WO2015193217A1 - Bet-protein inhibiting dihydropyrido[2,3-b]pyrazinone derivatives with para-substituted aromatic amino- or ether groups - Google Patents

Abstract

The invention relates to BET-protein-inhibiting, in particular BRD4-inhibiting, 3,4-dihydropyrido[2,3-b]pyrazinones with para-substituted aromatic amino or ether groups of general formula (I), in which A, X, Y, R¹, R², R³, R⁴, R⁵, R⁶, and n have the meanings indicated in the description, pharmaceutical agents containing the claimed compounds, and the prophylactic and therapeutic use of said pharmaceutical agents in the case of hyperproliferative diseases, in particular in the case of tumor diseases. The invention further relates to the use of BET protein inhibitors in the case of viral infections, neurodegenerative diseases, inflammatory diseases, and atherosclerotic diseases and in male fertility control.

Description

 BET protein-inhibiting dihydropyrido [2,3-b] pyrazinone derivatives having a para-substituted aromatic amino or ether group

The present invention relates to BET protein-inhibiting, in particular BRD4-inhibitory 3,4-dihydropyrido [2,3-b] pyrazinones with> ara-substituted aromatic amino or

 Ether group, pharmaceutical agents containing the compounds of the invention and their prophylactic and therapeutic use in hyper-proliferative diseases, especially in tumor diseases. Furthermore, this invention relates to the use of BET protein inhibitors in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.

The human BET family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and BRDT) containing two related bromodomains and one extra-terminal domain (Wu and Chiang, J. Biol. Chem., 2007 , 282: 13141-13145). The bromodomains are protein regions that recognize acetylated lysine residues. Such acetylated lysines are often found at the N-terminal end of histones (eg, histone H3 or histone H4) and are features for open chromatin structure and active gene transcription (Kuo and Allis, Bioessays, 1998, 20: 615-626 ). In addition, bromodomains can recognize additional acetylated proteins. For example, BRD4 binds to RelA, resulting in the stimulation of NF-κB and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell. Biol., 2009, 29: 1375-1387). BRD4 also binds to cyclin Tl and forms an active complex important for transcription elongation (Schröder et al., J. Biol. Chem., 2012, 287: 1090-1099). The extra-terminal domain of BRD2, BRD3 and BRD4 interacts with several proteins that have a role in chromatin modulation and regulation of gene expression (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). A role of BRD4 in the post-mitotic reactivation of gene transcription has been demonstrated (Zhao et al., Nat Cell Biol., 2011, 13: 1295-1304). BRD4 is essential for transcription elongation and recruits the elongation complex P-TEFb, which consists of CDK9 and cyclin Tl, resulting in the activation of RNA polymerase II (Yang et al., Mol. Cell, 2005, 19: 535-545; Schröder et al., J. Biol. Chem., 2012, 287: 1090-1099). Thus, expression of genes involved in cell proliferation, such as c-myc, cyclin D1, and aurora B, is stimulated (You et al., Mol. Cell. Biol., 2009, 29: 5094-5103; Zuber et al., Nature, 2011, doi: 10.1038). BRD2 is involved in the regulation of androgen receptor target genes (Draker et al., PLOS Genetics, 2012, 8, el003047). BRD2 and BRD3 bind to transcribed genes in hyperacetylated chromatin regions and promote transcription by RNA polymerase II (LeRoy et al., Mol. Cell, 2008, 30: 51-60).

 Knockdown of BRD4 or inhibition of interaction with acetylated histones in various cell lines results in a Gl residue (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040-9048, Mertz et al. Proc Natl Acad., 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 has been demonstrated (Dawson et al., Nature, 2011, 478: 529-533, Delmore et al., Cell, 2011, 146: 1-14, Mertz et al., Proc Natl Acad., USA, 2011, 108: 16669-16674). Inhibition of the expression of androgen-regulated genes and binding of BRD2 to corresponding regulatory regions has also been demonstrated (Draker et al., PLOS Genetics, 2012, 8, el003047).

 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). 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, 478, 524-528). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo. Further experiments with a BRD4 inhibitor show that BRD4 plays a role in various hematological tumors, such as multiple myeloma (Delmore et al., Cell, 2011, 146, 904-917) and Burkitt's Lymphoma (Mertz et al. Proc. Natl. Acad., USA, 2011, 108, 16669-16674). BRD4 also plays an important role in solid tumors, such as lung cancer (Lockwood et al., Proc Natl. Acad., USA, 2012, 109, 19408-19413). Increased expression of BRD4 was detected in multiple myeloma, as well as one

Amplification of the BRD4 gene has been found in patients with multiple myeloma (Delmore et al., Cell, 2011, 146, 904-917). Amplification of the DNA region containing the BRD4 gene has been detected in primary breast tumors (Kadota et al., Cancer Res, 2009, 69: 7357- 7365). Also for BRD2 there is data related to a role in tumors. A transgenic mouse that selectively overexpressing BRD2 in B cells develops B-cell lymphomas and leukemias (Greenwall et al., Blood, 2005, 103: 1475-1484).

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

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

Macrophages prevent a BRD4 inhibitor from expression of inflammatory genes, such as IL-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1119-1123).

BET proteins are also involved in the regulation of the ApoAl gene (Mirguet et al., Bioorg. Med. Chem. Lett., 2012, 22: 2963-2967). The corresponding protein is part of the

 Higher density lipoprotein (HDL), which plays an important role in atherosclerosis (Smith, Arterioscler, Thromb Vase, Biol., 2010, 30: 151-155). By stimulating ApoAl expression, BET protein inhibitors may increase the levels of cholesterol HDL and thus potentially be useful for the treatment of atherosclerosis (Mirgu et al., Bioorg. Med. Chem. Lett., 2012, 22: 2963-2967 ).

 The BET protein BRDT plays an essential role in spermatogenesis through the

Regulation of expression of several genes important during and after meiosis (Shang et al., Development, 2007, 134: 3507-3515; Matzuk et al., Cell, 2012, 150: 673-684).

Furthermore, BRDT is involved in the post-meiotic organization of chromatin (Dhar et al., J. Biol. Chem., 2012, 287: 6387-6405). In vivo experiments in mice show that treatment with a BET inhibitor that also inhibits BRDT results in a decrease in sperm production and infertility (Matzuk et al., Cell, 2012, 150: 673-684). All these studies show that the BET proteins play an essential role in various pathologies and also in male fertility. It would therefore be desirable to find potent and selective inhibitors that prevent the interaction between the BET proteins and acetylated proteins, particularly acetylated histone H4 peptides. These new inhibitors should also have suitable pharmacokinetic properties that allow in vivo, ie in the patient, to inhibit these interactions.

It has now been found that 3,4-dihydropyrido [2,3-b] pyrazinones having a> ara-substituted aromatic amino or ether group have the desired properties, i. show a BET protein, in particular a BRD4 protein inhibitory activity. The compounds according to the invention thus represent valuable active ingredients for prophylactic and therapeutic use in hyper-proliferative diseases, in particular in tumor diseases. Furthermore, the compounds according to the invention can be used in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control come.

State of the art

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

 6-phenyl-4H- [1,2] -isoxazolo

 4-phenyl-6H-thieno [3,2-f] [l, 2,4] triazolo

 [5,4-d] [2] benzazepine

[4,3-a] [l, 4] diazepine

 3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one 1,4-dihyro-pyrido [3,4-b] pyrazine-3 (2H) -one

 3,4-dihy drochinoxalin-2 (1H) -one 7,8-dihydropteridin-6 (5H) -one

Only a few types of BRD4 inhibitors have so far been described in terms of chemical structure (Chun-Wa Chung et al., Progress in Medicinal Chemistry 2012, 51, 1-55).

The first published BRD4 inhibitors were diazepines. So z. B. phenyl-thieno-triazolo-1,4-diazepines (4-phenyl-6-thieno [3,2- [1,2,4] triazolo [4,3-a] [1,4] diazepines) in

WO2009 / 084693 (Mitsubishi Tanabe Pharma Corporation) and as compound JQ1 in

WO2011 / 143669 (Dana Farber Cancer Institute). Replacement of the thieno by a benzo moiety also results in active inhibitors (J. Med. Chem., 2011, 54, 3827-3838, E. Nicodeme et al., Nature 2010, 468, 1119). Further 4-phenyl-6-thieno [3,2- | [l, 2,4] triazolo [4,3-a] [1,4] diazepines and related compounds with alternative rings as fusion partners instead of the benzo moiety are claimed generically or explicitly described in WO2012 / 075456 (Constellation Pharmaceuticals).

Azepines as BRD4 inhibitors are described recently in WO2012 / 075383 (Constellation

Pharmaceuticals). This application relates to 6-substituted 4i7-isoxazolo [5,4-cf] [2] benzazepines and 4i7-isoxazolo [3,4-cf] [2] benzazepines, including such compounds at position 6 optionally substituted phenyl and also analogues with alternative heterocyclic fusion partners instead of the benzo unit, such as thieno or Pyridoazepine. Another structural class of BRD4 inhibitors is described as 7-isoxazoloquinolines and related quinolone derivatives (Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967). In WO2011 / 054845 (GlaxoSmithKline) further benzodiazepines are described as BRD4 inhibitors.

Applicants' other BRD4 inhibitors are also described in the following applications: WO2013 / 030150 - 6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [4,3-a ] [l, 4] diazepines,

WO2014 / 128111 - 4-substituted pyrrolo and pyrazolo diazepines,

WO2014 / 128070 - pyrrolo and pyrazolo diazepines,

WO2014 / 026997 - 2,3-benzodiazepines,

WO2014 / 048945 - 5-aryl-triazolo azepines, WO 2014/095774 - Dihydropyridopyrazinones,

WO2014 / 202578 - 2,3-benzodiazepines,

WO2014 / 128067 - Bicyclic and spirocyclic substituted 2,3-benzodiazepines,

WO2015 / 004075 - dihydroquinoxalinones and dihydropyridopyrazinones, and WO2014 / 095775 - dihydroquinoxalinones.

Applicant's application WO 2015/011084 discloses dihydropyridopyazinone derivatives as dual inhibitors of BRD4 and polo-like kinase-1 (PLK-1). In contrast, the compounds according to the invention are substituted 3,4-

Dihydropyrido [2,3-b] pyrazine-2 (1H) -one derivatives with £> ara-substituted aromatic amino or ether groups which differ structurally in a variety of forms from the chemotypes of BRD4 inhibitors discussed above. Due to the significant structural differences, it was not to be assumed that the compounds claimed here are also BRD4-inhibitory. It is therefore surprising that the compounds according to the invention, despite the considerable Structural differences have a good inhibitory effect.

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

WO 2013/071217 (OSI Pharmaceuticals) discloses above all 7,8-dihydropteridin-6 (5H) -one, but also l, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives as inhibitors of kinases, in particular of RSK-1 and RSK-2, as medicaments, inter alia, for the treatment of various

Cancers. However, the compounds disclosed therein differ from the compounds according to the invention inter alia by the obligate aromatic substitution on the nitrogen atom immediately adjacent to the oxo group (N-5 in the dihydropteridones, or N-4 in the dihydropyrido [3,4-b ] pyrazinones). WO 2010/085570 (Takeda Pharmaceutical Company) describes poly-ADP-ribose polymerase (PARP) inhibitors derived from a variety of bi- and tricyclic scaffolds and 3,4-dihydropyrido [2,3-b] pyrazine -2 (lH) -one derivatives as drugs for the treatment of various diseases. The example compounds disclosed therein differ from the compounds according to the invention for example by the type and position of the substitution on the pyrido part of the dihydropyridopyrazinone skeleton.

WO 2006/005510 (Boehringer Ingelheim) describes 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives as inhibitors of PLK-1 for the treatment of hyperproliferative disorders. The position of the pyrido-nitrogen distinguishes the substances disclosed herein from the compounds of the invention.

WO 2008/117061 (Sterix Ltd) describes a number of bicyclic chemotypes as inhibitors of steroid sulfatase, inter alia, for use in inhibiting the growth of tumors. US 2006/0019961 (P.E. Mahaney et al.) Describes substituted 3,4-dihydroquinoxaline-2 (1H) -one derivatives as modulators of the estrogen receptor for the treatment of various inflammatory, cardiovascular and autoimmune diseases.

WO 2006/050054, WO 2007/134169 and US 2009/0264384 (Nuada LLC) describe a number of bicyclic chemotypes as inhibitors of tumor necrosis factor alpha (TNF-α) as well as of various isoforms of phosphodiesterase for the treatment of inter alia inflammatory diseases. WO 2012/088314 (Agios Pharmaceuticals) discloses a series of bicyclic chemotypes as modulators of pyruvate kinase M2. WO 2003/020722 and WO 2004/076454 (Boehringer Ingelheim) disclose 7,8-dihydropteridine-6 (5H) -ones as inhibitors of specific cell cycle kinases for the treatment of hyperproliferative diseases.

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

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

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

Treatment of hyperproliferative diseases.

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

WO 2007/022638 (Methylgene Inc.) generally discloses HDAC inhibitors of several chemotypes, however, the structures of the exemplified compounds disclosed differ significantly from the compounds of the present invention. WO 1999/050254 (Pfizer) describes a series of bicyclic chemotypes as inhibitors of

Serine proteases for antithrombotic therapy, however, these compounds differ significantly by the nature and position of the substituents of the inventive compounds.

Some of C-6 having an aromatic amino group, the phenyl group of which in turn is substituted with a para-position amide group, substituted 3,4-dihydroquinoxaline-2 (1H) -one derivatives (corresponding to 2-oxo-l, 2,3 , 4-tetrahydroquinoxaline derivatives) are indexed by Chemical Abstracts as "Chemical Library" substances without literature reference [see 4 {[(3R) -4-Cyclopentyl-3-O] ethyl 1-methyl-2-o-1, 2,3,4-tetrahydroquinoxalin-6-yl] amino} -3-methoxy- / V- [2-methyl-1 - (pyrrolidin-1-yl) propane] 2-yl] benzamide, CAS registry no. 1026451-60-4, / V- (1-benzylpiperidin-4-yl) -4- {[(3R) -4-cyclopentyl-13-dimethyl-2-oxo-l, 23,4-tetrahydroquinoxaline-6-yl ] amino} -3-methoxybenzamide, CAS registry no. 1026961-36-3, 4- {[(3R) -4-cyclohexyl-l, 3-dimethyl-2-oxo-l, 23,4-tetrahydroquinoxaline-6-yl] amino} -A ^r - [l- ( dimethylamino) -2-methylpropan-2-yl] -3-methoxybenzamide, CAS Registry-No. 1025882-57-8]. A therapeutic application is not yet described for these compounds.

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

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

in der

in the

A is -NH-, -N (C ₁ -C ₃ -alkyl) - or -O-,

X is -N-, -CH- or -CR ² -,

Y is -N-, -CH- or -CR ² -,

n is 0,1 or 2,

R is halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ , -S (= O) (= NR ⁸ ) R ⁹ , -C (= O) R ⁷ or

 -NR R stands,

 or

is 5-membered monocyclic heteroaryl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents from halogen, cyano, Ci-C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, halo-Ci-C ₄ alkyl, GC ₄ -

Alkoxy, halogeno-C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkylthio, halogeno-C 1 -C ₄ -alkylthio, -NR ¹⁰ R ^U , -C (= O) OR ¹² , -C (= O) NR ¹⁰ R ^u , -C (= O) R ¹² , -S (= O) ₂ R, -S (= O) ₂ NR ¹⁰ R ^u , or

represents 4- to 8-membered heterocycloalkyl-, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl or

Ci-C t -alkoxycarbonyl, with the proviso that the 4- to 8-membered

Heterocycloalkyl- is not bound to the rest of the molecule via a nitrogen atom,

is hydrogen, hydroxyl, halogen, cyano, C ₁ -C 3 -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, halogen-C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, Halogeno-C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkylthio or halogeno-C 1 -C ₄ -alkylthio, and if n is 2, R ² may be identical or different,

or

together for a group * -S (= 0) 2-CH 2 -CH 2 - ** or

* -S (= O) 2 -CH 2 -CH 2 -CH 2 - ** wherein "*" represents the point of attachment of R ¹ to the phenyl or 6-membered heteroaryl ring to which R ^{1 is} attached and wherein * "a carbon atom adjacent to this point of attachment

Ringes means

represents methyl or ethyl,

is hydrogen or C 1 -C 3 -alkyl-,

is hydrogen or C 1 -C 3 -alkyl-,

or

together represent C2-Cs-alkylene,

is Ci-Cö-alkyl-, which is unsubstituted or monosubstituted with Ci-C3-alkoxy, phenyl, Cs-Cs-cycloalkyl, or 4- to 8-membered

heterocycloalkyl,

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

 wherein Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-,

or

is Cs-Cs-cycloalkyl- or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl- or C ₁ -C ₄ -alkoxycarbonyl-,

or is phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, C 1 -C 3 -alkyl- or 4- to 8-membered heterocycloalkyl-,

in which the 4- to 8-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl- or C 1 -C ₄ -alkoxycarbonyl-,

is Ci-Cö-alkyl-, which is unsubstituted or monosubstituted with cyano, Ci-C3-alkoxy, Ci-C3-alkylamino, phenyl, Cs-Cs-cycloalkyl, or 4- to 8-membered heterocycloalkyl,

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 alkynyl C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkyl or C 1 -C ₄ -alkoxy-, and

wherein Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by C ₁ -C ₃ -alkyl-,

or

is halo-Ci-C ₄ alkyl,

or

is Cs-Cs-cycloalkyl- or 4- to 8-membered heterocycloalkyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl- or Ci-C ₄ -alkoxycarbonyl-, with the In that the 4- to 8-membered heterocycloalkyl group is not bonded via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ ,

is cyano, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl or -C (= O) OR ¹² ,

represents C ₁ -C ₆ -alkyl or C ₃ -C ₈ -cycloalkyl-,

independently of one another are hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxyl, oxo or Ci-C3-alkoxy-substituted Ci-C ₃ alkyl, or fluoro-C ₁ -C ₃ -alkyl or 4- to 8-membered heterocycloalkyl-,

in which the 4- to 8-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C ₁ -C ₃ -alkyl-,

or

together with the nitrogen atom to which they are attached for 4- to

8-membered heterocycloalkyl, heterospirocycloalkyl, heterobicycloalkyl or bridged heterocycloalkyl, which are unsubstituted or mono- or are substituted twice, identically or differently with hydroxyl, fluorine, oxo, cyano, C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, cyclopropylmethyl-C 1 -C 5 -alkylcarbonyl, C3-alkylamino _(Ci-C3 alkyl) - or

C ₁ -C 4 -alkoxycarbonyl, C ₁ -C -alkyl- or phenyl-C ₁ -C ₃ -alkyl-,

and their diastereomers, racemates, polymorphs and physiologically acceptable salts, surprisingly inhibit the interaction between BRD4 and an acetylated histone 4-peptide and thus inhibit the growth of cancer and tumor cells.

Preference is given to those compounds of the general formula (I)

in the

 A is -NH- or -N (methyl) -,

 X is -N- or -CH-,

 Y stands for -CH-,

n is 0,1 or 2,

R ^{1 is} halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

 or

represents isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl, trifluoromethyl, C 1 -C 3 -alkyl, Alkoxy, trifluoromethoxy or -NR ¹⁰ R ^U ,

 or

 is 5- to 6-membered heterocycloalkyl-, which is unsubstituted or monosubstituted with Ci-C3-alkyl- or Ci-C t-alkoxycarbonyl-, with the proviso that the 5- to 6-membered heterocycloalkyl- not over a nitrogen atom is attached to the rest of the molecule,

R ^{2 is} hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, trifluoromethyl,

Methoxy, ethyl or ethoxy, and if n is 2, R ² may be the same or different,

R ³ represents methyl or ethyl,

R ^{4 is} hydrogen, methyl or ethyl,

R ^{5 is} hydrogen, methyl or ethyl,

R ⁶ is C ₂ -C ₅ alkyl group, or

is methyl or ethyl which is monosubstituted with C 1 -C 3 -alkoxy,

Phenyl- or 4- to 8-membered heterocycloalkyl-,

wherein 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 or C ₁ -C ₃ -alkoxy-, and

 wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or monosubstituted or disubstituted by methyl,

or

is Cs-Cs-cycloalkyl- or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl- or C 1 -C 4 -alkoxycarbonyl-,

or

is phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl-,

 wherein the 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by methyl or ieri-butoxycarbonyl,

is C ₁ -C 6 -alkyl which is unsubstituted or monosubstituted by cyano, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylamino, phenyl or 4 to 8-membered

heterocycloalkyl,

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

in which the 4- to 8-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C ₁ -C ₃ -alkyl-,

or

represents fluoro-C ₁ -C ₃ -alkyl,

or

is Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C ₃ alkyl or Ci-C t -alkoxycarbonyl, with with the proviso that the 4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ , and

independently of one another are hydrogen or unsubstituted or monosubstituted or C ₁ -C ₃ -alkyl or hydroxy or oxo-substituted or for 5 to 6-membered Heterocycloalkyl stand,

 wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with C1-C3-alkyl-,

 or

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached for 4- to

 7-membered heterocycloalkyl, heterospirocycloalkyl or bridged

Heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, Ci-C3-alkyl, fluoro-Ci-C3-alkyl, cyclopropyl, cyclopropylmethyl, acetyl, teri-butoxycarbonyl or (H ₃ C) 2 N- (C ₁ -C ₃ -alkyl) -, and their diastereomers, racemates, polymorphs and physiologically acceptable salts.

Particular preference is given to those compounds of the general formula (I)

in the

 A stands for -NH-,

 X is -N- or -CH-,

Y stands for -CH-,

n is 0 or 1,

R ^{1 is} halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

 or

 isoxazolyl, oxazolyl or oxadiazolyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl-, or

represents piperidinyl or Pyrrohdinyl-, which are unsubstituted or monosubstituted with Ci-C3-alkyl, with the proviso that the piperidinyl and the Pyrrohdinyl- is not bound via a nitrogen atom to the remainder of the molecule, R ² is Is hydrogen, fluorine, chlorine, methyl, trifluoromethyl or methoxy,

R ^{3 is} methyl,

R ^{4 is} methyl or ethyl,

R ⁵ represents hydrogen,

R ^{6 is} C ₃ -C ₅ -alkyl-,

 or

is methyl which is monosubstituted with phenyl- or 4- to 6-membered heterocycloalkyl-, wherein the 4- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with methyl,

 or

 is Cs-Cs-cycloalkyl- or 4- to 6-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl- or C 1 -C 4 -alkoxycarbonyl-,

 or

 is phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,

 is Ci-C t-alkyl- which is unsubstituted or monosubstituted with cyano,

Phenyl or 5- to 6-membered heterocycloalkyl,

 wherein phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and

wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by C ₁ -C ₃ -alkyl,

 or

 is trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl, or

is 5- to 6-membered heterocycloalkyl- which is unsubstituted or monosubstituted with Ci-C ₃ -alkyl, with the proviso that the 5- to 6-membered

Heterocycloalkyl- is not bound via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ , and

 independently of one another represent hydrogen or C 1 -C 3 -alkyl or acetyl,

 or

 together with the nitrogen atom to which they are attached for 5- to

 6-membered heterocycloalkyl, heterospirocycloalkyl or bridged

Heterocycloalkyl- which are unsubstituted or monosubstituted with Ci-C ₃ alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, acetyl, ieri-butoxycarbonyl or 2- (N, N- Dimethylamino) ethyl, their diastereomers, racemates, polymorphs and physiologically acceptable salts.

