104: 13690-13695). A role of BRD4 in the control of the latency of H IV proviruses has also been demonstrated (Boehm et al., Cell Cycle, 2013, 1 2: 452-462). Human T-cell leukemia virus 1 (HTLV-1) is also controlled by BRD4 via the NF-κB pathway (Wu et al., J. Biol.

 Chem., 2013, 288: 36094-36105).

 0 BET proteins are also involved in inflammatory processes. BRD2 hypomorphic mice show reduced inflammation in adipose tissue (Wang et al., Biochem J., 2009, 425: 71-83). The infiltration of macrophages into white adipose tissue is also reduced in BRD2-deficient mice (Wang et al., Biochem J., 2009, 425: 71-83). It has also been shown that BRD4 regulates a number of genes involved in inflammation. In LPS-stimulated

In macrophages, a BRD4 inhibitor prevents the expression of inflammatory genes, such as II.-I or IL-6 (Nicodeme et al., Nature, 2010, 468: 1179-1123). BET proteins also regulate the expression of the ApoAl gene, which plays an important role in atherosclerosis and in inflammatory processes (Chung et al., J. Med. Chem., 2011, 54: 3827-3838). Apolipoprotein AI (ApoAl) is a major component of high density

Lipoproteins (HDL) and increased expression of ApoAl result in elevated blood cholesterol levels (Degoma and Rader, Nat. Rev. Cardiol., 201 1, 8: 266-277). Elevated HDL levels are associated with a decreased risk of atherosclerosis (Chapman et al., Eur. Heart J., 201 1, 32: 1345-1361). Increased expression of BRD4 was observed during cardiac hypertrophy and attributed to the regulation of atrial natriuretic factor expression (Spiltoir et al., J. Mol. Cell. Cardiol., 2013, 63: 175-179). Accordingly, BRD4 could also play an important role in heart failure.

All these studies show that the BET proteins play an essential role in various pathologies and also in male fertility. It is therefore desirable to find potent and selective inhibitors which prevent the interaction between the BET proteins, for example BRD2, BRD3, BRD4 and BRDT, and acetylated proteins, especially acetylated histone H4 peptides.

State of the art

The nomenclature used in the consideration of the structural state of the art is illustrated by the following figure:

 1-phenyl-4,5-dihydro-3 // - 2,3-benzodiazepines

As a result of the intensive studies of the functions of bromodomain proteins discussed above, in particular of BET proteins such as BRD4, in various pathologies, numerous inhibitors of these proteins from different types of chemo have been identified. Current overviews can be found, for example, in B. Haendler et "

al., Epigenomics 2015, 7 (3), 487-501, S.G. Smith et al, Chemistry & Biology 2014, 21, 573-582; D. Gallenkamp et al., ChemMedChem 2014, 9 (3): 438-464; J.-M. Garnier et al., Export Opin. Ther. Patents 2014, 24 (2): 185-198; S. Muller et al., Selective Inhibition of Acetyl Lysine Effector Domains of the Bromodomain Family in Oncology, ex Nuclear Signaling Pathways and Targeting Transcription in Cancer, Springer 2014, ISBN 978-1-4614-8038-6, pp. 279-298. L-aryl-4,5-dihydro-3i7-2,3-benzodiazepines have long been known, inter alia, as modulators or antagonists excitatory shear amino acid receptors, such as the AMPA receptor and are, among other things as a potential therapeutic agents for diseases central nervous Origin described.

 Thus, WO 2001/098280 (Annovis, Inc.) discloses 1-phenyl-4,5-dihydro-377-2,3-benzodiazepines as antagonists of the non-NMDA ionotropic excitatory amino acid (EAA) receptor. Of the exemplary compounds disclosed in this application, the

Compounds of the present invention, inter alia, by the substitution on the phenyl ring connected to C-1 of the B enzodiazepin skeleton.

 US 5,519,019 and EP 0 492 485 (Gyogyszerkutato Intezet) disclose N-acyl-2,3-benzodiazepines as excitatory amino acid receptor antagonists derived from the compounds of the present invention inter alia by the obligate methylenedioxy group at C-7 and C-8 of the B enzodiazepine scaffold differ.

The compounds according to the invention furthermore differ, inter alia, by the substitution on the aromatics associated with Cl of the B enzodiazepine skeleton of other known 2,3-benzodiazepines such as the numerous published AMPA antagonists (see, for example, WO 1997/28135 (Schering AG), US Pat. No. 5,807,851 , HU 0097000688, WO

2002/050044 and WO 2007/077469 (Egis Gyogyszergyar)), as well as antagonists of the MT2 receptors and inhibitors of the adenosine transporter (WO 2008/124075, Teva Pharmaceuticals).

WO 1997/034878 and US 5,891,871 (CoCensys Inc. / ACEA Pharmaceuticals) disclose 2,3-benzodiazepine-4-ones which differ from the compounds of the present invention by the oxo substitution at C -4 of the benzodiazepine skeleton Antagonists or positive modulators of the AMPA receptor.

Ligands of the gastrin and the cholecystokinin receptor are described in WO2006 / 051312 (James Black Foundation). They also include substituted 3,5-dihydro-417-2,3-benzodiazepine-4-ones, which differ from the compounds of the invention mainly by the obligatory oxoglobin in position 4 and by a mandatory carbonyl-containing alkyl chain in position 5. WO 2008/121877 discloses cyclic and acyclic hydrazone derivatives as inhibitors of the functional transmembrane conductance regulatory polypeptide in cystic fibrosis (CFTR), inter alia, for the treatment of diarrhea and polycystic kidney disease (PKD).

WO 2014/026997, WO 2014/128067 and WO 2014/202578 disclose 1-phenyl- and 1-heteroaryl-4,5-dihydro-3i7-2,3-benzodiazepines as inhibitors of ET Prot, in particular of BRD4 for the treatment of hyperproliferative diseases. Among the compounds disclosed in these applications, the compounds of the present invention differ by substitution on the phenyl or heteroaryl ring attached to C-1 of the benzodiazepine skeleton.

At the present time there are no inhibitors of bromodomain proteins as

Medicinal products, nor can such a marketing authorization be reliably expected for the foreseeable future. It is therefore desirable to find other novel compounds that have prophylactic and therapeutic properties that qualify them for the treatment of diseases in which bromodomain proteins are involved.

Thus, it is an object of the present invention to provide compounds and pharmaceutical compositions containing these compounds for a prophylactic and therapeutic use in hyperproliferative diseases, especially in cancer or tumor diseases and as BET protein inhibitors in viral infections in HIV-associated kidney diseases neurodegenerative diseases, inflammatory diseases, atherosclerotic erotic diseases, cardiac insufficiency, muscular strophi, such as fazio scapulohumeral muscular dystrophy, and males

Fertility Control are used.

Starting from the above-described prior art, there was no reason that

To modify structures of the prior art in such a way that structures are obtained which are suitable for the prophylaxis and therapy of hyperproliferative diseases and in particular cancer or tumor diseases, as well as in viral infections, in H IV-associated kidney diseases, in neurodegenerative diseases, in inflammatory diseases atherosclerotic erythroids, heart failure, muscular strophi, such as fazio scapulohumeral muscular dystrophy, and males

Fertility control can be used. Surprisingly, the compounds according to the invention inhibit the interaction between BET proteins, in particular BRD4, and an acetylated histone H4 peptide. In particular, they inhibit the growth of cancer or tumor cells and can also be used in viral infections, in HIV-associated diseases, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic erotic diseases, in heart failure, in muscular dystrophies such as, for example, the fazioskapulohumeral

Muscular dystrophy and in male fertility control.

They thus represent new compounds for the prophylaxis and therapy of human and animal diseases, in particular cancer or tumor diseases.

It has now been found that compounds of the general formula (I)

in welcher

in which

R ¹ for a group

 where "*" is the point of attachment to the rest of the molecule,

R is C ₁ -C ₃ -alkyl, trifluoromethyl or C ₃ -C ₄ -cycloalkyl, R is cyclopropyl, C ₁ -C ₃ -alkyl, C ₁ -C 8 -alkoxy, amino, cyclopropylamino or

 C 1 -C 3 -alkylamino stands,

R ⁴ and R ^{3 are} independently

 for hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine or bromine,

 or

 for C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, phenylamino,

 C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulphonyl, which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identical or different, by halogen, amino, hydroxyl,

Carboxy, C 1 -C 6 -acyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 4 -alkyl, C6-alkyl,

oder monocyclischem Heterocyclyl- mit 4 bis 8 Ringatomen „

or monocyclic heterocyclyl having 4 to 8 ring atoms "

or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted with G-C3-alkyl,

or

C 3 -C 10 -cycloalkyl- or C 4 -C 1 -cycloalkenyl- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen,

Amino, hydroxy, carboxy, C 1 -C 6 -alkylene, C 1 -C 6 -alkoxy,

C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl-, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl-, halogeno-C i -Ce-alkyl, halo-C 1 -Ce-alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ^{! !} , -S (= O) ₂ -NR ⁹ R ^i0, -S (= 0) -R ^n, -S (= 0) ₂ -R ', -NH-S (= 0) 2-R "or monocyclic heterocyclyl - with 4 to 8 ring atoms, or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, nitro, carboxy, C 1 -C 6 -alkyl-, Ce-alkoxy, Ci-Ce-alkoxy-Ci-Cö-alkyl, hydroxy-Ci-Ce-alkyl, Ci-Ce-alkylamino,

Amino-C ₁ -Ce-alkyl, C ₁ -C 6 -alkylamino-C ₁ -Ce-alkyl, halo-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, -C (= 0 ) -NR ⁹ R ^10, -C (= 0) -R ^n, -S (= 0) ₂ -NR ⁹ R ^10, -S (= 0) -R ^n, -S (= 0) ₂ -R ⁿ , -NH-S (= 0) ₂ -R ', C ₃ -C ₀ cycloalkyl or

monocyclic heterocyclyl having 4 to 8 ring atoms,

or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, carboxy, C 1 -C 6 -alkyl-, C 1 -C 4 -alkyl-, Ce-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylamino, amino-Ci-Ce-alkyl, C1-C6-alkylamino-C1-C6-alkyl -, hydroxy-C 1 -Ce-alkyl, halogen-C 1 -Ce-alkyl,

Halo-C 1 -Ce-alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ", -S (= O) ₂ -NR ⁹ R ¹⁰ , -S (= O ) -R ⁿ , -S (= O) ₂ -R ", -NH-S (= O) ₂ -R", C ₃ -Cio -cycloalkyl or

monocyclic heterocyclyl having 4 to 8 ring atoms,

or

for phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, nitro, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1-Ce-alkoxy-C 1 -Ce-alkyl,

C 1 -C -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylaminosulfonyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl-,

Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkoxy,

-C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -S (= O) ₂ -NR ⁹ R ¹⁰ , -S (= O) -R ", -S (= O ) ₂ -R ", -NH-S (= O); - R ", Cs-Cio-cycloalkyl or monocyclic heterocyclyl- with

4 to 8 ring atoms, for a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= 0) (= NR ¹³ ) R ¹² or -P (= 0 (R ¹⁴ ) R ¹⁵ , independently of one another, is hydrogen, halogen, hydroxyl, cyano, nitro or C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-,

Halogen-C i -Ce-alkyl, halogen-C i-Ce-alkoxy, C i -Ce-alkylsulfonyl, Cs-Cio-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms, independently of one another represent hydrogen or are unsubstituted or mono- or disubstituted by identical or different hydroxy, oxo or GC ₃ alkoxy-substituted G-C3-alkyl, or fluoro-G-C3-A!

or

together with the nitrogen atom to which they are attached, for

monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, Ci-C ₃ alkyl, fluoro-GC ₃ alkyl, Cs -Ce-cycloalkyl, cyclopropylmethyl, C i -C3 alkylcarbonyl or C 1 -C 4 alkoxycarbonyl -, for hydroxy, C 1 -C ₆ -alkyl, C 1 -C ₆ -alkoxy, halogeno-C 1 -C ₃ alkyl,

Hydroxy-C ₁ -C 8 -alkyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl or C ₃ -cycloalkyl-,

or

represents phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or mono- or disubstituted, identical or different, are substituted by halogen, Ci-C ₃ alkoxy or GC ₃ alkyl, is C Ce-alkyl, which is unsubstituted or GC is monosubstituted with cyano, ₃ alkoxy, C 1 -C ₃ alkylamino, phenyl, C ₃ -Cs-cycloalkyl , or with monocyclic heterocyclyl having 4 to 8 ring atoms,

in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted identically or differently with halogen, cyano, G-C4-alkyl-, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, Ci-C ₄ alkoxy, halo-Ci-C ₄ alkyl or halo-C i -C ₄ alkoxy, and

 wherein C3-Cs-cycloalkyl and monocyclic Heterocyclyl- with

 4 to 8 ring atoms are in turn unsubstituted or substituted once or twice, identically or differently, by G-C3-alkyl-,

 or

represents halogeno-C 1 -C ₄ -alkyl,

 or

C ₃ -C 8 -cycloalkyl- or monocyclic heterocyclyl having 4 to 8 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with G-Cs-alkyl- or C 1 -C ₄ -alkoxycarbonyl-, with with the proviso that the monocyclic heterocyclyl having 4 to 8 ring atoms not via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or

 Sulfoximino group is bonded in R ',

 or

is phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl , Trifluoromethoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -N (R ⁹ ) C (= O) -R ¹⁶ ,

-S (= O) ₂ -NR ⁹ R ¹⁰ or NR'R ^{i 0} , with the proviso that the monocyclic heteroaryl having 5 or 6 ring atoms does not have a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino R 1 is hydrogen, cyano, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl or -C (= O) OR ^{! 6} , independently of one another are C ₁ -C ₅ -alkyl-, phenyl-Ci-Cs-alkyl,

 Fluoro-C 1 -C 3 -alkyl- or phenyl-,

in which phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl-, C ₁ -C ₃ - Alkoxy, trifluoromethyl or trifluoromethoxy,

 or

together represent C ₂ -C 8 -alkylene and C ₁ -C 6 -alkyl- or phenyl-C ₁ -C ₃ -alkyl-, as well as their polymorphs, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically acceptable salts and solvates of these salts, are suitable as bromodomain protein inhibitors, in particular as BET protein inhibitors and preferably as BRD4 inhibitors, for a variety of prophylactic and therapeutic uses, in particular in hyperproliferative diseases, in cancer or

Tumor diseases, as well as in viral infections, in HTV-associated kidney diseases, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases, in heart failure, in muscular dystrophies such as the

Facioscapulohumeral muscular dystrophy and in male fertility control.

The present invention furthermore relates to compounds of the general formula (I) in which

R ¹ for a group

 in which * "in each case denotes the point of attachment to the remainder of the molecule, stands for C 1 -C 3 -alkyl-, trifluoromethyl- or C 3 -C 4 -cycloalkyl-, for cyclopropyl-, O-C 1 -alkyl-, C 1 -C 3 -alkoxy , Amino, cyclopropylamino or C i -C 3 -alkylamino-,

R ⁴ and W are independent of each other

 for hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine or bromine,

 or

for C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, phenylamino, Ci-C6-Alkylcarbonylamino-, Ci-C6-Alkylaminocarbonyl- or

Ci-Ce-Alkylaminosuifonyl-, which are unsubstituted or mono-, di- or trisubstituted, identically or differently, are substituted by halogen, amino, hydroxy, carboxy, O-Ce-alkyl, hydroxy-C i -Cö-alkyl- , Ci-Cö-alkoxy,

C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkylene,

-NH-S (= 0) .- R ^i! or monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted by C 1 -C 3 -alkyl-,

or

C 3 -C 10 -cycloalkyl- or C 4 -C 1 -cycloalkenyl- which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, carboxy, C 1 -C 6 -cycloalkyl- Alkyl, Ci-Ce-alkoxy,

C 1 -C -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl-, halogeno-C 1 -C 4 -alkyl-, Ce-alkyl, halogen-C i-Ce-alkoxy,

oder monocy cli s chem Heterocyclyl- mit 4 bis 8 Ringatomen, oder

or monocy clic chem heterocyclyl having 4 to 8 ring atoms, or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents

Halogen, amino, hydroxy, cyano, nitro, carboxy, C 1 -C ₆ -alkyl, C 1 -C -alkoxy, C 1 -C ₆ -alkoxy-C 1 -C ₆ -alkyl, hydroxy-C 1 -C ₆ -alkyl -, C iC ₆ -alkylamino, amino-C 1 -C ₆ alkyl, C 1 -Ce-alkylamino-C 1 -C ₆ alkyl, halogen-C i-Ce-alkyl, halogen-C i -Ce-alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -S (= O) ₂ -NR ⁹ R ¹⁰ ,

-S (= 0) -R ^n, -S (= 0) ₂ -R ', -NH-S (= 0) ₂ -R ^1!, C ₃ -C ₁₀ cycloalkyl, or

monocyclic heterocyclyl having 4 to 8 ring atoms,

or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, carboxy, C 1 -C 6 -alkyl-, Ce-alkoxy,

C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl-,

C 1 -Ce -alkylamino-C 1 -Ce-alkyl, hydroxy-C 1 -Ce-alkyl, halo-C 1 -Ce-alkyl, halo-C 1 -C 6 -alkoxy, -C (= 0 ) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -S (= O) ₂ -NR ⁹ R ¹⁰ ,

-S (= O) -R ", -S (= O) ₂ -R", -NH-S (= O) ₂ -R ⁿ , C ₃ -Cio -cycloalkyl or

monocyclic heterocyclyl having 4 to 8 ring atoms,

or phenyl, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, nitro, carboxy, G-Ce-alkyl, G-Ce-alkoxy-, Ci -ce-alkoxy-Ci-Ce-alkyl,

Ci-Ce-alkylamino, amino-Ci-Ce-alkyl, Ci-Ce-alkylaminocarbonyl, Ci-Ce-alkylaminosulfonyl, Ci-Ce-Aikylamino-Ci-alkyl,

Cs-Cio-Cycloalkyl- oder monocyclischem Heterocyclyl- mit 4 bis 8 Ringatomen, für eine Gruppe -SR¹², -S(=0)R¹², -S(=0)₂R'², -S(=0)(=NR¹³)R¹² oder -P(=0)(R¹⁴)R¹⁵ steht, unabhängig voneinander für Wasserstoff, Halogen, Hydroxy, Cyano, Nitro oder für Ci-Ce-Alkyl-, Ci-Ce-Alkoxy-, Ci-Ce-Alkoxy-Ci-Ce-Alkyl-, Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -S (= O). -NR 'R ^{! 0} , -S (= 0) -R ", -S (= 0) ₂ -R",

Cs-Cio-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms, for a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ' ² , -S (= O) ( = NR ¹³⁾ R ¹² or -P (= 0) (R ¹⁴⁾ R ^15, independently of one another hydrogen, halogen, hydroxy, cyano, nitro, or for Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci -ce-alkoxy-Ci-Ce-alkyl,

Halo-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, C ₁ -C 6 -alkylsulfonyl, C ₃ -C 10 -cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms, independently of one another represent hydrogen or is unsubstituted or mono- or disubstituted by identical or different hydroxy, oxo or Ci-C3-alkoxy-substituted Ci-C ₃ alkyl, or fluorine-GC ₃ alkyl stand,

or

together with the nitrogen atom to which they are attached, for

monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl , Cs-Ce-cycloalkyl, cyclopropylmethyl, Ci-Cs-alkylcarbonyl or Ci-C4-alkoxycarbonyl, for hydroxy, Ci-Ce-alkyl, G-Ce-alkoxy, halogen-C i-C3-alkyl -

Hydroxy-C ₁ -C 8 -alkyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl or C ₃ -C 10 -cycloacyl-,

or

is phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or mono- or di-substituted, same or different, substituted are halogen, O-Cs-alkoxy or O-Cs-alkyl, is O-Ce-alkyl which is unsubstituted or monosubstituted with cyano, G -C -alkoxy, C i -C 3 -alkylamino, Phenyl, C 3 -C 8 -cycloalkyl- or monocyclic heterocyclyl having 4 to 8 ring atoms,

in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl-, Ci-C ₄ alkoxy, halo-Ci-C ₄ alkyl or halogen-C 1 -C ₄ alkoxy, and

 wherein Cs-Cs-cycloalkyl and monocyclic Heterocyclyl- with

4 to 8 ring atoms are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl,

or

represents halogeno-C 1 -C ₄ -alkyl,

or

represents C ₃ -C 8 -cycloalkyl- or monocyclic heterocyclyl having 4 to 8 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl or C ₁ -C ₄ -alkoxycarbonyl-, with the proviso that the monocyclic heterocyclyl having 4 to 8 ring atoms not via a nitrogen atom to the sulfanyl, sulfmyl, sulfonyl or

Sulfoximino group is bound in R ⁶ ,

or

represents phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl-, O-C ₁ -alkoxy-, trifluoromethyl- or trifluoromethoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ^{! 1} or -N (R ⁹ ) C (= O) -R ¹⁶ , with the proviso that the monocyclic heteroaryl having 5 or 6 ring atoms does not have a nitrogen atom to the sulfanyl, sulfmyl, sulfonyl or sulfoximino group in R "is hydrogen, cyano, GC ₆ alkyl, C ₃ -C ₈ cycloalkyl or -C (= O) OR ¹⁶ , independently of one another are C ₁ -C ₃ -alkyl-, phenyl-GC ₃ alkyl,

 Fluoro-C 1 -C 3 -alkyl- or phenyl-,

in which phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl- in turn are unsubstituted or one or two times, same or different are substituted with halogen, cyano, GC ₃ alkyl, GC ₃ alkoxy, trifluoromethyl or trifluoromethoxy,

 or

R ¹ and R ¹⁵ together represent C 2 -C 8 -alkylene, and R ^{16 represents} G-C ₁ -C 4 -alkyl or phenyl-C ₁ -C ₃ -alkyl, and also their polymorphs, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

Preference is given to those compounds of the general formula (I) in R ^! for a group

 stands,

 where "*" is in each case the point of attachment to the rest of the molecule, R - is methyl,

R ^{3 is} cyclopropyl, Ci-C3-alkyl, cyclopropylamino or

 C 1 -C 3 -alkylamino stands,

R ⁴ and R ^{5 are} independently

 for hydrogen, hydroxy, cyano, amino, aminocarbonyl, fluorine, chlorine or

Bromine,

 or

for C 1 -C 6 -alkyl, G-C 1 -C -alkoxy, C 1 -C 6 -alkylamino, phenylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulfonyl, which unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents, halogen, amino, hydroxy, carboxy, C ₁ -C ₃ -alkyl, hydroxy-C ₁ -C ₃ -alkyl, C ₃ -C ₃ -alkoxy, C1-C3-alkoxy-C1-C. Alkyl, C 1 -C ₃ alkylamino, aminoC 1 -C ₃ alkyl, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl- with 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted by C1-C3-alkyl, or

monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by identical or different substituted with halogen, amino, hydroxy, cyano, carboxy, C1-C3 alkyl, GC ₃ alkoxy -, C 1 -C ₃ alkoxy-C 1 -C ₃ -alkyl, hydroxy-C iC ₃ alkyl, C iC ₃ alkylamino,

Amino-C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, fluoro-C 1 -C ₃ -alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms, or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, carboxy, GC ₃ -alkyl-, GC ₃ - Alkoxy, C 1 -C ₃ alkoxy-C 1 -C. -Alkyl, C 1 -C ₃ -alkylamino, amino-C 1 -C ₃ -alkyl-,

Ci-C ₃ -alkylamino-Ci-C ₃ alkyl, hydroxy-C 1 -C ₃ alkyl, fluoro-GC ₃ alkyl, fluoro-GC ₃ alkoxy, -C (= 0) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms, for a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , - S (= O) (= NR ¹³ ) R ¹² or -P (= O) (R ¹⁴ ) R ¹⁵ is hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or GC ₃ alkyl, GC ₃ - Alkoxy, C 1 -C ₃ -alkoxy-C 1 -C ₃ -alkyl, fluoro-GC ₃ -alkyl-,

Fluorine-GC ₃ -alkoxy- or GC ₃ -alkylsulfonyl stands independently of one another for hydrogen, GC ₃ -alkyl, acetyl, propionyl or for fluorine-C 1 -C ₃ -alkyl- stand,

or

together with the nitrogen atom to which they are attached, for

monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, cyano, GC ₃ alkyl, C ₃ -C 6 cycloalkyl, GC ₃ alkylcarbonyl or C 1 -C 4 alkoxy carbonyl, for hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₄ -alkoxy, fluoro-C ₁ -C ₃ -alkyl,

Hydroxy-Ci-C ₃ alkyl, Ci-C ₃ alkoxy-Ci-C ₃ alkyl or C ₃ -C ₇ cycloalkyl, or

represents phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or mono- or disubstituted, identical or different, are substituted by halogen, Ci-C ₃ alkoxy or C ₁ -C ₃ -alkyl-, C ₁ -C 6 -alkyl-, which is unsubstituted or monosubstituted by cyano, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylamino, phenyl, C ₃ - Cs-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms,

wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, fluorine-GC ₃ -alkyl or fluorine C 1 -C ₃ -alkoxy- and in which C ₃ -C 8 -cycloalkyl- and monocyclic heterocyclyl having 4 to 8 ring atoms are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with GC ₃ -alkyl-,

or

is fluoro-C 1 -C ₃ -alkyl-,

or

is C ₃ -C 8 -cycloalkyl- or monocyclic heterocyclyl having 4 to 8 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C ₃ alkyl or G-C4-alkoxycarbonyl, with with the proviso that the monocyclic heterocyclyl having 4 to 8 ring atoms not via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or

Sulfoximino group is bonded in R ',

or

represents phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl -, trifluoromethoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (<)) - RVN (R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ - NR 'R ^{i 0} or R 'R ^{! 0} , with the proviso that the monocyclic heteroaryl having 5 or 6 ring atoms is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ", for hydrogen, cyano , C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkylene or -C (= O) OR ¹⁶ , R ¹⁴ and R ¹⁵ independently of one another are C ₁ -C ₃ -alkyl, phenyl-G-Cs-alkyl,

Fluoro-C ₁ -C ₃ -alkyl or phenyl,

 in which phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C -alkoxy- , Trifluoromethyl or trifluoromethoxy,

 or

R ¹⁴ and R ¹⁵ together represent C 2 -C 8 -alkylene, and

R ^{16 is} C ₁ -C ₃ -alkyl or benzyl, and their polymorphs, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically tolerated salts and solvates of these salts.