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

in the stands for -NH-,

is -N- or -CH-,

stands for -CH-,

stands for 0 or 1,

represents halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

or

is isoxazolyl, which is unsubstituted or monosubstituted or disubstituted by methyl,

or

is piperidinyl, which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl is not bound to the rest of the molecule via a nitrogen atom,

represents hydrogen, fluorine, methyl, trifluoromethyl or methoxy, represents methyl,

stands for methyl,

stands for hydrogen,

stands for isopropyl,

or

represents cycloheptyl,

or

is tetrahydropyranyl or piperidinyl, which are unsubstituted or monosubstituted with methyl,

is C ₁ -C ₃ -alkyl which is unsubstituted or monosubstituted by cyano or

represents difluoromethyl,

or

is piperidinyl, which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl is not bound via a nitrogen atom via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ , and

independently of one another represent C ₁ -C ₃ -alkyl or acetyl,

or

together with the nitrogen atom to which they are attached represent 6-membered heterocycloalkyl which is unsubstituted or monosubstituted by C ₁ -C ₃ -alkyl, 2,2,2-trifluorofhyl, acetyl or 2 ( N, N-dimethylamino) ethyl, or for 2-azaspiro [3.3] heptyl, 2-oxa-6-azaspiro [3.3] heptyl, or 8-oxa-3-azabicyclo [3.2.1] octyl, their diastereomers, racemates, polymorphs and physiologically acceptable salts.

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

in the

 A stands for -NH-,

 X is -N- or -CH-,

 Y stands for -CH-,

n is 0 or 1,

R ¹ for bromine, cyano or for

steht, wobei "*" den Anknüpfungspunkt an den Rest des Moleküls bedeutet, R² für Wasserstoff, Fluor, Methyl-, Trifluormethyl- oder Methoxy- steht,

where "*" is the point of attachment to the rest of the molecule, R ^{2 is} hydrogen, fluorine, methyl, trifluoromethyl or methoxy,

R ^{3 is} methyl,

R ^{4 is} methyl, stands for hydrogen,

 stands for isopropyl,

 or

 represents cycloheptyl,

 or

 is tetrahydropyran-4-yl or / V-methyl-piperidin-4-yl-,

 their diastereomers, racemates, polymorphs and physiologically acceptable salts.

Furthermore, the present invention relates to compounds of general formula (I),

in the

A is -NH-, -N (C ₁ -C ₃ -alkyl) - or -O-,

X is -N-, -CH- or -CR ² -,

Y is -N-, -CH- or -CR ² -,

n is 0,1 or 2,

R ^{1 is} halogen, cyano, -S (= O) ₂ R ⁷ , -S (= O) (= NR ⁸ ) R ⁹ , -C (= O) R ⁷ or -NR ¹⁰ R ^U , or

 is a 5-membered monocyclic heteroaryl radical which is 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, halogeno-C ₁ -C ₄ -alkyl-, GC ₄ -

Alkoxy, halogeno-C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkylthio, halogeno-C 1 -C ₄ -alkylthio,

-NR ¹⁰ R ^U, -C (= 0) OR ^12, -C (= O) N ¹⁰ R ^u, -C (= 0) R ^12, -S (= 0) ₂ R ^12, -S (= O ) ₂ NR ¹⁰ R ^u , R ^{2 is} hydrogen, hydroxy, halogen, cyano, C ₁ -C ₃ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, halogeno-C ₁ -C ₄ - alkyl, C 1 -C ₄ -alkoxy, halogeno-C 1 -C ₄ -alkoxy, C 1 -C ₄ -

Alkylthio or halo-C 1 -C ₄ -alkylthio, and if n is 2, R ² may be identical or different,

 or

 or

R ¹ and R ² together represent a group * -S (= O) ₂ - CH ₂ -CH ₂ - ** or * -S (= O) ₂ - CH ₂ -CH ₂ -CH ₂ - ** in which "*" is the point of attachment of R ¹ to the phenyl- or 6-membered heteroaryl ring to which R ^{1 is} attached, and wherein "**" is a carbon atom of this ring adjacent to this point of attachment, R ^{3 is} methyl or ethyl .

R ^{4 is} hydrogen or C ₁ -C ₃ -alkyl-,

R ^{5 is} hydrogen or C ₁ -C ₃ -alkyl,

or together represent C 2 -C 5 -alkylene,

is Ci-Cö-alkyl- which is unsubstituted or monosubstituted with C1-C3-alkoxy, phenyl, Cs-Cs-cycloalkyl, or 4- to 8-membered heterocycloalkyl, in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, GC ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy , Halogeno-C 1 -C ₄ -alkyl or halogeno-C 1 -C ₄ -alkoxy-, and

 wherein Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-,

or

is Cs-Cs-cycloalkyl- or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl- or C 1 -C ₄ -alkoxycarbonyl-,

or

is phenyl or 5- to 6-membered heteroaryl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, C1-C3-alkyl or 4- to 8-membered heterocycloalkyl-,

in which the 4- to 8-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl- or C 1 -C ₄ -alkoxycarbonyl-,

is C ₁ -C 6 -alkyl which is unsubstituted or monosubstituted by cyano, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylamino, phenyl, C ₃ -C 8 -cycloalkyl, or 4 to 8 - heterozygous heterocycloalkyl,

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 alkynyl , GC ₄ alkoxy, haloCG ₄ alkyl or halo-Ci-C ₄ alkoxy, and

 wherein Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with G-Cs-alkyl-,

or

represents halogeno-C 1 -C ₄ -alkyl-,

or

for Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl, which are unsubstituted or mono- or disubstituted by identical or different substituents selected from Ci-C ₃ alkyl or Ci-C ₄ alkoxycarbonyl, with the proviso that the 4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl or sulfonyl group in R ¹ ,

R ^{8 is} cyano, C 1 -C 6 -alkyl, C ⁵ -C ⁸ -cycloalkyl or -C (= O) OR ¹² ,

R ^{9 is} C ₁ -C ₆ -alkyl or C ₃ -C ₈ -cycloalkyl-,

R ¹⁰ and R ¹¹ independently of one another are hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxy, oxo or Ci-C ₃ alkoxy-substituted Ci-C3-alkyl, or fluoro-C ₁ -C ₃ -alkyl or 4- to 8-membered heterocycloalkyl-,

in which the 4- to 8-membered heterocycloalkyl radical is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C 3-

alkyl,

 or

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached for 4- to

 8-membered heterocycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano,

C ₁ -C ₃ -alkyl, fluorine-C ₁ -C ₃ -alkyl, C ₃ -C ₆ -cycloalkyl, cyclopropylmethyl, C ₁ -C 3 -alkylcarbonyl or C ₁ -C 4 -alkoxycarbonyl-,

R ^{12 is} C ₁ -C 6 -alkyl or phenyl-C ₁ -C ₃ -alkyl-,

as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Also of great interest are those compounds of the general formula (I)

A is -NH- or -N (methyl) -,

X is -N- or -CH-,

 Y stands for -CH-,

n is 0,1 or 2,

R ^{1 is} halogen, cyano, -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

 or

is oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl-, trifluoromethyl-, C 1 -C 3 -alkoxy-, Trifluoromethoxy or -NR ¹⁰ R ^U ,

R ^{2 is} hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, methoxy, ethyl or

Ethoxy stands, and if n is 2, R ² may be the same or different,

R ³ represents methyl or ethyl,

R ^{4 is} hydrogen, methyl or ethyl, represents hydrogen, methyl or ethyl,

represents C ₂ -C ₅ -alkyl,

or

is methyl or ethyl which is monosubstituted with C 1 -C 3 -alkoxy,

Phenyl- or 4- to 8-membered heterocycloalkyl-,

 wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C3-alkyl or Ci-C3-alkoxy, and

 wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or monosubstituted or disubstituted by methyl,

or

is Cs-Cs-cycloalkyl- or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl- or C 1 -C 4 -alkoxycarbonyl-,

or

is phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl-,

 wherein the 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by methyl or ieri-butoxycarbonyl,

is Ci-Cö-alkyl-, which is unsubstituted or monosubstituted with cyano, Ci-C3-alkoxy, Ci-C3-alkylamino, phenyl or 4- to 8-membered

heterocycloalkyl,

 wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C3-alkyl or Ci-C3-alkoxy, and

 wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or substituted once or twice, identically or differently with C1-C3-alkyl-,

or

represents fluoro-C ₁ -C ₃ -alkyl,

or

is Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl- or Ci-C t-alkoxycarbonyl, with the In that the 4- to 8-membered heterocycloalkyl group is not bonded via a nitrogen atom to the carbonyl or sulfonyl group in R ¹ , and independently of one another are hydrogen or unsubstituted or monosubstituted or C 1 -C 3 -alkyl or hydroxy or oxo-substituted heterocycloalkyl-,

wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl-,

 or

 together with the nitrogen atom to which they are attached for 4- to

7-membered heterocycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, C ₁ -C ₃ -alkyl-, fluoro-C ₁ -C ₃ -alkyl-, cyclopropyl-, cyclopropylmethyl- , Acetyl or tert-butoxycarbonyl, and their diastereomers, racemates, polymorphs and physiologically acceptable salts.

Also of particular interest are those compounds of the general formula (I) in which

 A stands for -NH-,

X is -N- or -CH-,

 Y stands for -CH-,

n is 0 or 1,

R ^{1 is} halogen, cyano, -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

 or

is oxazolyl or oxadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl, R ^{2 is} hydrogen, fluorine, chlorine, methyl or methoxy,

R ^{3 is} methyl,

R ^{4 is} methyl or ethyl,

R ⁵ represents hydrogen,

R ^{6 is} C ₃ -C ₅ -alkyl-,

 or

 is methyl which is monosubstituted with phenyl- or 4- to 6-membered heterocycloalkyl-,

 wherein the 4- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with methyl,

or is Cs-Cs-cycloalkyl or 4- to 6-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl or C 1 -C 4 -alkoxycarbonyl-,

 or

 is phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,

R ^{7 is} C 1 -C ⁴ -alkyl which is unsubstituted or monosubstituted with cyano,

 Phenyl or 5- to 6-membered heterocycloalkyl,

 in which phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or

Methoxy, and

wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by C ₁ -C ₃ -alkyl,

 or

 is trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl, and

R ¹⁰ and R ¹¹ independently of one another represent hydrogen or C ₁ -C ₃ -alkyl,

 or

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, for 5- to

6-membered heterocycloalkyl which is unsubstituted or monosubstituted by C ₁ -C ₃ -alkyl-, trifluoromethyl-, difluoromethyl-, 2,2,2-

Trifluoroethyl or ieri-butoxycarbonyl, and their diastereomers, racemates, polymorphs and physiologically acceptable salts.

Also of particular interest are those compounds of the general formula (I) in which

 A stands for -NH-,

 X is -N- or -CH-,

Y stands for -CH-,

n is 0 or 1,

R ^{1 is} halogen, cyano, -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

 or

 is oxazolyl which is unsubstituted or monosubstituted or disubstituted by methyl,

R ^{2 is} hydrogen, methyl or methoxy,

R ^{3 is} methyl, R ^{4 is} methyl,

R ⁵ represents hydrogen,

R ^{6 is} isopropyl,

 or

 represents cycloheptyl,

 or

 is tetrahydropyranyl or piperidinyl, which are unsubstituted or monosubstituted with methyl,

R ^{7 is} C 1 -C ³ -alkyl which is unsubstituted or monosubstituted with cyano, or

 represents difluoromethyl-, and

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, for 6-membered

 Heterocycloalkyl- stand, which is unsubstituted or monosubstituted with

C ₁ -C ₃ -alkyl or 2,2,2-trifluoroethyl,

as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts.

Also of particular interest are those compounds of the general formula (I) in which

 A stands for -NH-,

 X is -N- or -CH-,

 Y stands for -CH-,

n is 0 or 1,

R ¹ for bromine, cyano or for

steht, wobei "*" den Anküpfungspunkt an den Rest des Moleküls bedeutet, für Wasserstoff oder Methoxy- steht,

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

 stands for methyl,

 stands for methyl,

 stands for hydrogen,

 stands for isopropyl,

 or

 represents cycloheptyl,

 or

 for tetrahydropyran-4-yl or / V-methyl-piperidin-4-yl-, their diastereomers, racemates, polymorphs and physiologically acceptable salts.

Preference is given to compounds of the general formula (I) in which A is -NH-.

Preference is given to compounds of the general formula (I) in which A is -O-.

Preference is given to compounds of the general formula (I) in which A is -NH- or -N (C ₁ -C ₃ -alkyl) -.

Preference is given to compounds of the general formula (I) in which A is -N (C 1 -C 3 -alkyl) -.

Preference is given to compounds of the general formula (I) in which A is -NH- or -N (methyl) -.

Preference is given to compounds of the general formula (I) in which A is -N (methyl) -.

Preference is given to compounds of the general formula (I) in which X is -N- or -CH-.

Preference is given to compounds of the general formula (I) in which X is -N-. Particular preference is given to compounds of the general formula (I) in which X is -CH-. Preference is given to compounds of the general formula (I) in which Y is -N- or -CH-. Preference is given to compounds of the general formula (I) in which Y is -N-. Particular preference is given to compounds of the general formula (I) in which Y is -CH-.

Preference is given to compounds of the general formula (I) in which X is -N- or -CH- and in which Y is -CH-.

Preference is given to compounds of the general formula (I) in which X is -CH- and in which Y is -CH-. Preference is given to compounds of the general formula (I) in which n is the number 0 or the number 1.

Preference is given to compounds of the general formula (I) in which n is the number 0. Preference is given to compounds of the general formula (I) in which n is the number 1.

Preference is given to compounds of the general formula (I) in which R ^{1 is} halogen, cyano,

-S (= 0) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

or

isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano,

C ₁ -C 8 -alkyl, trifluoromethyl, C ₁ -C ₃ -alkoxy, trifluoromefloxy or -NR ¹⁰ R ^U ,

or

is 5- to 6-membered heterocycloalkyl-, which is unsubstituted or monosubstituted with Ci-C ₃ alkyl- or Ci-C t-alkoxycarbonyl-, with the proviso that the 5- to 6-membered

Heterocycloalkyl does not have a nitrogen atom attached to the rest of the molecule.

Preference is given to compounds of the general formula (I) in which R ^{1 is} halogen, cyano, -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

or

is oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl, trifluoromethyl, C ₁ -C ₃ -alkoxy , Trifluoromefhoxy- or -NR ¹⁰ R ^U. Preference is given to compounds of the general formula (I) in which R ^{1 is} halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U. Preference is given to compounds of the general formula (I) in which R is halogen, cyano, -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U.

Preference is given to compounds of the general formula (I) in which R ^{1 is} halogen or cyano.

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

Preference is given to compounds of the general formula (I) in which R ^{1 is} cyano. Preference is given to compounds of the general formula (I) in which R ^{1 is} halogen.

Preference is given to compounds of the general formula (I) in which R ^{1 is} isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl, trifluoromethyl, C ₁ -C ₃ -alkoxy, trifluoromethoxy or -NR ¹⁰ R ^U.

Preference is given to compounds of the general formula (I) in which R ^{1 is} oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ¹ -C 3 Alkyl, trifluoromethyl, Ci-C3-alkoxy, trifluoromethoxy or -NR ¹⁰ R ^U.

Preference is given to compounds of the general formula (I) in which R ^{1 is} 5- to 6-membered heterocycloalkyl- which is unsubstituted or monosubstituted by C 1 -C 3 -alkyl- or C 1 -C 4 -alkoxycarbonyl-, with which Provided that the 5- to 6-membered heterocycloalkyl- is not bound via a nitrogen atom to the rest of the molecule.

Particular preference is given to compounds of the general formula (I) in which R ^{1 is} halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,

or isoxazolyl, oxazolyl or oxadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl,

or

is piperidinyl or pyrrolidinyl, which are unsubstituted or monosubstituted with Ci-C3-alkyl, with the proviso that the piperidinyl and the pyrrolidinyl- is not bound via a nitrogen atom to the rest of the molecule.

Particular preference is given to compounds of the general formula (I) in which R ^{1 is} halogen, cyano, -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U , or represents oxazolyl or oxadiazolyl which are unsubstituted or are mono- or disubstituted by identical or different substituents

C ₁ -C ₃ -alkyl-.

Particular preference is given to compounds of the general formula (I) in which R ^{1 is} isoxazolyl, oxazolyl or oxadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ¹ -C 3 -alkyl-.

Particular preference is given to compounds of the general formula (I) in which R ^{1 is} oxazolyl or oxadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ¹ -C 3 -alkyl-.

Particular preference is given to compounds of the general formula (I) in which R ^{1 is} -S (= O) ₂ R ⁷ . Particular preference is given to compounds of the general formula (I) in which R ^{1 represents} -S (= O) R ⁷ or -S (= O) ₂ R ⁷ .

Particular preference is given to compounds of the general formula (I) in which R ^{1 is} -S (= O) R ⁷ .

Particular preference is given to compounds of the general formula (I) in which R ^{1 is} -NR ¹⁰ R ^U.

Particular preference is given to compounds of the general formula (I) in which R ^{1 is} piperidinyl or pyrrolidinyl, which are unsubstituted or monosubstituted with C ¹ -C ³ -alkyl, with the proviso that the piperidinyl and the pyrrolidinyl is not bound by a nitrogen atom to the rest of the molecule.

Very particular preference is given to compounds of the general formula (I) in which R ^{1 is} halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U , or isoxazolyl - is unsubstituted or monosubstituted or disubstituted with methyl,

or is piperidinyl, which is unsubstituted or monosubstituted with methyl, provided that the piperidinyl is not bound to the rest of the molecule via a nitrogen atom. Very particular preference is given to compounds of the general formula (I) in which R ^{1 represents}

oder -NR¹⁰R^U steht, oder für Oxazolyl- steht, das unsubstituiert ist oder ein- oder zweifach substituiert ist mit Methyl-. Halogen, cyano,

or -NR ¹⁰ R ^U , or is oxazolyl which is unsubstituted or monosubstituted or disubstituted with methyl.

Very particular preference is given to compounds of the general formula (I) in which R ^{1 is} isoxazolyl, which is unsubstituted or monosubstituted or disubstituted by methyl.

Very particular preference is given to compounds of the general formula (I) in which R ^{1 is} oxazolyl, which is unsubstituted or monosubstituted or disubstituted by methyl. Very particular preference is given to compounds of the general formula (I) in which R ^{1 represents}

Piperidinyl is unsubstituted or monosubstituted with methyl, provided that the piperidinyl is not attached to the rest of the molecule via a nitrogen atom.

Very particular preference is given to compounds of the general formula (I) in which R ^{1 is} bromine, cyano or

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

Very particular preference is given to compounds of the general formula (I) in which R ^{1 is} bromine, cyano or

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

Preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, hydroxyl, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, ethyl or ethoxy. Preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, hydroxyl, fluorine, chlorine, cyano, methyl, methoxy, ethyl or ethoxy.

Preference is given to compounds of the general formula (I) in which R ^{2 is} C ¹ -C ³ -alkoxy. Preference is given to compounds of the general formula (I) in which R ^{2 is} ethoxy. Preference is given to compounds of the general formula (I) in which R ^{2 is} hydroxyl. Preference is given to compounds of the general formula (I) in which R ^{2 is} fluorine.

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

Particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, fluorine, chlorine, methyl, trifluoromethyl or methoxy. Particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, fluorine, chlorine, methyl or methoxy.

Particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, fluorine, methyl or methoxy.

Particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, fluorine or methoxy. Particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, methyl, trifluoromethyl or methoxy.

Particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, trifluoromethyl or methoxy.

Particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, methyl or methoxy.

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

Particular preference is given to compounds of the general formula (I) in which R ^{2 is} methoxy. Particular preference is given to compounds of the general formula (I) in which R ^{2 is} methyl.

Particular preference is given to compounds of the general formula (I) in which R ^{2 is}

Trifluoromethyl stands. Particular preference is given to compounds of the general formula (I) in which R ^{2 is} fluorine.

Particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen. Very particular preference is given to compounds of the general formula (I) in which R ^{2 is} hydrogen, fluorine, methyl, trifluoromethyl or methoxy. Preference is given to compounds of the general formula (I) in which R ^{3 is} methyl or ethyl. Preference is given to compounds of the general formula (I) in which R ^{3 is} ethyl.

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

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

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

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

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

Preference is given to compounds of the general formula (I) in which one substituent each of R ⁴ and R ^{5 is} methyl and one is hydrogen, so that with respect to the carbon atom bonded from R ⁴ , R ⁵ and the radical attached to R ⁴ and R ⁵ formed stereocenter results in a racemate.

Particularly preferred are compounds of general formula (I), in each of which a substituent of R ⁴ and R ⁵ and represents a methyl, hydrogen, so that with respect to the R ^4, R ⁵ and bonded to R ⁴ and R ⁵ Carbon atom formed stereocenter results in a mixture of isomers in which outweighs the (R) -form.

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

Preference is given to compounds of the general formula (I) in which R ^{6 is} C 2 -C 8 -alkyl-, is methyl or ethyl which is monosubstituted by C ₁ -C ₃ -alkoxy, phenyl or 4 to 8-membered heterocycloalkyl-,

wherein phenyl- in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C ₃ alkyl or

Ci-C ₃ -alkoxy, and

 wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with methyl,

or

C3-C8-cycloalkyl or 4- to 8-membered heterocycloalkyl, which are unsubstituted or mono- or disubstituted by identical or different substituents selected from Ci-C ₃ alkyl or

Ci-C t-alkoxycarbonyl,

or

is phenyl or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl-,

 wherein the 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with methyl or ieri-butoxycarbonyl.

Preference is given to compounds of the general formula (I) in which R ^{6 is} C 2 -C ⁵ -alkyl-.

Preference is given to compounds of the general formula (I) in which R ^{6 is} methyl or ethyl which is monosubstituted by C ₁ -C ₃ -alkoxy, phenyl or 4 to 8-membered

heterocycloalkyl,

wherein phenyl- in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C ₃ alkyl or

 Ci-C3-alkoxy, and

wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or mono- or disubstituted by methyl. Preference is given to compounds of the general formula (I) in which R ^{6 is} Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C _3- alkyl or Ci-C t-alkoxycarbonyl.

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

5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl, in which the 6-membered heterocycloalkyl is in turn unsubstituted or simply is substituted with methyl or ieri-butoxycarbonyl.

Particular preference is given to compounds of the general formula (I) in which R ^{6 is} C 3 -C ⁵ -alkyl-,

or

is methyl which is monosubstituted with phenyl or 4- to 6-membered

heterocycloalkyl,

 wherein phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and

 wherein the 4- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with methyl,

or

is C ₃ -C 8 -cycloalkyl- or 4- to 6-membered heterocycloalkyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C ₃ alkyl or

Ci-C t-alkoxycarbonyl,

or

is phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl. Particular preference is given to compounds of the general formula (I) in which R ^{6 is} C 3 -C ⁵ -alkyl-.