Preference is furthermore given to those compounds of the general formula (I), ^' R ^{1 being} a group

 stands,

 wherein "*" in each case the point of attachment to the remainder of the molecule is methyl, cyclopropyl, G-C3-alkyl, cyclopropylamino or

 C i -C3 -Alkylamino- stand independently of one another

 for hydrogen, hydroxy, cyano, amino, aminocarbonyl, fluorine, chlorine or

Bromine,

or for C 1 -C 6 -alkyl, G-C 6 -alkoxy, C 1 -C 6 -alkylamino, phenylamino,

Ci-Ce-Alkylcarbonylamino-, Ci-Ce-alkylaminocarbonyl or

Ci-Ce-Alkylaminosulfonyl-, which are unsubstituted or mono-, di- or trisubstituted, identical or different, are substituted by halogen, amino, hydroxy, carboxy, G-C3-alkyl, hydroxy-C i -C ₃ alkyl -, Ci-C3-alkoxy,

C 1 -C ₃ alkoxy-C 1 -C ₃ alkyl, C ₃ alkylamino, amino-Ci-Cs-alkyl,

-C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted by Cl -C ₃ alkyl, or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, carboxy, C 1 -C 3 -alkyl-, C 1 -C 5 -sym- alkoxy, C 1 -C ₃ alkoxy-C 1 -C ₃ -alkyl, hydroxy-C iC ₃ alkyl, _{Ci-C3-alkylamino,} amino-Ci-C ₃ alkyl, fluoro-Ci -C ₃ alkyl, fluoro-C 1 -C ₃ -alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms, or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, with halogen, amino, hydroxy, cyano, oxo, carboxy, Ci-C ₃ alkyl, Ci -C ₃ alkoxy, C 1 -C ₃ alkoxy-C 1 -C ₃ alkyl, C ₃ alkylamino, amino-Ci-C ₃ alkyl,

C 1 -C ₃ -alkylamino-C 1 -C ₃ -alkyl, hydroxy-C 1 -C ₃ -alkyl, fluoro-C 1 -C ₃ alkyl, fluoro-Ci-C ₃ alkoxy, - C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R "or monocyclic heterocyclyl having 4 to 8 ring atoms, for a group -SR ' ² , -S (= O) R ¹² , -S ( = 0) ₂ R ' ² , -S (= 0) (= NR ¹³ ) R ¹² or

-P (= 0) (R ¹⁴⁾ R ¹⁵ represents hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or GC ₃ alkyl, Ci-C ₃ alkoxy, C 1 -C ₃ alkoxy C 1 -C ₃ -alkyl, fluoro-C 1 -C ₃ -alkyl,

Fluoro-Ci-C ₃ alkoxy or C ₃ is alkylsulfonyl, independently of one another represent hydrogen, GC ₃ -Aikyl-, acetyl, propionyl or fluoro-C 1 -C ₃ alkyl are,

or

together with the nitrogen atom to which they are attached, for _

 - 2 1 -

monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, cyano, Ci-C3-alkyl, Cs-Ce-cycloalkyl, Ci-C3-alkylcarbonyl - or C i -C4-alkoxycarbonyl, for hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₄ -alkoxy, fluoro-C ₁ -C ₃ -alkyl,

Hydroxy-C ₁ -C 8 -alkyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl or C ₃ -C ₇ -cycloalkyl-, or

represents phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or mono- or disubstituted, identical or different, are substituted by halogen, Ci-C ₃ alkoxy or C ₁ -C ₃ -alkyl-, represents C ₁ -C 6 -alkyl-, which is unsubstituted or monosubstituted by cyano, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylamino, phenyl, C ₃ - Cs-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms,

wherein phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, GC ₃ alkyl, Ci-C ₃ alkoxy, fluoro-Ci-C ₃ alkyl or fluorine C 1 -C ₃ -alkoxy- and in which C ₃ -C 8 -cycloalkyl- and monocyclic heterocyclyl having 4 to 8 ring atoms are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with GC ₃ -alkyl-,

or

represents fluoro-C ₁ -C ₃ -alkyl,

or

is C ₃ -Cs-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C ₃ alkyl or Ci-C4-Aikoxycarbonyl-, with with the proviso that the monocyclic heterocyclyl having 4 to 8 ring atoms not via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or

Sulfoximino group is bonded in R ',

or

represents phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl - or trifluoromethoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or ^™ N (R ⁹ ) C (= O) -R ¹⁶ , with the In that the monocyclic heteroaryl group having 5 or 6 ring atoms is not bonded via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ', R ^{13 is} hydrogen, cyano, G-Ce-alkyl-, C ₃ -C ₈ -cycloalkyl- or -C (= O) OR ¹⁶ ,

R ¹⁴ and R ¹⁵ independently of one another represent G-Cs-alkyl-, phenyl-C 1 -C ³ -alkyl-,

 Fluoro-Ci-Cs-Aikyl- or phenyl,

 in which phenyl and the phenyl contained in phenyl-C 1 -C 3 -alkyl- are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, G-Cs-alkyl, G-Cs-alkoxy- , Trifluoromethyl or trifluoromethoxy,

 or

R ¹⁴ and R ¹⁵ together represent C 2 -C 8 -alkylene, and

R ^{16 is} C ₁ -C ₃ -alkyl or benzyl, and their polymo he, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

Particular preference is given to those compounds of the general formula (I) in IV for a group

 stands,

 where "*" is in each case the point of attachment to the rest of the molecule, R - is methyl,

R 'is Ci-Cs-alkylamino-, R ⁴ and R ^{5 are} independently

 for hydrogen, hydroxy, cyano, fluorine, chlorine or bromine,

 or

 for C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 1 -C 3 -alkylamino,

 or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, C ₁ -C ₃ -alkyl or GG-alkoxy-,

 or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, with fluorine, oxo, GG-alkyl, C ₁ -C ₃ -alkoxy, GG-alkylamino or -C (= O) -R ⁿ , R "for a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ^{! 3} ) R ¹² or

-P (= 0) (R ¹⁴ ) R ¹⁵ ,

R is hydrogen, fluorine, C ₁ -C ₃ -alkoxy- or C ₁ -C ₃ -alkylsulfonyl-, R ⁹ and R ¹⁰ are each independently hydrogen, methyl, ethyl or acetyl, or

R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached, for

 monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluoro, oxo, methyl, ethyl, cyclopropyl, acetyl or terf-butoxycarbonyl,

R "is hydroxy, C ₁ -C ₃ -alkyl or C ₁ -C ₄ -alkoxy,

R ^{12 is} GG-alkyl- which is unsubstituted or monosubstituted with G-C 3 alkylamino, phenyl, or with monocyclic heterocyclyl of 4 to 7

Ring atoms,

wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, G-G-alkyl, GG-alkoxy, trifluoromethyl or trifluoromethoxy, and wherein the monocyclic heterocyclyl having 4 to 7 ring atoms in turn is unsubstituted or monosubstituted by methyl, or

 represents trifluoromethyl-,

 or

 is C3-6 cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted with Ci-C3-alkyl or

C 1 -C 4 alkoxycarbonyl, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms is not bonded via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ⁶ , or

is phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, O-Cs-alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, trifluoromethoxy, - C (= 0) -NR ⁹ R ¹⁰ ,

-C (= O) -R ⁿ , -N (R ⁹ ) C (= O) -R ¹⁶ , -S (= O): - NR 'R ^] "or --NR ⁹ R ¹⁰ , R ¹³ for hydrogen , Cyano, C 1 -C ₃ -alkyl or -C (= O) OR ¹⁶ ,

R ¹⁴ and R ¹⁵ independently of one another for C ₁ -C ₃ -alkyl, benzyl, trifluoromethyl or for

 Phenyl,

 in which phenyl and the benzyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents

Fluorine, chlorine, bromine, cyano, C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, trifluoromethyl or trifluoromethoxy, and

R ^{16 is} C ₁ -C ₃ -alkyl-, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which represented by the carbon atom bound to R ^{2 center of} asymmetry (^ -configured, as well as their stereoisomeric mixtures in which those stereoisomers predominate in which the represented by the carbon atom bound to R ² asymmetric center (S) - is configured.

Particular preference is furthermore given to those compounds of the general formula (I), in R ¹ for a group

 stands,

 where "*" is the point of attachment to the rest of the molecule,

R ^{2 is} methyl,

R ^{3 is} Ci-Cs-alkylamino, R ⁴ and R ^{5 are} independently

 for hydrogen, hydroxy, cyano, fluorine, chlorine or bromine,

 or

 for C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 1 -C 3 -alkylamino,

 or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, GC ₃ -alkyl- or G-Cs-alkoxy-,

 or

 for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, with fluorine,

Oxo, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, G-C ₁ -alkylamino or -C (= O) -R ",

R 'represents a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ¹³ ) R ¹² or

-P (= 0) (R ¹⁴ ) R ¹⁵ ,

R is hydrogen, fluorine, GC ₃ -alkoxy- or C ₁ -C ₃ -alkylsulfonyl-,

R ⁹ and R ¹⁰ are independently hydrogen, methyl, ethyl or acetyl, or

R ⁹ and R ⁱ⁰ together with the nitrogen atom to which they are attached, for

monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, Oxo, methyl, ethyl, cyclopropyl, acetyl or ferf-butoxycarbonyl, is hydroxy, Ci-C3-alkyl or Ci-C4-alkoxy, is Ci-Ce-alkyl- which is unsubstituted or is monosubstituted by G-C3-alkylamino, phenyl, or monocyclic heterocyclyl having 4 to 7 ring atoms,

 wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, G-G-alkyl, GG-alkoxy, trifluoromethyl or trifluoromethoxy, and wherein the monocyclic heterocyclyl having 4 to 7 ring atoms in turn is unsubstituted or monosubstituted by methyl,

 or

 represents trifluoromethyl-,

 or

is C ₃ -C 6 cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms, which are unsubstituted or monosubstituted with GC ₃ alkyl or C i -C4 alkoxycarbonyl, with the proviso that the monocyclic heterocyclyl - With 4 to 7 ring atoms not bound via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ", or

is phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, C ₁ -C ₃ -alkyl, C ₃ -C ₃ -alkoxy, trifluoromethyl or trifluoromethoxy, -C (= 0) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or ~N (R ⁹ ) C (= O) -R ¹⁶ , for hydrogen, cyano, C 1 -C ₃ -alkyl or -C (= 0) OR ¹⁶ is independently of one another GC _3- alkyl, benzyl, trifluoromethyl or phenyl,

wherein phenyl and the benzyl-containing phenyl in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, GC ₂ alkyl, GC ₂ alkoxy, trifluoromethyl or trifluoromethoxy -, and represents GC ₃ -alkyl-, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, as well as their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R- is (^ -configured, as well as their mixtures of stereoisomers, in which those stereoisomers in which the asymmetric center (5) - represented by the carbon atom bound to R predominate - are configured.

Very particular preference is given to those compounds of the general formula (I) in which

R ¹ for a group

 stands,

 where "*" is the point of attachment to the rest of the molecule,

R - is methyl,

R ^{3 is} methylamino or dimethylamino,

R ^{4 is} methoxy,

R ^{3 is} methoxy, R ^{6 is} a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ¹³ ) R ¹² or

~ -P (= 0) (R ¹⁴ ) R ¹⁵ ,

R is hydrogen, fluorine, methoxy- or methylsulfonyl-, R 'and R ¹⁰ independently of one another represent hydrogen, methyl or ethyl,

 or

R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached, for monocyclic heterocyclyl having 5 to 7 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, methyl or ethyl, R "is hydroxy, methyl, ethyl, methoxy or ethoxy .

R ¹² is C 1 -C 3 -alkyl which is unsubstituted or monosubstituted with

 phenyl,

 wherein phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, cyano, methyl, methoxy or trifluoromethyl, or

 represents trifluoromethyl-,

 or

 is C3-C6-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted by methyl or tert-butyl

Butoxycarbonyl, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ", or

is phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, methyl, methoxy, trifluoromethyl, -C (= O) -R ⁿ , -N ( R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ -NR ⁹ R ¹⁰ or

NR 'R ^{i 0} , R ^{13 is} hydrogen, cyano, methyl or -C (= O) OR ¹⁶ ,

R ' ⁴ and R' ⁵ independently of one another represent methyl, ethyl or phenyl,

 wherein phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, and

R ^{16 is} methyl, as well as their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the by R in ^; bonded carbon atom represented asymmetry center (^ -konfiguriert is, as well as their stereoisomeric mixtures in which those stereoisomers predominate, in which is the asymmetric center (S) - represented by the carbon atom bonded to R ^: -.

Very particular preference is furthermore given to those compounds of the general formula (I) in 1 for a group

 stands,

 where "*" is the point of attachment to the rest of the molecule,

R is methyl, R 'is methylamino,

R ^{4 is} methoxy,

R ^{5 is} methoxy,

R 'represents a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ¹³ ) R ¹² or

-P (= 0) (R ¹⁴ ) R ¹⁵ ,

R ^{7 is} hydrogen, fluorine, methoxy- or methylsulfonyl-,

R 'is hydrogen, methyl or ethyl,

R "is hydroxy, methyl, ethyl, methoxy or ethoxy, R ^{12 is} Ci-Cj-alkyl- which is unsubstituted or monosubstituted with

 phenyl,

wherein phenyl is in turn unsubstituted or monosubstituted with Fluorine, chlorine, cyano, methyl, methoxy or trifluoromethyl, or

 represents trifluoromethyl-,

 or

is C3-C6 cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted by methyl or tert-butoxycarbonyl, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms not over a nitrogen atom is bonded to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ⁶ , or

is phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, methyl, methoxy, trifluoromethyl, -C (= O) -R "or -N ( R ⁹ ) C (= O) -R ^{! 6} , is hydrogen, cyano, methyl or -C (= O) OR ¹⁶ , independently of one another represent methyl, ethyl or phenyl,

 wherein phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, and

R ^{16 is} methyl, as well as their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R ^{2 is} (^ -configured , and their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetry center (S) - represented by the carbon atom bound to R ² - is configured.

Very particular preference is furthermore given to those compounds of the general formula (I) in R ^! for a group

 stands,

wherein "*" is the point of attachment to the rest of the molecule, R ^{2 is} methyl,

R ^{3 is} methylamino or dimethylamino, R ^{4 is} methoxy,

R ^{5 is} methoxy, R 'is a group -SR ¹² , -S (= O) R ¹² , -S (= O): R ¹² , -S (= O) (= NR ¹³ ) R ¹² or

-P (= 0) (R ¹⁴ ) R ¹⁵ ,

R ^{7 is} hydrogen, fluorine or methylsulfonyl-,

R ^{12 is} methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or a group

_

_

 - 32 -

 stands,

 where "*" is the point of attachment to the rest of the molecule,

R ^{13 is} hydrogen or methyl, and

R ¹⁴ and R independently of one another are methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically tolerated salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which by R bound carbon atom represented center of asymmetry (^ is configured, as well as their stereoisomeric mixtures in which predominate those stereoisomers in which the represented by the carbon atom bound to R ² asymmetry center (5) - is configured.

Very particular preference is furthermore given to those compounds of the general formula (I) in which R ^{1 is} a group

steht,

stands,

in which each represents the point of attachment to the rest of the molecule, R is methyl, 3 is methylamino,

R ^{4 is} methoxy,

R ^{5 is} methoxy, R ^{6 is} a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ' ² , -S (= O) (= NR ¹³ ) R ¹² or

-P (= 0) (R ¹⁴ ) R ^{! 5} ,

R is hydrogen, fluorine or methylsulfonyl; R ^{12 is} methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or one of a group

 stands,

 where "*" is the point of attachment to the rest of the molecule,

R ^{13 is} hydrogen or methyl, and

R ¹⁴ and R ' ⁵ are each independently methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which by the center of asymmetry centered on R (5) is conglomerated, as well as their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetric center (5) represented by the carbon atom bound to R ² is configured.

Very particular preference is furthermore given to those compounds of the general formula (I) in which R ^{1 is} a group

 stands,

wherein "*" is the point of attachment to the rest of the molecule, R ^{2 is} methyl, R 'is methylamino,

R ^{4 is} methoxy, R ^{5 is} methoxy,

R 'represents a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ¹³ ) R ¹² or

-P (= 0) (R ¹⁴ ) R ¹⁵ , R ^{7 is} hydrogen, fluorine, or methylsulfonyl-,

R ^{12 is} methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or one

 group

 stands,

 where "*" is the point of attachment to the rest of the molecule,

R ^{13 is} hydrogen, and

R ¹⁴ and R ^{15 are} independently methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which by the carbon center attached to R ² represents the center of asymmetry (^ -configured and their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetry center (S) - represented by the carbon atom bound to R ^" - is configured.

Very particular preference is furthermore given to those compounds of the general formula (I) in R ^] for a group

steht,

stands,

in which "*" in each case denotes the point of attachment to the remainder of the molecule, stands for methyl, stands for methylamino, stands for methoxy, stands for methoxy, for a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ' ² , -S (= ^O ) (= NR ¹³ ) R ¹² or -P (= ^O ) (R ¹⁴ ) R ¹⁵ is hydrogen, fluorine, or methylsulfonyl-, for Methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or a group

 stands,

 where "*" is the point of attachment to the rest of the molecule,

R ^{13 is} hydrogen, and

R ¹⁴ and R ^{15 are} independently methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which by the and the stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetric center (S) - represented by the carbon atom bound to R - is configured.

Most preferred are those compounds of general formula (I) in R ¹ for a group



oder für eine Gruppe

or for a group

worin "*" jeweils den Anknüpfungspunkt an den Rest des Moleküls bedeutet, für Methyl- steht, für Methylamino- steht, für Methoxy- steht, und für Methoxy- steht, sowie deren Polymorphe, Tautomere, Solvate, physiologisch verträglichen Salze und Solvate dieser Salze, sowie deren Razemate, sowie deren Enantiomere und Diastereomere, in denen das durch das an R² gebundene Kohlenstoffatom repräsentierte Asymmetriezentrum (^-konfiguriert ist, sowie deren Stereoisomerengemische, in denen diejenigen Stereoisomeren überwiegen, in denen das durch das an R gebundene Kohlenstoffatom repräsentierte Asymmetriezentrum (5)- konfiguriert ist. Überaus bevorzugt sind ferner solche Verbindungen der allgemeinen Formel (I), in der R^ä für eine Gruppe

in which "*" in each case denotes the point of attachment to the remainder of the molecule, stands for methyl, stands for methylamino, stands for methoxy, and stands for methoxy, as well as their polymorphs, tautomers, solvates, physiologically tolerable salts and solvates of these salts and their racemates, as well as their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R ^{2 is} (-configured, as well as their stereoisomeric mixtures in which those stereoisomers predominate in which the center of asymmetry represented by the carbon atom bound to R is predominant (5) - is configured. Also highly preferred are those compounds of the general formula (I) in which R ^{a represents} a group

oder für eine Gru e

or for a greeting

oder für eine Gruppe

or for a group

worin "*" jeweils den Anknüpfungspunkt an den Rest des Moleküls bedeutet, R² für Methyl- steht,

wherein "*" is the point of attachment to the rest of the molecule, R ^{2 is} methyl,

R ^{3 is} methylamino-,

R ^{4 is} methoxy, and

R ^{5 is} methoxy-, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R ² (^ -konfiguriert ist , and their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetry center (5) represented by the carbon atom bound to R is configured. Also highly preferred are those compounds of general formula (I), in R ^a for a group

 or for a group

-51 -

-51 -

or for a group

worin "*" jeweils den Anknüpfungspunkt an den Rest des Moleküls bedeutet,

where "*" is the point of attachment to the rest of the molecule,

R ^{2 is} methyl,

R ^{3 is} methylamino,

R ^{4 is} methoxy, and

R ^{5 is} methoxy,

and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom attached to R ^: is -configured, as well as their stereoisomeric mixtures in which those stereoisomers predominate in which the asymmetry center (S) - represented by the carbon atom bound to R ² - is configured.

oder für eine Gruppe Further preferred are those compounds of the general formula (I) in which R ^{1 is} a group

or for a group

worin "*" jeweils den Anknüpfungspunkt an den Rest des Moleküls bedeutet,

where "*" is the point of attachment to the rest of the molecule,

R ^{2 is} methyl,

R ^{3 is} methylamino,

R ^{4 is} methoxy, and

R ^{5 is} methoxy,

and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R ^{2 is} (^ -configured, as well as their stereoisomer mixtures in which those stereoisomers predominate in which the asymmetry center (5) - represented by the carbon atom bound to R ² - is configured.

Also highly preferred are those compounds of general formula (I), in R ^a for a group

 or for a group

worin "*" jeweils den Anknüpfungspunkt an den Rest des Moleküls bedeutet,

where "*" is the point of attachment to the rest of the molecule,

R ^{2 is} methyl, R ^{3 is} methylamino,

R ^{4 is} methoxy, and

R ^{5 is} methoxy,

and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R ^{2 is} (^ -configured, as well as their stereoisomer mixtures in which those stereoisomers predominate in which the asymmetry center (S) - represented by the carbon atom bound to R ² - is configured. Also highly preferred are those compounds of general formula (I), in R ^a for a Gru e

or for a group

 or for a group

worin "*" jeweils den Anknüpfungspunkt an den Rest des Moleküls bedeutet,

where "*" is the point of attachment to the rest of the molecule,

R is methyl, R ^{3 is} methylamino,

R ^{4 is} methoxy, and

R ^{3 is} methoxy,

and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which the center of asymmetry represented by the carbon atom bound to R ^{2 is} (^ -configured, as well as their stereoisomer mixtures in which those stereoisomers predominate in which the asymmetry center (5) - represented by the carbon atom bound to R ² - is configured.

Exceptionally preferred are the following compounds:

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (methylsulfonyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (cyclopropylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfonyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -1- [4- (benzylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -1- [4- (ethylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -l- {4 - [(4-acetamidophenyl) sulfonyl] phenyl} -7,8-Dimet ^^

2,3-benzodiazepine-3-carboxamide;

(48) - {4 - [(4-Ρ1υοη6ηγ1) 8υ1 & ηγ1] ρη ^

benzodiazepine-3-carboxamide; (4S) - {4 - [(3,4-dichloro) sulfonyl] phe ^

benzodiazepine-3-carboxamide;

(4S) -i {4 - [(3-acetamido-4-methoxyphenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;

3 - ({4 - [(4S) -7,8-Dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl-phenyl} sulfonyl) -benzoic acid;

(±) - 1- {3 - [(4-Fluorophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(±) -7,8-dimethoxy-N, 4-dimethyl-1- [3- (phenylsulfonyl) phenyl] -4,5-dilithio-3H-2,3-benzodiazepine-3-carboxamide; (±) -l- {3 - [(3,4-log ^ henyi) sulfony ^

benzodiazepine-3-carboxamide;

(±) - 1- [3- (benzylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(±) - 1- [3- (ethylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(±) - 1- [3- (Cyclopropylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(±) -7,8-dimethoxy-N, 4-dimethyl-1- [3- (methylsulfonyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepm 3-carboxamide; (±) -i- {3 - [(4-acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(±) -3 - ({3- [7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl-phenyl} sulfonyl) benzoic acid; (4S) -l- {3 - [(4-acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5

2,3-benzodiazepine-3-carboxamide;

(4S) -I- [3- (benzylsulfonyl) phenyl] -7,8-dimethoxy ^

benzodiazepine-3-carboxamide; (±) -l- [4-fluoro-3- (methylsulfonyl) phenyl] -7,8-dm

benzodiazepine-3-carboxamide;

(±) - 1- [3,4-bis (methylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-i- [4- (phenylsulfanyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; tert -Butyl 4 - ({4 - [(4S) -7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl] -phenyl } sulfanyl) piperidine-l-carboxylate;

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(1-methylpiperidin-4-yl) sulfanyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide; (4S) -1- [4- (Benzylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -1- [4 - [(4-acetamidophenyl) sulfanyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -1- [4- (ethylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -1- [4- (cyclopentylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-l- [4- (tetrahydro-2H-pyran-4-ylsulfanyl) phenyl] -4,5-dihydro-

3H-2,3-benzodiazepine-3-carboxamide; (±) -7,8-dimethoxy-N, 4-dimethyl-1- [3- (phenylsulfanyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(±) - 1- [3- (benzylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -Ameisensäure-7,8-dimethoxy-N, 4-dimeft ^

4,5-dihydro-3H-2,3-benzodiazepin-3-caxboxamid;

(±) - 1- {3 - [(4-acetamidophenyl) sulfanyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydrobenzodiazepine-3-carboxamide; (±) -7,8-dimethoxy-N, 4-dimethyl-l- [3- (tetrahydxo-2H-pyran-4-ylsulfanyl) phenyl] -4,5-di

 2,3-benzodiazepine-3-carboxamide;

(±) -tert-butyl 4 - ({3- [7,8-dimethoxy-4-methyl-3- (methylcaxbamoyl) -4,5-dihydro-3H-2

benzodiazepin-l-yl] phenyl} sulfanyl) piperidine-l-carboxylate;

(±) -l- [3- (Cyclopentylsulfanyl) phenyl] -7,8

benzodiazepine-3-carboxamide;

(±) - 1- [3- (ethylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfmyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (cyclopentylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; iert-butyl-4 - ({4 - [(4S) -7,8-dimethoxy-4-meihyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl] -phenyl } sulfinyl) piperidine-l-carboxylate;

(4S) -l- {4 - [(4-acetamidophenyl) sulfinyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -1- [4- (benzylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -1- [4- (ethylsulinyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepm-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (tetrahydro-2H-pyran-4-ylsulfmyl) -phenyl] -4,5-dihydro-2,3-benzodiazepine-3-carboxamide ;

(4S) -1- [4- (benzylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 1; (4S) - [4- (benzylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 2;

(±) - 1- [3- {cyclopentylsulfmyl) phenyl] -7,8-dimethoxy-N, 4 <limethyl-4,5Klihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -l- [3- (benzylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H

3-carboxamide;

(±) -i- {3 - [(4-acetamidophenyl) sulfinyl] phenyl} -7,8 ^

benzodiazepine-3-carboxamide;

(±) -l- [3- (ethylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2

carboxamide;

(±) -tert-butyl-4 - ({3- [7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl] -phenyl } sulfinyl) piperidin-l-carboxylai;

(4S) -1- [4- (Cyclopeniylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (tetrahydro-2H-pyran-4-ylsulphonyl) -phenyl] -4,5-dih ^ 3H-2,3-benzodiazepine-3 -carboxamide; tert -Butyl 4 - ({4 - [(4S) -7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl] phenyl sulfonyl) piperidine-1-carboxylate;

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(1-methylpiperidin-4-yl) sulfonyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(1-methyl-piperidin-4-yl) -sulfinyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;

(±) -7,8-dimethoxy-N, 4-dimethyl-1- [3- (tetrahydro-2H-pyran-4-ylsulfonylo) phenyl] -4,5-dihydro-2,3-benzodiazepine-3-carboxamide; (±) -i- [3- (cyclopentylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(±) -tert-butyl-4 - ({3- [7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepine-1-ylphenyl} sulfonyl ) piperidine-1-carboxylate; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (S-phenylsulfonimidoyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 1;

(4S) -7,8-dimethoxy-N, 4-dimethyl-l- [4- (S-p ^^

benzodiazepine-3-coxboxamide), diastereomer 2; (±) -i- [4- (dimethylphosphoryl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(±) -l- [4- (diethylphosphoryl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H

benzodiazepine-3-carboxamide;

(±) -7,8-dimethoxy-N, 4-dimethyl-1- {4- [methyl (phenyl) phosphoryl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -7,8-dimethoxy-1- {4 - [(2-methoxyphenyl) sulfonyl] phenyl} -N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -7,8-Dimethoxy-1- {4 - [(4-metlioxyphenyl) sulfonyl] phenyl} -N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- (4- {[4- (dimethylsulfamoyl) phenyl] sulfonyl} phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3 -carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(4-methylphenyl) sulfonyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide;

(4S) -7,8-Dimethoxy-1- {4 - [(2-methoxy-5-methylphenyl) sulfonyl] phenyl} -N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- (4 - {[3- (pyridinium-1-ylsulfonyl) -phenyl] -sulfonyl} -phenyi) -4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- (4 - {[4- (2-oxo-pyi-tolidin-1-yl) -phenyl] -sulfonyl} -phenyi) -4,5-dihydro-3H-2 , 3-benzodiazepin-3-carboxamide; (4S) -1- [4 - [(4-chlorophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydrobenzodiazepine-3-carboxamide;

(4S) -7,8-dimethoxy-N, 4-dimethyl-l- [4- (N-methyl-S-phenylsulfonimidoyl) phenyl] -4,5-dihydro-

3H-2,3-benzodiazepine-3-carboxamide, and (4S) -7,8-dimethoxy-N, N, 4-trimethyl-l- [4- (N- ^

 3H-2,3-benzodiazepine-3-carboxamide, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts.