Particular preference is given to compounds of the general formula (I) in which R ^{6 is} methyl which is monosubstituted by phenyl or 4- to 6-membered heterocycloalkyl-,

 wherein phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and

wherein the 4- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with methyl. Particular preference is given to compounds of the general formula (I) in which R ^{6 is}

Cs-Cs-cycloalkyl or 4- to 6-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C ₃ alkyl or

C _l -C ₄ alkoxycarbony 1-.

Particular preference is given to compounds of the general formula (I) in which R ^{6 is} phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl. Very particular preference is given to compounds of the general formula (I) in which R ^{6 is}

Isopropyl stands,

or

represents cycloheptyl,

or

is tetrahydropyranyl or piperidinyl, which are unsubstituted or monosubstituted with methyl. Very particular preference is given to compounds of the general formula (I) in which R ^{6 is} isopropyl.

Very particular preference is given to compounds of the general formula (I) in which R ^{6 is} cycloheptyl.

Very particular preference is given to compounds of the general formula (I) in which R ^{6 is} tetrahydropyranyl or piperidinyl, which are unsubstituted or monosubstituted by methyl. Most preferred are compounds of the general formula (I) in which R ^{6 is} isopropyl, or

represents cycloheptyl,

or

is tetrahydropyran-4-yl or / V-methyl-piperidin-4-yl.

Very particular preference is given to compounds of the general formula (I) in which R ^{6 represents}

Tetrahydropyran-4-yl or / V-methyl-piperidin-4-yl.

Very particular preference is given to compounds of the general formula (I) in which R ^{6 represents}

Tetrahydropyran-4-yl is.

Very particular preference is given to compounds of the general formula (I) in which R ^{6 represents}

N-methyl-piperidin-4-yl. Preference is given to compounds of the general formula (I) in which R ⁷ is C ₁ -C 6 -alkyl- which is unsubstituted or monosubstituted by cyano, C ₁ -C ₃ -alkoxy-, C ₁ -C ₃ -alkylamino-, phenyl or 4- to 8-membered heterocycloalkyl-, wherein phenyl- in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C ₃ alkyl or

 Ci-C3-alkoxy, and

in which the 4- to 8-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C ₁ -C ₃ -alkyl-,

or

represents fluoro-C ₁ -C ₃ -alkyl,

or

C3-C8-cycloalkyl or 4- to 8-membered heterocycloalkyl, which are unsubstituted or mono- or disubstituted by identical or different substituents selected from Ci-C ₃ alkyl or

Ci-C t-alkoxycarbonyl, with the proviso that the 4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ . Preference is given to compounds of the general formula (I) in which R ^{7 is} C 1 -C ⁶ -alkyl-, which is unsubstituted or monosubstituted by cyano, C 1 -C ³ -alkoxy, C 1 -C ³ -alkylamino, phenyl or cyano 4- to 8-membered heterocycloalkyl,

wherein phenyl- in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C ₃ alkyl or

 Ci-Cs-alkoxy, and

 in which the 4- to 8-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-,

or

represents fluoro-G-Cs-alkyl,

or

C3-C8-cycloalkyl or 4- to 8-membered heterocycloalkyl, which are unsubstituted or mono- or disubstituted by identical or different substituents selected from Ci-C ₃ alkyl or

Ci-C t-alkoxycarbonyl, with the proviso that the 4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl or sulfonyl group in R ¹ .

Preference is given to compounds of the general formula (I) in which R ⁷ is C ₁ -C 6 -alkyl- which is unsubstituted or monosubstituted by cyano, C ₁ -C ₃ -alkoxy-, C ₁ -C ₃ -alkylamino-, phenyl or 4- to 8-membered heterocycloalkyl-,

 wherein phenyl- in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C3-alkyl or

Ci-C ₃ -alkoxy, and

wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or mono- or is substituted twice, identically or differently with C 1 -C 3 -alkyl-.

Preference is given to compounds of the general formula (I) in which R ^{7 is} fluoro-C 1 -C ³ -alkyl-.

Preference is given to compounds of the general formula (I) in which R ^{7 is} Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3 With the proviso that the 4- to 8-membered heterocycloalkyl is not attached via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ .

Preference is given to compounds of the general formula (I) in which R ^{7 is} Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3 With the proviso that the 4- to 8-membered heterocycloalkyl- is not bound via a nitrogen atom to the carbonyl or sulfonyl group in R ¹ -alkyl or Ci-C t -alkoxycarbonyl.

Particular preference is given to compounds of the general formula (I) in which R ^{7 is} C 1 -C ⁴ -alkyl- which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,

 wherein phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and

 wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with Ci-C3-alkyl,

or

represents trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl-,

or

represents 5- to 6-membered heterocycloalkyl which is unsubstituted or monosubstituted with Ci-C3-alkyl, with the proviso that the 5- to 6-membered heterocycloalkyl- not via a nitrogen atom to the carbonyl, sulfinyl - or sulfonyl group is bound in R ¹ .

Particular preference is given to compounds of the general formula (I) in which R ^{7 is} C 1 -C ⁴ -alkyl- which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,

 wherein phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and

wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or simply substituted with Ci-C3-alkyl,

or

is trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl.

Particular preference is given to compounds of the general formula (I) in which R ^{7 is} C 1 -C ⁴ -alkyl- which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,

 wherein phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and

 wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with Ci-C3-alkyl-.

Particular preference is given to compounds of the general formula (I) in which R ^{7 is} C 1 -C ⁴ -alkyl, which is unsubstituted or monosubstituted with cyano.

Particular preference is given to compounds of the general formula (I) in which R ^{7 is} C 1 -C ⁴ -alkyl- which is unsubstituted or monosubstituted by phenyl-,

 in which phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy.

Particular preference is given to compounds of the general formula (I) in which R ^{7 is} C 1 -C ⁴ -alkyl- which is unsubstituted or monosubstituted by 5- to 6-membered heterocycloalkyl-, in which the 5- to 6-membered group Heterocycloalkyl- in turn is unsubstituted or monosubstituted with Ci-C3-alkyl-.

Particular preference is given to compounds of the general formula (I) in which R ^{7 represents}

Trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl stands.

Particular preference is given to compounds of the general formula (I) in which R ^{7 represents}

5- to 6-membered heterocycloalkyl which is unsubstituted or monosubstituted with Ci-C3-alkyl, with the proviso that the 5- to 6-membered heterocycloalkyl- not via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group is bound in R ¹ .

Very particular preference is given to compounds of the general formula (I) in which R ^{7 represents}

Ci-C3-alkyl- which is unsubstituted or monosubstituted with cyano,

or represents difluoromethyl,

or

is piperidinyl, which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl is not bound via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ .

Very particular preference is given to compounds of the general formula (I) in which R ^{7 represents}

Ci-C ₃ -alkyl- which is unsubstituted or monosubstituted with cyano,

or

represents difluoromethyl.

Very particular preference is given to compounds of the general formula (I) in which R ^{7 is} cyanomethyl, 1-cyanoethyl or difluoromethyl. Very particular preference is given to compounds of the general formula (I) in which R ^{7 is} C ₁ -C ₃ -alkyl, which is unsubstituted or monosubstituted with cyano.

Very particular preference is given to compounds of the general formula (I) in which R ^{7 is} cyanomethyl- or 1-cyanoethyl-.

Very particular preference is given to compounds of the general formula (I) in which R ^{7 is} difluoromethyl.

Very particular preference is given to compounds of the general formula (I) in which R ^{7 is} piperidinyl which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl does not have a nitrogen atom on the carbonyl, Sulfinyl or sulfonyl group is bound in R ¹ .

Preference is given to compounds of the general formula (I) in which R ¹⁰ and R ¹¹ independently of one another are hydrogen or unsubstituted or monosubstituted or C 1 -C 3 -alkyl or hydroxy or oxo-substituted heterocycloalkyl-,

in which the 5- to 6-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C ₁ -C ₃ -alkyl-,

or in those

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached for 4- to

7-membered heterocycloalkyl, heterospirocycloalkyl or bridged heterocycloalkyl are unsubstituted or monosubstituted or disubstituted by identical or different substituents Hydroxyl, fluorine, oxo, C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, cyclopropyl, cyclopropylmethyl, acetyl, ieri-butoxycarbonyl or (H ₃ C) 2 N - (C ₁ -C ₃ -alkyl ) -.

Preference is given to compounds of the general formula (I) in which R ¹⁰ and R ¹¹ independently of one another are hydrogen or unsubstituted or monosubstituted or C 1 -C 3 -alkyl or hydroxy or oxo-substituted heterocycloalkyl-,

 in which the 5- to 6-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-,

or in those

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached for 4- to

 7-membered heterocycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl-,

Cyclopropyl, cyclopropylmethyl, acetyl or ieri-butoxycarbonyl.

Preference is given to compounds of the general formula (I) in which R and R independently of one another are hydrogen or C ₁ -C ₃ -alkyl which is unsubstituted or monosubstituted by hydroxyl or oxo or is 5 to 6-membered heterocycloalkyl-,

wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or mono- or disubstituted by identical or different substituents with Ci-C ₃ alkyl.

Preference is given to compounds of the general formula (I) in which R ¹⁰ and R ^11, together with the nitrogen atom to which they are bonded, are 4- to 7-membered heterocycloalkyl-,

Heterospirocycloalkyl- or bridged Heterocycloalkyl- standing, which are unsubstituted or mono- or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, Ci-C ₃ alkyl, fluoro-Ci-C ₃ alkyl, cyclopropyl, Cyclopropylmethyl, acetyl, ieri-butoxycarbonyl or (H ₃ C) 2 N- (C 1 -C ₃ -alkyl) -.

Particular preference is given to compounds of the general formula (I) in which R ¹⁰ and R ^11, independently of one another, are hydrogen or C 1 -C 3 -alkyl or acetyl,

or in those

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, for 5- to

Are 6-membered heterocycloalkyl, Heterospirocycloalkyl- or bridged heterocycloalkyl, which are unsubstituted or monosubstituted with Ci-C ₃ alkyl, trifluoromethyl,

Difluoromethyl, 2,2,2-trifluoroethyl, acetyl, ieri-butoxycarbonyl or 2- (N, N-dimethylamino) ethyl.

Particular preference is given to compounds of the general formula (I) in which R ¹⁰ and R ¹¹ independently of one another represent hydrogen or C 1 -C 3 -alkyl-,

or in those

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, for 5- to

6-membered Heterocycloalkyl- which is unsubstituted or monosubstituted with Ci-C3-alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or ieri-butoxycarbonyl-.

Particular preference is given to compounds of the general formula (I) in which R ¹⁰ and R ^11, independently of one another, are hydrogen or C 1 -C 3 -alkyl or acetyl. Particular preference is given to compounds of the general formula (I) in which R ¹⁰ and R ^11, independently of one another, are hydrogen or C 1 -C 3 -alkyl-.

Particularly preferred are compounds of general formula (I) in which R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are bonded, represent 5- to 6-membered

Heterocycloalkyl, Heterospirocycloalkyl- or bridged Heterocycloalkyl- stand, which are unsubstituted or monosubstituted with Ci-C3-alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, acetyl, ieri-butoxycarbonyl or 2 - (N, N-dimethylamino) ethyl.

Particular preference is given to compounds of the general formula (I) in which R ¹⁰ and R ^11, together with the nitrogen atom to which they are bonded, are 5- to 6-membered

Heterocycloalkyl- which is unsubstituted or monosubstituted with Ci-C ₃ alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or ieri-butoxycarbonyl-.

Very particular preference is given to compounds of the general formula (I) in which R ¹⁰ and R ^11, independently of one another, are C 1 -C 3 -alkyl or acetyl,

or in those

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, 6-membered

Heterocycloalkyl- stand, which is unsubstituted or monosubstituted with

C ₁ -C ₃ -alkyl, 2,2,2-trifluoroethyl, acetyl or 2- (N, N-dimethylamino) ethyl,

or for 2-azaspiro [3.3] heptyl, 2-oxa-6-azaspiro [3.3] heptyl, or 8-oxa-3-azabicyclo [3.2.1] octyl.

Very particular preference is given to compounds of the general formula (I) in which R ¹⁰ and R ^11, together with the nitrogen atom to which they are attached, represent 6-membered heterocycloalkyl which is unsubstituted or monosubstituted by C 1 -C 3 -alkyl. Alkyl or

2,2,2-trifluoroethyl. Very particular preference is given to compounds of the general formula (I) in which R ¹⁰ and R ^11, independently of one another, are C 1 -C 3 -alkyl or acetyl.

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

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, 6-membered

Heterocycloalkyl- stand, which is unsubstituted or monosubstituted with

C ₁ -C ₃ -alkyl, 2,2,2-trifluorofhyl, acetyl or 2- (N, N-dimethylamino) ethyl,

or for 2-azaspiro [3.3] heptyl, 2-oxa-6-azaspiro [3.3] heptyl, or 8-oxa-3-azabicyclo [3.2.1] octyl.

Particular preference is given to compounds of the general formula (I) in which A is -NH-, X is -CH- or -N-, Y is -CH-, n is 0 or 1, R ^{2 is} hydrogen Is fluoro, methyl, trifluoromethyl or methoxy, R ^{3 is} methyl, R ^{4 is} methyl and R ^{5 is} hydrogen.

Particular preference is given to compounds of the general formula (I) in which A is -NH-, X is -CH-, Y is -CH-, n is 0 or 1, R ^{2 is} hydrogen, fluorine, methyl- .

Trifluoromethyl or methoxy, R ^{3 is} methyl, R ^{4 is} methyl and R ^{5 is} hydrogen.

Particular preference is given to compounds of the general formula (I) in which A is -NH-, X is -CH- or -N-, Y is -CH-, n is 0 or 1, R ^{2 is} hydrogen Is methyl or methoxy, R ^{3 is} methyl, R ^{4 is} methyl and R ^{5 is} hydrogen. Particular preference is given to compounds of the general formula (I) in which A is -NH-, X is -CH-, Y is -CH-, n is 0 or 1, R ^{2 is} hydrogen, methyl or methoxy - R ^{3 is} methyl, R ^{4 is} methyl and R ^{5 is} hydrogen.

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. Particular preference is furthermore given to the following compounds of the general

Formula (I):

(3R) -13-dimethyl-6- {[4- (propan-2-ylsulphonyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3- b] pyrazin-2 (lH) -one;

(3R) -l, 3-Dimethyl-6- {[4- (methylsulfonyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -6 - [(4-Bromophenyl) amino] -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (lH) -one;

(3R) -6- {[4- (3,5-dimethyl-l, 2-oxazol-4-yl) -phenyl] -amino} -l, 3-dimethyl-4- (tetrahydro-2H-pyran-4-yl ) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one;

(3R) -6- {[4- (4-Ethyl-piperazin-1-yl) -phenyl] -amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one;

(3R) -l, 3-dimethyl-6 - ({4- [4- (propan-2-yl) -piperazin-1-yl] -phenyl} -amino) -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one;

(3R) - 1, 3-Dimethyl-4- (tetrahydro-2H-pyran-4-yl) -6- ({4- [4- (2,2,2-trifluoroethyl) piperazin-1-yl] -phenyl} amino) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; 5- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3-b] pyrazine 6-yl] amino} pyridine-2-carbonitrile

(3R) -4-Cycloheptyl-1,3-dimethyl-6- {[4- (methylsulfonyl) phenyl] amino} -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one;

(3R) -l, 3-Dimethyl-4- (1-methylpiperidin-4-yl) -6- {[4- (methylsulfonyl) phenyl] amino} -3,4-dihydropyrido [2,3-b] pyrazine 2 (lH) -one;

(3R) -6- {[2-Methoxy-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazin-2 (lH) -one;

(3R) -4-Isopropyl-6- {[4- (isopropylsulfonyl) phenyl] amino} -1,3-dimethyl-3,4-dihydropyrido [2,3- b] pyrazin-2 (lH) -one;

(3R) -6- ({4 - [(Difluoromethyl) sulfonyl] phenyl} amino) -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3 -b] pyrazin-2 (lH) -one;

2 - [(4- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3- b] pyrazine-6-yl] amino} phenyl) sulfonyl] propanenitrile;

[(4- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3-b] pyrazine-6-yl] amino} phenyl) sulfonyl] acetonitrile;

(3R) -4-Cycloheptyl-1,3-dimethyl-6 - ({4 - [(1-methylpiperidin-4-yl) sulfonyl] phenyl} amino) -3,4-dihydropyrido [2,3-b] pyrazine -2 (lH) -one; (3R) -6- {[4- (2-azaspiro [3.3] hept-2-yl) -phenyl] -amino} -l, 3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one;

(3R) -l, 3-dimethyl-6- {[4- (2-oxa-6-azaspiro [3.3] hept-6-yl) -phenyl] -amino} -4- (tetrahydro-2H-pyran-4-yl ) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one;

(3R) -l, 3-dimethyl-6 - ({4 - [(lR, 5S) -8-oxa-3-azabicyclo [3.2.1] oct-3-yl] -phenyl} -amino) -4- (tetrahydro -2H-pyran-4-yl) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one;

(3R) -1,3-Dimethyl-6- ({4- [(1-methylpiperidin-4-yl) sulfonyl] phenyl} amino) -4- (tetrahydro-2H-pyran-4-yl) -3,4 -dihydropyrido [2,3-b] pyrazin-2 (lH) -one;

(3R) -l, 3-dimethyl-6 - ({4 - [(1-methylpiperidin-4-yl) sulfinyl] phenyl} amino) -4- (tetrahydro-2H-pyran-4-yl) -3,4 -dihydropyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -l, 3-dimethyl-6- {[2-methyl-4- (4-methyl-piperazin-1-yl) -phenyl] -amino} -4- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one;

(3R) -1,3-dimethyl-6- {[4- (morpholin-4-yl) -2- (trifluoromethyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one;

/ V- (4- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3- b] pyrazine-6-yl] amino} phenyl) - / V-methylacetamide; 6 - [(4- {4- [2- (dimethylamino) ethyl] piperazin-1-yl} phenyl) amino] -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; 6- {[2-Methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -amino} -13-dimethyl-4- (tetrahydro-2H-yl) -3,4-dihydropyrido [2,3-b] pyrazine -2 (lH) -one;

1,3-Dimethyl-6- {[4- (1-methylpiperidin-4-yl) -phenyl] -amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazin-2 (lH) -one;

6- {[4- (4-Acetyl-piperazin-1-yl) -phenyl] -amino} -13-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazin-2 (lH) -one;

(3R) - 1, 3-Dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazine-2 (1H) -one;

(3S) - 1, 3-Dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -

3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one; (3R) -6- {[4- (4-Acetylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one;

(3S) -6- {[4- (4-acetylpiperazin-1-yl) phenyl] amino} - 1, 3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one;

(3R) -6- {[2-Fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazine-2 (1H) -one, and

(3S) -6- {[2-Fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazin-2 (lH) -one; as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts. definitions:

By Ci-Cö-alkyl, or a Ci-Cö-alkyl group is meant a linear or branched, saturated, monovalent hydrocarbon radical, such. a methyl, ethyl, propyl, butyl, pentyl, hexyl, where-propyl, where-butyl, sec-butyl, tert-butyl, where-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-dimethylbutyl,

1,3-dimethylbutyl or 1,2-dimethylbutyl radical.

Preferably, Ci-Cö-alkyl or a Ci-Cö-alkyl group Ci-C4-alkyl, C2-C4-alkyl or C ₂ -Cs-alkyl, more preferably Ci-C3-alkyl or a methyl, ethyl , Propyl or isopropyl radical to understand.

C ₂ -C -alkylene, or a C ₂ -C -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, or propylene -, where-butylene, sec-butylene, ieri-butylene, where-pentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropylene, 1,2-dimethylpropylene, eo-pentylene or

1, 1-dimethylpropylene radical. By C2-C4-alkenyl, or a C2-C4-alkenyl group is meant a linear or branched, monovalent hydrocarbon radical having one or two C = C double bonds, such as an ethenyl, (£) -prop-2 -enyl, (Z) -prop-2-enyl, allyl (prop-l-enyl), allenyl-buten-1-yl, or buta-l, 3-dienyl radical. Preferred are ethenyl and allyl. C ₂ -C 4 -alkynyl, or a C ₂ -C 4 -alkynyl group, is to be understood as meaning a linear or branched, monovalent hydrocarbon radical having a C = C triple bond, such as, for example, an ethynyl, propargyl (propyl) inyl), or butyn-1-yl radical. Preferred are ethynyl and propargyl.

A C 1 -C 4 -alkoxy or C 1 -C 4 -alkoxy group is to be understood as meaning a linear or branched, saturated alkyl ether radical -O-alkyl, for example a methoxy, ethoxy, n-propoxy, isopropoxy or ieri.-butoxy radical.

C 1 -C 4 -alkoxy or C 1 -C 4 -alkoxy is preferably understood to mean C 1 -C 3 -alkoxy, particularly preferably a methoxy or ethoxy radical. C 1 -C 4 -alkylthio or a C 1 -C 4 -alkylthio group is to be understood as meaning a linear or branched, saturated alkylthioether radical -S-alkyl, for example a methylthio, ethylthio, n-propylthio, isopropylthio, or ferric butyl residual. Preferably, C 1 -C ₄ -alkylthio or a C 1 -C ₄ -alkylthio group is understood to mean C ₁ -C ₃ -alkylthio, particularly preferably a methylthio or ethylthio radical.

A C ₁ -C ₃ -alkylamino or a C ₁ -C ₃ -alkylamino group is understood to mean an amino radical having one or two (independently selected) alkyl substituents having 1 to 3 carbon atoms as defined above.

(C ₁ -C ₃ ) -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms per molecule

Alkyl substituent.

Examples include:

Methylamino, ethylamino, n-propylamino, isopropylamino, N-dimethylamino, N, V-diethylamino, ethylmethylamino, / V-methyl-Nn-propylamino and isopropyln-propylamino , By a heteroatom is meant -O-, NH-, = N- or -S-, including its oxidized forms -S (= 0) - and -S (= 0) 2- and one of -S (= 0) 2- derived sulfoximine -S (= 0) (= NH) -. The heteroatom -NH- can optionally be substituted by C ₁ -C ₃ -alkyl,

C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, or -S (= O) 2-C 1 -C 3 -alkyl. The NHNH of the abovementioned sulfoximine may optionally be substituted by C ₁ -C ₃ -alkyl,

C ₁ -C ₃ -alkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl-.

 Preference is given to an oxygen or a nitrogen atom.

By oxo, or an oxo substituent is meant a double 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 is to form a carbonyl group.

 Preference is further given to the binding of two double-bonded oxygen atoms to sulfur below

Formation of a sulfonyl group - (S = 0) 2-. By halogen is meant fluorine, chlorine, bromine or iodine.

Fluorine, chlorine, bromine or iodine which is optionally substituted on the phenyl ring can be in the ortho, meta or ortho position. Preference is given to fluorine or chlorine.

The preferred position is the meta and / or ara position.

A halogeno-C 1 -C ₄ -alkyl radical is a C 1 -C ₄ -alkyl radical having at least one

Halogen substituents, preferably having at least one fluorine substituent to understand. Preference is given to fluoro-C 1 -C 3 -alkyl radicals, for example difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl.