In the general formula (I), R ^{1 is} preferably a group

where "*" represents the point of attachment to the remainder of the molecule. In the general formula (I), R ¹ particularly preferably represents a group

wherein R is hydrogen, and wherein "*" is the point of attachment to the rest of the molecule. In the general formula (I) R ^! most preferably for a group _a

 - 68 -

where "*" represents the point of attachment to the remainder of the molecule.

In the general formula (I), R ¹ most preferably represents a group

where "*" represents the point of attachment to the remainder of the molecule.

In the general formula (I), R ¹ most preferably represents a group

wherein R is hydrogen, and wherein "*" is the point of attachment to the rest of the molecule.

In the general formula (I) R ^! s is preferred for a group

wherein R is hydrogen, and wherein "*" is the point of attachment to the rest of the molecule.

In the general formula (I), R ^{1 is more} preferably a group

oder für eine Gruppe

-73 -

or for a group

-73 -

or for a group

where "*" is the point of attachment to the rest of the molecule.

In the general formula (I), R ^{1 is more} preferably a group

-75 -

-75 -

10 or for a group

where "*" is the point of attachment to the rest of the molecule.

In the general formula (I), R ^{1 is more} preferably a group

-82-

-82-

or for a greeting

or for a group

wherein each represents the point of attachment to the remainder of the molecule.

In the general formula (I), R ^{1 is more} preferably a group

or for a greeting

or for a group

wherein each of """means the point of attachment to the remainder of the molecule. "

 - 87 -

In the general formula (I), ^{1 is more} preferably a group

where "*" is the point of attachment to the rest of the molecule.

oder für eine Gruppe In the general formula (I), R ^{1 is more} preferably a group

or for a group

oder für eine Gru e

or for a greeting

worin "*" jeweils den Anknüp fungspunkt an den Rest des Moleküls bedeutet.

where "*" is the point of attachment to the rest of the molecule.

In the general formula (I), R is preferably methyl or ethyl. In the general formula (I), R ^{2 is} preferably methyl.

In the general formula (I), R ^{3 is} preferably cyclopropyl, C 1 -C 8 -alkyl, cyclopropylamino or C 1 -C 3 -alkylamino. In the general formula (I), R ^{3 is} particularly preferably GC ₃ alkylamino. In the general formula (I), R ^{3 is} particularly preferably C 1 -C ² -alkylamino. In the general formula (I) R ^{3 is} very particularly preferably methylamino or

Dimethylamino.

In the general formula (I), R ³ very particularly preferably represents methylamino. In the general formula (I), R ⁴ and R ⁵ are each independently preferably

Hydrogen, hydroxy, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine,

or

for Ci-Ce-alkyl, G-Ce-alkoxy, Ci-Ce-alkylamino, phenylamino, Ci-Ce-alkylcarbonylamino, Ci-Ce-alkylaminocarbonyl or Ci-Ce-alkylaminosulphonyl, which is unsubstituted are monosubstituted, disubstituted, trisubstituted, identical or different, are substituted by halogen, amino, hydroxy, carboxy, C ₁ -C ₃ -alkyl, hydroxy-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy , C 1 -C ₃ -alkoxy-C 1 -C ₃ -alkyl-,

Ci-Cs-alkylamino, amino-Ci-C ₃ -alkyl-, -C (= O) -NR ⁹ R ⁱ⁰ , -C (= 0) -R ^1! or monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted by C ₁ -C ₃ -alkyl,

or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, with halogen, amino, hydroxy, cyano, carboxy, GC ₃ alkyl, C iC ₃ alkoxy -, C iC ₃ alkoxy-Ci-C ₃ alkyl, hydroxy-GC ₃ alkyl, C i -C ₃ alkylamino, amino-C i -C ₃ -alkyl, fluoro-C iC ₃ - alkyl, fluoro-C i -C ₃ alkoxy,

-C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms, or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, carboxy, GC ₃ -alkyl-, GC ₃ - Alkoxy, C i -C ₃ alkoxy-C i -C ₃ alkyl, C i -C ₃ alkylamino, aminoC iC ₃ alkyl, C i -C ₃ alkylamino, -C i -C _3- alkyl, hydroxy-C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, fluoro-C 1 -C ₃ -alkoxy, -C (OO) -NR ⁹ R ^{! 0} , -C ( = 0) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms.

In the general formula (I), R ⁴ and IV independently of one another are particularly preferably

Hydrogen, hydroxy, cyano, fluorine, chlorine or bromine,

or for G-C3-alkyl, G-Cs-alkoxy or C ₁ -C ₃ -alkylamino,

or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, C 1 -C 3 -alkyl- or C 1 -C 3 -alkoxy-,

or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by fluorine, oxo, C 1 -C 8 -alkyl-,

C ₁ -C ₃ -alkoxy, C 1 -C ₃ -alkylamino or -C (= O) -R ⁿ . in the general formula (I) R ⁴ particularly preferably represents hydrogen, hydroxy, cyano,

Fluorine, chlorine or bromine,

or

for C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 1 -C 3 -alkylamino,

or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, C ₁ -C ₃ -alkyl- or C ₁ -C ₃ -alkoxy-,

or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by fluorine, oxo, C 1 -C 3 -alkyl-,

C ₁ -C ₃ -alkoxy-, C 1 -C ₃ -alkylamino- or -C (0O) -R "in the general formula (I), R ⁴ particularly preferably stands for C ₁ -C ₃ -alkoxy- and R ⁵ particularly preferred for hydrogen, hydroxy, cyano, fluorine, chlorine or bromine,

or

for C 1 -C 8 -alkyl, C 1 -C 3 -alkoxy or C 1 -C 3 -alkylamino,

or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy,

or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by fluorine, oxo, G-C3-alkyl-,

C ₁ -C ₃ -alkoxy, C 1 -C ₃ -alkylamino or -C (= O) -R ⁿ . In the general formula (I), R ⁴ particularly preferably represents hydrogen, hydroxyl, cyano, fluorine, chlorine or bromine,

or

for G-C3-alkyl, G-C3-alkoxy or C 1 -C3 -alkylamino,

or

for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, G-Cs-alkyl- or C ₁ -C ₃ -alkoxy-,

or

for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by fluorine, oxo, C ₁ -C ₃ -alkyl-,

C ₁ -C ₃ -alkoxy, C 1 -C ₃ -alkylamino or -C (= O) -R ⁿ ,

and IV particularly preferably represents G-C3-alkoxy-. In the general formula (I), furthermore, R ⁴ and R ⁵ independently of one another particularly preferably represent G-C 3 -alkoxy. in the general formula (I), R ⁴ and R ⁵ very particularly preferably each represent methoxy. In the general formula (I), R 'is preferably a group SR ¹ ".

In the general formula (I), R "preferably represents a group ~S (= O) R ^12. In the general formula (I), R" preferably represents a group

In the general formula (I), R 'preferably represents a group ~S (= O) (= NR ¹³ ) R ¹² .

In the general formula (I), R "preferably represents a group ~P (= O) (R ¹⁴ ) R ^15. In the general formula (I), R preferably represents hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or for GC ₃ alkyl, Ci-C ₃ alkoxy, C 1 -C ₃ alkoxy-C 1 -C ₃ alkyl, fluoro-Ci-C ₃ alkyl, fluoro-C 1 -C 3 alkoxy - or C 1 -Cs-alkylsulfonyl.

In the general formula (I) R is preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano or methyl, methoxy, methoxymethyl, methoxyethyl, difluoromethyl, Trifluoromethyl, trifluoromethoxy or methylsulfonyl.

In the general formula (I), R preferably represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, methoxy or methylsulfonyl.

In the general formula (I), R is particularly preferably hydrogen, fluorine, C 1 -C 3 -alkoxy or C 1 -C 8 -alkylsulfonyl-.

In the general formula (I), R very particularly preferably represents hydrogen, fluorine, methoxy- or methylsulfonyl-.

In the general formula (I), R very particularly preferably represents hydrogen, fluorine or methylsulfonyl. In the general formula (I), R very particularly preferably represents hydrogen or fluorine.

In the general formula (I), R is very particularly preferably fluorine.

In the general formula (I) R is very particularly preferably methylsulfonyl.

In the general formula (I), R is very particularly preferably hydrogen.

In the general formula (I), R ⁹ and R ^{10 are} independently of each other preferably

Hydrogen, GC ₃ alkyl, acetyl, propionyl or fluoro-C i -C ₃ alkyl,

or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached are monocyclic heterocyclyl having 4 to 8 ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluoro, oxo, cyano, C ₁ C ₃ alkyl, Cs-Ce cycloalkyl, C ₁ -C ₃ alkylcarbonyl or C ₁ -C 4 alkoxycarbonyl. In the general formula (I), R ⁹ and R ¹⁰ independently of one another are preferably

Hydrogen, C ₁ -C ₃ alkyl, acetyl, propionyl or fluoro-GC ₃ alkyl.

In the general formula (I), R ⁹ and R ^{10 are} preferably taken together with the nitrogen atom to which they are bonded, for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents Fluorine, oxo, Cyan, Ci-C3-alkyl, Cs-Cö-cycloalkyl, G-Cs-alkylcarbonyl or G-C4-alkoxycarbonyl-.

In the general formula (I), R ⁹ and R ¹⁰ independently of one another particularly preferably represent hydrogen, methyl, ethyl or acetyl,

or R 'and R ¹⁰ are taken together with the nitrogen atom to which they are attached, for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, oxo. Methyl, ethyl, cyclopropyl, acetyl or tert. -Butoxycarbonyl-. In the general formula (I), R ⁹ and R ¹⁰ independently of one another particularly preferably represent hydrogen, methyl, ethyl or acetyl.

In the general formula (I), R ⁹ and R ^{10 are} particularly preferably together with the

Nitrogen atom to which they are bonded, for monocyclic heterocyclyl of 4 to 8

Ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, methyl, ethyl, cyclopropyl, acetyl or tert. -Butoxycarbonyl-.

In the general formula (I), R ⁹ and R ¹⁰ independently of one another very particularly preferably represent hydrogen, methyl or ethyl,

or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached, monocyclic heterocyclyl having 5 to 7 ring atoms which is unsubstituted or mono- or disubstituted by identical or different substituted with oxo, methyl or ethyl ,

In the general formula (I), R ⁹ and R ¹⁰ independently of one another very particularly preferably represent hydrogen, methyl or ethyl.

In the general formula (I), R ⁹ and R ^{10 are} particularly preferably together with the

Nitrogen atom to which they are bonded, for monocyclic heterocyclyl of 5 to 7

Ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, methyl or ethyl.

In the general formula (I), R ⁹ and R ¹⁰ independently of one another very particularly preferably represent hydrogen or methyl. In the general formula (I), R ⁹ and R ¹⁰ very particularly preferably each represent hydrogen. In the general formula (I), R 'and R ^! "very particularly preferably for methyl.

In the general formula (I), R ¹¹ preferably represents hydroxyl, C ₁ -C ₃ -alkyl, C ₁ -C 4 -alkoxy, fluoro-C ₁ -C ₃ -alkyl, hydroxy-C ₁ -C ₃ -alkyl, C ₃ alkoxy-C ₁ -C ₃ -alkyl or C ₃ -C 7 -cycloalkyl, or for phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or a - or doubly, the same or different, are substituted by halogen, Ci-Cj-alkoxy or Ci-C3-alkyl-. In the general formula (I), R ¹¹ particularly preferably represents hydroxy, C 1 -C 3 -alkyl or C 5 -O-alkoxy-.

In the general formula (I) R ^{! i} very particularly preferably for hydroxy, methyl, ethyl, methoxy or ethoxy. in the general formula (I) R ^{11 is} very particularly preferably hydroxy, methoxy or ethoxy.

In the general formula (I), R ¹¹ very particularly preferably represents methyl or ethyl.

In the general formula (I), R ¹¹ very particularly preferably represents hydroxyl, methyl or methoxy.

In the general formula (I), R ^{11 is} very particularly preferably hydroxyl.

In the general formula (I), R ^{i2 is} preferably C ₁ -C 6 -alkyl which is unsubstituted or monosubstituted with cyano, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylamino, phenyl, C C ₃ -C 5 cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms,

in which phenyl is in turn unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, C ₁ -C ₃ -alkyl, C ₃ -C ₃ -alkoxy-,

 Fluoro-C i -C 3 -alkyl or fluoro-C i -C 3 alkoxy, and

wherein C3-C8-cycloalkyl and monocyclic heterocyclyl having 4 to 8 ring atoms in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl or for fluorine-C 1 -C 3 -alkyl-,

or

for C 3 -C 8 -cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 8 -alkyl or C 1 -C 4 -alkoxycarbonyl, with the proviso that that the monocyclic

 Heterocyclyl- with 4 to 8 ring atoms not via a nitrogen atom to the sulfanyl, sulfinyl,

Sulfonyl or sulfoximino group is bonded in R ⁶ ,

or

for phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl- , Trifluoromethoxy, -C (= O) -NR ⁹ R ⁱ⁰ , -C (= O) -R ^{! 1} ,

~ N (R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ -NR ⁹ R ^{! 0} or NR 'R ¹⁰ , with the proviso that the monocyclic heteroaryl having 5 or 6 ring atoms does not exceed a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or Sulfoximino group is attached to R ". in the general formula (I), R ¹² preferably represents G-Ce-alkyl, which is unsubstituted or is monosubstituted by cyano , C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylamino, phenyl, C ₃ -C 8 -cycloalkyl or monocyclic heterocyclyl with 4 to 8 ring atoms,

 in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, cyano, G-C3-alkyl-, C 1 -C 3 -alkoxy-,

 Fluoro-C i -C 3 -alkyl or fluoro-C i -C 3 alkoxy, and

wherein Cs-Cs-cycloalkyl and monocyclic heterocyclyl having 4 to 8 ring atoms in turn are unsubstituted or mono- or disubstituted by identical or different substituents with GC ₃ alkyl or

for fluorine-C ₁ -C ₃ -alkyl,

or

for C3-Cs-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C ₃ alkyl or C ₁ -C4 alkoxycarbonyl, with the Provided that the monocyclic

 Heterocyclyl- with 4 to 8 ring atoms not via a nitrogen atom to the sulfanyl, sulfinyl,

Sulfonyl or sulfoximino group is bonded in R ",

or

phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, G-C3-alkyl, Ci-C ₃ alkoxy, trifluoromethyl or Trifluoromethoxy, -C (= O) -NR ⁹ R ^{! 0} , -C (= O) -R ^{! 1} or -N (R ⁹ ) C (= O) -R ¹⁶ , with the proviso that the monocyclic heteroaryl having 5 or 6 ring atoms does not have a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R " In the general formula (I), R ^{12 is} particularly preferably C 1 -C 6 -alkyl which is unsubstituted or monosubstituted by C 1 -C 3 -alkylamino, phenyl or monocyclic

Heterocyclyl having 4 to 7 ring atoms,

in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted, identically or differently, by fluorine, chlorine, bromine, cyano, C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy-, trifluoromethyl- or trifluoromethoxy-, and

 wherein the monocyclic heterocyclyl having 4 to 7 ring atoms in turn is unsubstituted or monosubstituted by methyl,

or

for trifluoromethyl,

or

C ₃ -C 6 cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms, which are unsubstituted or monosubstituted with C 1 -C 8 alkyl or C 1 -C 4 alkoxy carbonyl, with the proviso that the monocyclic heterocyclyl - with 4 to 7 ring atoms not bound via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ⁶ ,

or

for phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, trifluoromethoxy,

-C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -N (R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ -NR ⁹ R ¹⁰ or

NR 'R ^! ".

In the general formula (I), R ^{12 is} particularly preferably C ₁ -C 6 -alkyl which is unsubstituted or monosubstituted by C ₁ -C ₃ -alkylamino, phenyl or monocyclic

Heterocyclyl having 4 to 7 ring atoms,

 wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, O-Cs-alkyl, Ci-Cs-alkoxy, trifluoromethyl or trifluoromethoxy, and

 wherein the monocyclic heterocyclyl having 4 to 7 ring atoms in turn is unsubstituted or monosubstituted by methyl,

or

for trifluoromethyl, or

for C3-C6-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms, which are unsubstituted or monosubstituted with Ci-C3-alkyl or Ci-C4-alkoxycarbonyl, with the proviso that the monocyclic heterocyclyl with 4 until 7 ring atoms are not bonded via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',

or

for phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C ₃ alkyl, Ci-C ₃ alkoxy, trifluoromethyl or

Trifluoromethoxy, -C (= O) -NR ⁹ R ⁱ⁰ , -C (= O) -R ^{! 1} or -N (R ⁹ ) C (= 0) -R ¹⁶ .

In the general formula (I), R ¹² particularly preferably represents C 1 -C 4 -alkyl which is unsubstituted or monosubstituted by C 1 -C 3 -alkylamino, phenyl or monocyclic

Heterocyclyl having 4 to 7 ring atoms,

in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy-,

Trifluoromethyl or trifluoromethoxy, and

 wherein the monocyclic heterocyclyl having 4 to 7 ring atoms in turn is unsubstituted or monosubstituted by methyl,

or

for trifluoromethyl.

In the general formula (I), R ¹² particularly preferably represents Cs-Ce-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted by C ₁ -C ₃ -alkyl or C ₁ -C 4 -alkoxycarbonyl -, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms is not bound via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R '.

In the general formula (I), R ¹² particularly preferably represents phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano,

C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, trifluoromethoxy, -C (OO) -NR ⁹ R ^{! 0} , -C (= O) -R ⁿ , -N (R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ -NR ⁹ R ¹⁰ or ™ NR ⁹ R ¹⁰ .

In the general formula (I), R ¹² particularly preferably represents phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano,

C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl or trifluoromethoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or ~ N (R ⁹⁾ C (= 0) -R ^sixteenth

In the general formula (I), R ¹² very particularly preferably represents C ₁ -C ₃ -alkyl which is unsubstituted or monosubstituted by phenyl,

 wherein phenyl is in turn unsubstituted or monosubstituted with fluorine, chlorine,

Cyano, methyl, methoxy or trifluoromethyl,

or

for trifluoromethyl,

or

for Cs-Ce-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted by methyl or teri-butoxycarbonyl, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms does not have a

Nitrogen atom is bonded to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',

or

for phenyl, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, methyl, methoxy, trifluoromethyl, -C (= 0) -R ^1! .

-N (R ⁹ ) C (= O) -R ^{! 6} , -S (= O) ₂ -NR ⁹ R ¹⁰ or -NR ⁹ R ¹⁰ . In the general formula (I), R ¹² very particularly preferably represents C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by phenyl,

 in which phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, cyano, methyl, methoxy or trifluoromethyl,

or

for trifluoromethyl,

or

for C3-C6 cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted with methyl or terf-butoxycarbonyl, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms does not have a

Nitrogen atom is bonded to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',

or

for phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, methyl, methoxy, trifluoromethyl, -C (= 0) -R ⁿ or

-N (R ⁹ ) C (= 0) -R ¹⁶ . In the general formula (I), R ¹² very particularly preferably represents O-Cs-alkyl which is unsubstituted or monosubstituted with phenyl,

 wherein phenyl is in turn unsubstituted or monosubstituted with fluorine, chlorine,

Cyano, methyl, methoxy or trifluoromethyl,

or

for trifluoromethyl.

In the general formula (I), R ⁱ² very particularly preferably represents ^C 1 ^{-C 3 -alkyl-} which is unsubstituted or monosubstituted by phenyl-,

 wherein phenyl is in turn unsubstituted or monosubstituted with fluorine, chlorine,

Cyano, methyl, methoxy or trifluoromethyl.

In the general formula (I), R ¹² very particularly preferably represents Cs-Ce-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms, which are unsubstituted or monosubstituted by methyl or fer-butoxycarbonyl, with the proviso that that the monocyclic heterocyclyl having 4 to 7 ring atoms is not bound via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ".

In the general formula (I), R ⁱ² very particularly preferably represents phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, methyl, methoxy, trifluoromethyl, C (= O) -R ⁿ , -N (R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ -NR ⁹ R ⁱ⁰ or NR 'R ⁱ⁰ .

In the general formula (I), R ¹² very particularly preferably represents phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, methyl, methoxy, trifluoromethyl, C (= 0) -R ^1! or -N (R ⁹ ) C (= 0) -R ¹⁶ .

In the general formula (I), R ¹² very particularly preferably represents C ₁ -C ₃ -alkyl which is unsubstituted or monosubstituted by phenyl,

or

for C ₃ -C 5 -cycloalkyl, tetrahydropyranyl or piperidinyl,

wherein C ₃ -C 5 cycloalkyl and tetrahydropyranyl are unsubstituted, and

wherein piperidinyl is unsubstituted or monosubstituted with methyl or feri-butoxycarbonyl, with the proviso that the piperidinyl is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ⁶ , or

for phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents, fluorine, chlorine, methyl, methoxy, trifluoromethyl, -C (= O) -R ⁿ , -N (R ⁹ ) C ( = 0) -R ¹⁶ , -S (= O) ₂ - NR ⁹ R ¹⁰ or NR 'R ¹⁰ .

In the general formula (I), R ¹² very particularly preferably represents C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by phenyl,

or

for Cs-Cs-cycloalkyl, tetrahydropyranyl or piperidinyl,

wherein C ₃ -C 5 cycloalkyl and tetrahydropyranyl are unsubstituted, and

 wherein piperidinyl is unsubstituted or monosubstituted with methyl or butoxy-butoxycarbonyl, with the proviso that the piperidinyl is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',

or

for phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents, fluorine, chlorine, methyl, methoxy, trifluoromethyl, -C (= O) -R ⁿ or -N (R ⁹ ) C ( = 0) -R ¹⁶ .

In the general formula (I), R ¹² very particularly preferably represents C 1 -C 8 -alkyl, which is unsubstituted or monosubstituted with phenyl.

In the general formula (I), R ¹² very particularly preferably represents C ₃ -C 8 -cycloalkyl, T-undehydropyranyl or piperidinyl,

 wherein Cs-Cs-cycloalkyl and tetrahydropyranyl are unsubstituted, and

wherein piperidinyl is unsubstituted or monosubstituted with methyl or ieri-butoxycarbonyl, with the proviso that the piperidinyl is not attached via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R '. In the general formula (I) R ^{12 is} very particularly preferably phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl, methoxy, trifluoromethyl, -C (= 0 ) -R ¹¹ , -N (R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ -NR ⁹ R ⁱ⁰ or

NR 'R ¹ ". In the general formula (I) R ⁱ² very particularly preferably represents phenyl which is unsubstituted or mono- or disubstituted by identical or different substituents consisting of fluorine, chlorine, methyl, Methoxy, trifluoromethyl, -C (= O) -R ⁿ or -N (R ⁹ ) C (= O) -R ¹⁶ .

In the general formula (I), R ¹² very particularly preferably represents methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or one or more groups

where "*" is the point of attachment to the rest of the molecule.

In the general formula (I), R ¹² very particularly preferably represents methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or one or more groups

where "*" is the point of attachment to the rest of the molecule. in the general formula (I) R "is preferably hydrogen, cyano, C 1 -C 6 -alkyl-,

Cs-Cs-cycloalkyl- or -C (= O) OR ¹⁶ .

In the general formula (I), R ¹³ particularly preferably represents hydrogen, cyano, G-Cs-alkyl-, or -C (= O) OR ^{! 6} . in the general formula (I), R ^{13 is} particularly preferably hydrogen or C ¹ -C 3 -alkyl-. In the general formula (I), R ^{13 is} particularly preferably C ¹ -C ⁸ -alkyl-.

In the general formula (I), R ¹³ very particularly preferably represents hydrogen, cyano, methyl, or -C (= O) OR ¹⁶ .

In the general formula (I), R "is very particularly preferably hydrogen or methyl.

In the general formula (I), R ^{13 is} very particularly preferably hydrogen. In the general formula (I) R ^{13 is} very particularly preferably methyl. In the general formula (I), R ¹⁴ and R ¹⁵ are each independently preferably

C ₁ -C ₃ -alkyl, phenyl-C ₁ -C ₃ -alkyl, fluorine-GC ₃ -alkyl- or phenyl-, in which phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, Trifluoromethyl or trifluoromethoxy,

or R ¹⁴ and R ¹⁵ together are preferably C 1 -C 8 -alkylene.

In the general formula (I), R ¹⁴ and R ¹⁵ are each independently preferably

C ₁ -C 8 -alkyl, phenyl-C ₁ -C ₃ -alkyl, fluorine-C ₁ -C ₃ -alkyl or phenyl,

 in which phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen,

Cyano, Ci-C3-alkyl, Ci-Cs-alkoxy, trifluoromethyl or trifluoromethoxy.

In the general formula (I), R ^{! 4} and R ¹⁵ together are preferably C 2 -C 8 -alkylene. In the general formula (I), R ¹⁴ and R ^{! 5} independently of one another are particularly preferably C ₁ -C ₃ -alkyl-, benzyl-, trifluoromethyl- or phenyl-,

wherein phenyl and the benzyl-containing phenyl are in turn unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C ₂ alkyl, Ci-C2-alkoxy, trifluoromethyl - or trifluoromethoxy.

In the general formula (I), R ¹⁴ and R ¹⁵ independently of one another very particularly preferably represent methyl, ethyl or phenyl,

 wherein phenyl is in turn unsubstituted or monosubstituted with fluorine, chlorine,

Methyl, methoxy or trifluoromethyl.

In the general formula (I), R ¹⁴ and R ¹⁵ independently of one another very particularly preferably represent methyl, ethyl or phenyl.

In the general formula (I), R ⁱ⁴ and R ⁱ⁵ independently of one another very particularly preferably represent methyl or ethyl.

In the general formula (I), R ¹⁴ and R "are very particularly preferably each methyl.

In the general formula (I), R ¹⁴ and R ¹⁵ very particularly preferably each represent ethyl, ^

In the general formula (I) R ^{16 is} preferably Ci-Cs-alkyl or benzyl.

In the general formula (I), R ^{16 is} particularly preferably C 1 -C 3 -alkyl-. In the general formula (I), R ^{i6 is} very particularly preferably methyl.

In the general formula (I), R ^{2 is more} preferably methyl, R ^{3 is} methylamino, R ^{4 is} C ₁ -C ₃ -alkoxy and R ^{5 is} C ₁ -C ₃ -alkoxy. In the general formula (I), most preferably R ^{2 is} methyl, R ^{3 is}

Methylamino, R ⁴ for methoxy and R ⁵ for methoxy.

In the general formula (I), the carbon atom of the carbon atom bonded to R is

B enzo diazep in scaffold represented stereocenters preferentially either racemic or predominantly or fully in the (^ configuration

In the general formula (I), this is due to the carbon atom of the carbon atom bonded to R ²

B enzo diazep in framework represented stereocenters preferentially either racemic or predominant or at least 95% in the (. ^ - configuration.

In the general formula (I), the carbon atom of the carbon atom bonded to R is

Benzodiazepine scaffold represented stereocenter preferentially racemic.

In the general formula (I), the carbon atom of the carbon atom bonded to R is

Benzodiazepine skeleton represented stereocenter particularly preferably predominantly or completely in the (^ configuration before.

In the general formula (I), this is due to the carbon atom of the carbon atom bonded to R ²

B enzodiazepine framework represented stereocentre most preferably predominantly in the (S) configuration.

In the general formula (I), this is due to the carbon atom of the carbon atom bonded to R ²

Benzodiazepine skeleton represented particularly preferred stereocenter of at least 5% in the (. ^ - configuration. In the general formula (I), the stereocenter represented by the carbon atom of the benzodiazepine skeleton bonded to R ^{2 is} particularly preferably completely in the (S) configuration. The rest definitions given in detail in the respective combinations or preferred combinations of radicals are independent of the respective ones given

Combinations of the radicals optionally also replaced by radical definitions of other combinations.

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

The invention is based on the following definitions: Alkvl

 Alkyl stands for a linear or branched, saturated, monovalent hydrocarbon radical with generally 1 to 6 (C 1 -C 6 -alkyl), preferably 1 to 4 (C 1 -C 6 -alkyl), and particularly preferably 1 to 3 carbon atoms (C 1 -C 4 -alkyl). C3-Alk1-).

Examples and preferred are:

Methyl, ethyl, propyl, butyl, pentyl, hexyl, where-propyl, where-butyl, sec-butyl, feri-butyl, zso-pentyl, 2-methylbutyl, 1-methylbutyl , 1-ethylpropyl, 1, 2-dimethylpropyl, eo-pentyl, 1, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl , 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1, 1-dimethylbutyl, 2, 3 -Dimethyl-butyl-, 1,3-dimethylbutyl and 1, 2-dimethylbutyl.

Particularly preferred is a methyl, ethyl, propyl, isopropyl or ieri-butyl radical. AJkenyl-

C ₂ -C 4 -alkenyl, or a C ₂ -C 4 -alkenyl group is to be understood as meaning a linear or branched, monovalent hydrocarbon radical having one or two C =C double bonds, such as, for example, an ethenyl, (is) Prop-2-enyl, (Z) -prop-2-enyl, allyl (prop-1-enyl), allenyl-buten-1-yl, or buta- 1, 3 -dienyl radical. Preferred are ethenyl and allyl.

Alkynyl C2-C4-alkynyl, or a C2-C4-alkynyl group is to be understood as meaning a linear or branched, monovalent hydrocarbon radical having a C = C triple bond, for example a Ethynyl, propargyl (prop-1-ynyl), or eutin 1-yl radical. Preferred are ethynyl and propargyl. alkylene

C ₂ -C -alkylene, or a C ₂ -C 5 -alkylene group, is to be understood as meaning a linear or branched, saturated, divalent hydrocarbon radical, such as, for example, an ethylene, propylene, butylene,

Pentylene, z ^' so-propylene, where-butylene, see-butylene, fert-butylene, z ^' so pentylene, 2-methylbutylene, 1-methylbutylene, 1-Ethylpropylen-, 1, 2 -Dimethylpropylene, neo-pentylene or 1, 1-dimethylpropylene radical. Cvcloalkvl-

Cycloalkyl- stands for a monocyclic, saturated, monovalent hydrocarbon radical having generally 3 to 10 (C 3 -C 10 -cycloalkyl), preferably 3 to 8 carbon atoms

(C3-C8-Cy cloalkyl-) or 3 to 6 carbon atoms (Cs-Ce-cycloalkyl-). By way of example and with preference for monocyclic cycloalkyl radicals, mention may be made:

Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.

Cycloalkenyl C4-C6-cycloalkenyl, C4-C8-cycloalkenyl, C4-Cio-cycloalkenyl, or Cs-Cs-cycloalkenyl- is a monocyclic, mono- or polyunsaturated, non-aromatic, composed exclusively of carbon atoms Ring system with 4 to 6 atoms, 4 to 8 atoms, 4 to 10 atoms, or 5 to 8 atoms to understand. Examples are cyclobutene-1-yl,

Cyclopentene-1-yl, cyclohexene-2-yl, cyclohexene-1-yl and cycloocta-2,5-dienyl.

phenylalkyl

By phenyl-Ci-Cs-alkyl- is meant a group which is composed of an optionally substituted phenyl radical and a C 1 -C 3 alkyl group, and the via the C 1 -C 3 alkyl group to the rest of the molecule is bound. The alkyl radical here has the meanings given above under alkyl.

Examples which may be mentioned are benzyl, phenethyl, phenylpropyl, benzyl being preferred. Alkoxyj:

Alkoxy- represents a linear or branched, saturated alkyl ether radical of the formula -O-alkyl having generally 1 to 6 (C 1 -C 6 -alkoxy), preferably 1 to 4 (C 1 -C 4 -alkoxy), and particularly preferably 1 to 3 (C ₁ -C 3 alkoxy) carbon atoms.

Examples and preferred are:

Methoxy, ethoxy, w-propoxy, zso-propoxy, feri-butoxy, n-pentyloxy and ra-hexyloxy. Alkoxyalkvl- alkoxyalkyl stands for a substituted alkoxy radical, for example C 1 -C 6 alkoxy-C 1 - Ce alkyl or C iC ₃ alkoxy-C 1 -C ₃ alkyl.

 Ci-Ce-alkoxy-Ci-Ce-Allcyl- means that the alkoxyalkyl group is bonded via the alkyl moiety to the rest of the molecule. oxo

 Oxo, an oxo group or an oxo substituent is to be understood as meaning a doubly bonded oxygen atom = 0. Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to sulfur. Preferably, the bond to carbon to form a carbonyl group, and the

Binding of two double-bonded oxygen atoms to sulfur to form a sulfonyl group -S (= 0) ₂ -.

Alkylaminoalkylamino stands for an amino radical having one or two (independently selected) alkyl substituents with generally 1 to 6 (C 1 -C 6 -alkylamino), preferably 1 to 3 carbon atoms (C 1 -C 3 -alkylamino).

 (C 1 -C 3) -Alkylamino represents, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms each

Alkyl substituent.

 Examples include:

Methylamino, ethylamino, n-propylamino, where-propylamino, ierf-butylamino, ra-pentylamino, ra-hexylamino, N, -dimethylamino, AyV-E-ethylamino, N-ethyl-N-methylamino, , N-methyl-N-propylamino, N-zso-propyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N, N-pentylamino and N, N'-hexyl-N-methylamino -. phenylamino

Phenylamino- represents a radical Ph-NH- or a radical Ph-N (Ci-C3-alkyl) -.

Examples include:

N-phenylamino, N-methyl-N-phenylamino and N-ethyl-N-phenylamino. Preference is given to N-phenylamino.

alkylcarbonyl

A C 1 -C 4 -alkylcarbonyl radical is to be understood as meaning a C 1 -C 3 -alkyl-C (= 0) group. Preference is given to acetyl or propanoyl.

alkoxycarbonyl

zu verstehen. Among a C 1 -C 4 alkoxycarbonyl radical is a

to understand.

Preference is given to methoxycarbonyl, ethoxycarbonyl, and tert. -Butoxycarbonyl-.

Alkylaminocarbonvl-

Alkylaminocarbonyl represents the group alkylamino-C (= O) - having one or two (independently selected) alkyl substituents with generally 1 to 6 (C 1 -C 6 -alkylaminocarbonyl), preferably 1 to 3 carbon atoms (Ci C3-alkylaminocarbonyl).

alkylcarbonylamino

Alkylcarbonylamino- represents the group alkyl-C (= O) -H- with usually 1 to 6

(Ci-Ce-Alkylcarbonylamino-), preferably 1 to 4, and particularly preferably 1 to 3 carbon atoms in the alkyl part.

alkylsulfonyl

By a C 1 -C 6 -alkylsulfonyl radical is meant a C 1 -C 6 -alkyl-S (= O) 2 group. Preference is given to C 1 -C 3 -alkylsulfonyl, particularly preferably methylsulfonyl and ethylsulfonyl. AI k ylam i nosul onyl

Alkylamino sulfonyl- stands for the group alkylamino-S (= O) r- with one or two (independently selected) alkyl substituents with generally 1 to 6 (C 1 -C 6 -alkylaminosulfonyl), preferably 1 to 3 carbon atoms,

Examples and preferred are:

Methylaminosulfonyl, ethylaminosulfonyl, dimethylaminosulfonyl, heteroatoms

 Heteroatoms are oxygen, nitrogen or sulfur atoms. heteroaryl

Heteroaryl means a monovalent, mono- or bicyclic, aromatic ring system having at least one heteroatom. As heteroatoms, it is possible for stoichi atoms, oxygen atoms or sulfur atoms to occur. The bond valency may be at any aromatic carbon atom or at a nitrogen atom.

A monocyclic heteroaryl group according to the present invention has 5 or 6 ring atoms.

For example, heteroaryl radicals having 5 ring atoms include the rings:

Thienyl, thiazolyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl,

Isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl and thiadiazolyl.

Heteroaryl radicals having 6 ring atoms include, for example, the rings:

Pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. A bicyclic heteroaryl group has 9 or 10 ring atoms.

For example, heteroaryl radicals having 9 ring atoms include the rings:

 Phthalidyl, thiophthalidyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzofuryl,

Benzothienyl, benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl, indolinyl.

Heteroaryl radicals with 10 ring atoms include, for example, the rings:

 Isoquinolinyl, quinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- and 1, 8-naphthyridinyl, pteridinyl, chromanyl. Monocyclic heterocyclyl

Monocyclic heterocyclyl means a saturated or mono- or polyunsaturated but not aromatic monocyclic ring system having at least one heteroatom. When

Heteroatoms can occur as sto ffatoms, oxygen atoms or sulfur atoms.

A monocyclic heterocyclyl ring according to the present invention may have 4 to 8, preferably 4 to 7, more preferably 5 or 6 ring atoms.

Exemplary and preferred for monocyclic heterocyclyl radicals having 4 ring atoms are: azetidinyl, oxetanyl. By way of example and with preference for monocychic heterocyclyl radicals having 5 ring atoms, mention may be made of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, dioxolanyl, thiazolidinyl and tetrahydrofuryl radicals.

Exemplary and preferred for monocychic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl.

By way of example and with preference for monocychic heterocyclyl radicals having 7 ring atoms, mention may be made of azepanyl, oxepanyl, 1,3-diazepanyl, 1,4-diazepanyl-.

Exemplary and preferred for monocychsche Heterocyclylreste with 8 ring atoms are called: Oxocanyl-, Azocanyl-. Among the monocyclic heterocyclyl radicals, preference is given to 4 to 7-membered, saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S.

Particularly preferred are morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl. halogen

 The term halogen (or halo) includes fluorine, chlorine, bromine and iodine. HaloL cnal kyl -:

 Haloalkyl represents an alkyl radical having at least one halogen substituent.

A halo-C 1 -C 6 -alkyl radical is an alkyl radical having 1 to 6 carbon atoms and at least one halogen substituent. If several halogen substituents are present, they may also be different. Preference is given to fluoro-C 1 -C 6 -alkyl and fluoro-C 1 -C 4 -alkyl radicals, particular preference to fluorine-C 1 -C 3 -alkyl radicals. Examples and also preferred are:

 Trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,5,5,5-pentafluoropentyl or

3,3,4,4,5,5,5-Heptafluorpentyl-.

haloalkoxy

Haloalkoxy stands for an alkoxy radical with at least one halogen substituent.

A halo-C 1 -C 6 alkoxy radical is an alkoxy radical having 1 to 6 carbon atoms and at least a halogen substituent. If several halogen substituents are present, they may also be different. Preference is given to fluoro-C 1 -C 6 -alkoxy, fluoro-C 1 -C 4 -alkoxy, particularly preferably fluoro-C 1 -C 3 -alkoxy radicals. Examples and preferred are:

Trifluoromethoxy or 2,2,2-trifluoroethoxy.

hydroxyalkyl

Hydroxyalkyl represents an alkyl radical having at least one hydroxy substituent.

A hydroxy-C ₁ -C 6 -alkyl radical is an alkyl radical consisting of 1-6 carbon atoms and at least one hydroxy substituent. Preference is given to hydroxy-C 1 -C 3 -alkyl radicals, particularly preferably hydroxymethyl- and 2-hydroxyethyl-.

Aminoalkylaminoalkyl- stands for an alkyl radical having at least one amino substituent.

An amino-C 1 -C 6 -alkyl radical is an alkyl radical consisting of 1 -6 carbon atoms and at least one amino substituent. Preference is given to amino-C ₁ -C ₃ -alkyl radicals, particular preference is given to aminomethyl- and 2-aminoethyl-. alkylaminoalkyl

Alkylaminoalkyl- represents a substituted with alkylamino as defined above

Alkyl radical, for example, Ci-Ce-alkylamino-Ci-Ce-alkyl or Ci-Cs-alkylamino-Ci-Cs-alkyl.

Ci-Ce-alkylamino-Ci-Ce-alkyl means here that the alkylaminoalkyl group on the alkyl

Part is bound to the rest of the molecule.

Examples of alkylaminoalkyl are N, N-dimethylaminoethyl, N, N-dimethylaminomethyl, N, N-

Diethylaminoethyl, NN-dimethylaminopropyl, N-methylamino ethyl, N-methylaminomethyl.

The term "leaving group" refers to an atom or group of atoms that is displaced in a chemical reaction as a stable species with entrainment of the bonding electrons. Examples of leaving groups according to the present invention are halogen, in particular fluorine, chlorine, bromine or iodine, (methylsulfonyl) oxy, [(trifluoromethyl) sulfonyl] oxy, [(nonafluorobutyl) sulfonyl] oxy, (phenylsulfonyl) oxy, [(4-methylphenyl) sulfonyl] oxy,

[(4-Bromophenyl) sulfonyl] oxy, [(4-nitrophenyl) sulfonyl] oxy, [(2-nitrophenyl) sulfonyl] oxy, [(4-isopropylphenyl) sulfonyl] oxy, [(2,4,6-triisopropylphenyl ) sulfonyl] oxy,

[(2,4,6- [trimethylphenyl) sulfonyl] oxy, [(4-tert-butylphenyl) sulfonyl] oxy and oxy [(4-methoxyphenyl) sulfonyl].

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, of the compounds of the formula (I) mentioned below

Formulas and their salts, solvates and solvates of the salts as well as those of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as in the case of the compounds of formula (I), the following compounds 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 which are preferred in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of

 Hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically acceptable salts of the compounds of the invention further include base addition salts of, for example, alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, or ammonium salts derived from ammonia or organic amines containing from 1 to 16 carbon atoms, such as for example, methylamine, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methylglucamine, dimethylglucamine, ethylglucamine, 1 , 6-hexadiamine, glucosamine, sarcosine, serinol,

Tris (hydroxymethyl) aminomethane, aminopropanediol, Sovak base, or 1-amino-2,3,4-butanetriol. Furthermore, the compounds according to the invention can form base addition salts with quaternary ammonium ions which, for example, by Qarternisierung corresponding Amines with agents such as lower alkyl halides, for example methyl, ethyl, propyl and butyl chlorides, bromides and iodides, dialkyl sulfates such as dimethyl, diethyl dibutyl and diamyl sulfate, long-chain halides such as decyl, lauryl, myristyl and Stearyl chlorides, - bromides and iodides, or arylalkyl halides such as benzyl bromide or phenethyl bromide can be obtained. Examples of such quaternary ammonium ions are

Tetramethylammonium, T etraethylammonium, tetra (.propropyl) ammonium, tetra (n-butyl) ammonium, and benzyltrimethylammonium.

Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs can be present either as a single polymorph or as a mixture of several polymorphs in all concentration ranges.

Another object of the present invention are pharmaceutical compositions containing the compounds of the invention and at least one or more other active ingredients, in particular for

Prophylaxis and / or therapy of tumor diseases.

As solvates in the context of the invention, those forms of the compounds according to the invention are referred to which in solid or liquid state by coordination with

Solvent molecules form a complex. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

The inventive compounds can, depending on their structure in

exist different stereoisomeric forms, ie in the form of configuration isomers or optionally as conformational isomers. The compounds according to the invention have an asymmetric center on the carbon atom to which R is bonded (C-4). They can therefore be present as pure enantiomers, racemates, but also as diastereomers or mixtures thereof, if one or more of the substituents described in the formula (I) contains a further asymmetric element, for example a dural carbon atom. The present invention therefore also encompasses diastereomers and their respective mixtures. From the mixtures mentioned, the pure enantiomers and diastereomers can be isolated in a known manner; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on dural or achiral phase. As a rule, the stereoisomers according to the invention inhibit the target to different degrees and are active in different ways in the cancer cell lines investigated. The more active stereoisomer is preferred, which is often the one in which the center of asymmetry represented by the carbon atom attached to R is (-configured.

Another object of the present invention are stereoisomeric mixtures of (45) - configured compounds of the invention with their (4i?) - isomers, in particular the corresponding racemates, the other diastereomer and Enantiomerengemische in which outweighs the (45) form.

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

The present invention also includes all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated in a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ^: H (deuterium), Ή (tritium), "C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ^ls O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ C1, ^{82 Br,! 23} 1, ¹²⁴ 1, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound according to the invention, in particular those in which one or more radioactive isotopes are incorporated, may be of use, for example for the investigation of the mechanism of action or distribution of active substance in the body the comparatively slight manufacturing and detectability for this purpose are in particular ^* H - or ¹⁴ C isotopes suitable labeled compounds Furthermore, the incorporation of isotopes, such as deuterium, some specific therapeutic benefits as a result of greater metabolic stability of the compound. lead, such as an extension of the half-life in the body or a reduction of the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the processes known to those skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by corresponding isotopic modifications of the respective reagents and / or

Starting compounds are used. In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).

The compounds according to the invention can act systemically and locally. For this purpose, it may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these routes of administration, the compounds of the invention can be used in suitable

Administration forms are administered. For oral administration are functioning according to the prior art

 Forms of administration which deliver the compounds according to the invention rapidly and modified, and which may contain the compounds according to the invention in crystalline, amorphized or dissolved form, such as e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed dissolving or insoluble

Coatings which control the release of the compound of the invention), in

Oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, pellets, powders,

Emulsions, suspensions, aerosols or solutions. Parenteral administration can be accomplished by bypassing a Κββθ ίϊοηββοητϊΐΐββ (e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and

In fusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicines (i.a.

Powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or

Eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as Plasters), milk, pastes, foams, powder, implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g.

Sodium dodecyl sulfate, polyoxysorbitanoleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g.

Antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides) 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 by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.

As excipients, for example, vehicles, fillers, disintegrants,

Binders, fillers, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers are used. Reference may be made to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).

The pharmaceutical formulations can

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.

For the purposes of the invention, auxiliaries may be, for example, salts, saccharides (mono-, di-, tri-, Oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils,

Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically. 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 present invention relates to the compounds of the invention.

 They can be used for the prophylaxis and treatment of human diseases, in particular tumors.

The compounds of the invention can be used in particular to the

To inhibit or reduce cell proliferation and cell division and to induce apoptosis.

The compounds according to the invention are particularly suitable for the prophylaxis and therapy of hypersoluble diseases such as, for example

 Psoriasis,

 - keloids and other skin-related hyperplasias

 benign prostatic 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, hematological tumors are treatable

- multiple myeloma,

 Lymphomas or

 Leukemias.

For example, treatable as breast tumors are:

- Breast cancer with positive hormone receptor status

 Breast cancer with negative hormone receptor status

Her-2 positive breast cancers Hormone receptor and 2 negative breast cancers

 BRCA-associated breast cancer

 inflammatory breast cancer. For example, tumors of the respiratory tract are treatable

 Lung carcinomas,

 non-small cell lung carcinomas, such as squamous cell carcinoma, adenocarcinoma, large cell carcinoma and

 small cell bronchial carcinomas.

For example, tumors of the brain are treatable

 gliomas,

 glioblastomas,

 astrocytomas,

- Meningiomas and

 Medulloblastomas.

For example, tumors of the male reproductive organs are treatable:

 Prostate cancers, such as androgen receptor-positive prostate cancers and androgen receptor-negative prostate cancers,

 Malignant epididymal tumors,

 Malignant testicular tumors and

 Penis cancer. For example, tumors of the female reproductive organs are treatable:

 endometrial

 cervical cancer

 ovarian cancer

 Vaginalkarzimome

- Vulvar carcinomas

 choriocarcinoma

For example, tumors of the gastrointestinal tract are treatable:

 Colorectal carcinomas

- Anal carcinomas

 gastric cancers

pancreatic cancer Ösophagukarzinome

 Gallbladder carcinomas

 Small intestine cancer

 Sickle gland carcinomas

- Neuroendocrine tumors

 Gastrointestinal stromal tumors

For example, tumors of the urogenital tract are treatable:

 Bladder carcinomas or bladder carcinomas

- renal carcinomas, such as renal cell carcinomas

 Carcinomas of the renal pelvis and the urinary tract

For example, tumors of the eye are treatable:

 retinoblastoma

- Intraocular melanomas

For example, tumors of the liver are treatable:

 Hepatocellular carcinomas

 Cholangiocellular carcinomas

For example, tumors of the skin are treatable:

 Melanomas, for example malignant melanomas

 Basal cell carcinomas

 squamous

- Kaposi's sarcoma

 Merkel cell carcinoma

For example, tumors of the head and neck are treatable:

 laryngeal cancer

- Carcinoma of the pharynx and oral cavity

 Carcinomas of the midline structures (such as NMC, CA French, Annu Rev. Pathol.

7: 247-265)

 Rhabdomyosarcoma For example, sarcomas are treatable:

 Soft tissue sarcomas

osteosarcomas As lymphomas, for example, treatbax:

 B-cell lymphomas

 Non-Hodgkin's lymphoma

- Hodgkin lymphoma

 Cutaneous lymphoma

 Lymphomas of the central nervous system

 AIDS-associated lymphomas For example, treatable as leukemias are:

 Acute myeloid leukemias

 Chronic myeloid leukemias

 Acute lymphocytic leukemia

 Chronic lymphocytic leukemia

- Lymphoblastic leukemia

 Hairy cell leukemia

Advantageously, the compounds according to the invention can be used for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias,

Prostate cancer, especially androgen receptor-positive prostate cancer,

Cervical carcinoma, breast cancer, especially of hormone receptor negative,

Hormone receptor-positive or BRCA-associated breast cancers, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung cancers, endometrial carcinomas and colorectal

Carcinomas.

The compounds according to the invention can be used particularly advantageously for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,

Breast cancer, in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.

Advantageously, the compounds according to the invention can furthermore be used for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and

Lymphoblastic leukemias, lymphomas, especially B cell lymphomas,

Prostate cancer, especially androgen receptor-positive prostate cancer, Ovarian carcinoma, choriocarcinoma, bladder carcinoma, renal carcinoma, melanoma, lung carcinoma and rhabdomyosarcoma.

The compounds according to the invention can also be used with particular advantage for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and lymphoblastic leukemias, B-cell lymphomas, androgen receptor-positive

Prostate cancer, melanoma and rhabdomyo sar comen.

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

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

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

 Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes: chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatous s, in particular Boeck's disease

 Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic or proliferative processes: all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms in degenerative joint disease

 (Arthroses); traumatic arthritis; Collagenoses of any genesis, e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjgren's syndrome, Still's syndrome, Felty syndrome

Allergies associated with inflammatory or proliferative processes: all forms of allergic reactions, eg, Quincke's edema, hay fever, insect sting, allergic Reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic rather shock, urticaria, contact dermatitis

 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 induced by different noxae, e.g.

Blasting, chemicals, burns etc .; bullous dermatoses; Diseases of the lichenoid type; pruritus; Seborrheic dermatitis; rosacea; Pemphigus vulgaris; Erythema exudative multiforme; balanitis; vulvitis; Hair loss such as alopecia areata; cutaneous T-cell lymphomas

 Ni diseases that are associated with inflammatory, allergic and / or proliferative processes: nephrotic syndrome; all nephritis

 Diseases associated with inflammatory, allergic or proliferative processes: acute liver cell decay; acute hepatitis of different causes, e.g. viral, toxic, drug-induced; Chronic aggressive and / or chronic intermittent hepatitis

 Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes: regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, e.g.

native sprue

 Proctological diseases associated with inflammatory, allergic and / or proliferative processes: analgesic; fissures; Hemorrhoids; idiopathic proctitis Eye diseases associated with inflammatory, allergic or proliferative processes: allergic keratitis, uveitis, 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; External otitis, e.g. due to contact problems, infection, etc .; Otitis media

Neurological diseases associated with inflammatory, allergic or proliferative processes: brain edema, especially tumor-related cerebral edema; Multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, e.g. BNS-seizures

 Blood disorders associated with inflammatory, allergic or proliferative processes: acquired hemolytic anemia; idiopathic thrombocytopenia

Tumor diseases associated with inflammatory, allergic and / or proliferative processes Accompany: acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in mammary, bronchial and prostate carcinoma

 Endocrine disorders associated with inflammatory, allergic or proliferative

 Associated processes: endocrine orbitopathy; thyrotoxic crisis; Thyroiditis de

Quervain; Hashimoto's thyroiditis; Graves' disease

 Organ and tissue transplantation, graft-sus-sus disease

 Severe states of shock, e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)

 - Substitution therapy in: congenital primary adrenal insufficiency, e.g. Congenital adrenogenital syndrome; acquired primary adrenal insufficiency, e.g. Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc; never have secondary adrenal insufficiency, e.g. congenital hypopituitarism; acquired secondary adrenal insufficiency, e.g. postinfectious, tumors, etc

 - Emesis associated with inflammatory, allergic or proliferative processes, e.g. in combination with a 5-HT 3 antagonist in the case of cytostatic vomiting, pain in inflammatory genesis, e.g. lumbago

The compounds according to the invention are also suitable for the treatment of viral

Diseases such as infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses, including HIV-associated kidney disease.