By phenyl-C 1 -C 3 -alkyl is meant a group which is composed of an optionally substituted phenyl radical and a C 1 -C 3 -alkyl group and which are bonded via the C 1 -C 3 -alkyl group to the rest of the molecule is. Benzyl is preferred.

A halo-C 1 -C 4 -alkoxy radical is a C 1 -C 4 -alkoxy radical having at least one

Halogen substituents, preferably having at least one fluorine substituent to understand.

Preference is given to fluoro-C 1 -C 3 -alkoxy radicals, for example difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy radicals.

A halogeno-C 1 -C 4 -alkylthio radical is to be understood as meaning a C 1 -C 4 -alkylthio radical having at least one halogen substituent, preferably having at least one fluorine substituent.

Preference is given to fluorine-C 1 -C 3 -alkylthio radicals, in particular trifluoromethylthio radicals.

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

Preferred is methoxycarbonyl, ethoxycarbonyl, and ferric. Butoxycarbonyl.

A C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl radical is to be understood as meaning a C 1 -C 4 -alkyl radical substituted by C 1 -C 4 -alkoxy, such as, for example, B.Methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl.

By aryl is meant an unsaturated fully conjugated system made up of carbon atoms which has 3, 5 or 7 conjugated double bonds, e.g. Phenyl, naphthyl or phenanthryl. Preference is given to phenyl. Heteroaryl is to be understood as meaning ring systems which have an aromatic-conjugated ring system and contain at least one and up to five heteroatoms as defined above. These ring systems may have 5, 6 or 7 ring atoms or, in the case of condensed or benzo-fused ring systems, also combinations of 5- and 6-membered ring systems, 5- and 5-membered ring systems or also 6- and 6-membered ring systems , Examples include ring systems such as pyrrolyl, pyrazolyl,

Imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, indolyl, benzimidazolyl, Indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzofuryl, benzothienyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, imidazopyridinyl or benzoxazinyl. Preference is given to 5- to 6-membered monocyclic heteroaryl, for example pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl.

 Also preferred is 5-membered monocyclic heteroaryl, for example, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl.

By C3-C6-cycloalkyl, C3-Cs-cycloalkyl, or Cs-Cs-cycloalkyl is meant a monocyclic, built exclusively from carbon atoms, saturated ring system having 3 to 6, 3 to 8 atoms, or 5 to 8 atoms. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Under C t -C 6 -cycloalkenyl, C t -Cs -cycloalkenyl, or Cs-Cs-cycloalkenyl is a monocychal, monocyclic or polyunsaturated, non-aromatic ring system with 4 to 6, 4 to 8 atoms, or exclusively composed of carbon atoms, respectively To understand 5 to 8 atoms. Examples are cyclobuten-1-yl, cyclopenten-1-yl, cyclohexene-2-yl, cyclohexene-1-yl and cycloocta-2,5-dienyl.

Heterocycloalkyl is to be understood as meaning a 4- to 8-membered monocyclic, saturated ring system which has 1 to 3 heteroatoms as defined above, in any desired combination. Preference is given to 4- to 7-membered heterocycloalkyl groups, particularly preferred are 5- to 6-membered heterocycloalkyl groups. By way of example, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, azepanyl, morpholinyl,

Thiomorpholinyl and piperazinyl.

Under Heterospirocycloalkyl- is a bicyclic, saturated ring system with a total of 6 to 11 ring atoms to understand in which the two rings share a common atom, and which has 1 to 3 heteroatoms as defined above, in any combination. Examples are azaspiro [2.3] hexyl, azaspiro [3.3] heptyl, oxaazaspiro [3.3] heptyl,

Thiaazaspiro [3.3] heptyl, oxaspiro [3.3] heptyl, oxazaspiro [5.3] nonyl, oxazaspiro [4.3] octyl, oxazaspiro [5.5] undecyl, diazaspiro [3.3] heptyl, thiazaspiro [3.3] heptyl, thiazaspiro [4.3] octyl, azaspiro [5.5] decyl.

By Heterobicycloalkyl- is a bicyclic, saturated ring system with altogether 6 to 10 To understand ring atoms in which the two rings share two directly adjacent atoms, and which has 1 to 3 heteroatoms as defined above, in any combination. Examples are azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl,

Diazabicyclo [4.3.0] nonyl, oxazabicyclo [4.3.0] nonyl, thiazabicyclo [4.3.0] nonyl or

Azabicyclo [4.4.0] decyl.

By "bridged heterocycloalkyl-" is meant a bicyclic, saturated ring system having a total of 6 to 10 ring atoms, in which the two rings share two two atoms which are not directly adjacent to each other, and which has 1 to 3 heteroatoms as defined above, in any combination. Examples are azabicyclo [2.2.1] heptyl,

Oxazabicyclo [2.2.1] heptyl, thiazabicyclo [2.2.1] heptyl, diazabicyclo [2.2.1] heptyl,

Azabicyclo [2.2.2] octyl, diazabicyclo [2.2.2] octyl, oxazabicyclo [2.2.2] octyl,

Thiazabicyclo [2.2.2] octyl, azabicyclo [3.2.1] octyl, diazabicyclo [3.2.1] octyl,

Oxazabicyclo [3.2.1] octyl, thiazabicyclo [3.2.1] octyl, azabicyclo [3.3.1] nonyl,

Diazabicyclo [3.3.1] nonyl, oxazabicyclo [3.3.1] nonyl, thiazabicyclo [3.3.1] nonyl,

Azabicyclo [4.2.1] nonyl, diazabicyclo [4.2.1] nonyl, oxazabicyclo [4.2.1] nonyl,

Thiazabicyclo [4.2.1] nonyl, azabicyclo [3.3.2] decyl, diazabicyclo [3.3.2] decyl,

Oxazabicyclo [3.3.2] decyl, thiazabicyclo [3.3.2] decyl or azabicyclo [4.2.2] decyl. Heterocycloalkenyl is a 4- to 8-membered monocyclic, mono- or polyunsaturated, non-aromatic ring system which has 1 to 3 heteroatoms as defined above, in any desired combination. Preference is given to 4- to 7-membered heterocycloalkyl groups, particularly preferred are 5- to 6-membered heterocycloalkyl groups. Examples which may be mentioned are 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, [1,3] dioxolyl, 4H- [1,3,4] thiadiazinyl, 2,5-dihydrofuranyl, 2,3- Dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, and 4H- [1,4] thiazinyl.

Compounds of the invention are the compounds of the general formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas below and their salts, solvates and solvates of the salts of the general formula (I) and of the general formula (I) included, hereinafter referred to as exemplary embodiments

Compounds and their salts, solvates and solvates of the salts, as far as the compounds of the general formula (I) mentioned below are not already salts, solvates and solvates of the salts.

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

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

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, 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. Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs can be present either as a single polymorph or as a mixture of several polymorphs in all concentration ranges. The present invention also relates to pharmaceutical compositions containing the inventive

 Compounds together with at least one or more further active ingredients, in particular for the prophylaxis and / or therapy of tumor diseases.

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

The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers. The compounds of the invention can am

Carbon atom to which the substituents R ⁴ and R ^{5 are} bonded (C-3), a

Asymmetric center. They may therefore be present as pure enantiomers, racemates but also as diastereomers or mixtures thereof, if one or more of the substituents described in the formula (I) contains a further asymmetric element, for example a chiral carbon atom. The present invention therefore also encompasses diastereomers and their respective mixtures. From such mixtures, the pure stereoisomers in known Isolate way; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on chiral or achiral phase.

As a rule, the enantiomers according to the invention inhibit the different degrees of inhibition

Target proteins and are different active in the investigated cancer cell lines. The more active enantiomer is preferred, which is often that at which the center of asymmetry represented by the carbon atom attached to R ⁴ and R ^{5 is} (R) -configured.

Another object of the present invention are enantiomeric mixtures of the (3R) - configured compounds of the invention with their (3S) enantiomers, in particular the corresponding racemates and mixtures of enantiomers in which outweighs the (3R) 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 of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the

Compound according to the invention is exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass usually or predominantly occurring in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ^U C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ C1, ⁸² Br, ¹²³ 1, ¹²⁴ 1, ¹²⁹ I and ¹³¹ L Certain isotopic variants of a compound of the invention, such as in particular those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or distribution of active ingredient in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. In addition, the incorporation of isotopes, such as deuterium, may confer certain therapeutic benefits as a result of greater metabolic stability

Lead compound, 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 methods known to the person skilled in the art, for example by the methods described below and the instructions given in the exemplary embodiments, by corresponding isotopic modifications of the respective reagents and / or Starting compounds are used.

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

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

 (For example, intravenously, intraarterially, intracardially, intraspinal or intralumbar) or with the involvement of a resorption (for example, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration are suitable as application forms u.a.

Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are, for example, inhalant medicaments (including powder inhalers, Vernebier), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or

Ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, scattering powders, implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a manner known to those skilled in the art by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, but are not limited to, excipients (eg, microcrystalline cellulose, lactose, mannitol), solvents (For example, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example, sodium dodecyl sulfate, Polyoxysorbitanoleat), binders (for example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin),

Stabilizers (for example, antioxidants such as ascorbic acid), dyes (for example, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

Another object of the present invention are pharmaceutical compositions containing the compounds of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients and their use for the purposes mentioned above.

The formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se to the person skilled in the art by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.

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

Binders, humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents,

Colorants, preservatives, stabilizers, wetting agents, salts to change the osmotic pressure or buffers are used. Reference may be made to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).

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

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

As solid tumors according to the invention, for example, tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland, are treatable Bone and connective tissue and metastases of these tumors. For example, as a hematological tumor, multiple myelomas, lymphomas or leukemias are treatable.

Breast tumors, for example, are treatable breast cancers with positive breast cancers

Hormone receptor status, breast cancers with negative hormone receptor status, Her-2 positive breast cancers, hormone receptor and Her-2 negative breast cancers, BRCA-associated breast cancers and inflammatory breast cancer.

For example, non-small cell cancers are treatable as tumors of the respiratory tract

Bronchial carcinomas and small cell lung carcinomas.

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

 Prostate carcinomas, malignant epididymal tumors, malignant testicular tumors and penile carcinomas.

For example, tumors of the female reproductive organs are treatable

Endometrial carcinoma, cervical carcinoma, ovarian carcinoma, vaginal carcinoma and

Vulvarkarzinome. For example, treatable tumors of the gastrointestinal tract are colorectal carcinomas, anal carcinomas, gastric carcinomas, pancreatic carcinomas, esophageal carcinomas.

Gallbladder carcinomas, small bowel carcinomas, salivary gland carcinomas, neuroendocrine tumors and gastrointestinal stromal tumors.

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

For example, tumors of the eye are treatable retinoblastomas and intraocular Melanoma.

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

For example, treatable tumors of the skin are malignant melanomas, basaliomas,

Spinaliomas, Kaposi's sarcomas and Merkel cell carcinomas.

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

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

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

Treatable as leukemias, for example, are acute myeloid leukemias, chronic myeloid leukemias, acute lymphatic leukemias, chronic lymphocytic leukemias and hair cell leukemias. Advantageously, the compounds according to the invention can be used for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias,

Prostate cancer, especially androgen receptor-positive prostate cancer,

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

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

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

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

The compounds according to the invention are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as, for example, endometriosis, leiomyoma and benign prostatic hyperplasia. The compounds according to the invention are also suitable for the prophylaxis and / or therapy of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.

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

Pulmonary diseases with inflammatory, allergic and / or proliferative

 Associated processes: chronic obstructive pulmonary disease of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatoses, in particular Boeck's disease, - Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes: all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms in degenerative joint disease

 (Arthroses); traumatic arthritis; Collagenosis of any genesis, for example systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren's syndrome, still syndrome, Felty syndrome,

Allergies associated with inflammatory and / or proliferative processes: all forms of allergic reactions, such as Quincke's edema, hay fever,

 Insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis,

Vasculitides: Panarteritis nodosa, temporal arteritis, erythema nodosum,

Dermatological disorders associated with inflammatory, allergic and / or

 associated with 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 eczema; rosacea; Pemphigus vulgaris; Erythema exudative multiforme; balanitis; vulvitis; Hair loss such as alopecia areata; cutaneous T-cell lymphoma,

Kidney diseases associated with inflammatory, allergic and / or proliferative processes: nephrotic syndrome; all nephritis, Liver diseases associated with inflammatory, allergic and / or proliferative processes: acute liver cell decay; acute hepatitis of various causes, such as viral, toxic, drug-induced; chronic aggressive and / or chronic intermittent hepatitis,

Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes: regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, for example, gluten-sensitive enteropathy (native sprue),

Proctological diseases associated with inflammatory, allergic and / or proliferative processes: analgesic; fissures; Hemorrhoids; idiopathic proctitis,

Eye diseases associated with inflammatory, allergic and / or proliferative processes: allergic keratitis, uveitis, iritis; conjunctivitis; blepharitis; Neuritis nervi optici; Chlorioditis; Opthalmia sympathica,

Diseases of the ear, nose and throat, which are associated with inflammatory, allergic and / or proliferative processes: allergic rhinitis, hay fever; Otitis externa, for example due to contact xem, infection, etc .; Otitis media,

Neurological diseases associated with inflammatory, allergic and / or proliferative processes: brain edema, especially tumor-related cerebral edema; multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, such as BNS cramps,

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

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

Endocrine disorders associated with inflammatory, allergic and / or proliferative processes: endocrine orbitopathy; thyrotoxic crisis; Thyreoditis de Quervain; Hashimoto's thyroiditis; Graves' disease,

Organ and tissue transplants, graft-versus-host disease,

Severe states of shock, such as anaphylactic shock, systemic inflammatory response syndrome (SIRS),

Substitution therapy for: congenital primary adrenal insufficiency, e.g. Congenital adrenogenital syndrome; acquired primary adrenal insufficiency, e.g. Addison's disease, autoimmune adrenalitis, for example, postinfectious, tumors, metastases, etc; Congenital secondary adrenal insufficiency, such as congenital

 hypopituitarism; acquired secondary adrenal insufficiency, for example, postinfectious, tumors, etc.,

Emesis associated with inflammatory, allergic and / or proliferative processes, for example in combination with a 5-HT3 antagonist in cytostatic vomiting,

Pain of inflammatory genesis, e.g. Lumbago.

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

Diseases such as infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses. The compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, peripheral vascular disorders, cardiovascular disorders, angina, pectoris, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.

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

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

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

Another object of the present invention relates to the use of

Compounds according to the invention as medicaments, in particular for the prophylaxis and / or therapy of tumor diseases.

Another object of the present invention relates to the use of

Compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular

Androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, especially of hormone receptor-negative, hormone receptor-positive or BRCA-associated Breast carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma,

Endometrial carcinomas and colorectal carcinomas.

Another object of the present invention relates to the use of

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 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 relates to the use of

Compounds according to the invention for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases.

Another object of the present application relates to the use of

Compounds according to the invention for the production of a medicament for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas,

Breast cancer, in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinoma, pancreatic carcinoma, renal cell carcinoma,

Hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal carcinomas.

Another object of the present invention relates to the use of

Compounds according to the invention for the preparation of a medicament for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, breast carcinomas, in particular estrogen receptor-alpha negative breast carcinomas, melanomas or multiple myelomas.

Another object of the present invention relates to the use of

Compounds according to the invention for the prophylaxis and / or therapy of tumor diseases.

Another object of the present invention relates to the use of

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, cervical carcinomas, breast cancers, especially of hormone receptor-negative, hormone receptor-positive or BRCA-associated Breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas,

Endometrial carcinoma and colorectal carcinoma.

Another object of the present invention relates to the use of

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 carcinoma, melanoma or multiple myeloma.

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

Prostate 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, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal

Carcinomas.

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

Prostate cancer, especially androgen receptor-positive prostate cancer,

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

Another object of the invention relates to the use of the invention

Compounds for the treatment of diseases associated with proliferative processes.

Another object of the invention relates to the use of the invention

Compounds for the treatment of benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and

neurodegenerative diseases. The compounds according to the invention can be used alone or as needed in combination with one or more further pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. Another object of the present invention are therefore pharmaceutical compositions containing a novel Compound and one or more other active ingredients, in particular for the prophylaxis and / or therapy of the aforementioned diseases.

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

As suitable combination active ingredients may be mentioned by way of example, without this enumeration being conclusive:

Abiraterone acetate, abraxane, acolbifen, actimmun, actinomycin D (dactinomycin), afatinib, affinitak, afinitor, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, alpharadine, altretamine, amino-iglutethimide, aminopterin, amifostine, amrubicin, amsacrine , Anastrozole, Anzmet, Apatinib, Aranesp, Arglabine, Arsenic trioxide, Aromasin, Arzoxifen, Asoprisnil, L-asparaginase, Atamestan, Atrasentan, Avastin, Axitinib, 5-Azacytidine, Azathioprine, BCG or tice-BCG, Bendamustine, Bestatin, Beta methasone acetate, betamethasone sodium phosphate, bexarotene, bicalutamide, bleomycin sulfate, broxuridine, bortezomib, bosutinib, busulfan, cabazitaxel, calcitonin, campath, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, Casodex, CCI-779, CDC-501 , Cediranib, cefeson, celebrex, celmoleukin, cerubidine, cediranib, chlorambucil, cisplatin, cladribine, clodronic acid, clofarabine, colaspase, copanlisib, corixa, crisnatol, crizotinib, cyclophosphamide, cyproterone acetate, cytarabine , Dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, DaunoXome, Decadron, Decadron Phosphate, Decitabine, Degarelix, Delestrogen, Denileukin Diftitox, Depomedrol, Deslorelin, Dexrazoxane,

Diethylstilbestrol, diflucan, 2 ', 2'-difluorodoxycytidine, DN-101, docetaxel, doxifluridine, doxo-irubicin (adriamycin), dronabinol, dSLIM, dutasteride, DW-166HC, edotecarin,

 Eflornithine, Eligard, Elitek, Ellence, Emend, Enzalutamide, Epirubicin, Epoetin-alfa, Epogen, Epothilone and its Derivatives, Eptaplatin, Ergamisol, Erlotinib, Erythro-Hydroxynonyladenine, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinylestradiol, Ethyol, Etidronic Acid,

Etopophos, etoposide, everolimus, exatecan, exemestane, fadrozole, farston, fenretinide, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), flu-ioxy-imesterone, flutamide , Folotin, Formestan, Fosteabin, Fotemustin, Fulvestrant, Gammagard, Gefitinib, Gemcitabine, Gemtuzumab, Gleevec, Gliadel, Goserelin, Gossypol, Granisetron hydrochloride, Hexamethylmelamine, Histamine dihydrochloride, Histrelin, Holmium-166-DOTPM, Hycamtin, Hydrocorton, erythro Hydroxynonyladenine, hydroxyurea, hydroxyprogesterone caproate, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide,

Imatinib, iniparib, interferon alpha, interferon alpha 2, interferon alpha 2a, interferon alpha 2ß, Interferon-alpha-nl, Interferon-alpha-n3, Interferon-beta, Interferon-gamma-αα, Interleukin-2, Intron A, Iressa, Irinotecan, Ixabepilone, Keyhole limpet Hemocyanin, Kytril, Lanreotide, Lapatinib, Lasofoxifen, Lenalidomide, Lentinan Sulfate, lestaurtinib, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolic acid calcium salt, levothroid, levoxyl, libra, liposomal MTP-PE, lomustine, lonafarnib, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol Acetate, melphalan, menest, 6-mercaptopurine, mesna, methotrexate, metvix, miltefosine, minocycline, minodronate, miproxifen, mitomycin C, mitotane, mitoxantrone, modrenal, MS-209, MX-6, myocet, nafarelin, nedaplatin, nelarabine, nemorubicin , Neovastat, Neratinib, Neulasta, Neumega, Neupogen, Nilotimib, Nilutamide, Nimustin, Nolatrexed, Nolvadex, NSC-631570, Obatoclax, Oblimersen, OCT-43, Octreotide, Olaparib, Ondansetron hydrochloride, Onko-TCS, Orapred, Osidem, Oxaliplatin , Paclitaxel, pamidronate dinatr ium, pazopanib, pediapred, pegaspargase, pegasys, pemetrexed, pentostatin, N-phosphonoacetyl-L-aspartate, picibanil, pilocarpine hydrochloride, pirarubicin, plerixafor, plicamycin, PN-401, porfimer sodium, prednimustine, prednisolone, prednisone, Premarin, Procarbazine, Procrit, QS-21, Quazepam, R-1589, Raloxifene, Raltitrexed, Ranpirnas, RDEA119, Rebif, Regorafenib, 13-cis Retinoic Acid, Rhenium 186 Etidronate, Rituximab, Roferon-A, Romidepsin, Romurtide, Ruxolitinib, Salagen, Salinomycin, Sandostatin, Sargramostim, Satraplatin, Semaxatinib, Semustin, Seocalcitol, Sipuleucel-T, Sizofiran, Sobuzoxan, Solu-Medrol, Sorafenib, Streptozocin, Strontium-89 chloride, Sunitinib, Synthroid, T-138067, Tamoxifen, Tamsulosin, Tarceva, Tasonermin, Tastolactone, Taxoprexin, Taxoter, Teceleukin, Temozolomide, Temsirolimus, Teniposide, Testosterone Propionate, Testred, Thalidomide, Thymosin-alpha-1, Thioguanine, Thiotepa, Thyrotropin, Tiazorufin,

Tiludronic acid, tipifarnib, tirapazamine, TLK-286, toceranib, topotecan, toremifene,

Tositumomab, Tastuzumab, Teosulfan, TransMID-107R, Tretinoin, Trexall, Trimethylmelamine, Trimetrexate, Triptorelin Acetate, Triptorelin Pamoate, Trofosfamide, UFT, Uridine, Valrubicin, Valspodar, Vandetanib, Vapreotide, Vatalanib, Vemurafinib, Verte-porfin, Vesnarinone, Vinblastine, Vincristine, Vindesine, Vinflumine, Vinorelbine, Virulizine, Vismodegib, Xeloda, Z-100, Zinecard, Zinostatin Stimalamer, Zofran, Zoledronic Acid

In particular, the compounds of the invention can be reacted with antibodies such as e.g.

Aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab,

Combine denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, ofatumumab, panitumumab, pertuzumab, rituximab, tositumumab or trastuzumab and with recombinant proteins.

In particular, the compounds of the invention can be used in combination with anti-angiogenic therapies such as bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib, lenalidomide, copanlisib or thalidomide. Combinations with antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.

Combinations with P-TEFb and CDK9 inhibitors are also particularly suitable because of the possible synergistic effects. 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 to use the chemotherapeutic agents used in lower doses than in monotherapy;

• the possibility of a more tolerable therapy with fewer side effects compared to a single dose;

• the ability to treat a wider range of tumors; · Achieving a higher response rate to therapy;

• longer patient survival compared to today's standard therapy.

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

Preparation of the compounds according to the invention:

In the present specification mean: NMR signals are given with their respective recognizable multiplicity or their combinations. Where s = singlet, d = doublet, t = triplet, q = quartet, qi = quintet, sp = septet, m = multiplet, b = broad signal. For example, signals with combined multiplicity are given as dd = doublet of doublet. The chemical shifts δ are given in ppm (parts per million). ACN acetonitrile

 BOC ieri-butoxycarbonyl

 Eg example

 (+) - BINAP (R) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (CAS 76189-55-4)

(+) - BINAP 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (racemic, CAS 98327-87-8) CDCl3 deuterochloroform

 CHAPS 3- {Dimethyl [3- (4- {5,9,16-trihydroxy-2,15-dimethyltetracyclo

 [8.7.0.02,7.011, 15] heptadecan-14-yl} pentanamido) propyl] azaniumyl} propane-1-sulfonate

 DAD diode array detector

dba dibenzylideneacetone

 DCC dicyclohexylcarbodiimide

 DMA V, V-dimethylacetamide

 DMF V, V-Dimethylformamide

 DMSO-d6 deuterated dimethyl sulfoxide

DMSO dimethyl sulfoxide

 EE ethyl acetate

 FCS fetal calf albumin

 H ATU (7-aza- 1H-benzotriazole-1-yl) -1,3,3,3-tetramethyluronium

 hexafluorophosphate

HEPES 2- {4- (2-hydroxyethyl) -l-piperazinyl} -ethanesulfonic acid

 HPLC high pressure liquid chromatography

 KOtBu potassium ferric butoxide

 LCMS liquid chromatography coupled with mass spectrometry

 RP-HPLC Reversed Phase High Pressure Liquid Chromatography

RT room temperature

 Retention time

T3P 2,4,6-tripropyl-1, 3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBTU (benzotriazole-1-ylxy) bis-dimethylaminomethylium fluoroborate

THF tetrahydrofuran

 TFA trifluoroacetic acid

 UPLC Ultra high performance chromatography

Xanthphos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene

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

In the following, general methods which are used for the preparation of the compounds of the general formula (I) according to the invention are described with reference to the Schemes 1, 2, 3 and 4. In addition to the synthetic sequences described in the above-mentioned schemes, according to the general knowledge of those skilled in organic chemistry, further synthetic routes for the synthesis of compounds of the general formula (I) according to the invention can be followed. The order of the synthetic steps shown in the following schemes is not binding, and synthetic steps from various of the schemes shown below may optionally be combined into new sequences. In addition, interconversions of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ can be carried out before or after the synthesis steps shown. Examples of such transformations are the introduction or removal of protective groups, reduction or oxidation of functional groups, reductive amination, 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 removal are known to those skilled in the art (see, for example, T.W. Greene and P.G.M. Wuts in: Protective Groups in Organic Synthesis, 3rd Edition, Wiley 1999). 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, in which different substituents R ⁴ and R ⁵ are present, are chiral and can be used as

Enantiomerengemische, for example racemates, or occur as pure enantiomers. The enantiomer mixtures mentioned can be prepared by those familiar to the person skilled in the art

Separation methods, such as preparative HPLC on a chiral stationary phase, separate into the enantiomers. Scheme 1 illustrates the construction of intermediates of formula (VIII) from simple

Pyridine derivatives such as 3-amino-2,6-dichloropyridine ((II), CAS No. 62476-56-6). For this purpose, nitrogen atom-protected amino acids of the formula (III) in which R ⁴ and R ^{5 are} defined as in the general formula (I), and in which PG is a protective group such as Boc, Cbz or Fmoc, with suitable aminopyridine Derivatives, for example, 3-amino-2,6-dichloropyridine ((II), CAS No. 62476-56-6). These are known to the skilled person

Coupling reagents such as T3P, TBTU, HATU or DCC used. The conversion of carboxylic acids to their amides is generally described in reference books such as "Compendium of Organic Synthetic Method ", Volume I-VI (Wiley Interscience) or" The Practice of Peptide Synthesis ", Bodansky (Springer Verlag). Compounds of the formula (III) are known to the person skilled in the art and are commercially available. The compounds of the formula (IV) obtained are then converted by deprotection of the protective group PG on the amine by suitable methods to give the compounds of the formula (V). For this purpose, a variety of methods are known, which can be read in standard works (see eg TW Greene and PGM Wuts in: Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). The further conversion to compounds of the formula (VI) with the introduction of the radical R ⁶ which is defined as for the general formula (I) can preferably be carried out by the reductive amination known to the person skilled in the art (for representative instructions, see, for example, US Pat. No. 101059590) AI). In this case, the primary amine (V), as a free base or in salt form, is reacted with an appropriate for the introduction of R ⁶ aldehyde or ketone in situ to an imine and this then by adding a suitable

Reductant such as sodium triacetoxyborohydride to the secondary amine of formula (VI) transformed. The secondary amines of the formula (VI) can be converted by cyclization to give dihydropyridopyrazinones of the formula (VII). For this purpose, it is possible to react compounds of the formula (VI) in the presence of a suitable base, for example a trialkylamine, such as triethylamine or diisopropylethylamine, under elevated temperature (see also WO2010 / 96426 A2, Example 16). The subsequent alkylation to compounds of formula (VIII) can be carried out by reaction with R ³ -LG wherein R ^{3 is} defined as in general formula (I) and wherein LG is a leaving group, preferably iodide or bromide, in the presence of a suitable Base such as sodium hydride, according to known to those skilled conditions.

Scheme 1: Synthesis of intermediates of formula (VIII) from 3-amino-2,6-dichloropyridine (II). The preparation of intermediates of the formula (VIIa) in which R ^{6 is} unsubstituted or substituted phenyl as defined for R ⁶ in the general formula (I) is described in Scheme 2.

3-Amino-2,6-dichloropyridine ((II), CAS No. 62476-56-6) is reacted with compounds of the formula (IX) in which R ⁴ and R ^{5 are} defined as for the general formula (I ), and in which LG and LG 'are each independently a leaving group, preferably chlorine or bromine, such as 2-bromopropionyl bromide (CAS 563-76-8). In this case, under conditions known to those skilled in the reaction with a geeineten solvent such as dichloromethane or THF and with the addition of a base such as triethylamine, -Diisopropylethylamin or pyridine implemented. The base can also be used as a solvent. In this case, compounds of the formula (X) are obtained. These intermediates (X) are reacted with anilines of the formula R ⁶ -NH ₂ , in which R ^{6 is} optionally substituted phenyl as defined for R ⁶ in the general formula (I), to give compounds of the formula (XI). This reaction can be carried out by reaction in various solvents such as toluene or acetonitrile and with the addition of a base such as potassium carbonate, A ^ -Diisopropylefhylamin or triethylamine at elevated temperature (Org. Lett. (2008), 10, p 2905 ff, SP Marsden et al.).

Dihydropyridopyrazinones of the formula (VIIa) in which R ^{6 represents} optionally substituted phenyl as defined for R ⁶ in the general formula (I) are obtained by

Cyclization of the compounds of formula (XI) in the presence of a suitable base such as triethylamine, A ^ -Diisopropylethylamin or potassium carbonate under elevated temperature in solvents such as dimethylformamide, A ^ -Dimethylacetamid, N-methylpyrrolidone or dimethyl sulfoxide (see also WO2010 / 96426 A2, Example 16). From these intermediates of formula (VIIa) can be prepared according to Schemes 1 and 3, the corresponding compounds of formula (I) according to the invention, in which R ^{6 is} optionally substituted phenyl according to the definition of R ⁶ in the general formula (I). The said compounds of the formula (I) are obtained as racemates, provided that R ⁴ and R ⁵ are different from one another. If appropriate, these can be separated into the enantiomers using the separation methods familiar to the person skilled in the art, for example preparative HPLC on a chiral stationary phase.

 (XI) (VIIa)

Scheme 2: Preparation of intermediates of formula (VIIa) from 3-amino-2,6-dichloropyridine (II).

The compounds of the formula (I) according to the invention are prepared according to Scheme 3. Here, compounds of the formula (VIII) can be reacted with compounds of the formula (XII) in which A, X, Y, R ¹ , R ² and n are defined as in of the general formula (I), in a palladium-catalyzed coupling reaction according to Buchwald and Hartwig, are converted directly to the compounds of the formula (I) according to the invention (for example in K. Malagu et al., Bioorg.Med.Chem.Lat., (2009 ), vol 19, p5950-53, P. Fernandez et al., WO2011 / 101644). In an alternative process variant, the chlorinated intermediates of the formula (VIII) can be obtained by reaction with an aminating reagent, for example 1,1-diphenylmethanimine (XIII), in the presence of a catalytically active palladium reagent, for example

Tris (dibenzylideneacetone) palladium (0) into which corresponding amines of formula (XIV) are converted (eg, in J. Kempson, Bioorg Med Med Chem (2009), vol 19, p2646-49). Hereinafter, in a palladium-catalyzed coupling reaction with compounds of the formula (XV) in which X, Y, R ¹ , R ² and n are defined as in the general formula (I), and in which LG is a leaving group, preferably iodo is, according to Buchwald and Hartwig directly to the compounds of formula (Ia) according to the invention are reacted, which is a subset of the general formula (I), with the proviso that A is -NH-.

Scheme 3: Preparation of the compounds of the formula (I) according to the invention from compounds of the formulas (VIII) and (XII).

Compounds of the formulas (XII) and (XV) are commercially available in many cases, or the

Compounds themselves or for their preparation suitable methods are the

Specialist known. For example, they can be obtained by reacting commercially available fluoro-nitroarenes of the formula (XVI) with appropriate substitution, e.g.

4-fluoronitrobenzene (CAS 350-46-9) or 2-fluoro-5-nitroanisole (CAS 454-16-0) with thiols of the formula R ⁷ -SH in which R ^{7 is} defined as in the general formula (I) For example, methanethiol, ethanethiol, propanethiol, propan-2-thiol, cyclopropanethiol or the other homologous thiols with the addition of a base such as sodium, cesium or potassium carbonate, triethylamine or sodium hydride (eg analogously U. Luecking et al., US2011 / 251222; Kondoh, et al., Tetrahedron (2006), vol 62, p2357-60). Thiols of the formula R ⁷ -SH are known to the person skilled in the art and are commercially available or are described in great structural variety.

In this case, compounds according to (XVII) are obtained in which X, Y, R ² , R ⁷ and n are defined as in the general formula (I). Compounds of the general formula (XVIII) in which X, Y, R ² , R ⁷ and n are defined as in the general formula (I) can be obtained by oxidation of the sulfur atom of the compounds of the formula (XVII) with suitable reagents such as Potassium peroxosulphate (Oxone®, CAS 70693-62-8), meto-chloroperbenzoic acid or

Hydrogen peroxide (eg analogous to JM Zapico, Org. Biomol. Chem., (2011), vol 9, P4587-99). The sulfones of the general formula (XVIII) can be obtained in pure form or as mixtures with the corresponding sulfoxides, which are known in the art let it separate.

For the preparation of compounds of the general formula (XIIa) in which AH is NH ₂ and X, Y, R ² , R ⁷ and n are defined as in the general formula (I), a reduction of the compounds known to those skilled in the art (XVIII) with hydrogen and a suitable catalyst or the use of iron, zinc or tin dichloride as a reducing agent. Palladium or platinum, which may be fixed on various heterogeneous supports such as activated carbon, aluminum oxide or other common supports, or also, for example, Raney nickel, are suitable as catalyst for the reduction with hydrogen. The reduction of the nitro group using a metal or metal salt is often carried out with the addition of an acid such as hydrochloric acid, acetic acid or ammonium chloride.

 Compounds of the general formula (XII) in which A is -N (C 1 -C 3 -alkyl) - corresponding to general formula (I) can be prepared by reaction of compounds of the formula (XIIa) generally known to the person skilled in the art with corresponding aldehydes, such as formaldehyde , Acetaldehyde or propionate dehyd and a reducing agent such as Sodium triacetoxyborohydride or sodium cyanoborohydride, or also by reduction with hydrogen and a corresponding catalyst, e.g. Palladium be obtained on activated carbon.

 Compounds of the general formula (XII) in which A represents -O- corresponding to the general formula (I) can be obtained by reactions which are generally known to the person skilled in the art

Compounds of formula (Xlla) can be obtained for example with sodium nitrite in aqueous acidic solution and subsequent heating with a copper catalyst. This reaction is generally known to those skilled in the art as the Sandmeyer reaction.

(XVI) (XVII) (XVIII) (XIIa) Scheme 4: Preparation of intermediates of formula (XIIa) from compounds of formula (XVI). Amines of the general formula (XIX) in which A, X, Y, R ² , R ¹⁰ , R ¹¹ and n are defined as in the general formula (I) are known to the person skilled in the art, are often commercially available or known from the literature, and can be described with US Pat those skilled in the art, as described for some of the intermediates of formula (XIX) in the Experimental part, are obtained.

 (XIX)

 embodiments

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

First, the preparation of the intermediates will be described, which are finally preferably used for the preparation of the compounds of the invention. IUPAC names were created using the nomenclature software ACD Name batch, version

12.01, from Advanced Chemical Development, Inc., and adapted as needed, for example, to the German-speaking nomenclature.

Stoichiometry of salt forms

When a compound in the form of a salt of the corresponding base or acid is listed in the synthesis intermediates and embodiments of the invention described below, the exact stoichiometric composition of such a salt, as according to the respective preparation and / or purification process was received, 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, the stoichiometric composition (if defined type) is not known. Preparation of the intermediates

Intermediate 1:

 N- (2,6-dichloropyridin-3-yl) -D-alanineamide hydrochloride

 HCl

A solution of 50 g of 3-amino-2,6-dichloropyridine (CAS62476-56-6) and 56.3 g of D-Boc-alanine in 400 ml of pyridine was slowly added at 0 ° C with a 886 ml of a 50% solution of T3P ( in

Ethyl acetate). The mixture was further stirred for 4 hours at 0 ° C and 16 hours at RT. It was added to ice-water and cautiously treated with potassium carbonate until the solution was basic. The batch was extracted with ethyl acetate, the organic phase washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated completely in vacuo. 73 g of {(2R) -1 - [(2,6-dichloropyridin-3-yl) amino] -1-oxopropan-2-yl} tert-butylcarbamate were obtained. These were taken up in 370 ml dioxane and concentrated at RT with 89 ml conc.

Hydrochloric acid added. It was 90 min. stirred at RT, treated with 1000 ml of ethyl acetate and the pH adjusted alkaline with sodium hydroxide. The suspension was decanted, the phases were separated and the organic phase was concentrated completely in vacuo. The residue was taken up in diethyl ether and treated slowly with 260 ml of IN HCl (solution in diethyl ether). The mixture was cooled to 0 ° C and the precipitate was filtered off with suction. The precipitate was washed with a little diethyl ether and dried in a drying oven. 45.6 g of N- (2,6-dichloropyridin-3-yl) -D-alanineamide hydrochloride were obtained.

1 H NMR (400 MHz, DMSO-d 6): δ = 1.50 (d, 3H); 4.23 (bq, 1H); 7.63 (d, 1H); 8.15 (d, 1H); 8.42 bs, 1H); 10.58 (s, 1H).

Intermediate 2:

 N- (2,6-dichloropyridin-3-yl) -N (tetrahydro-2H-pyran-4-yl) -D-alaninamide

A suspension of 20 g of Intermediate 1 and 9.6 g of tetrahydro-4H-pyran-4-one in 1.07 L

Dichloromethane was added at 0 ° C with 12.1 g of sodium acetate and 47 g of sodium triacetoxyborohydride. It was stirred for 16 hours while warming to RT. The reaction was carefully poured into saturated aqueous sodium bicarbonate solution and stirred. The phases were separated and the aqueous phase extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was removed completely in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient). (Tetrahydro-2H-pyran-4-yl) -D-alaninamide - 15 g / V- (2,6-Dichloro-pyridin-3-yl) -A ^r2 was obtained.

Ή NMR (400 MHz, CDCL): δ = 1.35-1.57 (m, 2H); 1.44 (d, 3H); 1.84 (dq, 1H); 1.95 (dq, 1H); 2.63-2.82 (m, 1H); 3.38 (td, 1H); 3.45 (q, 1H); 3.91-4.08 (m, 2H); 7.28 (d, 1H); 8.84 (d, 1H).

Intermediate 3:

 (3A) -6-chloro-3-methyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one

A solution of 7.8 g of intermediate 2 and 31.7 ml / V-Diisopropylefhylamin in 170 ml of DMF was distributed to 4 individual, sealed pressure vessels and they were heated for 10 hours at 175 ° C bath temperature. The solutions were re-combined after cooling to RT, diluted with ethyl acetate and extracted three times with half-saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent was completely removed in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol gradient). This gave 4.1 g of (3R) -6-chloro-3-methyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one ,

Ή-NMR (300 MHz, CDCl ₃ ): δ = 1.32 (d, 3H); 1.65 (d, 1H); 1.82 (dq, 1H); 1.98 (dq, 1H); 2.07 (d, 1H); 3.57 (qd, 2H); 4.03-4.12 (m, 2H); 4.25 (q, 1H); 4.55 (tt, 1H); 6.65 (d, 1H); 6.92 (d, 1H); 8.92 (s, 1H).

Intermediate 4:

 (3 f) -6-chloro-1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one

A solution of 3.2 g of Intermediate 3, 647 mg of sodium hydride (60% in white oil) and 1.01 ml of methyl iodide in 137 ml of DMF was stirred for 16 hours at RT. The reaction was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated ammonium chloride solution and semisaturated sodium chloride solution, dried over sodium sulfate and the solvent was removed completely in vacuo. 2.8 g of (3R) -6-chloro-1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) were obtained. -one. Ή-NMR (300 MHz, CDCL): δ = 1.24 (d, 3H); 1.66 (dq, 1H); 1.82 (dq, 1H); 1.97 (qd, 1H); 2.06 (dq, 1H); 3.32 (s, 3H); 3.57 (tdd, 2H); 4.01-4.13 (m, 2H); 4.32 (q, 1H); 4.55 (tt, 1H); 6.70 (d, 1H); 7.01 (d, 1H).

Chiral HPLC: Rt = 5.92 min (97% ee)

Instrument: Waters Alliance 2695; Column: Chiralpak IC 5μιη 100x4.6 mm; Eluent: hexane / 2-

Propanol 70:30; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm. Intermediate 5:

 N (1-methylethyl) -N- (2,6-dichloropyridin-3-yl) -D-alanineamide

In analogy to the preparation of intermediate 2, / V ² - (1-methylethyl) - / V- (2,6-dichloropyridin-3-yl) -D-alaninamide starting from 0.5 g of intermediate 1, 0.27 ml of acetone, 303 mg of sodium acetate and 1.18 g of sodium triacetoxyborohydride in 40 ml of dichloromethane at 0 ° C. 420 mg / V ² - (1-methylethyl) - / V- (2,6-dichloropyridin-3-yl) -D-alaninamide was obtained. This was used directly in the synthesis of the next step.

Ή-NMR (400 MHz, DMSO-d6): δ = 1.02 (d, 3H); 1.05 (d, 3H); 1.27 (d, 3H); 2.77 (sp, 1H); 3.30 (q, 1H); 7.58 (d, 1H); 8.67 (d, 1H).

Intermediate 6:

 (3 f) -6-chloro-3-methyl-4- (propan-2-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one

In analogy to the synthesis of intermediate 3, (3R) -6-chloro-3-methyl-4- (propan-2-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one starting from 420 mg of intermediate 5 and 2.1 ml of N, N-diisopropylethylamine in 40 ml of DMF by heating for 72 hours at 170 ° C bath temperature. 320 mg of (3R) -6-chloro-3-methyl-4- (propan-2-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one were obtained.

Ή-NMR (300 MHz, DMSO-d6): δ = 1.16 (d, 3H); 1.24 (d, 3H); 1.27 (d, 3H); 4.16 (q, 1H); 4.43 (sp, 1H); 6.65 (d, 1H); 7.00 (d, 1H); 10.56 (s, 1H). Intermediate 7:

 (3E) -6-chloro-l 3-dimethyl-4- (propane-2-yl) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one

In analogy to the preparation of intermediate 4, (3R) -6-chloro-1,3-dimethyl-4- (propan-2-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -on starting from 320 mg Intermediate 6, 80 mg

Sodium hydride (60% in white oil) and 0.13 ml of methyl iodide in 20 ml of DMF. After purification by chromatography on silica gel (hexane / ethyl acetate 2: 1), 280 mg of (3R) -6-chloro-1,3-dimethyl-4- (propan-2-yl) -3,4-dihydropyrido [2 3-b] pyrazin-2 (lH) -one.

Ή-NMR (400 MHz, DMSO-d6): δ = 1.12 (d, 3H); 1.23 (d, 3H); 1.27 (d, 3H); 3.22 (s, 3H); 4.32 (q, 1H); 4.47 (sp, 1H); 6.76 (d, 1H); 7.31 (d, 1H).

Intermediate 8:

 N -cycloheptyl-N- (2,6-dichloropyridin-3-yl) -D-alaninamide

In analogy to the preparation of intermediate 2, / V ² -cycloheptyl- / V- (2,6-dichloropyridin-3-yl) -d-alaninamide starting from 1.5 g of intermediate 1, 809 mg of cycloheptanone, 909 mg of sodium acetate and 3.5 g of sodium triacetoxyborohydride in 80 ml of dichloromethane at 0 ° C. 1.4 g / V ² -cycloheptyl / V- (2,6-dichloropyridin-3-yl) -D-alaninamide were obtained.

H-NMR (400 MHz, DMSO-d6): δ = 1.26 (d, 3H); 1.29-1.42 (m, 4H); 1.42-1.55 (m, 4H); 1.55- 1.69 (m, 3H); 1.75-1.88 (m, 2H); 2.56-2.67 (m, 1H); 3.30 (m, 1H); 7.58 (d, 1H); 8.68 (d, 1H). Intermediate 9:

 (3 f) -6-chloro-4-cycloheptyl-3-methyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -

In analogy to the synthesis of intermediate 3, (3R) -6-chloro-4-cycloheptyl-3-methyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one starting from 1.4 g of intermediate 8 and 5.77 ml of N, N-diisopropylethylamine in 70 ml of DMF by heating for 72 hours at 170 ° C bath temperature. 1.18 g of (3R) -6-chloro-4-cycloheptyl-3-methyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one was obtained.

H-NMR (300 MHz, DMSO-d6): δ = 1.16 (d, 3H); 1.37-1.63 (m, 6H); 1.63-2.00 (m, 6H); 3.96-4.09 (m, 1H); 4.17 (q, 1H); 6.64 (d, 1H); 6.98 (d, 1H); 10.57 (s, 1H).

Intermediate 10:

 (3E) -6-chloro-4-cycloheptyl-l, 3-dimethyl-3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -

In analogy to the preparation of intermediate 4, (3R) -6-chloro-4-cycloheptyl-1,3-dimethyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one starting from 1.18 g Intermediate 9, 241 mg

Sodium hydride (60% in white oil) and 0.38 ml of methyl iodide prepared in 50 ml of DMF. To

Purification by chromatography on silica gel (hexane / ethyl acetate 3: 1) gave 1.11 g of (R) -6-chloro-4-cycloheptyl-1,3-dimethyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (lH) -one.