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

The compounds according to the invention are also suitable for the treatment of

Muscular dystrophies such as fazioskapulohumeral muscular dystrophy.

The compounds according to the invention are also suitable for the treatment of

neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease.

These diseases are well characterized in humans but also exist in others Mammals.

Another object of the present invention are the compounds of the invention for the prophylaxis and / or treatment of hyperproliferative diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, II IV-associated kidney disease, vascular disease, atherosclerotic erotic diseases, heart failure and neurodegenerative diseases ,

Another object of the present application are the compounds of the invention for use as medicaments, in particular for the prophylaxis and therapy of

Tumor diseases.

The present invention furthermore relates to the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias and lymphoblastic leukemias, lymphomas, in particular B cell lymphomas, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,

Ovarian carcinoma, choriocarcinoma, bladder carcinoma, renal carcinoma, melanoma, lung carcinoma and rhabdomyosarcoma. Another object of the present invention are the compounds of the invention for the prophylaxis and / or therapy of leukemias, especially acute myeloid leukemias and lymphoblastic leukemias, B-cell lymphomas, androgen receptor-positive

Prostate cancer, melanoma and rhabdomyo sar comen. The present invention further relates to the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas,

Cervical carcinoma, breast cancer, especially 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

Carcinomas.

The present invention further relates to the compounds according to the invention for the prophylaxis and therapy of leukemias, in particular acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, Breast cancer, in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.

Another object of the invention is the use of the compounds of the invention for the manufacture of a medicament.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of hyperproliferative diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, HIV-associated ne renerkrankungen,

Vascular diseases, atherosclerotic erotic diseases, heart failure and neurodegenerative diseases.

Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and therapy of

Tumor diseases.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of

Leukemias, in particular acute myeolemic leukemias and lymphoblastic leukemias, lymphomas, in particular of B cell lymphomas, prostate carcinomas, in particular

Androgen receptor-positive prostate cancer, ovarian cancer, choriocarcinoma, bladder cancer, renal carcinoma, melanoma, lung carcinoma and rhabdomyosarcomen. Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of

Leukemias, in particular acute myeolemic leukemias and lymphoblastic leukemias, B-cell lymphomas, androgen receptor-positive prostate carcinomas, melanomas and

Rhabdomyosarcomas.

Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of

Leukemias, in particular acute myeolemic 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 carcinomas, hepatocellular carcinomas, Melanoma and other skin tumors, non-small cell lung carcinomas,

Endometrial carcinomas and colorectal carcinomas.

Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular

Androgen receptor-positive prostate carcinomas, breast cancers, in particular

Estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma. Another object of the present invention is the use of the compounds of the invention for the prophylaxis and treatment of hyperproliferative diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, HIV-associated diseases Nener, vascular diseases, atherosclerotic erotic diseases, heart failure and neurodegenerative diseases ,

Another object of the present application is the use of the compounds of the invention for the prophylaxis and therapy of tumor diseases.

The present invention further relates to the use of the compounds according to the invention for the prophylaxis and therapy of leukemias, in particular acute myeolemic leukemias and lymphoblastic leukemias, lymphomas, in particular B-cell lymphomas, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, ovarian carcinomas, choriocarcinomas, bladder carcinomas , Renal carcinoma, melanoma, lung carcinoma and rhabdomyosarcomen.

Another object of the present invention is the use of the compounds of the invention for the prophylaxis and therapy of leukemias, in particular acute myeolemic leukemias and lymphoblastic leukemias, B-cell lymphomas, androgen receptor-positive prostate carcinomas, melanomas and Rhabdomyo sar comen.

The present application further relates to the use of the compounds according to the invention for the prophylaxis and therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular of hormone receptor-negative,

Hormone receptor-positive or BRCA-associated breast carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, Non-small cell lung carcinoma, endometrial carcinoma and colorectal

Carcinomas.

The present application further relates to the use of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, breast cancers, in particular estrogen receptor-alpha-negative breast carcinomas, melanomas or multiple myelomas. Another object of the present invention are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of hyp erproli ferative diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, I IIV- associated kidney diseases , Vascular diseases, atherosclerotic erotic diseases, heart failure and neurodegenerative diseases.

Another object of the present invention are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or therapy of tumor diseases.

Another object of the present invention are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of leukemias, especially acute myeloid leukemia and

Lymphoblastic leukemias, lymphomas, especially B cell lymphomas,

Prostate cancer, especially androgen receptor-positive prostate cancer,

 Ovarian carcinoma, choriocarcinoma, bladder carcinoma, renal carcinoma, melanoma, lung carcinoma and rhabdomyosarcoma.

Another object of the present invention are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of leukemias, especially acute myeloid leukemia and

Lymphoblastic leukemias, B cell lymphomas, androgen receptor positive

Prostate cancer, melanoma and rhabdomyo sar comen. Another object of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias,

Prostate cancer, especially androgen receptor-positive prostate cancer,

Cervical carcinoma, breast cancer, especially of hormone receptor negative,

Hormone receptor-positive or BRCA-associated breast carcinomas, pancreatic carcinomas, neuronal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal tumors

Carcinomas.

A further subject of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias,

Prostate cancer, especially androgen receptor-positive prostate cancer,

Breast cancer, in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.

Another object of the present invention is the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.

Another object of the present invention is the use of the compounds of the invention for the treatment of benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and

neurodegenerative diseases.

Another object of the present invention is a method for the prophylaxis and / or treatment of hyperproliferative diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, HIV-associated

Niac diseases, vascular diseases, atherosclerotic erotic diseases, cardiac insufficiency and neurodegenerative diseases, comprising administration of an effective amount of one of the compounds according to the invention to one of the abovementioned

Illnesses suffering patients.

Another object of the present invention is a method for the prophylaxis and / or therapy of tumor diseases, comprising the administration of an effective amount of one of the compounds of the invention to a patient suffering from a tumor disease. A further subject matter of the present invention is a method for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias and lymphoblastic leukemias, lymphomas, in particular B cell lymphomas, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, ovarian carcinomas,

Choriocarcinomas, carcinomas, renal carcinomas, melanomas, lung carcinomas and rhabdomyosarcomas comprising administering to a patient suffering from one of the above-mentioned disorders an effective amount of one of the compounds of the invention. Another object of the present invention is a method for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias and lymphoblastic leukemias, B cell lymphomas, androgen receptor positive prostate carcinomas, melanomas and rhabdomyosarcomen, comprising administering an effective amount of one of Compounds according to the invention to a patient suffering from one of the aforementioned diseases.

The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. A further subject of the present invention are therefore medicaments comprising a compound according to the invention and one or more further active compounds, in particular for the prophylaxis and therapy of the abovementioned disorders.

For example, the compounds according to the invention can be used with known anti-hyperproliferative, cytostatic or cytotoxic substances which are used for the treatment of

 Can also be combined with those substances which have a supporting or constructive property, or it can also be combined with those compounds which are known in the art

Angiogenesis show positive effects.

As suitable pharmacologically active substances which are suitable for a combination are mentioned by way of example, without this enumeration being conclusive:

1311-chTNT, abarelix, abiraterone, aclarubicin, aflibercept, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, bevacizumab, bexarotene, bexarotene , bicalutamide, bisantrene, bleomycin, bortezomib, bosutinib, brentuximab, buserelin, busulfan, cabazitaxel, cabozantinib-s-malate, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cediranib, cetuximab, chlorambucil, chlormadinone, chloromethine, cisplatin, cladribine, clodronic acid, clofarabine , copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, debrafenib, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dexrazoxane hydrochlorite, dibrospidium chlorides, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, duvelisib, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitropanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulves, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxime, goserelin, histamine dibydrochloride, histrelin,

hydroxycarbamides, 1-1 25 seeds, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, imiquimod, improsulfan, interferon alfa, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim , lentinan, letrozole, leuprorelin, leucovorin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, mesna, methotrexate, methoxsalen, methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, mitobuolone, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, nivolumab, obatoclax, obinutuzumab, ofatumumab, omacetaxine mepesuccinate, omeprazole e, oprelvekin, oxaliplatin, ozogamicin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron hydrochloride, pamidronic acid, Pamidronate disodium, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, pertuzumab, picibanil, pidilizumab, pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide-K, pomalidomide, pomatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, quinagolide, radium-223 chlorides, raloxifene, raltitrexed, ramucirumab, rasburicase, ranimustine, razoxane, refametinib, regorafenib, risedronic acid, rituximab, romidepsin, romiplostim, roniciclib, ruxolitinib, sargramostim, selinexor, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin, sunitinib, talaporfin, talc, tamibarotene, tamibarotene, tamoxifen, tasonermine, teceleukin, tegafur, tegafur + gimeracil + oteracil, tazemetostat, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalid omide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, I 131 tositumomab, trametinib, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, ublituximab, valrubicin, valatinib, vandetanib, vapreotide, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

Also, the combination of the inventive compound with a P-TEFb or CDK9 inhibitor is particularly indicated.

In a promising way, the compounds according to the invention can also be combined with recombinant proteins.

The compounds according to the invention can also be used in combination with antihormones and steroidal metabolic enzyme inhibitors, which are particularly suitable because of their favorable side effect profile.

The combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.

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. . ""

Svnthcscroutc for the preparation of the compounds of general formula (I)

Compounds of the general formula (I) can be prepared by the synthetic route shown in Schemes 1 to 5. Therein the preparation of compounds of the formulas (Ia), (Ib), (Ic), (Id), le), (If), (Ig), (Ih), (Ij), (Ik), (Im) and (In) which are subsets of the general formula (I).

 In addition to the synthetic sequence described in the above-mentioned scheme, according to the general knowledge of those skilled in organic chemistry, other

Synthesis routes for the synthesis of compounds of the general formula (I) are used. In addition, conversions of substituents such as RR ⁴ , R ⁶ R, R and R ^{8 may be} carried out before or after the synthetic steps shown. Examples of such conversions are the introduction or removal of protective groups, reduction or oxidation of functional groups, reductive aminations, halogenation, metallation, metal-catalyzed coupling reactions, substitution reactions or other reactions known to the person skilled in the art. These reactions include reactions that introduce a functional group that allows further conversion of substituents. suitable

Protecting groups as well as methods for their introduction and cleavage are known to those skilled in the art (see, for example, T.W. Greene and P.G.M. Wuts in: Protective Croups in Organ ic Synthesis, 4th Edition, Wiley 2006). Furthermore, the combination of two or more reaction steps without intermediate workup in a manner known in the art is possible (for example, in so-called "one-pot" reactions).

 Compounds of the general formula (I) and their precursors described below have an asymmetric center on the carbon atom to which R is bonded (C-4). They can therefore be present as pure enantiomers or as mixtures of enantiomers, for example racemates. Furthermore, they may also be present as diastereomers or mixtures thereof, if one or more of the substituents described in formula (I) contains a further asymmetric element, for example a dural carbon atom. The abovementioned enantiomer mixtures and diastereomer mixtures can be separated into the pure stereoisomers by the separation methods familiar to the person skilled in the art, for example preparative HPLC on a chiral stationary phase.

The synthesis of compounds of general formula (I) can proceed from B enzodiazepinderivaten of formula (IIa) or (IIb), in which R ² , R \ R ^' \ R \ R and R ^{8 are} defined as for the general formula (I. ), and in which LG is a leaving group, for example chlorine, bromine, iodine or trifluoromethylsulfonyloxy, preferably bromine. These can be prepared by the methods described in WO 2014/026997. For example, sulfones of formulas (Ia) and (Ib) as shown in Scheme 1, starting from benzodiazepine derivatives of the formula (IIa) or (IIb) in which R ^2, R ^3, R ^4, R \ R and R ⁸ are defined as for the general formula (I), and in which LG is a leaving group, for example chlorine, bromine, iodine or trifluoromethylsulfonyloxy, preferably bromine, prepared by reaction with sulfinate salts of the formula (III). In the formula (III), R ^{12 is} defined as for the general formula (I), and M ^' is an alkali metal cation or an ammonium ion (R ^A ^ N ⁺ , in which again the groups R ^A independently, identical or different, are hydrogen or C 1 -C 4 -alkyl- Preferably in the formula (III), M ^' stands for a sodium ion Na ⁺ The said reaction of compounds of the formula (IIa) or (IIb) with sulfinate salts of Formula (III) is in the presence of a 1,2-diamine, preferably (±) -trans-cyclohexane-1, 2-diamine, and a copper (I) salt, for example, copper (I) chloride (CuCl), copper ( I) bromide (CuBr), copper (I) iodide (Cul) or copper (I) trifluoromethanesulfonate (CuOTf) performed in free or complexed form.

Preferably, the implementation of said reaction in the presence of

 Copper (I) trifluoromethanesulfonate Benzene complex (CAS [42152-46-5]). Preferably, said reaction takes place in dimethyl sulfoxide as solvent and at a temperature in a range of 60 ° C to 160 ° C, preferably 80 ° C to 140 ° C, more preferably 100 ° C to 120 ° C instead.

Schema 1: Herstellung von Sulfonen der Formeln (Ia) beziehungsweise (Ib) aus B enzodiazepinderivaten der Formeln (IIa) beziehungsweise (IIb). Des weiteren lassen sich Thioether der Formeln (Ic) beziehungsweise (Id), wie in Schema 2 gezeigt, ausgehend von B enzodiazepinderivaten der Formel (IIa) beziehungsweise (IIb), in denen R\ R ^', R\ R\ R und R⁸ definiert sind wie für die allgemeine Formel (I), und in denen LG für eine Abgangsgruppe, beispielsweise Chlor, Brom, lod oder Trifluormethylsulfonyloxy-, bevorzugt für Brom steht, durch Umsetzung mit Thiolen der Formel (IV), in denen R¹² definiert ist wie für die allgemeine Formel (I), herstellen.

Scheme 1: Preparation of sulfones of the formulas (Ia) or (Ib) from B enzodiazepine derivatives of the formulas (IIa) or (IIb). Furthermore, thioethers of the formulas (Ic) or (Id), as shown in Scheme 2, can be prepared starting from B enzodiazepine derivatives of the formula (IIa) or (IIb) in which R 1 R ^' , R 1 R 1 and R ⁸ are defined as for the general formula (I), and in which LG is a leaving group, for example chlorine, bromine, iodine or trifluoromethylsulfonyloxy, preferably bromine, by reaction with thiols of the formula (IV), in which R ^{12 is} defined as for the general formula (I).

 The said reaction of compounds of the formula (IIa) or (IIb) with thiols of the formula (IV) can be carried out in the presence of an amine, for example a tertiary aliphatic amine, preferably a tertiary aliphatic amine of the formula (C 1 -C 3 -alkyl) ) 3N, as the base, in the presence of a palladium species

Tris (dibenzylideneacetone) dipalladium (0) (CAS [53164-51-3], and a ligand, preferably xanthphos (CAS [161265-03-8]), in dioxane as a solvent, at a temperature in the range of 80 ° C to 150 ° C, preferably 100 ° C to 140 ° C, optionally using a

Microwave reactor.

Schema 2: Herstellung von Thioethern der Formeln (Ic) beziehungsweise (Id) aus B enzodiazepinderivaten der Formeln (IIa) beziehungsweise (IIb).

Scheme 2: Preparation of thioethers of the formulas (Ic) or (Id) from B enzodiazepine derivatives of the formulas (IIa) or (IIb).

The thus obtained thioethers of the formulas (Ic) or (Id) can be oxidized according to Scheme 3 using known methods to sulfoxides of the formulas (Ie) or (If) and to the sulfones of the formulas (Ia) or (Ib).

Preferably mefa-chloroperbenzoic acid is used as the oxidizing agent (see, for example, Synthesis 2013, 45, 2875); the reaction is carried out in a solvent such as dichloromethane, chloroform or methanol, optionally with the addition of

 Trifluoroacetic acid which may be added as described for example in US 2012/0245144 for protection against undesired formation of N-oxides.

 Depending on the reaction conditions and on the amount of oxidant used, either the sulfoxides of the formulas (Ie) or (If), the sulfones of the formulas (Ia) or (Ib) or as mixtures of sulfoxide and sulfone are obtained

Use of known methods, for example column chromatography or preparative II PIX. let separate. In the sulfoxides of the formulas (Ie) or (If), the sulfur atom represents a (further) asymmetric center; the resulting stereoisomers can be separated from one another using known methods, for example preparative HPLC, optionally on a dural stationary phase.

Scheme 3: Preparation of sulfoxides of the formulas (Ie) or (Ii) and sulfones of the formulas (Ia) or (Ib) from thioethers of the formulas (Ic) or (Id).

The sulfoxides of the formulas (Ie) or (If) obtainable according to Scheme 3 can be reacted according to Scheme 4 to give sulfoximine derivatives of the formulas (Ig) or (Ih). For this purpose, a number of methods are familiar to the person skilled in the art (for a review of sulfoximines, see, for example, U. Lücking, Angew Chem. 2013, 125, 9570). Preference is given to the reaction of sulfoxides of the formulas (Ie) or (If) in which R, R ³ , R ⁴ , R \ R. R ⁸ and R ^{12 are} defined as for the general formula (I), with 2,2,2-trifluoroacetamide and

Diacetoxyiodobenzene (CAS [3240-34-4] in the presence of magnesium oxide as well

Rhodium (II) acetate dimer (Rh ₂ OAc ₄ ; CAS [15956-28-2]), followed by cleavage of the N-2,2,2-trifluoroacetylsulfoximine intermediately formed by reaction with potassium carbonate in methanol (C. Bolm et al., Chem. Soc. Rev., 2015, 44, 3378-3390). In the resulting

Sulfoximines of the formulas (Ig) or (Ih) R ^{13 is} hydrogen; Compounds of the formulas (Ij) and (Ik) in which R ' ^{3 is} defined as in the general formula (I) but different from hydrogen can be obtained therefrom by a number of known methods:

Alkylation: see, for example, a) U. Lücking et al, US 2007/0232632; b) CR. Johnson, J. Org. Chem. 1993, 58, 1922; c) C. Bolm et al, Synthesis, 2009. 10, 1601.

 Acylation: see, for example, a) C. Bolm et al, Chem. Europ. J. 2004, 10, 2942; b) C. Bolm et al, Synthesis 2002. 7, 879; c) C. Bolm et al, Chem. Europ. J. 2001. 7, 1 118.

 Arylation: see, for example, a) C. Bolm et al, Tet. Lett. 1998, 39, 5731; b) C. Bolm et al., .1. Org. Chem. 2000. 65, 169; c) C. Bolm et al, Synthesis 2000. 7, 91 1; d) C. Bolm et al, J. Org. Chem. 2005, 70, 2346; e) U. Lücking et al, WO2007 / 71455.

 Reaction with isocyanates: see, for example, a) V.J. Bauer et al, J. Org. Chem. 1966, 31, 3440; b) C.R. Johnson et al, .1. At the. Chem. Soc., 1970, 92, 6594; c) S. Allenmark et al, Acta Chem.

Scand. Ser. B 1983, 325; d) U. Lücking et al., US2007 / 0191393.

 Reaction with sulfonyl chlorides: see, for example, a) DJ. Cram et al, J. At the. Chem. Soc., 1970, 92, 7369; b) CR. Johnson et al, .1. Org. Chem. 1978. 43, 4136; c) A.C. Barnes, .1. Med. Chem. 1979. 22, 418; d) D. Craig et al, Tet. 1995. 51, 6071; e) U. Lücking et al., US2007 / 191393. Reaction with chloroformic acid esters: see, for example, a) P.B. Kirby et al., DE2129678; b) DJ. Cram et al, .1. At the. Chem. Soc. 1974. 96, 2183; c) P. Stoss et al, Chem. Ber. 1978. 1 11, 1453; d) U. Lücking et al., WO2005 / 37800.

Reaction with cyanogen bromide: see, for example, a) DT Sauer et al., Inorganic Chemistry 1972. 11, 238; b) C. Bolm et al, Org. Lett. 2007, 9, 2951; c) U. Lücking et al, WO 201 1/29537.

Scheme 4: Preparation of sulfoximines of the formulas (Ig), (Ih), (Ij) or (Ik) from sulfoxides of the formulas (Ie) or (Ii).

Phosphorus compounds of the formulas (Im) or (In) can, as shown in Scheme 5 and in analogy to methods described in WO 2009/143389, starting from B enzodiazepinderivaten of the formula (IIa) or (IIb) in which R ² , R \ R ", R \ R and R ^{8 are} defined as for the general formula (I), and in which LG is a leaving group, for example chlorine, bromine, iodine or trifluoromethylsulfonyloxy, preferably bromine, by reaction with phosphine oxides of the formula (V) in which R ¹⁴ and R ^{15 are} defined as in the general formula (I) Formula (IIa) or (IIb) with phosphine oxides of the formula (V) is for example carried out in the presence of an alkali metal phosphate or alkali carbonate as the base, preferably potassium phosphate, and in the presence of a Palladiumsp ezie s, preferably palladium (II) acetate, and a ligand, preferred Xanthphos (CAS [161265-03-8]), in N, N-dimethylformamide solvent, at a temperature in the range from 80 ° C to 180 ° C, preferably from 1 00 ° C to 160 ° C, particularly preferably from 120 ° C to 140 ° C, optionally using a

Microwave reactor.

Scheme 5: Preparation of organophosphorus compounds of the formulas or (In) from B enzodiazepine derivatives of the formulas (IIa) or (IIb).

Abbreviations:

 BPR Backpressure Regulator (SFC)

 CDCls deuterochloroform

 TLC thin layer chromatography

 DMF dimethylformamide

 DM SO dimethylsulfoxide

d. Th. Of theory

eq. equivalent to

 ESI El ektrospray ionization (in MS)

h hour

 H I high pressure, high performance liquid chromatography

 LCMS liquid chromatography-coupled mass spectrometry min minutes

 MS mass spectrometry e

 MW molecular weight [g / mol]

 MWD Multi wavelet Detector

 NMR nuclear magnetic resonance spectroscopy

R _f Retention index (at IX)

 RP-HPLC reverse phase HPLC

 RT room temperature

 SFC supercritical fluid chromatography

 (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphine)

Xanthphos

Percentage yield data (in% of Th) may be purity-adjusted.

C MS Methods:

Method 1: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μπι, 50x2.1mm; Eluent A: water + 0.1% by volume formic acid (99%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 ml / min; Temperature: 60 ° C; DAD scan: 210-400 nm.

Method 2: Instrument: Waters Acquity UPLCMS Single Quad; Column: Kinetex C18 (Phenomenex) 2.6 μιη, 50x2.1mm; Eluent A: water + 0.05% by volume of formic acid (99%), eluent B: acetonitrile + 0.05% formic acid; Gradient: 0-0.2 min 98% A, 0.2-1.7 min 98-10% A, 1.7-1.9 min 10% A, 1.9-2.0 min 10-98% A, 2.0-2.5 min 98% A; flow 1.3 ml / min; Temperature: 60 ° C; DAD scan: 210-400 nm

Method 3: Instrument: Agilent 1290 UHPLCMS Tof; Column: BEH C 18 (Waters) 1.7 μπι, 50x2.1mm; Eluent A: water + 0.05% by volume formic acid (99%), eluent B: acetonitrile + 0.05% formic acid; Gradient: 0-1.7 min 98-10% A, 1.7-2.0 min 10% A, 2.0-2.5 min 10-98% A, flow 1.2 ml / min; Temperature: 60 ° C; DAD scan: 210-400 nm

Method 4: Instrument: Waters Acquity UPLCMS Single Quad; Column: BEH C 18 (Waters) 1.7 μπι, 50x2.1mm; Eluent A: water + 0.05% by volume formic acid (99%), eluent B: acetonitrile +

0.05% formic acid; Gradient: 0-0.2 min 98% A, 0.2-1.7 min 98-10% A, 1.7-1.9 min 10% A, 1.9-2.0 min 10-98% A, 2.0-2.5 min 98% A; flow 1.3 ml / min; Temperature: 60 ° C; DAD scan: 210-400 nm

The term "preparative RP-HPLC" refers to purification on commercial preparative H PI. ( ^' Plants using commercially available

"Reversed phase" materials as stationary phase Gradients of water and acetonitrile, optionally with the addition of small amounts of formic acid, trifluoroacetic acid or ammonia as additives, are used as the mobile phase. Analytical HPLC Methods:

Method A: Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μ 100x4.6mm; Eluent A: methanol + 0.1% by volume diethylamine (99%); Eluent B: ethanol; isocratic: 50% A + 50% B; Flow 1.4 ml / min; Temperature: 25 ° C; DAD @ 254 nm

Method B: Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μ 100x4.6mm; Eluent A:

Hexane + 0.1% by volume diethylamine (99%); Eluent B: ethanol; isocratic: 80% A + 20% B; Flow 1.0 ml / min; Temperature: 25 ° C; DAD @ 254 nm

 Method C: Instrument: Agilent HPLC 1260; Column: Chiralpak ID 3μ 100x4.6mm; Eluent A: tert-butyl methyl ether + 0.1% by volume diethylamine (99%); Eluent B: acetonitrile; isocratic:

50% A + 50% B; Flow 1.4 ml / min; Temperature: 25 ° C; DAD @ 280 nm

 Method D: Instrument: Agilent HPLC 1260; Column: Chiralpak IB 3μ 100x4.6mm; Eluent A:

Hexane + 0.1% by volume diethylamine (99%); Eluent B: ethanol; isocratic: 50% A + 50% B; Flow 1.4 ml / min; Temperature: 25 ° C; DAD @ 325 nm

 Method E: Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μ 100x4.6mm; Eluent A: methanol + 0.1% by volume diethylamine (99%); Eluent B: ethanol; isocratic: 50% A + 50% B; Flow 1.4 ml / min; Temperature: 25 ° C; DAD @ 254 nm

 Method F: Instrument: Agilent HPLC 1260; Column: Chiralpak ID 3μ 100x4.6mm; Eluent A: tert-butyl methyl ether + 0.1% by volume o diethylamine (99%); Eluent B: acetonitrile; isocratic:

50% A + 50% B; Flow 1.4 ml / min; Temperature: 25 ° C; DAD @ 280 nm

Method G: Instrument: Agilent: 1260, Aurora SFC Module; Column: Chiralpak ID 5μιη 100x4.6mm; Eluent A: C02. Eluent B: 2-propanol; isocratic: 31% B; Flow 4.0 ml / min; Temperature: 37.5 ° C; BPR: 100bar; MWD @ 254nm

sake

When in the below-described synthesis intermediates and embodiments of the invention, a compound in the form of a salt of the corresponding base or acid is listed, the exact sto chiometr i cal composition of such a salt, as it depends on the respective manufacturing and / or purification process was obtained, usually unknown. Unless specified otherwise, name and structural formula additives such as "hydrochloride", "trifluoroacetate", "sodium salt" or "xHCl", "xCF ₃ COOH", "xNa ⁺ " in such salts are therefore examples not to understand stoichiometrically, but solely descriptive of the contained salt-forming components.

The same applies mutatis mutandis to the case that synthesis intermediates or embodiments or salts thereof according to the described preparation and / or purification processes in the form of Solvates, such as hydrates, were obtained whose stoichiometric composition (if defined type) is not known.

'H NMR data

Ή-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, br = broad signal. For example, signals with combined multiplicity are given as dd = doublet of doublet. The chemical shifts of the signals (δ) are given in ppm (parts per million).

Chemical nomenclature

 Substance names of Zwischenverbindngen and example substances were with the

Program 'ACD / Name batch version 12.01' produced by the company AD LABS, and adjusted if necessary.

Preparation of the intermediate compounds

Example 1A

 (4S) -l- (3-bromophenyl) -7,8-limetho

caxboxamid

 3.38 g of Example 1A were prepared starting from 8.1 g (18.17 mmol) of racemic (±) -l- (3-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide, whose synthesis is described in WO 2014026997, by enantiomer separation by HPLC on a chiral phase under the following conditions.

 Instrument: Labomatic HD3000, AS-3000, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: Chiralpak IC 5μ 250x50mm No.019; Eluent A: hexane + 0.1% by volume diethylamine (99%); Eluent B: ethanol; Isocratic: 80% A + 20% B; Flow 1 10.0 ml / min; UV @ 254 nm. Example 1A: (4S) -1- (3-Bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

HPLC (Method B): R- = 5.69 min

Rotation: [a] _D ²⁰ = 129.9 ° +/- 0.24 ° (c = 1.0, methanol)

LCMS (Method 3): R _t = 1.25 min; mz = 434 (M + H) ⁺

Under these separation conditions, 3.58 g of the enantiomer (4R) -i - (3-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(Example 2A) are isolated. Example 2A: (4R) - (3-Bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

HPLC (Method B): R _t = 6.69 min

Rotation: [a] _D ²⁰ = -125.4 ° +/- 0.42 ° (c = 1.0, methanol)

LCMS (Method 3): R, = 1.25 min; m / z = 434 (M + H) ⁺

The following examples describe the preparation of the compounds according to the invention without restricting the invention to these examples.

Preparation of the compounds of the general formula I according to the invention

Ausführungsheispiele

Example 1 (4S) -7,8-Dimethoxy-N, 4-dimethyl-1- [4- (methylsulfonyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

100 mg (229 μπιοΐ) (¥ ₁ S) -1- (4-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, which can be prepared analogously to the procedure described in WO 2014202578 (Example 29-2A), 4 ml of DMSO were initially charged and the solution was degassed with argon. There were 37 mg (346 μηιοΐ) of sodium methanesulfinate, 10.7 mg (94 μπιοΐ) (±) - trans-cyclohexane-1, 2-diamine (CAS [1121-22-8]) and 12.8 mg (23 μιηοΐ) copper (I) trifluoromethanesulfonate benzene complex (CAS [42152-46-5]). The mixture was degassed again, saturated with argon and then stirred at 110 ° C for 16 hours. After cooling, the mixture was filtered and purified by preparative RP-HPLC. 56 mg (56% of theory) of the desired product were obtained as a solid.

I.CMS (Method 3): R, = 0.9 min; m / z = 432 (M + H) ⁺

»H NMR (400MHz, CDC1 ₃ ): δ = 0.96 (d, 3H), 2.89-2.97 (m, 4M). 3.14 (s, 3H), 3.19 (d, IH), 3.67 (s, 3H), 3.96 (s, 3H), 5.50-5.60 (m, IH), 6. 1 (s, 1H), 6.53-6.62 ( m, 1H), 6.74 (s, 1H), 7.69 (d, 2H), 7.99 (d, 2H).

Rotation: [a] _D ²⁰ = -105.8 ° +/- 0.27 ° (c = 1.00, methanol) Analogously to Example 1 were from (¥ 5) -l - (4-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide and the corresponding commercially available sulfomates

folgende Beispielverbindungen hergestellt:

following example connections are made:

No. Structure Name Analytical data

Ή-NMR (400MHz, CDC1 ₃ ): δ =

0.97 (d, 3H), 1.07-1.14 (m, 2H),

(4S) -l- [4-1 .39- 1 .45 (m, 2H), 2.50-2.58 (m,

(Cyclopropylsulfonyl) p 1H), 2.92 (dd, 1H), 2.93 (d, 3H), henyl] -7.8 -dimethoxy-3.19 (dd, 1H), 3.67 (s, 3H), 3.97 (s,

2N, 4-dimethyl-4,5- 311). 5.50-5.59 (m, 1H), 6.52 (s, dihydro-3H-2,3-1H), 6.54-6.61 (m, 1H), 6.74 (s, benzodiazepine-3 - 1H), 7.67 (d, 2H) , 7.94 (d, 2H).

 carboxamide

LCMS (Method 2): R, = 1.02 min; m / z = 458 (M + H) ⁺

min; m / z = 538 (M + H) ⁺

Analogously to Example 1, from (±) -l- (3-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide and the corresponding commercially available sulfinates the following example compounds:

=

=

- (t,

= (m, (s,

(s, (m,

Nr. Struktur Name Analytische Daten

No. Structure Name Analytical data

min; m / z = 432 (M + H) ⁺

 Ή NMR (400MHz, CDCl3): δ = 0.95 (d, 3H), 2.23 (s, 3H), 2.86-

(±) -l- {3 - [(4- 2.95 (m, 4H), 3.15 (dd, IH), 3.55 acetamidophenyl) sulfo (s, 3H), 3.97 (s, 3H), 5.48-5.57 (m, nyl] phenyl} -7,8-IH), 6.43 (s, IH), 6.46-6.55 (m,

18ά, dimethoxy-N, 4 -HH), 6.74 (s, IH), 7.47 (s, br, IH), dimethyl -4, 5 -dihydro-7.56 (t, IH), 7.65-7.75 (m, 3H ), 3 H -2,3 -bznzixi ia / ep in - 7.91 (d, 2H), 7.95-8.01 (m, 211).

 3-carboxamide

LCMS (Method 3): R _t = 0.99 min; m / z = 551 (M + H) ⁺

Ή NMR (400MHz, CDC1 ₃ ): δ = 0.96 (d, 3H), 2.90 (s, 3H), 2.92 (dd, IH), 3.17 (dd, I ii). 3.56 (s,

(±) -3 - ({3- [7.8-3H], 3.97 (s, 3H), 5.54 (m, IH), dimethoxy-4-methyl-3-6.43 (s, IH), 6.52 (s , br, IH), 6.74 (methylcarbamoyl) -4.5- (s, IH), 7.59 (t, IH), 7.69 (t, IH),

19 dihydro-3H-2,3-7.74 (d, IH), 8.03 (d, IH), 8.08 (t, benzodiazepine-1 -

° Xj ⁰ IH), 8.22 (dt IH), 8.33 (dt, IH), ylphenyl} sulfonyl) - 8.66 (t, IH).

 benzoic acid

LCMS (Method 3): R, = 1.00 min; m / z = 538 (M + H) ⁺

Example 18.1

 (4S) -l- {3 - [(4-acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4, ^

2,3-benzodiazepine-3-carboxamide

 22 mg of Example 18.1 was prepared from 4 mg of (±) -l - {3 - [(4-acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H -2,3-benzodiazepine-3-carboxamide

(Example 18) by enantiomer separation by HPLC on a chiral phase under the following conditions.

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, Column: Chiralpak IC 5μ 250x30mm; Eluent A: methanol + 0.1% by volume diethylamine (99%); Eluent B: ethanol; Isocratic: 50% A + 50% B; Flow 40.0 ml / min; UV @ 254 nm.

Example 18.1: (4S) -l - {3 - [(4-Acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3 -carboxamide

HPLC (Method A): R, = 2.41 min

Rotation: [a] _D ²⁰ = -85.5 ° +/- 0.34 ° (c = 1.0, methanol)

LCMS (Method 3): R, = 0.99 min; m / z = 551 (M + H) ⁺

Furthermore, at the separation 22 mg

 Example 18.2: (4R) -1 - {3 - [(4-Acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3 Carboxamide can be obtained.

HPLC (Method A): R _t = 3.02 min

Rotation: [a] _D ²⁰ = + 82.9 ° +/- 0.36 ° (c = 1.0, methanol)

LCMS (Method 3): R, = 0.99 min; m / z = 551 (M + H) ⁺

Step Example! 14.1

 (4R) -1- [3- (Benzylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

1 5 mg of Example 14.1 was prepared starting from 49 mg of (±) -l- [3- (benzylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide (Example 14) by enantiomer separation by SFC on a dural phase under the following conditions.

Instrument: Sepiatec: Prep SFC100; Column: Chiralpak ID 5μιη 250x30mm; Eluent A: CCh, eluent B: 2-propanol; isocratic: 31% B; Flow 100.0 ml / min temperature: 40 ° C; BPR: ISObar; MWD @ 254nm. Example 14.1: (4R) - [3 ^ benzylsulfonyl) phenyl] -7,8-imidoxy-N, 4KlimethyM, 5 <lihydro-3H-

2,3-benzodiazepine-3-carboxamide: HPLC (method G): R, = 2.75 min

Rotation: [a] _D ²⁰ = + 10.8 ° +/- 0.14 ° (c = 1.0, methanol)

LCMS (Method 3): R _t = 1.12 min; m / z = 508 (M + H) ⁺

Furthermore, at the separation 15 mg

 Step Example! 14.2

 (4S) -l- [3- (benzylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide.

HPLC (method G): R _t = 3.44 min

Rotation: [a] _D ²⁰ = -51.9 ° +/- 0.81 ° (c = 1.0, methanol)

LCMS (Method 3): R _t = 1.12 min; m / z = 508 (M + H) ⁺

Example 20

(±) - [4-fluoro-3 - (methylsulfo ^

benzodiazepine-3-carboxamide

42 mg (89 μιηοΐ) (±)-l -(3-Brom-4-fluo henyl)-7,8-dimethoxy-N,4 iimethyl-4,5-dihydΓO-3H-2,3- benzodiazepin-3 -carboxamid, welches analog zu einer in WO 2014202578 (Beispiel 31A) beschriebenen Vorschrift hergestellt werden kann, wurden 2.1 ml DM SO vorgelegt und die Lösung mit Argon entgast. Es wurden 14.4 mg (134 μιηοί) Natriummethansul finat, 4 mg (36 μηιοΐ) (±)-trans-Cyclohexan- 1 ,2-diamin (CAS [1121-22-8]) und 5 mg (9 μπιοΐ) Kupfer(I) trifluormethansulfonat Benzolkomplex (CAS [42152-46-5]) zugegeben. Die Mischung wurde erneut entgast, mit Argon gesättigt und dann 3 Stunden bei 110°C gerührt. Nach dem Abkühlen wurde die Mischung filtriert und mittels präparativer RP-HPLC gereinigt. Man erhielt 4 mg (10% d. Th.) des gewünschten Produkts als Feststoff.

42 mg (89 μιηοΐ) of (±) -1- (3-bromo-4-fluoro-phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3 - carboxamide, which can be prepared analogously to a method described in WO 2014202578 (Example 31A), 2.1 ml of DM SO were presented and the solution was degassed with argon. There were 14.4 mg (134 μιηοί) Natriummethansul finat, 4 mg (36 μηιοΐ) (±) trans-cyclohexane-1, 2-diamine (CAS [1121-22-8]) and 5 mg (9 μπιοΐ) copper (I. ) trifluoromethanesulfonate benzene complex (CAS [42152-46-5]). The mixture was degassed again, saturated with argon and then stirred at 110 ° C for 3 hours. After cooling, the mixture was filtered and purified by preparative RP-HPLC. 4 mg (10% of theory) of the desired product were obtained as a solid.

LCMS (Method 2): R, = 0.94 min; m / z = 450 (M + fff H-NMR (400 MHz, CDCl ₃ ): δ = 0.96 (d, 3H), 2.91 (dd, IH), 2.93 (d, 3H), 3.15 (dd, IH), 3.29 (s, 3H), 3.68 (s, 3H), 3.96 (s, 3H), 5.49-5.60 (m, IH), 6.48 (s, IH), 6.44-6.53 (m, IH), 6.74 (s, IH), 7.30 (t, IH), 7.77 (m, IH), 8.12 (dd, IH).

Example 21

(±) -l- [3,4-bis (methylsulfonyl) phenyl] -7,8-dim ^

benzodiazepine-3-carboxamide

Beispiel 21 wurde analog der Herstellung von Beispiel 20 synthetisiert. Die Reaktionszeit betrug allerdings 16h bei 110°C. Man erhielt so ausgehend von 80 mg (159 μηιοΐ) (±)-l-(3-Brom-4- fluo henyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydl -3H-2,3-benzodiazepin-3-carboxamid 50 mg (57% d. Th.) des gewünschten Produkts als Feststoff.

Example 21 was synthesized analogously to the preparation of Example 20. However, the reaction time was 16 hours at 110 ° C. Starting with 80 mg (159 μηιοΐ) of (±) -l- (3-bromo-4-fluoro-5-yl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydyl-3H-2, 3-benzodiazepine-3-carboxamide 50 mg (57% of theory) of the desired product as a solid.

LCMS (Method 2): R _t = 0.96 min; m / z = 510 (M + H) ⁺ Ή-NMR (400 MHz, CDCl ₃ ): δ = 0.95 (d, 3H), 2.94 (d, 3H), 2.96 (dd, 1H), 3.18 (dd, 1H) , 3.49 (s, 3H). 3.51 (s, 3H). 3.70 (s, 3H), 3.98 (s, 3H), 5.54-5.63 (m, 1H), 6.51 (s, IH), 6.56 (q, 1H), 6.76 (s, 1H), 7.95 (dd, 1H) , 8.36 (d, 1H), 8.50 (d, 1H).

Example 22 (4S) -7,8-Dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfanyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

400 mg (0.92 mmol) of (4S) -1- (4-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3- Benzodiazepine-3-carboxamide, which can be prepared analogously to the procedure described in WO 2014202578 (Example 29-2A), was initially charged in 12 ml of dioxane and the solution was degassed with argon. There were 474 mg (3.66 mmol) of N, N-diisopropylethylamine, 42 mg (0.046 mmol) of tris (dibenzylideneacetone) dipalladium (0) (CAS [51364-51-3]) and 53 mg (0.092 mmol) of xanthphos (CAS [161265 -03-8]) and finally 151 mg (1.37 mmol) of benzenethiol was added. The mixture was degassed again, saturated with argon and then heated at 120 ° C for 1 hour in the microwave. After cooling, the mixture was added with a little water and extracted twice with ethyl acetate. After removal of the solvent, 70 mg of the residue was purified by preparative RP-HPLC. 46 mg (1% of theory) of the desired product were obtained.

LCMS (Method 3): R _t = 1.43 min; m / z = 462 (M + H) ⁺

Ή NMR (400MHz, CDC1 ₃ ): δ = 1.03 (d, 3H), 2.83 (dd, 1H), 2.89 (d, 3H), 3.09 (dd, 1H), 3.70 (s, 3H), 3.96 (s , 3H), 5.39-5.49 (m, 1H), 6.38-6.48 (m, 1H), 6.60 (s, 1H), 6.74 (s, 1H), 7.31 (d, 2H), 7.34-7.42 (m, 3H ), 7.44-7.50 (m, 4H).

Analogously to Example 22, from (4S) -1- (4-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide or the enantiomer ( 4R) -1- (4-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (see WO

 2014202578, Example 29-1A) and the corresponding commercially available thiols

folgende Beispielverbindungen hergestellt:

=

following example connections are made:

=

3H), (d, 2H),).

= (dd,). 3.97 (s, IH),

= 4H), (m,

(D,

min; m / z = 462 (M + H) ⁺

Analogously to Example 22, (±) -l- (3-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide and the corresponding compounds were obtained commercially available thiols the following example compounds:

No. Structure Name Analytical data

(±) -7,8-dimethoxy-Ή-NMR (400MHz, CDC1 ₃ ): δ =

CH N, 4-dimethyl-1- [3-0.97 (d, 3H), 2.84 (dd, 1H), 2.86

 (phenylsulfanyl) phenyl (d, 3H), 3.12 (dd, 1H), 3.66 (s,

31

j-4.5-dihydro-3H-2.3- 3H), 3.95 (s, 3H), 5.41-5.50 (m, benzodiazepine-3 - 1H), 6.34-6.44 (m, 1H), 6.57 (s, carboxamide 1H), 6.71 (s, 1H), 7.29-7.40 (m,

min; m / z = 414 (M + H) ⁺

Example 39

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfinyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

700 mg (1.52 mmol) of (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfanyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 22) were dissolved in 60 ml of chloroform and brought to 0 ° C cooled. 408 mg (1.82 mmol) of meia-chloroperbenzoic acid were added and the mixture was stirred at 0 ° C. for 1 h and then at RT for a further 16 h. The solution was treated with saturated aqueous sodium bicarbonate solution and aqueous sodium thiosulfate solution, 30 min. stirred at RT and then extracted three times with chloroform. After removal of the solvent, the residue was purified by preparative RP-HPLC. 288 mg (39% of theory) of the desired product were obtained as a mixture of two diastereomers.

[.CMS (Method 3): R _t = 1.16 min; m / z = 478 (M + fff

Ή NMR (500MHz, CDC1 ₃ ): δ = 0.94 (d, 3H), 2.86 (dd, IH), 2.88 (d, 3H), 3.11 (dd, IH), 3.62 (d, 3H). 3.93 (d, 3H), 5.44-5.52 (m, IH), 6.47 (d, IH), 6.47-6.53 (m, IH), 6.70 (s, IH), 7.46-7.53 (m, 3H), 7.57 ( dd, 2H), 7.66-7.72 (m, 4H).

Analogously to the preparation of example 39, examples 28-23, 26, 25, 27, 29 and 30 were prepared by oxidation as a mixture of diastereomers:

=

=

2H),

=

6.74 2H),

= 3.17 IH),

min; m / z = 478 (M + H) ⁺

Example 43.1

 (4S) -l- [4- (Benzylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 1

27 mg von Beispiel 43.1 wurden ausgehend von 68 mg (4S)- 1 - [4-(B enzylsulfmyl)phenyl] -7,8- dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepin-3-carboxamid (Beispiel 43) durch Diastereomerentrennung durch HPLC an einer chiralen Phase unter den folgenden Bedingungen hergestellt.

27 mg of Example 43.1 were prepared starting from 68 mg of (4S) -1- [4- (Benzenylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide (Example 43) prepared by diastereomer separation by HPLC on a chiral phase under the following conditions.

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, Column: Chiralpak ID 5μ 250x30mm; Eluent A tert-butyl methyl ether + 0.1% by volume diethylamine (99%); Eluent B: acetonitrile; isocratic: 50% A + 50% B; Flow 50.0 ml / min; UV @ 280 nm.

Example 43.1: (4S) -1- [4- (Benzylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 1 :

HPLC (Method F): R, = 2.38 min

Rotation: [a] _D ²⁰ = + 129.3 ° +/- 0.33 ° (c = 1.0, methanol)

 LCMS (Method 3): R, = 1.06 min; m / z = 492 (M + Hf) 25 mg of

Example 43.2

 (4S) -l- [4- (benzylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 2 ,

 HPLC (Method F): R = 1.96 min

Rotation: [a] _D ²⁰ = -52.3 ° +/- 5.5 ° (c = 1.0, methanol)

LCMS (Method 3): R _t = 1.06 min; mz = 492 (M + H) ⁺ .

Analogously to the preparation of example 39, the following example compounds were prepared from examples 37, 32, 34, 38 and 36 by oxidation as a mixture of diastereomers:

 min; m / z = 585 (M + fff

 Example 52

(4S) -i- [4- (cyclopentylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

60 mg (0.131 mmol) of (4S) -1- [4- (cyclopentylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5- Dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 28) was dissolved in 4 ml of methanol and cooled to 0 ° C. 44 mg (0.196 mmol) of meta-chloroperbenzoic acid were added and the mixture was stirred for 1 h. After removal of the solvent, the residue was purified by preparative RP-HPLC. 44 mg (68% of theory) of the desired product were obtained. I MS (Method 3): R _s = 0.98 min; m / z = 502 (M + H) ⁺

Ή NMR (400MHz, CDC1 ₃ ): δ = 0.96 (d, 3H), 1.57-1.73 (m, 2H). 1.76-2.00 (m, 4H), 2.07-2.21 (m, 2H), 2.92 (dd, 1H), 2.94 (d, 3H), 3.19 (dd, 1H), 3.51-3.61 (m, 1H), 3.66 ( s, 3H), 3.96 (s, 3H), 5.50-5.59 (m, 1H), 6.49 (s, 1H), 6.58 (q, 1H), 6.74 (s, 1H), 7.67 (d, 2H), 7.94 (d, 2H).

Analogously to the preparation of Example 52, the following sulfones were prepared from Examples 29, 23, 30 by oxidation:

Example 56

(4S) -7,8-dimethoxy-N, 4-dimethyl-1 - {4 - [(1-methylpiperidin-4-yl) sulfonyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine -3-carboxamide

125 mg (0.259 mmol) of (4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(1-methylpiperidin-4-yl) sulfanyl] phenyl} -4,5-dihydro-3H- 2,3-benzodiazepine-3-carboxamide (Example 24) was dissolved in 8 ml of dichloromethane, cooled to 0 ° C and added 32 μΐ (0.415 mmol) of trifluoroacetic acid. Then 4 mg (0.311 mmol) of ffiefa-chloroperbenzoic acid were added and stirred for 1 h. After removal of the solvent, the residue was purified by preparative RP-HPLC. This gave 3.8 mg (3% of theory) of the desired product (Example 56) in addition to 29 mg of (4S) -7,8-dimethoxy-N, 4-dimethyl-1 - {4 - [(1-methylpiperidine-4 -yl) sulfinyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 57). LC MS (Method 3): R, = 0.67 min; m / z = 515 (M + H) ⁺

Ή NMR (400MHz, CDC1 ₃ ): δ = 0.96 (d, 3H). 1.49-1.90 (m, 3H), 1.92-2.26 (m, 4H), 2.26-2.44 (m, 3H), 2.92 (dd, 1H), 2.94 (d, 3H), 2.96-3.13 (s, br, 2H). 3.19 (dd, 1H), 3.66 (s, 3H), 3.96 (s, 3H), 5. 1 -5.61 (m, IH), 6.48 (s, IH), 6.60 (q, IH), 6.74 (s, 1H), 7.67 (d, 2H), 7.90 (d, 2H). Example 57

(4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(1-methylpiperidin-4-yl) sulfinyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide

LCMS (Method 3): Rt = 0.60 min; m / z = 499 (M + H) ⁺

Ή NMR (400MHz, CDCl3): δ = 0.97 (dd, 3H), 1.57-1.89 (m, 4H). 1.91-2.09 (m, 2H), 2.295 (s, 3H), 2.64-2.74 (m, IH), 2.90 (dd, IH), 2.93 (dd, 3H). 2.94-3.05 (m, 2H), 3.17 (d, IH), 3.65 (s, 3H), 3.96 (s, 3H). 5.48-5.58 (m, IH), 6.52 (d, IH), 6.54-6.63 (m, IH), 6.74 (s, I H), 7.61-7.69 (m, 4H).

Analogously to the preparation of example 52, the following example compounds were prepared from examples 35, 37 and 36 by oxidation:

No. Structure Name Analytical data

'H NMR (400MHz, CDC1 ₃ ): δ =

(±) -7,8-dimethoxy-0.96 (d, 3H), 1.72-1.87 (m, 2H),

N, 4-dimethyl-1 - [3- 1.89-2.05 (m, 2H), 2.92 (d, 3H), (tetrahydro-2H-pyrane-2.93 (dd, IH), 3.14-3.24 (m, 211).

(m, IH), 6.51 (s, IH), 6.55 (q, IH), carboxamid 58 4-ylsulfonyl) phenyl] - 3.36 (tt, 2H), 3.66 (s, 3H), 3.97 (s, 4,5-dihydro-3H-2,3- 3H), 4.03-4.13 (m, 2H), 5.50-5.60 benzodiazepine-3 -

(m, IH), 6.51 (s, IH), 6.55 (q, IH), carboxamide

6.75 (s, IH), 7.65 (t, IH), 7.85 (dt, No. Structure Name Analytical data

 1H), 7.91 (dt, 1H), 7.96 (t, 1H).

LCMS (Method 3): R _t = 0.97 min; m / z = 502 (M + H) ⁺

¹ II NMR (400MHz, CDC1 ₃ ): δ = 0.96 (d, 3H), 1.57-1.73 (m, 2H), 1.75-2.00 (m, 411) .2.02-2.20 (m,

(±) -l- [3- 211) .2.87-2.98 (m, 4H) .3.18 (d,

CH ₃ (cyclopentylsulfonyl) p

 IH), 3.53 (pent, 1H), 3.65 (s, 3H).

^H < _AisSN ^/ henyl] -7,8-dimethoxy-N-CH ₃ 3.96 (s, 3H) .5.49-5.59 (m, 1H),

59 N, 4-dimethyl-4,5-6.51 (s, 1H), 6.51-6.61 (m, 1H), dihydro-3H-2,3-6.74 (s, 1H), 7.62 (t, 1H), 7.80 (dt, o O benzodiazepine-3 - 1H), 7.94 (dt, 1H), 8.01 (t, 1H). carboxamide

LCMS (Method 3): R, = 1.12 min; m / z = 486 (M + H) ⁺

 Ή-NMR (400MHz, CDC1.): Δ = 0.97 (d, 311) .1.45 (s, 9H), 1.57-1.72 (m, 211), 2.03 (dd, 211), 2.60-

(±) -tert-butyl-4 - ({3-2,77 (m, 211), 2.89-2.98 (m, 411), [7,8-dimethoxy-4-3,08 (tt, 1H), 3.18 (dd, lH), 3.66methyl-3- (s, 3H), 3.97 (s, 311) .4.1 -4.34 (m, (methylcarbamoyl) -4,5-

60 211) .5.50-5.60 (m, 1H), 6.51 (s, dihydro-3H-2,3-1H), 6.51-6.60 (m, IH), 6.75 (s, benzodiazepine-1 - 1H), 7.65 ( t, IH), 7.85 (dt, IH), yl] phenyl} sulfonyl) pip

 7.90 (dt, IH), 7.98 (t, IH).

 eridine-1-carboxylate

LCMS (Method 3): R _s = 1.22 min; m / z = 601 (M + H) ⁺ Examples 61.1 and 61.2

(4S) -7,8-dimethoxy-N, 4-dimethyl-l- [4- (S-phenylsulfonimidoyl) phenyl] -4,5-d

benzodiazepine-3-carboxamide (diastereomers 1 and 2)

418 mg (0.875 mmol) (4S)-7,8-Dimethoxy-N,4-dimethyl-l -[4-(phenylsulfmyl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepin-3-carboxamid (Beispiel 39) wurden in 17 ml Dichlormethan unter Argon vorgelegt und 423 mg (1.313 mmol) Diacetoxyiodbenzol [CAS 3240-34-4], 198 mg (1.75 mmol) 2,2,2-Trifluoacetamid, 39 mg (0.088 mmol) Rhodium(II)-acetat Dimer [CAS 15956-28-2] und 141 mg (3.5 mmol) Magnesiumoxid zugegeben. Es wurde für 16h bei RT gerührt. Das Rohgemisch wurde filtriert und vom Lösungsmittel befreit. Man erhielt das gewünschten Zwischenproduktes (4S)-7,8-Dimethoxy-N,4-dimethyl-l-{4-[S-phenyl-N-(trifluoracetyl)sulfonimidoyl]phenyl}-4,5- dihydro-3H-2,3-benzodiazepin-3-carboxamid als Diastereomerengemisch, welches ohne weitere Aufreinigung umgesetzt wurde. 130 mg (0.221 mmol) (4S)-7,8-Dimethoxy-N,4-dimethyl-l -{4-[S- phenyl-N-(trifluoracetyl)sulfonimidoyl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepin-3-carboxamid wurden in 5 ml Methanol vorgelegt und 153 mg (1.1 mmol) Kaliumcarbonat zugegeben. Es wurde für 16h bei RT gerührt. Nach Entfernen des Lösungsmittels wurde der Rückstand mittels präp. RP- HPLC gereinigt. Man erhielt 14 mg (12% d. Th.). des Produktes (Beispiel 61.1, Diastereomer 1) und 14 mg (12% d. Th.) des diastereomeren Produktes (Beispiel 61.2, Diastereomer 2).