H-NMR (300 MHz, DMSO-d6): δ = 1.13 (d, 3H); 1.38-1.63 (m, 6H); 1.63-1.84 (m, 4H); 1.83- 2.03 (m, 2H); 3.21 (s, 3H); 4.00-4.14 (m, IH); 4.32 (q, IH); 6.75 (d, IH); 7.29 (d, IH).

Intermediate 11:

(3 f) -6-amino-1,3-dimethyl-4- (tetrahydro-2H-yran-4-yl) -3,4-dihydropyrido [2,3-b] py 2 (1H) -one

Eine Mischung von 1.0 g Intermediat 4, 699 mg 1,1-Diphenylmethanimin (CAS 1013-88-3), 147 mg Tris(dibenzylidenaceton)dipalladium(0) (CAS 51364-51-3), 505 mg Kalium- ieri-butanolat und 200 mg (+)-BINAP in 20 ml Toluol wurde 4 Stunden unter einer Argonatmosphäre bei 110°C und 14 Stunden bei RT gerührt. Der Ansatz wurde durch Celite filtriert und mit Ethylacetat nachgewaschen. Das Lösungsmittel wurde im Vakuum entfernt und der Rückstand in 40 ml THF aufgenommen. Dazu wurden bei RT 10 ml HCl in Dioxan Lösung (4M) zugegeben und 4 Stunden gerührt. Der Ansatz wurde durch Zugabe von Natronlauge (2N) auf pH = 10 eingestellt und mit Dichlormethan extrahiert. Die organische Phase wurde über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt. Der Rückstand wurde durch Chromatographie an Kieselgel (Hexan / Ethylacetat Gradient bis 100 % Ethylacetat Anteil) gereinigt. Man erhielt 670 mg (3R)-6- Amino-l,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazin-2(lH)-on.

A mixture of 1.0 g of Intermediate 4, 699 mg of 1,1-diphenylmethanimine (CAS 1013-88-3), 147 mg of tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 505 mg of potassium iperi-butoxide and 200 mg of (+) - BINAP in 20 ml of toluene was stirred for 4 hours under argon atmosphere at 110 ° C and 14 hours at RT. The reaction was filtered through Celite and washed with ethyl acetate. The solvent was removed in vacuo and the residue taken up in 40 ml of THF. To this was added 10 ml of HCl in dioxane solution (4M) at RT and stirred for 4 hours. The batch was adjusted to pH = 10 by addition of sodium hydroxide solution (2N) and extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 100% ethyl acetate content). 670 mg of (3R) -6-amino-1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) were obtained. -one.

^X H NMR (300 MHz, 25 ° C, DMSO-d6): δ = 1.03 (d, 3H); 1.48-1.55 (m, IH); 1.75 (qd, IH); 1.90-1.92 (m, 2H); 3.14 (s, 3H); 3.33-3.42 (m, 2H); 3.88-3.97 (m, 2H); 4.11 (q, IH); 4.37 (tt, IH); 5.42 (s, 2H); 5.86 (d, IH); 7.06 (d, IH). Intermediate 12:

 A ^ - (l-benzylpiperidin-4-yl) -N- (2,6-dichloropyridin-3-yl) -D-alaninamide

A solution of 10 g of Intermediate 1 and 8.89 g of 1-benzylpiperidone (CAS 3612-20-2) in 100 ml of dichloromethane was admixed at RT with 18.2 g of sodium triacetoxyborohydride. After 16 hours, the reaction was poured carefully onto saturated sodium bicarbonate solution, the phases were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (heptane / ethyl acetate gradient). This gave 15.1 g / V ² - (1-benzylpiperidin-4-yl) - / V- (2,6-dichloropyridin-3-yl) -D-alaninamide.

Ή NMR (400 MHz, 25 ° C, CDCl ₃ ): δ = 1.17 (bs, 1H), 1.37-1.52 (m, 5H), 1.86 (d, 1H), 1.91-2.04 (m, 3H), 2.48 ( bs, 1H), 2.83-2.88 (m, 2H), 3.38 (q, 1H), 3.51 (s, 2H), 7.22-7.33 (m, 6H), 8.82 (d, 1H), 10.4 (bs, 1H) ,

Intermediate 13:

 (3 f) -4- (1-Benzylpiperidin-4-yl) -6-chloro-3-methyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one

A solution of 15.1 g Intermediate 12 and 32.3 ml / V, / V-Diisopropylethylamine in 277 ml DMA was stirred for 48 hours at 170 ° C bath temperature in a tightly closed vessel. After cooling, the reaction was diluted with water and extracted three times with ethyl acetate. The Combined organic phases were concentrated in vacuo. It was mixed with toluene and again completely concentrated in vacuo. The residue was stirred in a heptane / water mixture, the precipitate was filtered off with suction and then dried by distillation with toluene. 13.8 g of (3R) -4- (1-benzylpiperidin-4-yl) -6-chloro-3-methyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one was obtained.

H NMR (400 MHz, 25 ° C, CDC1 ₃ ): δ = 1.27 (d, 3H), 1.54-1.81 (m, 3H), 1.86-2.26 (m, 3H), 2.90-3.05 (m, 2H), 3.54 (s, 2H), 4.22-4.39 (m, 2H), 6.60 (d, IH), 6.87 (d, IH), 7.25-7.32 (m, 5H), 8.72 (bs, IH).

Intermediate 14:

 (f) -4- (1-Benzylpiperidin-4-yl) -6-chloro-1,3-dimethyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one

A solution of 13.1 g of intermediate 13 in 131 ml of DMF was added in portions at 0 ° C with 2.08 g of sodium hydride (60% in white oil). It was still 30 min. stirred at RT, then cooled again to 0 ° C and added 2.28 ml of methyl iodide. After approx. 10 min. was quickly added to ice water under an argon atmosphere and the precipitate was filtered off with suction and washed with heptane. This gave 12.7 g of (R) -4- (1-benzylpiperidin-4-yl) -6-chloro-1,3-dimethyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one , H NMR (400 MHz, 25 ° C, CDCl 3): δ = 1.19 (d, 3H), 1.57-1.79 (m, 2H + H ₂ 0), 1.92 (bq, IH), 2.04-2.22 (m, 3H) , 2.96 (bs, 2H), 3.28 (s, 3H), 3.54 (s, 2H), 4.30-4.35 (m, 2H), 6.65 (d, IH), 6.96 (d, IH), 7.31-7.37 (m , 5H). Intermediate 15:

 (3A) -6-chloro-1,3-dimethyl-4- (piperidin-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) hydrochloride

Eine Lösung von 12.2 g Intermediat 14 und 4.46 ml 1-Chlorethylcarbonochloridat (CAS 50893-53- 3) in 131 ml 1,2-Dichlorethan wurde 4 Stunden unter Rückfluss erhitzt. Der Ansatz wurde vollständig eingedampft und in Ethylacetat / Heptan (1 : 1) aufgenommen. Diese Lösung wurde durch Kieselgel filtriert und zunächst mit Heptan, dann mit Ethylacetat nachgewaschen. Der eluierte Rückstand wurde in Methanol erhitzt und anschließend wieder eingedampft. Man erhielt 8.2 g (3R)-6-Chlor-l,3-dimethyl-4-(piperidin-4-yl)-3,4-dihydropyrido[2,3-b]pyrazin-2(lH)-on Hydrochlorid.

A solution of 12.2 g of Intermediate 14 and 4.46 ml of 1-chloroethylcarbonochloridate (CAS 50893-53- 3) in 131 ml of 1,2-dichloroethane was refluxed for 4 hours. The reaction was completely evaporated and taken up in ethyl acetate / heptane (1: 1). This solution was filtered through silica gel and washed first with heptane, then with ethyl acetate. The eluted residue was heated in methanol and then evaporated again. This gave 8.2 g of (3R) -6-chloro-1,3-dimethyl-4- (piperidin-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one hydrochloride.

Ή NMR (400 MHz, 25 ° C, DMSO-d6 ₃ ): δ = 1.22 (d, 3H), 1.94-2.01 (m, IH), 2.13 (dq, IH), 2.23- 2.37 (m, 2H), 3.16 (tt, 2H), 3.30 (s, 3H), 3.43-3.53 (m, 2H), 4.28 (q, IH), 4.39 (tt, IH), 6.80 (d, IH), 7.07-7.21 (m, IH), 7.32 (d, IH).

Intermediate 16:

 (3 f) -6-chloro-1,3-dimethyl-4- (1-methylpiperidin-4-yl) -3,4-dihydropyrido [2,3-b] py

2 (lH) -one

A solution of 8.2 g of intermediate 15 in 77.1 ml of methanol was first treated at RT with 77.1 ml of formaldehyde solution (37% in water) and then with 2.19 g of sodium cyanoborohydride and 3.49 g of acetic acid. It was stirred for 16 hours and then treated with 2 N sodium hydroxide solution. The reaction solution was extracted with ethyl acetate, the organic phase dried over sodium sulfate and the solvent removed in vacuo. The residue was through

Chromatography on silica gel (start with heptane / ethyl acetate 1: 1 gradient to ethyl acetate / triethylamine / methanol 92: 5: 3). There were obtained 6.7 g of (3R) -6-chloro-1,3-dimethyl-4- (1-methylpiperidin-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one ,

Ή NMR (400 MHz, 25 ° C, CDC1 ₃ ): δ = 1.20 (d, 3H), 1.62-1.68 (m, IH), 1.75 (dq, IH), 1.95 (dq, IH), 2.07-2.21 ( m, 3H), 2.31 (s, 3H), 2.94 (d, 2H), 3.29 (s, 3H), 4.25-4.35 (m, 2H), 6.66 (d, IH), 6.97 (d, IH).

Intermediate 17:

l- (4-nitrophenyl) -4- (2,2,2-trifluoroethyl) piperazine

A mixture of 1 g of 4-fluoronitrobenzene, 1.19 g of 1- (2,2,2-trifluoroethyl) piperazine and 1.96 g of potassium carbonate in 10 ml of acetonitrile was stirred at 90 ° C for 5 hours. The reaction was poured onto water and extracted three times with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 100% ethyl acetate content). This gave 1.3 g of 1- (4-nitrophenyl) -4- (2,2,2-trifluoroethyl) piperazine.

H-NMR (400 MHz, CDCl ₃ ): δ = 2.80-2.88 (m, 4H); 3.06 (q, 2H); 3.42-4.50 (m, 4H); 6.83 (d, 2H); 8.13 (d, 2H).

Intermediate 18:

 4- [4- (2,2,2-trifluoroethyl) piperazin-l-yl] aniline

A suspension of 1.3 g of intermediate 22 and 130 mg of palladium on activated carbon (10%) in 43 ml of methanol was shaken at RT under a hydrogen atmosphere of 1 bar for 7 hours. The catalyst was filtered off and the solution was concentrated in vacuo. This gave 1.1 g of 4- [4- (2,2,2-trifluoroethyl) piperazin-1-yl] aniline.

Ή-NMR (400 MHz, DMSO-d6): δ = 2.69-2.76 (m, 4H); 2.87-2.93 (m, 4H); 3.20 (q, 2H); 4.55 (bs, 2H); 6.48 (d, 2H); 6.68 (d, 2H).

Intermediate 19:

 2-methoxy-4- (methylsulfanyl) -l-nitrobenzene

A solution of 7.5 g of 5-fluoro-2-nitroanisole in 251 ml of DMF was added portionwise at RT with a solution of sodium thiomethoxide (3M in water) and 4.85 g of potassium carbonate. The mixture was stirred at RT for 23 hours, then water was added and extracted several times with ethyl acetate. The The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. This approach was performed a second time with 7.5 g of 5-fluoro-2-nitroanisole. A total of 12.6 g of 2-methoxy-4- (methylsulfanyl) -1-nitrobenzene was obtained.

'H NMR (300 MHz, 25 ° C, CDC1 ₃ ): δ = 2.55 (s, 3H); 3.97 (s, 3H); 6.81 (dd, 1H); 6.86 (d, 1H); 7.90 (d, 1H).

Intermediate 20:

 2-methoxy-4- (methylsulfonyl) -l-nitrobenzene

Eine Suspension von 6.25 g Intermediat 19 in 88.5 ml Aceton, 88.5 ml Wasser und 8.9 ml

A suspension of 6.25 g of Intermediate 19 in 88.5 ml of acetone, 88.5 ml of water and 8.9 ml

Methanol was added in portions at 0 ° C with a total of 12.7 g of potassium peroxymonosulfate (Oxone®, CAS 70693-62-8) and then stirred for 14 hours at RT. Then another 6 g of potassium peroxymonosulfate (Oxone®, CAS 70693-62-8) was added, stirred for 15 min at RT, and then a further 5 g of potassium peroxymonosulfate (Oxone®, CAS 10361-76-9) was added and the reaction continued for a further 4 hours at RT touched. It was diluted with ethyl acetate, the solid was filtered off and the

Wash the precipitate with ethyl acetate. This approach was repeated a second time with 6.25 g Intermediate 19. The combined organic phases were concentrated in vacuo to 1/3 of the total volume, then water was added and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent was removed completely in vacuo. The residue was stirred with diethyl ether and filtered with suction. 10.6 g of 2-methoxy-4- (methylsulfonyl) -1-nitrobenzene were obtained.

Ή-NMR (300 MHz, 25 ° C, CDCl ₃ ): δ = 3.12 (s, 3H); 4.06 (s, 3H); 7.62 (dd, 1H); 7.67 (d, 1H); 7.95 (d, 1H). Intermediate 21:

 2-methoxy-4- (methylsulfonyl) aniline

A suspension of 9.6 g of intermediate 20 and 11.6 g of iron powder in 84 ml of ethanol and 30 ml of saturated aqueous ammonium chloride solution was stirred for 1 hour while heating to reflux. The reaction was filtered through diatomaceous earth and washed with boiling ethanol. After adding water, the organic solvent was removed in vacuo. The resulting precipitate was filtered off with suction and stirred in ethyl acetate and washed with diethyl ether. This gave 6.51 g of 2-methoxy-4- (methylsulfonyl) aniline.

H NMR (400 MHz, 25 ° C, CDCl ₃ ): δ = 3.00 (s, 3H); 3.90 (s, 3H); 4.34 (bs, 2H); 6.73 (d, 1H); 7.25 (s, 1H); 7.37 (d, 1H).

Intermediate 22:

ieri-butyl-4 - [(4-nitrophenyl) sulfonyl] piperidin-l-carboxylate

A solution of 10.0 g of ieri-butyl-4 - [(4-nitrophenyl) sulfanyl] piperidine-1-carboxylate (preparation described in WO2011060321, Method L, Example L, pp. 135-136) in 200 ml of methanol was charged with 17.25 g Oxone (CAS 37222-66-5) and stirred for 16 hours at RT. The reaction was concentrated in vacuo, diluted with dichloromethane and washed with 1N aqueous hydrochloric acid. The organic phase was washed with saturated sodium chloride solution, over sodium sulfate dried and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 100% ethyl acetate). This gave 2.9 g of tert-butyl-4 - [(4-nitrophenyl) sulfonyl] piperidine-1-carboxylate. H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.30-1.42 (m, 11H); 1.84 (bd, 2H); 2.61-2.83 (bs, 2H); 3.66 (tt, 1H); 4.00 (bd, 2H); 8.13 (d, 2H); 8.47 (d, 2H).

Intermediate 23:

4 - [(4-Nitrophenyl) sulfonyl] piperidine, TFA salt

A solution of 2.9 g of intermediate 22 in 58 ml of dichloromethane was mixed carefully with 8.7 ml of trifluoroacetic acid and stirred at RT for 5 hours. The mixture was then concentrated under reduced pressure, twice more with toluene and repeatedly concentrated. 2.6 g of 4 - [(4-nitrophenyl) sulfonyl] piperidine as TFA salt were obtained.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.72 (qd, 2H); 2.02 (bd, 2H); 2.85 (q, 2H); 3.37 (bd, 2H); 3.76 (tt, 1H); 8.14 (d, 2H); 8.50 (d, 2H).

Intermediate 24:

l-methyl-4 - [(4-nitrophenyl) sulfonyl] piperidine

A solution of 2.6 g of intermediate 23 in 71.3 ml of dichloromethane and 2.5 ml of triethylamine was added at RT with 2.1 ml of formalin solution (35% in water) and stirred for 5 min. 7.75 g of sodium triacetoxyborohydride were added thereto and the mixture was stirred at RT for 14 hours. The mixture was diluted with dichloromethane and extracted with dilute sodium hydroxide solution. The organic phase was washed with half-saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. 2.2 g of 1-methyl-4 - [(4-nitrophenyl) sulfonyl] piperidine were obtained.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.52 (dq, 2H), 1.72-1.89 (m, 4H); 2.11 (s, 3H); 2.74-2.87 (m, 2H); 3.37 (tt, 1H); 8.12 (d, 2H); 8.46 (d, 2H).

Intermediate 25:

 4 - aniline [(l-methylpiperidin-4-yl) sulfonyl]

A mixture of 2.2 g of intermediate 24 and 220 mg of palladium on carbon (10%) in 200 ml of methanol was shaken at RT under a hydrogen atmosphere of 1 bar for 7 hours. The mixture was then filtered through diatomaceous earth and the clear solution was concentrated in vacuo. 2.1 g of 4 - [(1-methylpiperidin-4-yl) sulfonyl] aniline are obtained, which was sufficiently pure for further reactions.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.45 (dq, 2H); 1.72-1.85 (m, 4H); 2.10 (s, 3H); 2.73-2.82 (m, 2H); 2.96 (tt, 1H); 6.15 (bs, 2H); 6.91 (d, 2H); 7.56 (d, 2H).

Intermediate 26:

ieri-butyl-4 - [(4-nitrophenyl) sulfinyl] piperidine-l-carboxylate

In the preparation of Intermediate 22, after chromatography, 1.2 g of ieri-butyl-4 - [(4-nitrophenyl) sulfinyl] piperidine-1-carboxylate was also obtained as a second product. H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.23 (bd, IH); 1.31-1.42 (m, 10H); 1.47 (qd, IH); 1.94 (bd, IH); 2.60-2.84 (m, 2H); 3.12 (tt, IH); 3.89-4.09 (m, 2H); 7.90 (d, 2H); 8.42 (d, 2H).

Intermediate 27:

4 - [(4-Nitrophenyl) sulfinyl] piperidine, TFA salt

In analogy to the preparation of intermediate 23, starting from 1.2 g of intermediate 25 and 4.1 ml of trifluoroacetic acid in 27 ml of dichloromethane, 1.3 g of 4 - [(4-nitrophenyl) sulfinyl] piperidine were obtained as TFA salt.

UPLC-MS: Rt = 0.5 min [M ⁺ + l = 255 (esi-MS)]

Instrument: Waters Acquity UPLC-MS SQD; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.1% by volume formic acid (99%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 ml / min; Temperature: 60 ° C; Injection: 2 μΐ; DAD scan: 210-400 nm. Intermediate 28:

l-methyl-4 - [(4-nitrophenyl) sulfinyl] piperidine

In analogy to the preparation of intermediate 24, starting from 1.3 g of intermediate 26 and 1.01 ml of formalin (35% in water) with 2.83 g of sodium triacetoxyborohydride, 680 mg of 1-methyl-4 - [(4-nitrophenyl) sulfinyl] piperidine were obtained.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.17-1.27 (m, 1H); 1.55 (qd, 1H); 1.63 (qd, 1H); 1.73-1.83 (m, 1H); 1.84-1.93 (m, 2H); 2.11 (s, 3H); 2.72-2.89 (m, 3H); 7.90 (d, 2H); 8.41 (d, 2H).

Intermediate 29:

 4 - aniline [(l-methylpiperidin-4-yl) sulfinyl]

Analogously to the preparation of intermediate 25, starting from 660 mg of intermediate 27 and 66 mg of palladium on carbon (10%) in 100 ml of methanol with 1 bar hydrogen pressure, 600 mg of 4 - [(1-methylpiperidin-4-yl) sulfinyl] aniline were obtained ,

'H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.17-1.26 (m, 1H); 1.48-1.69 (m, 2H); 1.73-1.93 (m, 3H); 2.11 (s, 3H); 2.72-2.89 (m, 3H); 7.90 (d, 2H); 8.41 (d, 2H). Intermediate 30:

 2- (4-nitrophenyl) -2-azaspiro [3.3] heptane

A mixture of 1.0 g of 4-fluoronitrobenzene (CAS 350-46-9), 947 mg of 2-azaspiro [3.3] heptane hydrochloride (1: 1) (CAS 665-04-3) and 1.96 g of potassium carbonate in 10 ml of acetonitrile was used for Stirred for 6 hours at 80 ° C bath temperature. The mixture was added to water, the solution extracted twice with ethyl acetate, the combined organic phases with saturated

 Washed sodium chloride solution, dried over sodium sulfate and concentrated completely in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 100% ethyl acetate content). 950 mg of 2- (4-nitrophenyl) -2-azaspiro [3.3] heptane were obtained.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.82 (qi, 2H); 2.20 (t, 4H); 4.01 (s, 4H); 6.40 (d, 2H); 8.03 (d, 2H).

Intermediate 31:

 aniline 4- (2-azaspiro [3.3] hept-2-yl)

In analogy to the preparation of Intermediate 25 were starting from 950 mg of intermediate 30 and 95 mg of palladium on carbon (10%) in 40 ml of methanol with 1 bar hydrogen pressure 800 mg of 4- (2-azaspiro [3.3] hept-2-yl) aniline.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.80 (qi, 2H); 2.12 (t, 4H); 3.58 (s, 4H); 4.33 (s, 2H); 6.18 (d, 2H); 6.45 (d, 2H).

Intermediate 32:

 6- (4-nitrophenyl) -2-oxa-6-azaspiro [3.3] heptane

In analogy to the preparation of intermediate 30, starting from

352 mg 4-fluoronitrobenzene (CAS 350-46-9), 720 mg 2-oxa-6-azaspiro [3.3] heptane oxalate (2: 1) (CAS 1045709-32-7) and 690 mg potassium carbonate in 3.5 ml acetonitrile 445 mg of 6- (4-nitrophenyl) -2-oxa-6-azaspiro [3.3] heptane.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 4.21 (s, 4H); 4.73 (s, 4H); 6.44 (d, 2H); 8.04 (d, 2H).

Intermediate 33:

 4- aniline (2-oxa-6-azaspiro [3.3] hept-6-yl)

In Analogie zur Herstellung von Intermediat 25 wurden ausgehend von 430 mg Intermediat 32 und 43 mg Palladium auf Kohle (10%) in 20 ml Methanol mit 1 bar Wasserstoffdruck 435 mg 4-(2- Oxa-6-azaspiro[3.3]hept-6-yl)anilin erhalten.

In analogy to the preparation of Intermediate 25 starting from 430 mg of intermediate 32 and 43 mg of palladium on carbon (10%) in 20 ml of methanol with 1 bar hydrogen pressure 435 mg of 4- (2-oxa-6-azaspiro [3.3] hept-6 -yl) aniline.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 3.77 (s, 4H); 4.38 (bd, 2H); 4.67 (s, 4H)

2H); 6.46 (d, 2H).

Intermediate 34:

(LAE, 5S) -3- (4-nitrophenyl) -8-oxa-3-azabicyclo [3.2.1] octane

In analogy to the preparation of intermediate 30, starting from

1.0 g of 4-fluoronitrobenzene (CAS 350-46-9), 1.06 mg of 8-oxa-3-azabicyclo [3.2. lycoctane hydrochloride (CAS 54745-74-3) and 1.96 g potassium carbonate in 10 ml acetonitrile 370 mg (IR, 5S) -3- (4-nitrophenyl) -8-oxa-3-azabicyclo [3.2. l] octane obtained.

Ή-ΝΜΡ: (400 MHz, 25 ° C, DMSO-d6): δ = 1.72-1.90 (m, 4H); 3.02 (d, 1H); 3.03 (dd, 2H); 3.63 (d, 2H); 4.47 (d, 2H); 6.94 (d, 2H); 8.06 (d, 2H).

Intermediate 35:

 4 - [(1, 5S) -8-oxa-3-azabicyclo [3.2.1] oct-3-yl] aniline

In Analogie zur Herstellung von Intermediat 25 wurden ausgehend von 350 mg Intermediat 34 und 33 mg Palladium auf Kohle (10%) in 14 ml Methanol mit 1 bar Wasserstoffdruck 310 mg 4- [(lR,5S)-8-Oxa-3-azabicyclo[3.2.1]oct-3-yl]anilin erhalten. ^-NMR: (400 MHz, 25°C, DMSO-d6): δ = 1.74-1.88 (m, 4H); 2.65 (dd, 2H); 3.12 (d, 2H); 4.32- 4.37 (m, 2H); 4.46 (s, 2H); 6.48 (d, 2H); 6.59 (d, 2H).

In analogy to the preparation of intermediate 25 starting from 350 mg of intermediate 34 and 33 mg of palladium on carbon (10%) in 14 ml of methanol with 1 bar hydrogen pressure 310 mg 4- [(lR, 5S) -8-oxa-3-azabicyclo [3.2.1] oct-3-yl] aniline. ^ -NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.74-1.88 (m, 4H); 2.65 (dd, 2H); 3.12 (d, 2H); 4.32-4.37 (m, 2H); 4.46 (s, 2H); 6.48 (d, 2H); 6.59 (d, 2H).

Preparation of the compounds of the invention

Example 1:

 (3 f) -l, 3-Dimethyl-6 - {[4- (propan-2-ylsulphonyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2 , 3-b] pyrazin-2 (lH) -one

A mixture of 84 mg Intermediate 4, 85 mg 4- (isopropylsulfonyl) aniline (CAS 25355-76-4), 3.9 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 138 mg cesium carbonate and 7.2 mg Xanthophos (CAS 161265-03-8) in 10 ml of dioxane was taken for 20 hours under a

Argon atmosphere stirred at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη

100x30mm, mobile phase: acetonitrile / water (0.1% by volume formic acid) gradient). 70 mg of (3R) -l, 3-dimethyl-6- {[4- (propan-2-ylsulphonyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4- dihydropyrido [2,3-b] pyrazin-2 (lH) -one. H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.10 (d, 3H); 1.12-1.17 (m, 6H); 1.60-1.67 (m, 1H); 1.81 (qd, 1H); 1.91-2.06 (m, 2H); 3.22 (s, 3H); 3.41-3.55 (m, 2H); 3.94-4.05 (m, 2H); 4.27 (q, 1H); 4.37 (tt, 1H); 6.35 (d, 1H); 7.32 (d, 1H); 7.65 (d, 2H); 7.83 (d, 2H); 9.46 (s, 1H). Example 2:

(3 f), 3-Dimethyl-6 - {[4- (methylsulfonyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine -2 (lH) -one

Eine Mischung von 200 mg Intermediat 4, 165 mg 4-Methylsulfonylanilin (CAS 5470-49-5), 8.8 mg Tris(dibenzylidenaceton)dipalladium(0) (CAS 51364-51-3), 314 mg Caesiumcarbonat und 16 mg Xanthphos (CAS 161265-03-8) in 20 ml Dioxan wurde 20 Stunden unter einer

A mixture of 200 mg Intermediate 4, 165 mg 4-methylsulfonylaniline (CAS 5470-49-5), 8.8 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 314 mg cesium carbonate and 16 mg xanthophos (CAS 161265-03-8) in 20 ml of dioxane was 20 hours under a

Argon atmosphere stirred at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 110 mg of (3R) -l, 3-dimethyl-6- {[4- (methylsulfonyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazin-2 (lH) -one.

'H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.10 (d, 3H); 1.63 (bd, 1H); 1.82 (qd, 1H); 1.91-2.05 (m, 2H); 3.13 (s, 3H); 3.22 (s, 3H); 3.44-3.57 (m, 2H); 3.94-4.08 (m, 2H); 4.27 (q, 1H); 4.39 (tt, 1H); 6.34 (d, 1H); 7.32 (d, 1H); 7.73 (d, 2H); 7.84 (d, 2H); 9.45 (s, 1H). Chiral HPLC: Rt = 9.52 min (95% ee)

Instrument: Agilent 1290; Column: Chiralpak IF 3μιη 100x4.6 mm; Eluent: hexane / ethanol gradient to 50% ethanol content; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml methanol); DAD 996 scan: 280 nm. Example 3:

 (3 f) -6 - [(4-Bromophenyl) amino] -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine 2 (lH) -one

A mixture of 540 mg Intermediate 11, 663 mg of 1-bromo-4-iodobenzene (CAS 589-87-7), 54 mg of tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 955 mg of cesium carbonate and 100 mg Xanthphos (CAS 161265-03-8) in 16 ml of dioxane was stirred for 16 hours under argon atmosphere at 120 ° C. The reaction was filtered through Celite and washed with ethyl acetate. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 100% ethyl acetate content). 340 mg of (3R) -6- [(4-bromophenyl) amino] -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b ] pyrazin-2 (lH) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.56-1.66 (m, 1H); 1.78 (qd, 1H); 1.86- 2.02 (m, 2H); 3.20 (s, 3H); 3.38-3.54 (m, 2H); 3.91-4.06 (m, 2H); 4.23 (q, 1H); 4.34 (tt, 1H); 6.23 (d, 1H); 7.26 (d, 1H); 7.36 (d, 2H); 7.60 (d, 2H); 8.98 (s, 1H).

Example 4:

 (3A) -6 - {[4- (3,5-dimethyl-l, 2-oxazol-4-yl) -phenyl] -amino}, 3-dimethyl-4- (tetrahydro-pyran-4-yl) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one

A mixture of 100 mg of Example 3, 40 mg of (3,5-dimethyl-l, 2-oxazol-4-yl) boric acid (CAS 16114-47-9), 25 mg of tetrakis (triphenylphosphine) palladium (0) (CAS 14221 -01-3), 47 mg

Sodium carbonate and 19 mg of lithium chloride in 3.6 ml of toluene and 0.9 ml of ethanol was stirred for 5 hours under argon atmosphere at 95 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 100% ethyl acetate content). This prepurified substance was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, Mobile phase:

Acetonitrile / water (0.1% by volume formic acid) gradient). 14 mg of (3R) -6- {[4- (3,5-dimethyl-1,2,3-oxazol-4-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran -4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.58-1.68 (m, IH); 1.77 (qd, IH); 1.86- 2.06 (m, 2H); 2.22 (s, 3H); 2.39 (s, 3H); 3.21 (s, 3H); 3.38-3.52 (m, 2H, signal covered by water peak); 3.91-4.05 (m, 2H); 4.24 (q, IH); 4.39 (tt, IH); 6.26 (d, IH); 7.22 (d, 2H); 7.26 (d, IH); 7.70 (d, 2H); 8.96 (s, IH). Example 5:

 (3 / f) -6 - {[4- (4-Ethyl-piperazin-l-yl) phenyl] aim

3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one

A mixture of 100 mg Intermediate 4, 138 mg 4- (4-ethylpiperazin-1-yl) aniline (CAS 115619-01-7), 14.4 mg palladium (II) acetate (CAS 3375-31-3), 523 mg cesium carbonate and 40 mg of (+) - BINAP in 7.2 ml of toluene was stirred for 4.5 hours under argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC

 Purified by chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 50 mg of (3R) -6- {[4- (4-ethylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3 were obtained, 4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 0.99-1.11 (m, 6H); 1.57-1.65 (m, 1H); 1.75 (qd, 1H); 1.85-2.00 (m, 2H); 2.34-2.42 (m, 2H); 2.99-3.07 (m, 4H); 3.18 (s, 3H); 3.38-3.50 (m, 2H, signal covered by water peak); 3.92-4.03 (m, 2H); 4.20 (q, 1H); 4.37 (tt, 1H); 6.15 (d, 1H); 6.84 (d, 2H); 7.19 (d, 1H); 7.45 (d, 2H); 8.47 (s, 1H). Example 6:

 (3 f), 3-Dimethyl-6 - ({4 4- (propan-2-yl) -piperazin-1-yl] -phenyl} -a-amino) -4- (tetrahydro-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazin-2 (lH) -one

A mixture of 200 mg Intermediate 4, 282 mg 4- (4- (propan-2-yl) -piperazin-1-yl) aniline (CAS 443914-86-1), 29 mg palladium (II) acetate (CAS 3375- 31-3), 1.05 g of cesium carbonate and 80 mg of (+) - BINAP in 13.3 ml of toluene was stirred for 6 hours under argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 115 mg of (3R) -l, 3-dimethyl-6 - ({4- [4- (propan-2-yl) -piperazin-1-yl] -phenyl} -amino) -4- (tetrahydro-2H-pyran-1-one) were obtained. 4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one. H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.00 (d, 6H); 1.07 (d, 3H); 1.55-1.65 (m, 1H); 1.74 (qd, 1H); 1.83-2.02 (m, 2H); 2.54-2.62 (m, 4H); 2.96-3.06 (m, 4H); 3.18 (s, 3H); 3.38-3.51 (m, 2H, signal from water peak covered); 3.91-4.05 (m, 2H); 4.20 (q, 1H); 4.37 (tt, 1H); 6.14 (d, 1H); 6.83 (d, 2H); 7.19 (d, 1H); 7.45 (d, 2H); 8.48 (s, 1H). Example 7:

 (3A), 3-dimethyl-4- (tetrahydro-2H-yran-4-yl) -6 ^ {4 4- (2,2,2-trifluoroethyl) -piperazin-1-yl] -phenyl} -amino) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one

A mixture of 300 mg Intermediate 4, 500 mg Intermediate 18, 43 mg Palladium (II) acetate (CAS 3375-31-3), 1.57 g cesium carbonate and 120 mg (+) BINAP in 20 ml toluene was stirred for 5 hours under an argon atmosphere stirred at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 100% ethyl acetate content). This prepurified substance was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, Mobile phase:

Acetonitrile / water (0.1% by volume formic acid) gradient). 260 mg of (3R) -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -6 - ({4- [4- (2,2,2-trifluoroethyl) -piperazine-1] yl] phenyl} amino) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.07 (d, 3H); 1.55-1.66 (m, 1H); 1.74 (qd, 1H); 1.82- 2.02 (m, 2H); 2.70-2.80 (m, 4H); 2.99-3.08 (m, 4H); 3.14-3.30 (m, 5H); 3.36-3.52 (m, 2H); 3.91-4.55 (m, 2H); 4.20 (q, 1H); 4.37 (tt, 1H); 6.14 (d, 1H); 6.84 (d, 2H); 7.19 (d, 1H); 7.46 (d, 2H); 8.50 (s, 1H). Example 8:

 5 - {[(3A) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3-b] pyrazine] 6-yl] amino} pyridine-2-carbonitrile

A mixture of 150 mg Intermediate 4, 86 mg 5-amino-2-cyanopyridine (CAS 55338-73-3), 6.6 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 235 mg cesium carbonate and 12 mg xanthophos (CAS 161265-03-8) in 15 ml of dioxane was taken for 20 hours under a

Argon atmosphere stirred at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη

100x30mm, mobile phase: acetonitrile / water (0.1% by volume formic acid) gradient). 30 mg of 5- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3- b] pyrazine-6-yl] amino} pyridine-2-carbonitrile.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.10 (d, 3H); 1.58-1.67 (m, IH); 1.79 (qd, IH); 1.88 - 2.02 (m, 2H); 3.22 (d, 3H); 3.44-3.54 (m, 2H); 3.93-4.05 (m, 2H); 4.28 (q, IH); 4.35 (tt, IH); 6.37 (d, IH); 7.35 (d, IH); 7.87 (d, IH); 8.29 (dd, IH); 8.83 (d, IH); 9.71 (s, IH).

Example 9:

 (3 f) -4-Cycloheptyl-1,3-dimethyl-6 - {[4- (methylsulfonyl) -phenyl] -amino} -3,4-dihydropyribl-pyrazine-2 (1H) -one

A mixture of 150 mg Intermediate 10, 118 mg 4-methylsulfonylaniline (CAS 5470-49-5), 22 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 226 mg cesium carbonate and 27 mg xanthophos (CAS 161265-03-8) in 4 ml of dioxane was stirred for 8 hours under argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 60 mg of (3R) -4-cycloheptyl-1,3-dimethyl-6- {[4- (methylsulfonyl) phenyl] amino} -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) were obtained. -one. Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.10 (d, 3H); 1.43-1.84 (m, 10H); 1.85-1.96 (m, 1H); 2.03-2.13 (m, 1H); 3.12 (s, 3H); 3.21 (s, 3H); 4.22-4.35 (m, 2H); 6.31 (d, 1H); 7.29 (d, 1H); 7.69 (d, 2H); 7.85 (d, 2H); 9.41 (see 1H).

Example 10:

 (3 / f), 3-dimethyl-4- (1-methylpiperidin-4-yl) ^^

dihydropyrido [2,3-b] pyrazin-2 (lH) -one

A mixture of 150 mg Intermediate 16, 118 mg 4-methylsulfonylaniline (CAS 5470-49-5), 21.1 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 226 mg cesium carbonate and 26.7 mg xanthophos (CAS 161265-03-8) in 3.9 ml of dioxane was 4 hours under a

Argon atmosphere stirred at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 6 mg of (3R) -1,3-dimethyl-4- (1-methylpiperidin-4-yl) -6- {[4- (methylsulfonyl) phenyl] amino} -3,4-dihydropyrido [2,3- b] pyrazin-2 (lH) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.10 (d, 3H); 1.52- 1.65 (m, 2H); 1.73-2.19 (m, 6H); 2.24 (s, 3H); 2.81-3.01 (m, 4H); 3.13 (s, 3H); 3.21 (s, 3H); 4.14 (tt, IH); 4.24 (q, IH); 6.33 (d, IH); 6.78 (d, IH); 7.31 (d, IH); 7.71 (d, 2H); 7.85 (d, 2H); 8.20 (s, IH); 9.44 (s, IH).

Example 11:

 (3 f) -6 - {[2-Methoxy-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2 , 3-b] pyrazin-2 (lH) -one

A mixture of 150 mg Intermediate 4, 145 mg Intermediate 21, 22.1 mg

Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 235 mg of cesium carbonate and 27.9 mg of xanthphos (CAS 161265-03-8) in 4.1 ml of dioxane was stirred for 8 hours under argon atmosphere at 120 ° C. Again 22.1 mg of tris (dibenzylideneacetone) dipalladium (0) and 27.9 mg of xanthphos were added and the mixture was stirred at 120 ° C. under an argon atmosphere for a further 8 hours. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC

Purified by chromatography (column: X-Bridge C18 5μηι 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 60 mg of (3R) -6- {[2-methoxy-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4- dihydropyrido [2,3-b] pyrazine-2 (1H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.10 (d, 3H); 1.62 (bd, 1H); 1.80 (qd, 1H); 1.90-2.03 (m, 2H); 3.17 (s, 3H); 3.22 (s, 3H); 3.40-3.54 (m, 2H); 3.93-4.06 (m + s, 5H); 4.26 (q, 1H); 4.37 (tt, 1H); 6.68 (d, 1H); 7.31 (d, 1H); 7.39 (d, 1H); 7.42 (dd, 1H); 8.38 (s, 1H); 8.60 (d, 1H). Example 12:

 (3 f) -4-isopropyl-6 - {[4- (isopropylsulfonyl) phenyl] amino} -1,3-dimethyl-3,4-dihydropyr b] pyrazine-2 (1H) -one

A mixture of 100 mg Intermediate 7, 118 mg 4- (propan-2-ylsulfonyl) aniline (CAS 25355-75- 4), 18 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 192 mg Cesium carbonate and 22.8 mg of xanthphos (CAS 161265-03-8) in 10 ml of dioxane were stirred for 20 hours under argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 45 mg of (3R) -4-isopropyl-6- {[4- (isopropylsulfonyl) phenyl] amino} -1,3-dimethyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) were obtained. -on.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): 5 = 1.11 (d, 3H); 1.14 (d, 6H); 1.27 (d, 3H); 1.35 (d, 3H); 3.22 (s, 3H); 3.27 (sept, 1H, signal partly below water peak); 4.28 (q, 1H); 4.60 (sept, 1H); 6.33 (d, 1H); 7.30 (d, 1H); 7.65 (d, 2H); 7.85 (d, 2H); 9.42 (s, 1H). Example 13:

 (3 f) -6 - ({4 - [(difluoromethyl) sulfonyl] phenyl} amino) -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazin-2 (lH) -one

A mixture of 100 mg Intermediate 4, 105 mg 4 - [(difluoromethyl) sulfonyl] aniline (CAS 24906- 77-2), 9.3 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 165 mg

 Cesium carbonate and 15.7 mg of xanthphos (CAS 161265-03-8) in 4.2 ml of dioxane were stirred for 20 hours under argon atmosphere at 120 ° C. 2.3 mg of palladium (II) acetate and 6.3 mg of BEN AP were added and the mixture was stirred at 120 ° C. under an argon atmosphere for a further 20 hours. The reaction was concentrated in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.2 vol% ammonia (32%)) gradient). 32 mg of (3R) -6 - ({4-

[(Difluoromethyl) sulfonyl] phenyl} amino) -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) - on. H-NMR: (400 MHz, 25 ° C, CDCl ₃ ): δ = 1.26 (d, 3H); 1.70 (bd, IH); 1.88 (qd, IH); 1.98-2.14 (m, 2H); 3.34 (s, 3H); 3.55 (ddt, 2H); 4.08-4.18 (m, 2H); 4.34 (q, IH); 4.50 (tt, IH); 6.35 (d, IH); 6.80 (s, IH); 7.10 (d, IH); 7.63 (d, 2H); 7.84 (d, 2H). - HO -

Example 14:

 2 (4 - {[(3A) -1,3-Dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl), 2,3,4-etrahydropyrido [2,3-b] pyrazine-6 -yl] amino} phenyl) sulfonyl] propanenitrile

A mixture of 130 mg Intermediate 4, 131 mg of 2 - [(4-aminophenyl) sulfonyl] propanenitrile (CAS 1251042-34-8), 19.1 mg of tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 204 mg

Cesium carbonate and 24.2 mg of xanthphos (CAS 161265-03-8) in 3.5 ml of dioxane were stirred for 8 hours under argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 88 mg of 2 - [(4- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido] were obtained. 2,3-b] pyrazin-6-yl] amino} phenyl) sulfonyl] propanenitrile. Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): 5 = 1.11 (d, 3H); 1.51 (d, IH); 1.63 (bd, IH); 1.74-2.05 (m, 3H); 3.22 (s, 3H); 3.35-3.46 (m, 2H); 3.95-4.06 (m, 2H); 4.27 (q, IH); 4.37 (tt, IH); 5.09 (dq, IH); 6.38 (d, IH); 7.34 (d, IH); 7.76 (d, 2H); 7.90 (d, 2H); 9.67 (s, IH). Example 15:

 [(4 - {[(3A) -1,3-Dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3-b] pyrazin-6-yl] amino} phenyl) sulfonyl] acetonitrile

A mixture of 130 mg Intermediate 4, 122 mg [(4-aminophenyl) sulfonyl] acetonitrile (CAS 797036-00-1), 7.7 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 204 mg

Cesium carbonate and 9.7 mg of xanthphos (CAS 161265-03-8) in 3.5 ml of dioxane were stirred for 11 hours under argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous

Washed sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 15 mg of [(4- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2, 3 -b] pyrazine-6-y 1] amino} phenyl) sulfony 1] acetonitrile. 'H-NMR: (400 MHz, 25 ° C, DMSO-d6): 5 = 1.11 (d, 3H); 1.64 (bd, 1H); 1.83 (qd, 1H); 1.92-2.05 (m, 2H); 3.22 (s, 3H); 3.43-3.55 (m, 2H); 3.96-4.07 (m, 2H); 4.28 (q, 1H); 4.38 (tt, 1H); 5.09 (s, 2H); 6.38 (d, 1H); 7.34 (d, 1H); 7.78 (d, 2H); 7.89 (d, 2H); 9.64 (s, 1H). Example 16:

 (3 f) -4-Cycloheptyl-1,3-dimethyl-6 - ({4 (1-methylpiperidin-4-yl) sulfonyl] phenyl} aminothihydropyrido [2,3-b] pyrazine-2 (1H) - on

Eine Mischung von 150 mg Intermediat 4, 177 mg Intermediat 25, 27 mg

A mixture of 150 mg Intermediate 4, 177 mg Intermediate 25, 27 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 226 mg cesium carbonate and 21 mg xanthophos (CAS 161265-03-8) in 7.5 ml dioxane was stirred for 6 hours under argon atmosphere at 120 ° C. An additional 27 mg of tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3) and 21 mg of xanthphos (CAS 161265-03-8) were added and stirring was continued for 7 hours under an argon atmosphere at 120 ° C. The batch was added to water and washed twice

Extracted ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη

100x30mm, mobile phase: acetonitrile / water (0.1% by volume formic acid) gradient). 45 mg of (3R) -4-cycloheptyl-1,3-dimethyl-6- ({4 - [(1-methylpiperidin-4-yl) sulfonyl] phenyl} amino) -3,4-dihydropyrido [2,3 -b] pyrazine-2 (1H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.10 (d, 3H); 1.41-1.97 (m, 15H); 2.00-2.10 (m, 1H); 2.14 (s, 3H); 2.77-2.87 (m, 2H); 3.03 (tt, 1H); 3.21 (s, 3H); 4.21-4.33 (m, 2H); 6.31 (d, 1H); 7.29 (d, 1H); 7.59 (d, 2H); 7.82 (d, 2H); 9.47 (s, 1H). In analogy to Example 16, the following examples from Table 1 were prepared: TABLE 1

Beispiel 25:

Example 25:

 6 (4- {4 2- (dimethylamino) ethyl] piperazine ^ -y ^

2H-pyran-4-yl) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one

A mixture of 100 mg Intermediate 4, 126 mg 4- {4- [2- (dimethylamino) ethyl] piperazin-1-yljaniline (CAS 643087-82-5), 9.3 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364 -51-3), 39 mg sodium feri-butoxide and 13.3 mg of 2 '- (dicyclohexylphosphanyl) -A ^r, A ⁱ -dimethylbiphenyl-2-amine (CAS 213697-53-1) in 4 ml THF was less than 3 hours an argon atmosphere at 75 ° C stirred. The batch was concentrated and the residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5 μm 100 × 30 mm, mobile phase: acetonitrile / water (0.2% by volume ammonia (32%) gradient), giving 108 mg of 6 - [( 4- {4- [2- (Dimethylamino) ethyl] piperazin-1-yl} phenyl) amino] -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazine-2 (1H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6, some signals covered by DMSO): δ = 1.07 (d, 3H); 1.60 (bd, 1H); 1.74 (qd, 1H); 1.85-2.00 (m, 2H); 2.15 (s, 6H); 2.30-2.46 (m, 4H); 2.97-3.06 (m, 4H); 3.18 (s, 3H); 3.38-3.50 (m, 2H); 3.92-4.04 (m, 2H); 4.19 (q, 1H); 4.37 (tt, 1H); 6.14 (d, 1H); 6.83 (d, 2H); 7.19 (d, 1H); 7.45 (d, 2H); 8.47 (s, 1H). In analogy to Example 25, the following examples from Table 2 were prepared: TABLE 2

Example 29:

 (3 f), 3-Dimethyl-6 - {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2 , 3-b] pyrazin-2 (lH) -one

100 mg of 1,3-dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazine-2 (1H) -one (Example 27) were separated by chiral HPLC (Chiralpak IC 5μηι 250x30 mm, acetonitrile / ethanol / diethylamine 90: 10: 0.1 (v / v)) into the enantiomers. 45 mg of (3R) -l, 3-dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3 were obtained, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one.