418 mg (0.875 mmol) of (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfmyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 39) were initially charged in 17 ml of dichloromethane under argon and 423 mg (1.313 mmol) of diacetoxyiodobenzene [CAS 3240-34-4], 198 mg (1.75 mmol) of 2,2,2-trifluoroacetamide, 39 mg (0.088 mmol) of rhodium (II) acetate Dimer [CAS 15956-28-2] and 141 mg (3.5 mmol) of magnesium oxide added. It was stirred for 16 h at RT. The crude mixture was filtered and freed from the solvent. The desired intermediate (4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4- [S-phenyl-N- (trifluoroacetyl) sulfonimidoyl] phenyl} -4,5-dihydro-3H-2 was obtained , 3-benzodiazepine-3-carboxamide as a mixture of diastereomers, which was reacted without further purification. 130 mg (0.221 mmol) of (4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4- [S-phenyl-N- (trifluoroacetyl) sulfonimidoyl] phenyl} -4,5-dihydro-3H- 2,3-benzodiazepine-3-carboxamide were initially charged in 5 ml of methanol and 153 mg (1.1 mmol) of potassium carbonate were added. It was stirred for 16 h at RT. After removal of the solvent, the residue was purified by prep. RP-HPLC purified. 14 mg (12% of theory) were obtained. of the product (example 61.1, diastereomer 1) and 14 mg (12% of theory) of the diastereomeric product (example 61.2, diastereomer 2).

(4S) -7,8-Dimethoxy-N, 4-dimethyl-1- [4- (S-phenylsulfonimidoyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 61.1) , Diastereomer 1:

LCMS (Method 3): R _t = 1.1 1 min; m / z = 493 (M + H) ⁺

»H-NMR (500 MHz, CDC1 ₃ ): δ = 0.92 (d, 3H), 2.86 (dd, 1H), 2.87 (dd, 311), 3.12 (d, 1H), 3.62 (d, 3H), 3.93 ( d, 3H), 5.44-5.52 (m, 1H), 6.47 (d, 1H), 6.47-6.52 (m, 1H), 6.70 (s, 1H), 7.49-7.59 (m, 5H), 8.04-8.1 1 (m, 4H). (4S) -7,8-dimethoxy-N, 4-dimethyl-l- [4- (S-phenylsulfom

benzodiazepine-3-coxboxamide (Example 61.2), diastereomer 2:

LCMS (Method 4): R _t = 1.16 min; m / z = 493 (M + H) ⁺

Ή-NMR (500MHz, CDC1 ₃ ): δ = 0.94 (d, 3H), 2.86 (dd, 1H), 2.88 (d, 3H), 3.12 (d, 1H), 3.62 (d, 3H), 3.93 (i.e. , 3H), 5.44-5.52 (m, 1H), 6.47 (d, 1H), 6.47-6.52 (m, 1H), 6.70 (s, 1H), 6.46-7.53 (m, 3H). 7.55-7.59 (m, 2H), 7.66-7.72 (m, 4H).

Example 62

(±) -l- [4- (dimethylphosphoryi) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

200 mg (0.463 mmol) of (±) -l- (4-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide were obtained in 4 submitted to DMF and the solution was degassed with argon. 108 mg (0.51 mmol) potassium phosphate, 5 mg (0.023 mmol) palladium (II) acetate, 16 mg (0.028 mmol) (9,9- (dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphine) (CAS [161265-03-8]) and finally 40 mg (0.51 mmol) Dimethylpho sphinoxid.The mixture was again degassed, saturated with argon and then heated for 20 min at 130 ° C in the microwave.The crude product was purified by preparative RP HPLC was obtained to give 90 mg (45% of theory) of the desired product LCMS (Method 3): R _s = 0.75 min, m / z = 430 (M + H) ⁺

Ή NMR (400MHz, CDC1 ₃ ): δ = 0.98 (d, 3H), 1.82 (dd, 611). 2.90 (dd, 1H), 2.92 (d, 311). 3.16 (dd, 1H), 3.66 (s, 3H), 3.96 (s, 3H). 5.47-5.56 (m, 1H), 6.56 (s, 1H), 6.53-6.62 (m, 1H), 6.74 (s, 1H), 7.63 (dd, 2H). 7.78 (dd, 2H). Analogously to Example 62, from (±) -l- (4-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide and the corresponding commercially available

 phosphine

folgende Beispielverbindungen hergestellt:

following example connections are made:

From (5) -l- (4-bromophenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine-3-carboxamide and the corresponding commercially available sulfinates

 following example connections are made:

=

=

(m, IH), (m,

= 3.62 (m, (m, 211).

= 3.63 3H), (d,

min; m / z = 528.1 (M + H) ⁺

Example 73 (¥ i9-7,8-dimethoxy-N, 4-dimethyl-l- [4- (N-me

3H-2,3-benzodiazepine-3-carboxamide

100 mg (0.203 mmol) of (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (S-phenylsulfonimidoyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3 caxboxamide (Example 61.1) were dissolved in 4 ml of DMF and 12.2 mg (0.31 mmol) of sodium hydride and then 43 mg (0.31 mmol) of iodomethane were added. It was stirred for 1 h at RT. The crude mixture was poured onto ice water and washed twice

Extracted dichloromethane. The combined organic phases were concentrated in vacuo. After removal of the solvent, the residue was purified by prep. Purified RP-HPLC. 29 mg (28% of theory) were obtained. of the product (Example 73) as a mixture of diastereomers.

LCMS (Method 3): R = 1.09 min; m / z = 507.2 (M + Fff

»H-NMR (400MHz, CDC1 ₃ ): δ = 0.92 (d, 3H), 2.82-2.90 (m, 7H), 3.12 (d, 1H), 3.61 (d, 3H), 3.93 (s, 3H), 5.44-5.52 (m, 1H), 6.46 (d, 1H), 6.50 (q, 1H), 6.70 (s, 1H), 7.49-7.60 (m, 5H), 7.95-8.02 (m, 4H). Furthermore, in the reaction after separation by prep. RP-HPLC 10 mg (9% of theory). of the product Example 74 are isolated as a mixture of diastereomers. Example 74

(4S) -7,8-dimethoxy-N, N, 4-trimethyl-l- [4- (N-methyl-S-phenylsulfonimidoyl) phenyl] -4

3H-2,3-benzodiazepine-3-carboxamide

IC MS (Methode 3): R_t= 1.10 min; m/z = 521.2 (M+H)

IC MS (Method 3): R _t = 1.10 min; m / z = 521.2 (M + H)

»H-NMR (400MHz, CDC1 ₃ ): δ = 1.15 (d, 3H), 2.60 (dd, 1H), 2.82 (s, 6H), 2.86 (d, 3H) .2.96 (dd, 1H), 3.70 ( s, 3H), 3.95 (s, 3H), 4.95-5.05 (m, 1H), 6.47 (s, 1H), 6.79 (s, 1H), 7.46-7.58 (m, 3H), 7.76 (d, 2H) .7.98 (m, 4H).

Bioiogical activity of the compounds of the invention

Protein-protein proteins: Assay for binding 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 (i) 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. The recombinant BRD4 (1) protein produced in house by Filippakopoulos et al., Cell, 2012, 149: 214-231 was expressed in E. coli and purified by (Ni-NTA) affinity and (Sephadex G-75)

 Size exclusion chromatography purified. The Ac-H4 peptide may be derived from e.g. Biosyntan (Berlin, Germany).

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 μΜ, 0.51 μΜ, 1.7 μΜ, 5.9 μΜ and 20 μΜ) were measured as duplicates on the same microtiter plate. For this purpose, 100-fold concentrated solutions in DM SO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Grein er Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany). The test was started by the addition of 2 μΐ of a 2.5-fold concentrated BRD4 (1) solution (usually 10 nM final concentration in the 5 μΐ of the reaction volume) in aqueous

Assay buffer [50 mM HEPES pH 7.5, 50 mM sodium chloride (NaCl), 0.25 mM CT I APS and 0.05% serum albumin (BSA)] to the substances in the assay plate. This was followed by a 10 minute incubation step at 22 ° C for the pre-equilibration of putative complexes between BRD4 (i) and the substances. Subsequently, 3 μΐ 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) and 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 were determined by measuring the resonance energy transfer from the

Streptavidin-Eu-cryptate to the anti-6His-XL665 antibody in the reaction. The fluorescence emission at 620 nm and 665 nm after excitation at 330-350 nm in a TR-FRET meter, e.g. a Rubystar or Pherastar (both from BMG Lab Technologies, Offenburg, 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-114 complex 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 DM SO (100%) were used. 100% inhibition was the mean of the measurements from a set of controls (typically 32 data points) containing all reagents except BRD4 (1). The IC value was determined by regression analysis based on a 4-parameter equation (minimum, maximum, IC ₅₀ , Hill, Y = Max + (Min-Max) / (1 +

(X / IC ₅ o) Hill).

2. Assay Description BRD4-Bromodomänc 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. The recombinant BRD4 (2) protein produced in house by Filippakopoulos et al., Cell, 2012, 149: 214-231 was expressed in E. coli and purified by (Ni-NTA) affinity and (Sephadex G-75) size exclusion chromatography. The Ac-H4 peptide may be derived from e.g. Biosyntan (Berlin, Germany).

The assay typically involved 11 different concentra tions of each substance (0.1 nM, 0.33 ιιΜ, 1.1 iiM, 3.8 nM, 13 nM, 44 nM, 0.15 μΜ, 0.51 μΜ, 1.7 μΜ, 5.9 μΜ and 20 μΜ) as duplicates on the same microtiter Plate measured. For this purpose, 100-fold concentrated solutions in DM SO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Grein er Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany). The test was started by the addition of 2 μΐ of a 2.5-fold concentrated BRD4 (2) solution (usually 100 nM final concentration in the 5 μΐ 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 m CHAPS and 0.05% serum albumin (BSA)] to the substances in the test plate. This was followed by a 10 minute incubation at 22 ° C for the pre-equilibration of putative

Complexes between BRD4 (2) and the substances. Subsequently, 3 μΐ of a 1.67-fold concentrated solution (in the assay buffer) consisting of Ac-H4 peptide (83.5 nM) and TR-FR ET detection reagents [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 were determined by measuring the resonance energy transfer from the

Streptavidin-Eu-chelate to the anti-6His-XL665 antibody in the reaction. For this, the fluorescence emission at 620 nm and 665 nm after excitation at 330-350 nm in a TR-FR ET meter, e.g. 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) / AcH4 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 DM SO (100%) were used. Inhibition of 100% o corresponded to the mean of the readings of a set of controls (typically 32 data points) containing all reagents except BRD4 (2). The determination of the IC50 value was carried out by regression analysis on the basis of a 4-parameter equation (minimum, maximum, _IC50, Hill; Y = Max + (Min - Max) / (1 +

(X / IC ₅₀ ) Hill)). 3. Zeli Assay Cell Proliferation Assay

In accordance with the invention, the ability of the substances to inhibit cell proliferation was determined. Cell viability was determined using the alamarBlue® reagent (In vi trogen) in a Victor X3 Multilabel Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelength was 590 nM.

 The 5637 cells (ATCC HTB-9) were seeded to a concentration of 1000 cells / well in 30 μl growth medium (RPM 114040.10% FCS, Pen / Strep) on 384 well microtiter plates. The C4-2B cells (Chen et al., J. Biol. Chem., 1998, 273: 17618-17625) were added to a concentration of 4000 cells / well in ΙΟΟμΙ growth medium (RPM 114040 and glutamine, 10% FCS ) seeded on 96well microtiter plates.

The Caki-2 cells (ATCC HTB-47) were seeded to a concentration of 1000 cells / well in 30μl growth medium (DMEM / Ham ^'s F12 and glutamine, 10% FCS. Pen / Strep) on 384 well microtiter plates.

 The CCRF-CEM cells (ATCC CCL-1 19) were seeded to a concentration of 16,000 cells / well in Ι ΟΟμΙ growth medium (DM EM and glutamine, 10% FCS) on 96 well microtiter plates.

The CH I.-! Cells (ATCC CR 1.-9446) were seeded to a concentration of 1000 cells / well in Ι ΟΟμΙ growth medium (DM EM and glutamine, 10% FCS) on 96-well microtiter plates.

The DU-145 cells (ATCC HTB-81) were seeded to a concentration of 1000 cells / well in 30μl growth medium (DMEM / ham ^'s and glutamine, 10% FC S, Pen / Strep) on 384 well microtiter plates.

 The HB1-1 cells (Nozawa et al., Tohoku .1 Exp. Med., 1988, 156: 319-330) were added to a concentration of 1000 cells / well in 30 μl growth medium (RPM II 640 and glutamine , 10% FCS. Pen / Strep) seeded on 96well microtiter plates.

The J82 cells (ATCC HTB-1) were seeded to a concentration of 1000 cells / well in 30μl growth medium (M EM Earle ^'s medium and glutamine, 10% FCS. Pen / Strep) on 384 well microtiter plates.

The JEG-3 cells (ATCC HTB-36) were seeded to a concentration of 1000 cells / well in 30 μl growth medium (DMEM / Ham ^'s F 1 2 and glutamine, 10% FCS. Pen / Strep) on 384 well microtiter plates.

The MV4-1 1 cells (ATCC CRL-9591) were grown to a concentration of 1000 cells / well in 30μl growth medium (Iscove ^'s MDM medium and glutamine, 10% FCS, Pen / Strep) Seeded 384well microtiter plates.

 The NCI-H292 cells (ATCC CRL-1848) were seeded to a concentration of 2000 cells / well in ΙΟΟμΙ growth medium (RPMI1640 and glutamine, 10% FCS) on 96-well microtiter plates.

The NCI-H520 cells (ATCC HTB 182) were seeded to a concentration of 2000 cells / well in 30 μl growth medium (RPMI 1640.120% FCS) on 384 well microtiter plates.

The OVCAR3 cells (ATCC HTB-161) were seeded to 384well microtiter plates to a concentration of 3000 cells / well in 30 μl growth medium (RPMI1640, 20% FCS, 10 μg / ml insulin).

The RD cells (ATCC CCL-136) were seeded to a concentration of 2000 cells / well in 30 μl growth medium (DMEM and glutamine, 10% FCS) on 384 well microtiter plates. The SK-MEL-3 cells (ATCC HTB-69) were added to a concentration of 1000 cells / well in 30μl growth medium (McCoy's 5A medium and glutamine, 10% FCS) at 384well

Seeded microtiter plates.

The TMD-8 cells (Tohada et al., Leuk. Res., 2006, 30: 1385-1390) became one

 Concentration of 2000 cells / well seeded in ΙΟΟμΙ growth medium (RPMI1640 and glutamine, 10% FCS) on 96well microtiter plates.

 The VCaP cells (ATCC CRL-2976) were seeded to a concentration of 16,000 cells / well in ΙΟΟμΙ growth medium (DMEM and glutamine, 10% FCS) on 96 well microtiter plates.

After an overnight incubation at 37 ° C., the fluorescence values were determined (CI values). After an overnight incubation at 37 ° C., the fluorescence values were determined (CI values). The plates were then treated with various dilutions of the substance (1E-5M, 3E-6M, 1E-6M, 3E-7M, 1E-7M, 3E-8M, 1E-8M) and during 72 (5637, Caki-2, CCRF-CEM, DU-145, HBL-1, J82, JEG-3, NCI-H520, MV4-I 1, OVCAR3, RD-, SK-MEL-3 Cells), 96 (CHL-1 - NCI-H292, TMD-8 cells) or 168 C4-2B-, VCaP cells) for 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 ICio values (substance concentration necessary for a 50% inhibition of cell proliferation) were calculated therefrom. The above protocol uses the cell lines of Table 1, which exemplify the indicated indications.

Table 1 :

 Cell line source indication

 5637 ATCC bladder carcinoma

 Chen et al., J. Biol. Chem., 1998,

 C4-2B prostate carcinoma

 273: 17618-17625

 Caki-2 ATCC carcinoma

CCRF-CEM ATCC Lymphoblastic leukemia

CHL-1 ATCC melanoma

 DU-145 ATCC prostate carcinoma

 Nozawa et al., Tohoku J. Exp.

 HBL-1 B-cell lymphoma

 Med., 1988, 156: 319-330

 J82 ATCC bladder cancer

JEG-3 ATCC choriocarcinoma

MV4-11 ATCC Acute myeloid leukemia

NCI-H292 ATCC lung carcinoma

NCI-H520 ATCC lung carcinoma

OVCAR3 ATCC ovarian carcinoma

RD ATCC rhabdomyosarcoma

SK-MEL-3 ATCC melanoma

 Tohada et al., Leuk. Res., 2006,

 TMD-8 B-cell lymphoma

 30: 1385-1390

VCaP ATCC prostate cancer

4. Results: 4.1 binding assay

Table 2 shows the results from the BRD4 (1) and BRD4 (2) binding assay.

Table 2:

Example ICso | BRD4 (1) 1 (nmol / 1) ICso | BRD4 (2) | (Nmol /!)

1 90 900

 2 30 500

 3 10 340

 4 90 1760

5 50 640

 6 10 40

 7 10 170

 8 30 200

 9 10 70

 10 10 130

 11 300 141 0

 12 340 1 540

 13 1 130 421 0

 14 1020 3450

 14.1 3570> 20000

 14.2 350 1050

 15,380 1,300

 16 270 700

 17 580 3310

 18 240 1600

 18.1 110 1 130

 18.2 4570> 20000

 19 170 1070

20 230 1740 Step Example! ICso | B D4 (1) | (nmol / l) ICso | BRD4 (2) | (Nmol / l)

21 320 1710

 22 200 540

 23 240 90

 24 82 270

 25 150 300

 26 30 190

 27 50 270

 28 100 520

 29 20 90

 30 6230> 20000

31 260 1 520

 32 340 1460

 33 380 321 0

 34,130,500

 35 240 1230

 36 970 3300

 37 470 2200

 38 60 680

 39 40 320

 40 30 250

 41 50 540

 42 10 130

 43.1 260 1 240

 43.2 280 1340

 44 20 140

 45 10 230

 46 4050> 20000

 47 690 2050

 48 590 670

 49 130 640

50 440 2190 Step Example! ICso | BR 4 (1) | (nmol / l) ICso | BRD4 (2) | (Nmol / l)

51 1930 11300

52 10 190

 53 20 450

 54 70 320

 55 1910 17900

56 200 1040

 57 330 1 180

 58 1320 1950

 59 520 780

 60 2830 10500

61.1 10 70

 61.2 10 90

 62 100 600

 63 140 980

 64 30 330

 65 30 280

 66 20 160

 67 30 100

 68 30 300

 69 30 300

 70 40 260

 71 10 40

 72 40 240

 73 20 270

74 1480 5670 4.2 proliferation assay

Table 3 shows the results of proliferation assay in CHL-1, HBL-1, J82, NCI-H292 and TMD-8 cells.

Table 3:

Step Example! ICso [CHL-1] ICso [HBL-1] ICso [J82] ICso [NCI-ICso [TMD-8]

 (nmol / l) (nmol / l) (nmol / l) H292] (nmol / l) (nmol / l)

1 1 1 10 1970> 10000> 10000 1 270

2 640 990> 10000> 10000 810

3 220 280 6540> 60000 200

4 2020 2380> 7400> 10000 3240

5 500 890 5760> 6500 590

6 60 30 1280 1640 50

7 1 10 190 1 160 3340 1 40

8 200 140 1 150 3600 280

9 50 80 1830 3040 60

10> 10000> 10000> 10000> 10000> 10000

11 4620> 6800> 10000> 10000 6000

12 5250> 6100> 10000> 10000 6190

13 7170> 6500

 14 4330 2300

 14.1> 10000> 5200

 14.2 1 130 1080> 7000> 7000 1 750

15> 4000 1570> 10000> 10000 3420

16 2200 3250> 10000> 10000 3220

17 3910 6930> 10000> 10000 5660

18 3800 1600> 10000> 10000 4260

18.1 2930 2 1 50> 10000> 10000 4760

18.2> 10000> 10000

 19> 10000> 10000> 10000> 10000> 10000

20 2140 3280> 10000> 10000 3060

21 2320 4440>10000> 10000 3 130 Example ICso [CHL-1] ICso [HBL-1] ICso | J82 | ICso | NCI-ICso [TMD-8] (nmol / 1) (nmol / l) (nmol /!) H292 | (nmol / l) (nmol / l)

22 420 520 2440> 10000 670

23 1 100 1 150 840 1720 770

24 190 380> 6500> 7500 270

25 900 390> 60000> 60000 1 240

26 180 170 1360 4690 330

27 320 370 29 10> 10000 390

28 300 400 1740> 6000 390

29 100 90 460 1 170 1 10

30> 10000> 10000

 31 2080 2870> 7000> 10000 2900

32 3310 2360 8700> 1000 4200

33 1610> 6500> 10000> 10000 2430

34 640 620> 6000> 10000 620

35 1850 2950> 10000> 10000 3290

36 5090 6220 91 50> 10000 7800

37 4770 2290> 10000> 10000 5260

38 1 190 1 170> 6500> 10000 1330

39 220> 3400 5400> 10000 230

40 360 380 53 10> 6000 550

41 920 1 170 8250> 6500 1 240

42 180 180> 5500> 10000 1 50

43.1 1000 740 5660> 6000 1490

43.2 1370 920 8240> 10000 2 1 30

44 270 390 5000> 7000 380

45 780 690> 10000> 10000 970

46> 10000> 10000

 47> 6500 5050> 10000> 10000 4250

48 1520 1680> 10000> 10000 1730

49 1060 1010> 10000> 10000 1080

50 3720 2360>10000> 10000 4430 Example ICso [CHL-1] ICso [HBL-1] ICso [J82] ICso | NCI-ICso [TMD-8] (nmol / l) (nmol / l) (nmol / l) H2 2 | (nmol / l) (nmol / l)

51> 10000> 7000

 52 470 760 5760 5540 690

53 360 490 4750> 6500 600

54> 6500> 10000> 10000> 10000> 10000

55> 5500 1990

 56 1200 620> 10000> 10000 1400

57 1510 141 0> 10000> 7000 1290

58> 7000> 6000> 10000> 10000 7540

59 3490 1 740> 10000> 10000 5490

60> 10000> 7000

 61.1 210 450 3330> 6500 210

61.2 380 660 55 10> 10000 360

62 2520 6340

 63 1710 1490

 64 510 510

 65 490

 66 160

 67,200

 72,330

Table 4 shows the results of proliferation assay in C4-2B, MV4-11, DU-145 and 5637 cells.

table

Step Example! ICso [C4-2B] ICso 1 MV 4-1 11 ICso [DU-145] ICso [5637]

 (nmol / l) (nmol / l) (nmol / l) (nmol / l)

1 2380 780

 3 360 90 4860 2200

 5 1280 320

6 200 30> 5500 640 Example ICso IC4-2B] ICso [MV4-11] ICso [DU-145] ICso [5637] (nmol / l) (nmol / l) (nmol / l) (nmol / l)

7 1950 1 190

9 240 290> 5500 1000

10> 10000> 10000

18 4610 1380

 20> 10000

 25 1400> 6500

 28 430 150

 31> 10000> 9000

37 9220 1730

 38 2510 490

 39 400 1 10

 45 1860 480

 52 900 270

 65 5080 1700

66 1750 590

 67 1230 720

72 1830 600

Table 5 shows the results of proliferation assay in Caki-2, CCRF-CEM, JEG-3 and

NCI-H520 cells.

 Table 5:

Example ICso | Caki-2 | ICso [CCRF-CEM] ICso [JEG-3] ICso [NCI-H520]

 (nmol / l) (nmol / l) (nmol / l) (nmol / i)

3> 6500 770 8510 2380

6> 4000 220> 3900 350

7 45 1 0 530 3330 1060

9> 5500 700 5050 890

10> 10000> 10000> 10000> 10000

31> 6000 4950> 10000> 10000

65> 7400 Example ICso [aki-21 ICso [CCRF-CEM] ICso [JEG-3] ICso [NCI-H520] (nmol / l) (nmol / l) (nmol / l) (nmol / l)

66 2630

 67 2820

 72 2270

Table 6 shows the results of proliferation assay in OVCAR3, RD, SK-MEL-3 and

VCAP cells.

 Table 6:

Step Example! ICso [OVCAR3] ICso [RD] (nmol I) ICso [SK-MEL-3] ICso | V CaP |

 (nmol / l) (nmol l) (nmol / l)

1 1050

3 4770 940 1 440 160

5 570

6 2050 190 370 60

7 4750 520 770

 9 5310 430 580 70

10> 10000 8000 8000

 18 2940

25,840

28 250

31> 10000 5440 1 1200

 37 3830

38 980

39 180

45 750

52,450

65 1760

 66,760

 67,810

 72 1040

Claims

 claims 1 . Compounds of the general formula (I)

in which for a group]

 in which "*" in each case denotes the point of attachment to the rest of the molecule, stands for C 1 -C 3 -alkyl-, trifluoromethyl- or C 3 -C 4 -cycloalkyl-, for cyclopropyl-, C 1 -C 5 -alkyl-, C 1 -C 3 -alkyl Alkoxy, amino,  Cyclopropylamino- or Ci-Cs-alkylamino stands, independently of one another  for hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluoro, Chlorine or bromine,  or for C ₁ -C 6 -alkyl, C ₁ -C 6 -alkoxy, C ₁ -C 6 -alkylamino, phenylamino, C ₁ -C 6 -alkylcarbonylamino, C ₁ -C 6 -alkylaminocarbonyl or Ci-Ce-Alkylaminosulfonyl-, which are unsubstituted or mono-, di- or trisubstituted by identical or different substituents, with halogen, amino, hydroxy, carboxy, Ci-Cö-alkyl, hydroxy-C i -Ce-alkyl- , Ci-Cö-alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl-,

-NH-S (= O): - R "or monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted by C1-C3-alkyl-, or for C ₃ -C 10 -cycloalkyl- or C 4 -C 10 -cycloalkenyl, which are unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, carboxy, C ₁ -C 6 -alkyl -, O-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkylamino, amino-Ci-C6-alkyl, C 1 -Ce-alkylamino-C 1 -C ₆ Alkyl, halo-C ₁ -C ₆ -alkyl, ^Halo- C ¹ -C ^{6 -alkoxy} , -C (OO) -NR ⁹ R ⁱ⁰ , -C (= O) -R ⁿ , -S (= O) ₂ -NR ⁹ R ⁱ⁰ , -S (= 0) -R ^H , -S (= O) ₂ -R ", -NH-S (= O) ₂ -R ^u or monocyclic Heterocyclyl having 4 to 8 ring atoms, or for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, nitro, carboxy, C 1 -C 6 -alkyl-, Ce-alkoxy, C 1 -C 6 -alkoxy-C 1 -C -alkyl-, Hydroxy-O-Ce-alkyl, Ci-Ce-alkylamino, amino-Ci-C6-alkyl, C 1 -Ce-alkylamino-C 1 -C ₆ -alkyl, halogen-C iC ₆ -alkyl-, Halo-d-Ce-alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -S (= O) ₂ -NR ⁹ R ¹⁰ , -S (= 0) -R ⁿ , -S (= O) ₂ -R ", -NH-S (= O) ₂ -R ⁿ , C ₃ -Cio -cycloalkyl- or monocyclic heterocyclyl- having 4 to 8 ring atoms, or for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, oxo, carboxy, C 1 -C 6 -alkyl-, Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, C1-C6-alkylamino, amino-C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl-hydroxy-C1-C6-alkyl, halogeno-C 1 - (, - Alkyl, halogen-C 1 -C 6 -alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -S (= O) ₂ -NR ⁹ R ¹⁰ , -S (= 0) -R ", -S (= O) ₂ -R", -NH-S (= O) ₂ -R ⁿ , C ₃ -C 10 -cycloalkyl- or monocyclic heterocyclyl- having 4 to 8 ring atoms, or phenyl, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, nitro, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 4 -alkyl -C 1 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylaminosulfonyl, C 1 -Ce -Alkylamino-C i -Ce-alkyl, Hydroxy-C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, halogen-C 1 -C 4 -alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -S (= O) ₂ -NR ⁹ R ¹⁰ , -S (= O) -R », -S (= O) ₂ -R",

C 3 -C 10 -cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms, for a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ' ² , -S (= 0) (= NR ¹³ ) R ¹² or -P (= O) (R ^{! 4} ) R ^{! 5} is, independently of one another, hydrogen, halogen, hydroxy, cyano, nitro or C ₁ -C ₆ -alkyl-, C ₁ -C ₄ -alkyl-, Alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₄ -alkoxy, G-C ₆ -alkylsulfonyl, C 3 -C 10 -cycloalkyl or monocyclic heterocyclyl of 4 to 8 Ring atoms are, independently of one another, hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxyl, oxo or C ₁ -C ₃ -alkoxy-substituted GG-alkyl- or fluorine-GG-alkyl-, or together with the nitrogen atom to which they are attached are monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, G-C3-alkyl - Fluoro-C ₁ -C ₃ -alkyl, C ₃ -C 6 -cycloalkyl, cyclopropylmethyl, C 1 -C ₃ -alkylcarbonyl or G-C4-alkoxycarbonyl, for hydroxy, G -C -alkyl, G-Ce-alkoxy, halo-C 1 -C ₃ -alkyl, hydroxy-C 1 -C 8 -alkyl -, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl- or Cs-Go cycloalkyl stands, or for phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents, are substituted by halogen, C 1 -C 3 -alkoxy- or C 1 -C 3 -alkyl-, for C 1 -C 6 -alkyl- which is unsubstituted or monosubstituted with cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl-, Cs-Cs-cycloalkyl-, or with monocyclic heterocyclyl- having 4 to 8 ring atoms, wherein phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents from Ci-C with halo, cyano, ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ -Alkinyi- .  C 1 -C 4 alkoxy, halo C 1 -C 4 alkyl or halo C 1 -C 4 alkoxy, and wherein C3-Cs-cycloalkyl and monocyclic heterocyclyl having 4 to 8 ring atoms in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C ₃ alkyl, or represents halogeno-C 1 -C 4 -alkyl-, or is C3-Cs-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with G-Cs-alkyl or C1-C4-alkoxycarbonyl, with the proviso in that the monocyclic heterocyclyl having 4 to 8 ring atoms is not bonded via a nitrogen atom to the sulfanyl, sulfmyl, sulfonyl or sulfoximino group in R ", or represents phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, GC ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, trifluoromethoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -N (R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ -NR ⁹ R ¹⁰ or NR 'R ¹⁰ , with the proviso that the monocyclic heteroaryl having 5 or 6 ring atoms does not have a nitrogen atom to the sulfanyl, sulfmyl, sulfonyl or sulfoximino Group is bound in R " is hydrogen, cyano, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl or -C (= O) OR ^: R ¹⁴ and R ¹⁵ independently of one another are C ₁ -C ₃ -alkyl-, phenyl-C ₁ -C ₃ -alkyl-, Fluoro-C ₁ -C ₃ -alkyl or phenyl,  in which phenyl and the phenyl-C 1 -C 3 -alkyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, Trifluoromethyl or trifluoromethoxy,  or R ¹⁴ and R ¹⁵ together represent C 2 -C 8 -alkylene, and R ^{16 is} C ₁ -C 6 -alkyl or phenyl-C ₁ -C ₃ -alkyl, and also their polymorphs, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically tolerated salts and solvates of these salts. Compounds of general formula (I), according to claim 1, in R ¹ for a group

 stands,  where "*" is the point of attachment to the rest of the molecule, R - is methyl, R is cyclopropyl, Ci-Cs-alkyl, cyclopropylamino or  C 1 -C 3 -alkylamino stands, R ⁴ and R ^{3 are} independently for hydrogen, hydroxy, cyano, amino, aminocarbonyl, fluorine, chlorine or bromine, or for C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, phenylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulfonyl, which are unsubstituted or mono-, di- or trisubstituted by identical or different substituents, are substituted by halogen, amino, hydroxyl, carboxy, C ₁ -C ₃ -alkyl-, hydroxy-C ₁ -C ₃ - Alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C 1 -C ₃ -alkyl, C ₁ -C ₃ -alkylamino, amino-C 1 -C ₃ -alkyl, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or ^{monosubstituted by} C ¹ -C ₃ - alkyl, or for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, amino, hydroxyl, cyano, carboxy, C ₁ -C ₃ -alkyl, C 1 -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C 1 -C ₃ -alkyl, Hydroxy-C 1 -C ₃ -alkyl, C 1 -C ₃ -alkylamino, amino-C ₁ -C ₃ -alkyl, fluoro-dC ₃ -alkyl, fluoro-C 1 -C ₃ -alkoxy, -C (= 0) -NR ⁹ R ¹⁰ , -C (= O) -R "or monocylyl heterocyclyl- with 4 to 8 ring atoms, or for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents, with halogen, amino, hydroxy, cyano, oxo, carboxy, Ci-C ₃ alkyl, Ci -C ₃ alkoxy, C i -C ₃ alkoxy-C i -C ₃ alkyl, C i -C ₃ alkylamino, amino C i -C ₃ alkyl, C i -C ₃ alkylamino C i -C ₃ -alkyl, hydroxy-C i -C ₃ alkyl, fluoro C 1 -C ₃ -alkyl, fluoro-C 1 -C ₃ -alkoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ or monocyclic heterocyclyl having 4 to 8 ring atoms , for a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ¹³ ) R ¹² or -P (= 0) (R ¹⁴ ) R ¹⁵ is hydrogen, fluorine, chlorine, bromine, hydroxy, cyano or for C ₁ -C ₃ -alkyl, C 1 -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C 1 -C ₃ -alkyl, Fluoro-C ₁ -C ₃ -alkyl, fluoro-C 1 -C ₃ -alkoxy or C 1 -C ₃ -alkylsulfonyl-, independently of one another for hydrogen, C 1 -C 3 -alkyl-, acetyl-, Propionyl or fluoro-C 1 -C 3 -alkyl, or together with the nitrogen atom to which they are attached, represent monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono- or disubstituted by identical or different substituents with fluorine, oxo, cyano, C ₁ -C ₃ -alkyl- , C ₃ -C 6 -cycloalkyl, C ₁ -C ₃ -alkylcarbonyl or G-Czj-alkoxyearbonyi, for hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₄ -alkoxy, fluoro-C ₁ -C ₃ - alkyl, Hydroxy-Ci-C ₃ alkyl, Ci-C ₃ alkoxy-Ci-C ₃ alkyl or C ₃ -C ₇ cycloalkyl, or represents phenyl, monocyclic heterocyclyl having 4 to 8 ring atoms or monocyclic heteroaryl having 5 or 6 ring atoms, which in turn are unsubstituted or mono- or disubstituted, identical or different, are substituted by halogen, Ci-C ₃ alkoxy or Ci-C ₃ alkyl, is C Ce-alkyl, which is unsubstituted or is monosubstituted by cyano, Ci-C ₃ alkoxy, C 1 -C ₃ alkylamino, phenyl, C ₃ - Cs-cycloalkyl or with monocyclic heterocyclyl having 4 to 8 ring atoms, in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, fluoro-C ₁ -C ₃ -alkyl- or fluoro-Ci-C ₃ - alkoxy, and wherein C ₃ -Cs-Cycloalkyi- and monocyclic Heterocyclyl- with 4 to 8 ring atoms in turn are unsubstituted or mono- or disubstituted by identical or different substituents with Ci-C ₃ alkyl, or represents fluoro-C ₁ -C ₃ -alkyl, or represents C ₃ -Cs-cycloalkyl or monocyclic heterocyclyl having 4 to 8 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with GC ₃ alkyl or C 1 -C 4 alkoxy carbonyl, with the proviso that the monocyclic Heterocyclyl having 4 to 8 ring atoms is not bonded via a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino group in R ',  or  represents phenyl or monocyclic heteroaryl having 5 or 6 ring atoms which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl-, C ₁ -C ₃ alkoxy, trifluoromethyl, trifluoromethoxy, -C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -N (R ⁹ ) C (= ^O ) -R ⁱ⁶ , -S (= O) ₂ -NR ⁹ R ¹⁰ or NR 'R ⁱ⁰ , with the proviso that the monocyclic heteroaryl having 5 or 6 ring atoms does not have a nitrogen atom to the sulfanyl, sulfinyl, sulfonyl or sulfoximino Group in R "is hydrogen, cyano, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl or -C (= O) OR ¹⁶ , independently of one another represents C ₁ -C ₃ -alkyl-, phenyl -C iC ₃ alkyl,  Fluoro-Ci-Cs-alkyl or phenyl, in which phenyl and the phenyl-C ₁ -C ₃ -alkyl- contained phenyl- in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, Ci-C3-alkyl, Ci-Cs-alkoxy , Trifluoromethyl or trifluoromethoxy,  or together represent C 2 -C 5 -alkylene and C 1 -C 3 -alkyl or benzyl, and their polymorphs, enantiomers, diastereomers, stereoisomer mixtures, tautomers, solvates, physiologically tolerated salts and solvates of these salts. Compounds of the general formula (I) according to Claims 1 and 2, in R ¹ for a group

 each point of attachment to the rest of the molecule R is methyl, R ^{3 is} C ¹ -C 8 -alkylamino, R ⁴ and R ^{5 are} independently  for hydrogen, hydroxy, cyano, fluorine, chlorine or bromine, or for C iC ₃ alkyl, GC ₃ alkoxy or Ci-C ₃ alkylamino, or  for monocyclic heteroaryl having 5 or 6 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by halogen, Ci-Cs-alkyl or Ci-C3-alkoxy, or for monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or mono-, di- or trisubstituted, identically or differently, by fluorine, oxo, G-Cs-alkyl-, G-C3-alkoxy-, C1-C3 Alkylamino or -C (= O) -R ⁿ , R ^{6 represents} a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ^{! 3} ) R ¹² or -P (= 0) (R ¹⁴ ) R ¹⁵ , R is hydrogen, fluorine, G-Cs-alkoxy- or C 1 -C 3 -alkylsulfonyl-, R ⁹ and R ⁱ⁰ independently of one another represent hydrogen, methyl, ethyl or acetyl, or together with the nitrogen atom to which they are attached are monocyclic heterocyclyl having 4 to 8 ring atoms, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, oxo, methyl, ethyl, cyclopropyl, Acetyl or feri-butoxycarbonyl, for hydroxy, Ci-C ₃ alkyl or Ci-C alkoxy, is Ci-Cö-alkyl-, which is unsubstituted or monosubstituted with Ci-C3-alkylamino -, phenyl- or monocyclic heterocyclyl- with 4 to 7 ring atoms, in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy-, trifluoromethyl- or trifluoromethoxy- , and  wherein the monocyclic heterocyclyl having 4 to 7 ring atoms in turn is unsubstituted or monosubstituted by methyl, or represents trifluoromethyl-, or is C3-C6-cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms, which are unsubstituted or monosubstituted with Ci-Cs-alkyl or Ci-C4-alkoxycarbonyl, with the proviso that the monocyclic heterocyclyl with 4 to 7 ring atoms are not bonded via a nitrogen atom to the sulfanyl, sulfmyl, sulfonyl or sulfoximino group in R ', or is phenyl, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, O-Cs-alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, trifluoromethoxy, - C (= O) -NR ⁹ R ¹⁰ , -C (= O) -R ⁿ , -N (R ⁹ ) C (= O) -R ¹⁶ , -S (= O) ₂ -NR ⁹ R ¹⁰ or NR 'R ^{! 0} , is hydrogen, cyano, Ci-C ₃ alkyl or -C (= 0) OR ¹⁶ , independently of one another for Ci-Cs-alkyl, Ben / vi-, trifluoromethyl or for phenyl,  in which phenyl and the benzyl-containing phenyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, C 1 -C 2 -alkyl-, C 1 -C 2 -alkoxy-, trifluoromethyl- or trifluoromethoxy, and R ¹⁶ is d-Cj-alkyl-, as well as their Polymoφhe, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which represented by the bonded to R ² carbon atom Asymmetriezentrum (^ -konfiguriert, as well as their stereoisomeric mixtures in which predominate those stereoisomers in which the bound by the R ² Carbon atom represented center of asymmetry (^ -configured. Compounds of the general formula (I) according to Claims 1 to 3, in which R ¹ for a group

 stands,  where "*" is the point of attachment to the rest of the molecule, R - is methyl, R ^{3 is} methylamino or dimethylamino, R ^{4 is} methoxy, R ^{5 is} methoxy, R 'represents a group -SR ¹² , -S (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ¹³ ) R ¹² or -P (= O) (R ¹⁴ ) R ¹⁵ is hydrogen, fluorine, methoxy- or methylsulfonyl-, independently of one another represent hydrogen, methyl or ethyl, or together with the nitrogen atom to which they are attached are monocyclic heterocyclyl having 5 to 7 ring atoms which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, methyl or ethyl, for hydroxy, methyl Is ethyl, methoxy or ethoxy, is C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by phenyl,  wherein phenyl is in turn unsubstituted or monosubstituted by fluorine, chlorine, cyano, methyl, methoxy or trifluoromethyl, or represents trifluoromethyl-, or is C3-C6 cycloalkyl or monocyclic heterocyclyl having 4 to 7 ring atoms which are unsubstituted or monosubstituted with methyl or tert-butoxycarbonyl, with the proviso that the monocyclic heterocyclyl having 4 to 7 ring atoms not over a nitrogen atom is bonded to the sulfanyl, sulfmyl, sulfonyl or sulfoximino group in R ', or is phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, methyl, methoxy, trifluoromethyl, -C (= O) -R ", -N ( R ⁹ ) C (= 0) -R ¹⁶ , -S (= 0) ₂ -NR ⁹ R ¹⁰ or NR 'R ^{! U} , is hydrogen, cyano, methyl or -C (= O) OR ¹⁶ , independently of one another are methyl, ethyl or phenyl, in which phenyl is in turn unsubstituted or monosubstituted with Fluorine, chlorine, methyl, methoxy or trifluoromethyl, and R ^{16 is} methyl, as well as their polymorphs, tautomers, solvates, physiologically acceptable salts and Solvates of these salts, as well as their racemates, as well as their enantiomers and diastereomers, in which the represented by the bonded to R ² carbon atom Asymmetriezentrum (^ -konfiguriert, as well as their stereoisomeric mixtures in which predominate those stereoisomers in which the bound by the R ²  Carbon atom represented center of asymmetry (^ -configured. 5. Compounds of general formula (I), according to claims 1 to 4, in the R ¹ for a group

 stands, in which "*" in each case denotes the point of attachment to the remainder of the molecule, is methyl, represents methylamino- or dimethylamino-, stands for methoxy, stands for methoxy, for a group -SR ¹² , -S (= 0) R ¹² , -S (= O) ₂ R ¹² , -S (= O) (= NR ¹³ ) R ¹² or -P (= O) (R ¹⁴ ) R ¹⁵ , R ^{7 is} hydrogen, fluorine or methylsulfonyl-, R ^{! :} For methyl, ethyl, benzyl, cyclopropyl, cyclopentyl, phenyl or a group

 stands, in which "*" in each case denotes the point of attachment to the remainder of the molecule, represents hydrogen or methyl, and independently of one another represents methyl, ethyl or phenyl, and their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, as well as their enantiomers and diastereomers, in which the represented by the carbon atom bonded to R represents asymmetric center

is, as well as their stereoisomeric mixtures in which predominate those stereoisomers in which bound by the bound to R Carbon atom represented center of asymmetry (^ -configured. Compounds of the general formula (I) according to Claims 1 to 5, in which R ¹ for a group

-214-

-216-

-217-

where "*" is the point of attachment to the rest of the molecule means R ^{2 is} methyl, R ^{3 is} methylamino, R ^{4 is} methoxy, and R ^{5 is} methoxy-, as well as their polymorphs, tautomers, solvates, physiologically acceptable salts and solvates of these salts, and their racemates, and their enantiomers and diastereomers, in which represented by the bound to R ² carbon atom asymmetric center

is, as well as their stereoisomeric mixtures in which predominate those stereoisomers in which bound by the bound to R ²  Carbon atom represented center of asymmetry (^ -configured. 7. Compounds of the general formula (I) according to Claims 1 to 6: (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (methylsulfonyl) phenyl] -4,5-dihydro- 3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (cyclopropylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfonyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (Benzylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -i - [4- (ethylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1 - {4 - [(4-acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1 - {4 - [(4-Fluorophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H- 2,3-benzodiazepin-3-carboxamide; (4S) -1 - {4 - [(3,4-dichlorophenyl) sulfonyi] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3 carboxamide; (4S) -1 - {4 - [(3-Acetamido-4-methoxyphenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide; 3 - ({4 - [(4S) -7,8-Dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl] phenyl} sulfonyl) benzoic acid ; (±) -1- {3 - [(4-Ρ1υοφΚ6 ^ 1) 8υ1ίο ^ 1] ^^ 2,3-benzodiazepin-3-carboxamide; (±) -7,8-dimethoxy-N, 4-dimethyl-1- [3- (phenylsulfonyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -1- {3 - [(3,4-ΟϊοΜο Κε ^ 1) 8υ1ίο ^ 3H-2,3-benzodiazepine-3-carboxamide; (±) - 1- [3- (benzylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) - 1- [3- (ethylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) - 1- [3- (cyclopropylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -7,8-dimethoxy-N, 4-dimethyl-1- [3- (methylsulfonyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -l - {3 - [(4-acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-difatty-3H-2,3-benzodiazepine-3-carboxamide; (±) -3 - ({3- [7,8-Dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl] -phenyl} sulfonyl) -benzoic acid ; (4S) -1- [3 - [(4-acetamidophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [3- (benzylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) - 1- [4-fluoro-3- (methylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) - 1- [3,4-bis (methylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfanyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; tert -Butyl 4 - ({4 - [(4S) -7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl] -phenyl } sulfanyl) piperidine-1-carboxylate; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(1-methylpiperidin-4-yl) sulfanyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide; (4S) -1- [4- (benzylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1 - {4 - [(4-acetamidophenyl) sulfanyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (ethylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (cyclopentylsulfanyi) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-Dimethoxy-N, 4-dimethyl-1- [4- (1-tetrahydro-2H-pyran-4-ylsulfanyl) -phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3 -carboxamide; (±) -7,8-dimethoxy-N, 4-dimethyl-1- [3- (phenylsulfanyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) - 1- [3- (benzylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -formic acid-7,8-dimethoxy-N, 4-dimethyl-1- {3 - [(1-methylpiperidin-4-yl) sulfanyl] phenyl} -4,5-dihydro-3H-2,3 - benzodiazepine-3-carboxamide; (±) -l- {3 - [(4-acetamidophenyl) sulfanyl] pta 3H-2,3-benzodiazepine-3-carboxamide; (±) -7,8-dimethoxy-N, 4-dimethyl-1- [3- (tetrahydro-2H-pyran-4-ylsulfanyl) -phenyl] -4-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -tert-butyl-4 - ({3- [7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-benzodiazepin-1-yl] -phenyl} sulfanyl) -piperidine l-carboxylate; (±) - 1- [3- (cyclopentylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) - 1- [3- (ethylsulfanyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (phenylsulfmyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (cyclopentylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; tert -Butyl 4- ({4 - [(4S) -7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5-dihydro-3H-2,3-benzodiazepin-1-yl] -phenyl } sulfinyl) piperidine-l-carboxylate; (4S) -1 - {4 - [(4-Acetamidophenyl) sulfinyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (benzylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -1- [4- (ethylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (tetrahydro-2H-py] -an-4-ylsulfinyl) -phenyl] -4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide; (4S) -i- [4- (benzylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 1; (4S) -1- [4- (benzylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 2; (±) - [3- (cyclopentylsulfmyl) phenyl] -7,8-dimethoxy-N, 4-limethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) - 1- [3- (benzylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-trimethyl-4,5 <-lihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -l- {3 - [(4-acetamidophenyl) sulfinyl] phenyl} ^^ 3H-2,3-benzodiazepine-3-carboxamide; (±) - [3- (ethylsulfinyl) phenyl] -7,8-dimethoxy-N, 4-limethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (d =) tert-Butyl-4 - ({3- [7,8-dimethoxy-4-methyl-3- (methylcarbamoyl) -4,5 benzodiazepin-l-yl] phenyl} sulfinyl) piperidine-l-carboxylate; (4S) -1- [4- (cyclopentylsulfonyl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-limethyl-1- [4- (tetrahydro-2H-pyran-4-ylsulfonyl) -phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3 -carboxamide; tert-butyl-4 - ({4 - [(4S) -7,8-dimethoxy-4-me] benzodiazepin-1-ylphenyl} sulfonyl) piperidine-1-carboxylate; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(1-methyl-piperidin-4-yl) -sulfonyl] -ph-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-l- {4 - [(l- ^ dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -7,8-Dimethoxy-N, 4-Dimethyl-1- [3- (tetrahydro-2H-pyran-4-ylsulfonyl) -phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3 carboxamide; (±) -I- [3- (Cyclopentylsulfonyi) phenyl] -7,8-dm benzodiazepine-3-carboxamide; (±) -tert-butyl 4 - ({3- [7,8-dimethoxy-4-m ^ benzodiazepin-1-ylphenyl} sulfonyl) piperidine-1-carboxylate; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (S-phenylsulfonimidoyl) phenyl] -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, diastereomer 1; (4S) -7,8-dimethoxy-N, 4-dimethyl-l- [4- (S-ph ^ 2,3-benzodiazepine-3-carboxamide), diastereomer 2; (±) -l- [4- (dimethylphosphoryl) phen ^^ benzodiazepine-3-carboxamide; (±) - 1- [4- (diethylphosphoryl) phenyl] -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (±) -7,8-dimethoxy-N, 4-dimethyl-l- {4- ^ 3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-1- {4 - [(2-methoxyphenyl) sulfonyl] phenyl} -N, 4-dimethyl-4,5-dihyd 3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-1- {4 - [(4-methoxyphenyl) sulfonyl] phenyl} -N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -l- (4 - {[4- (dimethylsulfamoyl) phenyl] sulfonyl} phenyl) -7,8-dimethoxy-N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3 -carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- {4 - [(4-methylphenyl) sulfonyl] phenyl} -4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-1- {4 - [(2-methoxy-5-methylphenyl) sulfonyl] phenyl} -N, 4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine 3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- (4 - {[3- (pyrrolidin-1-ylsulphonyl) phenyl] sulphonyl} phenyl) -4,5-dihydro-3H-2,3 benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- (4 - {[4- (2-oxopyrrolidin-1-yl) phenyl] sulfonyl} phenyl) -4,5-dihydro-3H-2 , 3-benzodiazepin-3-carboxamide; (4S) -1- [4 - [(4-chlorophenyl) sulfonyl] phenyl} -7,8-dimethoxy-N, 4-dimethyl-4,5-dillydro-3H-2,3-benzodiazepine-3-carboxamide; (4S) -7,8-dimethoxy-N, 4-dimethyl-1- [4- (N-methyl-S-phenylsulfonimidoyl) -phenyl dihydro-3H-2,3-benzodiazepine-3-carboxamide, and (4S) -7,8-dimethoxy-N, N, 4-trimethyl-1- [4- (N-methyl-S-phenylsulfonimidoyl) phen dihydro-3H-2,3-benzodiazepine-3-carboxamide, as well as their polymorphs, tautomers, solvates, physiologically acceptable salts and Solvates of these salts. 8. Compounds according to any one of claims 1 to 7 for the prophylaxis and / or therapy of hyperproliferative diseases, benign hyperplasia, inflammatory  Diseases, autoimmune diseases, sepsis, viral infections, HIV-associated kidney diseases, vascular diseases, atherosclerotic erotic diseases,  Heart failure and neurodegenerative diseases. 9. A compound according to any one of claims 1 to 7 for the prophylaxis and / or therapy of Tumor diseases. 10. A compound according to any one of claims 1 to 7, in the male fertility control. 11. A compound according to any one of claims 1 to 7 for the prophylaxis and / or treatment of acute myeloid leukemias, lymphoblastischen leukemias, B cell lymphomas, androgen receptor-positive prostate carcinomas, melanomas or Rhabdomyosarcomen. 12. Use of a compound according to claim 1 to 7 for the preparation of a  Drug. 13. Use of a compound according to any one of claims 1 to 7 for the prophylaxis  and / or therapy of human or other mammalian diseases. 14. A compound according to any one of claims 1 to 7 in combination with a further pharmaceutical agent. 15. A pharmaceutical formulation containing a compound according to any one of claims 1 to 7.