Chiral HPLC: Rt = 6.67 min

Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: acetonitrile / ethanol / diethylamine 90: 10: 0.1; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Example 30:

(3S), 3-Dimethyl-6 - {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazin-2 (lH) -one

Bei der Trennung von l,3-Dimethyl-6-{ [4-(l-methylpiperidin-4-yl)phenyl]amino}-4-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazin-2(lH)-on (Beispiel 27) zu (3R)-l,3-dimethyl-6- { [4-(l-methylpiperidin-4-yl)phenyl]amino }-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrido[2,3- b]pyrazin-2(lH)-on (Beispiel 29) wurden auch 13 mg (3_lS')-l,3-dimethyl-6-{ [4-(l-methylpiperidin- 4-yl)phenyl]amino}-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrido[2,3-b]pyrazin-2(lH)-on erhalten.

In the separation of 1,3-dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazine-2 (1H) -one (Example 27) to give (3R) -l, 3-dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4 - (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one (Example 29) were also 13 mg (3 _l S ') - l, 3-dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one obtained.

Chiral HPLC: Rt = 5.00 min

 Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: acetonitrile / ethanol / diethylamine 90: 10: 0.1; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Example 31: (3 f) -6 - {[4- (4-Acetyl-piperazin-1-yl) -phenyl] -amino}, 3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2 , 3-b] pyrazin-2 (lH) -one

92 mg of 6- {[4- (4-acetylpiperazin-1-yl) phenyl] amino} - 1, 3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazine-2 (1H) -one (Example 28) were separated into the enantiomers by chiral HPLC (Chiralpak IC 5μιη 250x20 mm, methanol / ethanol 50:50 (v / v)). 62 mg of (3R) -6- {[4- (4-acetylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3 were obtained, 4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one.

Chiral HPLC: Rt = 7.82 min

Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: methanol / ethanol / diethylamine 50: 50: 0.1; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Example 32:

 (3S) -6 - {[4- (4-acetylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) 3,4-dihydropyrido [2 , 3-b] pyrazin-2 (lH) -one

In the separation of 6- {[4- (4-acetylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazine-2 (1H) -one (Example 28) to give (3R) -6- {[4- (4-acetylpiperazin-1-yl) -phenyl] -amino} -1,3-dimethyl-4 - (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one (Example 31) were also 12 mg (3S) -6- {[4 - (4-acetylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (lH) -one obtained.

Chiral HPLC: Rt = 9.33 min

Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: methanol / ethanol / diethylamine 50: 50: 0.1; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Example 33:

 (3 f) -6 - {[2-Fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2 , 3-b] pyrazin-2 (lH) -one

A mixture of 100 mg Intermediate 4, 126 mg 2-fluoro-4- (methylsulfonyl) aniline (CAS 832755- 13-2), 9.6 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 40 mg sodium ieri- butoxide and 13.7 mg of 2 '- (dicyclohexylphosphanyl) -A ^i, / V-dimethylbiphenyl-2-amine (CAS 213697-53- 1) in 4 ml of THF was stirred under argon atmosphere at 75 ° C for 2 hours. The batch was concentrated and the residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5 μm 100 × 30 mm, mobile phase: acetonitrile / water (0.2% by volume ammonia (32%) gradient). 2-Fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 ( lH) -one.

These were separated by chiral HPLC (Chiralpak IC 5μιη 250x20 mm, acetonitrile / diethylamine 100: 0.1 (v / v)) into the enantiomers. 27 mg of (3R) -6- {[2-fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4- dihydropyrido [2,3-b] pyrazine-2 (1H) -one. 'H-NMR: (400 MHz, 25 ° C, DMSO-d6): 5 = 1.11 (d, 3H); 1.62 (bd, 1H); 1.80 (qd, 1H); 1.90-2.03 (m, 2H); 3.21 (s, 3H); 3.23 (s, 3H); 3.38-3.54 (m, 2H); 3.93-4.04 (m, 2H); 4.28 (q, 1H); 4.34 (tt, 1H); 6.64 (d, 1H); 7.34 (d, 1H); 7.64 (dd, 1H); 7.70 (dd, 1H); 8.83 (t, 1H); 9.04 (d, 1H).

Chiral HPLC: Rt = 5.87 min

Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: acetonitrile / diethylamine 100: 0.1; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (lmg / ml

Ethanol / methanol, 1: 1); DAD 996 scan: 280 nm. Example 34:

 (3S) -6 - {[2-Fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazin-2 (lH) -one

In the separation of 6- {[2-fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazine-2 (1H) -one to give (3R) -6- {[2-fluoro-4- (methylsulfonyl) phenyl] amino} -13-dimethyl-4- (tetrahydro-2H-pyran-4-yl) yl) -3,4-dihydropyridoP b] pyrazine-2 (1H) -one (Example 33) were also 7 mg (3 ^ -6- {[2-Ρ1υοΓ-4-

(Methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one.

Chiral HPLC: Rt = 4.34 min

Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: methanol / ethanol / diethylamine 50: 50: 0.1; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Biological activity of the compounds according to the invention

The following examples describe the effectiveness of the compounds of the invention.

Protein-Protein Interaction Assay: Binding Assay BRD4 / Acetylated Peptide H4 1. Assay Description BRD4 Bromodomain 1 [BRD4 (1)]

To assess the BRD4 (1) binding potency of the substances described in this application, their ability to dose-dependently inhibit the interaction between BRD4 (1) and acetylated histone H4 was quantified. For this purpose, a time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used, demonstrating the binding between N-terminal His6-tagged BRD4 (1) (amino acids 67-152) and a synthetic acetylated histone H4 (acylated histone H4). H4) peptide with sequence

GRGK (Ac) GGK (Ac) GLGK (Ac) GGAK (Ac) RHGSGSK-biotin. 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 DMSO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany). The 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 CHAPS and 0.05% serum albumin (BSA)] to the substances in the assay plate. This was followed by a 10 minute incubation step at 22 ° C for the pre-equilibration of putative complexes between BRD4 (1) and the substances. 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 was determined by measuring the resonance energy transfer from the streptavidin-Eu cryptate to the anti-6His-XL665 antibody that is in the reaction. For this, the fluorescence emission at 620 nm and 665 nm after excitation at 330-350 nm in a TR-FRET meter, 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-H4 complexes formed.

The data obtained (ratio) were normalized with 0% inhibition equal to the mean of the measurements of a set of controls (typically 32 data points) containing all reagents. Instead of test substances, 50 μl of DMSO (100%) were used. 100% inhibition was the mean of the measurements from a set of controls (typically 32 data points) containing all reagents except BRD4 (1). The IC50 value was determined by regression analysis based on a 4-parameter equation (minimum, maximum, IC50, Hill, Y = Max + (Min-Max) 1 (1 +

(X / IC ₅₀ ) Hill).

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

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

For this purpose, a time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used, demonstrating the binding between N-terminal His6-tagged BRD4 (2) (amino acids 357-445) and a synthetic acetylated histone H4 (acylated histone H4). H4) peptide with sequence

 SGRGK (Ac) GGK (Ac) GLGK (Ac) GGAK (Ac) RHRKVLRDNGSGSK-biotin. 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).

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) as duplicates on the same microtiter plate. Plate measured. For this purpose, 100-fold concentrated solutions in DMSO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany). The 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 mM CHAPS and 0.05% serum albumin (BSA)] to the substances in the test plate. This was followed by a 10 minute incubation step at 22 ° C for the pre-equilibration of putative

Complexes between BRD4 (2) and the substances. Subsequently, 3 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 [83.5 nM anti-6His XL665 (Cisbio Bioassays, Codolet, France ) and 12, 52 nM streptavidin-Eu), (Perkin Elmer, # W1024)] in the assay buffer.

The mixture was then incubated in the dark for one hour at 22 ° C and then for at least 3 hours and at most overnight at 4 ° C. The formation of BRD4 (2) / Ac-H4 complexes was determined by measuring the resonance energy transfer from the streptavidin-Eu chelate to the anti-6His-XL665 antibody that is in the reaction. For that were 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 (2) / Ac-H4 complexes formed.

The data obtained (ratio) were normalized with 0% inhibition equal to the mean of the measurements of a set of controls (typically 32 data points) containing all reagents. Instead of test substances, 50 μl of DMSO (100%) were used. 100% inhibition was the mean of the measurements from a set of controls (typically 32 data points) containing all reagents except BRD4 (2). The determination of the IC5 ₀ value was carried out by regression analysis on the basis of a 4-parameter equation (minimum, maximum, IC50, Hill; Y = Max + (Min - Max) 1 (1 +

(X / IC ₅₀ ) Hill)). 3. Cell 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 (Invitrogen) in a Victor X3 Multilabel Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelength was 590 nM.

 The MOLM-13 cells (DSMZ, ACC 554) were seeded to a concentration of 4000 cells of AVELL in ΙΟΟμΙ growth medium (RPMI1640, 10% FCS) on 96 well microtiter plates (Method 1).

 Alternatively, the MOLM-13 cells (DSMZ, ACC 554) were seeded to a concentration of 500 cells / well in 5μl growth medium (RPMI1640, 10% FCS) on 1536 well microtiter plates (Method 2).

The MOLP-8 cells (DSMZ, ACC 569) were seeded to a concentration of 4000 cells / well in ΙΟΟμΙ growth medium (RPMI1640, 20% FCS) on 96 well microtiter plates.

The B16F10 cells (ATCC, CRL-6475) were seeded to a concentration of 300-500 cells / well in ΙΟΟμΙ growth medium (DMEM with phenol red, 10% FCS) on 96 well microtiter plates.

The CHL-1 cells (ATCC, CRL-9446) were seeded to a concentration of 1000 cells AAVELL in ΙΟΟμΙ growth medium (DMEM with glutamine, 10% FCS) on 96 well microtiter plates.

 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 96 (MOLM-13 , B16F10, CHL-1 cells) or 120 (MOLP-8 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 IC 50 values (substance concentration necessary for 50% inhibition of cell proliferation) were calculated therefrom.

 In method 2, after a 3-day incubation with the inhibitor, the ATP concentration was determined as a readout for the cell number with the CellTiterGlo kit (Promega). The measurement was carried out in a luminometer.

The substances were investigated in the cell lines of Table 3, which exemplify the indicated indications: Table 3:

4. Results: 4.1 binding assay

Table 4 shows the results from the BRD4 (1) binding assay. Table 4:

ICso [BRD4 (1)]

 example

 (Nmol / 1)

 1 78

 2 97

 3 465

 4 221

 5,348

 6 461

 7 483

 8 169

 9,293

 10 122

 11 96

 12 166

 13 125

 14 141

 15 136

16 143 IC ₅₀ [BRD4 (1)]

example

 (Nmol / 1)

17 1410

18 509

19,475

20 91

21 367

22,558

23 617

24 132

25 184

26 395

27 184

28,206

29,291

30 5740

31 228

32 3880

33 138

34> 20000

Table 5 shows the results from the BRD4 (2) binding assay.

Table 5:

IC ₅₀ [BRD4 (2)] IC ₅₀ [BRD4 (2)]

Example example

 (nmol / 1) (nmol / 1)

1 96 18 505

2 76 19 462

3 332 20 84

4 285 21 235

5 171 22 396

6 246 23 634

7 314 24 131

8 139 25 90

9 98 26 244

10 127 27 425

11 63 28 344

12 78 29 268

13 102 30 1890

14 113 31 150

15 113 32 67

16 41 33 177

17 1680 34> 20000

4.2 Cell proliferation assay

Table 4 shows the results from the cell proliferation assays. Table 6:

The ability of the compounds of the invention to inhibit the proliferation of various cell lines was determined.

IC ₅₀ IC ₅₀ IC ₅₀ IC ₅₀ IC ₅₀ (MOLM-13) (MOLM-13) (MOLP-8) (B16F10) (CHL-1)

example

 (nmol / 1) (nmol / l) (nmol / l) (nmol / l) (nmol / l) Method 1 Method 2

 1 288 161 430 179

2 329 242 365 223

3 2850

 4 2180

 5 1880 802 1520

 6 1860

 7 3440

 8,546,411,607,398

9 697 615 648 445

10,294

 11 225 147 250 147

12 666

 13 270 213 286 243

14 376 429 598 456

15 631 583 992 556

16,366

 17 1780

 18 1230

 19 1410

20 217 180 468 154 IC ₅₀ IC ₅₀ IC ₅₀ IC ₅₀ IC ₅₀ (MOLM-13) (MOLM-13) (MOLP-8) (B16F10) (CHL-1)

example

 (nmol / 1) (nmol / l) (nmol / l) (nmol / l) (nmol / l) Method 1 Method 2

 21,842

 22 1600

 23 1250

 24 556 376 592 362

25 774 644 1470 498

26 969

 27,736

 28 1300

 29 541

 30> 10000

 > 2860

 31 1220

 32 5260

 33,560

 34> 10000

Claims

claims Compounds of the general formula (I)

in the A is -NH-, -N (C ₁ -C ₃ -alkyl) - or -O-, X is -N-, -CH- or -CR ² -, Y is -N-, -CH- or -CR ² -,  n is 0,1 or 2, for halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ , -S (= O) (= NR ⁸ ) R ⁹ , -C (= O) R ⁷ or -NR ¹⁰ R ^U stands,  or is 5-membered monocyclic heteroaryl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents from halogen, cyano, Ci-C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, halo _Ci-C4 alkyl, Ci-C ₄ alkoxy, halo-Ci-C ₄ alkoxy, Ci-C ₄ alkylthio, halo-Ci-C ₄ - Alkylthio, -NR ¹⁰ R ^U , -C (= O) OR ¹² , -C (= O) NR ¹⁰ R ^u , -C (= O) R ¹² , -S (= O) ₂ R ¹² , -S (= O) ₂ NR ¹⁰ R ^u ,  or represents 4- to 8-membered heterocycloalkyl which is 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 until 8-membered heterocycloalkyl- is not bound to the rest of the molecule via a nitrogen atom, R is hydrogen, hydroxy, halogen, cyano, C ₁ -C ₃ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C -alkynyl, halogen-C ₁ -C 4 -alkyl, C ₁ -C 4 -alkoxy, halogeno-C ₁ -C 4 -alkyl, Alkoxy, C 1 -C ₄ -alkylthio or halogeno-C 1 -C ₄ -alkylthio, and if n is 2, R ² may be identical or different, or together for a group * -S (= 0) 2-CH 2 -CH 2 - ** or  * -S (= 0) 2-CH 2 -CH 2 -CH 2 - **, where "*" is the point of attachment of R ^{1 represents} the phenyl or 6-membered heteroaryl ring to which R ^{1 is} attached, and wherein "**" is adjacent to this point of attachment Carbon atom of this ring means represents methyl or ethyl, is hydrogen or C 1 -C 3 -alkyl-, is hydrogen or C 1 -C 3 -alkyl-, or together represent C ₂ -Cs-alkylene, is Ci-Cö-alkyl- which is unsubstituted or monosubstituted with Ci-C3-alkoxy, phenyl, Cs-Cs-cycloalkyl, or 4- to 8-membered Heterocy cloalkyl-, 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 alkynyl C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkyl or C 1 -C ₄ -alkoxy-, and  wherein Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-, or C3-C8-cycloalkyl or 4- to 8-membered heterocycloalkyl, which are unsubstituted or mono- or disubstituted by identical or different substituents selected from Ci-C3 alkyl or Ci-C ₄ alkoxycarbonyl, or is phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen,  Ci-C3-alkyl or 4- to 8-membered heterocycloalkyl, wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl or C 1 -C ₄ -alkoxycarbonyl, by C 1 -C 6 -alkyl-, is unsubstituted or monosubstituted with cyano, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylamino, phenyl, C ₃ -C 8 -cycloalkyl-, or 4- to 8-membered heterocycloalkyl, 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 alkynyl C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkyl or C 1 -C ₄ -alkoxy-, and in which C 5 -C 8 -cycloalkyl and C ₄ -C 8 -yloxy heterocycloalkyl are in turn unsubstituted or mono- or disubstituted by identical or different substituents with C 1 -C 3 -alkyl-, or is halo-Ci-C ₄ alkyl, or C3-C8-cycloalkyl or 4- to 8-membered heterocycloalkyl, which are unsubstituted or mono- or disubstituted by identical or different substituents selected from Ci-C3 alkyl or Ci-C ₄ alkoxycarbonyl, with the In that the 4- to 8-membered heterocycloalkyl group is not bonded via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ , is cyano, C ₁ -C ₆ -alkyl, C ₅ -C ₈ -cycloalkyl or -C (0O) OR ¹² , represents C ₁ -C ₆ -alkyl or C ₃ -C ₈ -cycloalkyl-, independently of one another are hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxyl, oxo or C 1 -C 3 -alkoxy-substituted C 1 -C 3 -alkyl-, or by fluorine-C 1 -C 3 -alkyl- or 4 to 8 -membered heterocycloalkyl-,  wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents C ₁ -C ₃ -alkyl, or together with the nitrogen atom to which they are bonded, for 4- to 8-membered heterocycloalkyl, heterospirocycloalkyl, Heterobicycloalkyl- or bridged Heterocycloalkyl- stand, which are unsubstituted or mono- or disubstituted by identical or different substituents with hydroxy, fluorine, oxo, cyano, Ci-C ₃ alkyl, Fluoro-C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, cyclopropylmethyl-, C ₁ -C ₃ -acylcarbonyl, C ₁ -C ₃ -alkylamino- (C ₁ -C ₃ -alkyl) - or - C 1 -C ₄ alkoxycarbonyl, for C ₁ -C 6 -alkyl- or phenyl-C ₁ -C ₃ -alkyl-, their diastereomers, racemates, polymorphs and physiologically tolerable salts. 2. Compounds of general formula (I), according to claim 1, in which  A is -NH- or -N (methyl) -,  X is -N- or -CH-,  Y stands for -CH-,  n is 0,1 or 2, R ^{1 is} halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,  or  isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl-, Trifluoromethyl, Ci-C ₃ alkoxy, trifluoromethoxy or -NR ¹⁰ R ^U , or is 5- to 6-membered heterocycloalkyl-, which is unsubstituted or monosubstituted with Ci-C ₃ alkyl or Ci-C t-alkoxycarbonyl, with the proviso that the 5- to 6-membered heterocycloalkyl not about one Nitrogen atom is bound to the rest of the molecule, R ^{2 is} hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, trifluoromethyl, Methoxy, ethyl or ethoxy, and if n is 2, R ² may be the same or different, R ³ represents methyl or ethyl, R ^{4 is} hydrogen, methyl or ethyl, R ^{5 is} hydrogen, methyl or ethyl, R ⁶ is C ₂ -C ₅ alkyl group,  or  is methyl or ethyl which is monosubstituted with C ₁ -C ₃ -alkoxy, phenyl or 4 to 8-membered heterocycloalkyl-,  wherein phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C3-alkyl or Ci-C3-alkoxy, and wherein the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or mono- or disubstituted by methyl, or is C3-C8-cycloalkyl- or 4- to 8-membered heterocycloalkyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl- or Ci-C t -alkoxycarbonyl-, or is phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl-, wherein the 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by methyl or ieri-butoxycarbonyl, is Ci-Cö-alkyl-, which is unsubstituted or monosubstituted with cyano, Ci-C ₃ -alkoxy-, C ₁ -C ₃ -alkylamino, phenyl or 4 to 8-membered heterocycloalkyl-, wherein 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 or C ₁ -C ₃ -alkoxy-, and  in which the 4- to 8-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-, or represents fluoro-C ₁ -C ₃ -alkyl, or is C3-C8-cycloalkyl- or 4- to 8-membered heterocycloalkyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl- or Ci-C t-alkoxycarbonyl, with the In that the 4- to 8-membered heterocycloalkyl group is not bonded via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ , and independently of one another for hydrogen or for unsubstituted or monosubstituted or C ₁ -C ₃ -alkyl or for hydroxyalkyl or oxo 6-membered heterocycloalkyl-, in which the 5- to 6-membered heterocycloalkyl radical is in turn unsubstituted or substituted once or twice, identically or differently, by C ₁ -C ₃ -alkyl-, or together with the nitrogen atom to which they are attached for 4- to 7-membered heterocycloalkyl, heterospirocycloalkyl or bridged heterocycloalkyl groups which are unsubstituted or mono- or di-twice, are substituted identically or differently with hydroxy, fluorine, oxo, C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, cyclopropyl, cyclopropylmethyl, acetyl, tert-butoxycarbonyl or (H ₃ C) ₂ N - (Ci-C3-alkyl) -, their diastereomers, racemates, polymorphs and physiologically acceptable salts. 3. Compounds of general formula (I), according to claims 1 and 2, in the  A stands for -NH-,  X is -N- or -CH-,  Y stands for -CH-,  n is 0 or 1, R ^{1 is} halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U ,  or isoxazolyl, oxazolyl or oxadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl,  or  is piperidinyl or pyrrolidinyl, which are unsubstituted or monosubstituted with Ci-C3-alkyl, with the proviso that the Piperidinyl and the pyrrolidinyl does not have a nitrogen attached to the rest of the molecule, R ^{2 is} hydrogen, fluorine, chlorine, methyl, trifluoromethyl or methoxy, R ^{3 is} methyl, R ^{4 is} methyl or ethyl, R ⁵ represents hydrogen, R ^{6 is} C ₃ -C ₅ -alkyl-,  or  is methyl which is monosubstituted by phenyl- or 4- to 6-membered heterocycloalkyl-,  wherein the 4- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by methyl, or represents C ₃ -C 8 -cycloalkyl- or 4- to 6-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl- or C ₁ -C 4 -alkoxycarbonyl-, or is phenyl, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl, R ^{7 is} Ci-C t-alkyl- which is unsubstituted or monosubstituted with  Cyano, phenyl or 5- to 6-membered heterocycloalkyl, in which phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluoro, chloro, cyano, methyl or methoxy, and wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by Ci-C ₃ alkyl, or  is trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl, or represents 5- to 6-membered heterocycloalkyl which is unsubstituted or monosubstituted by C ₁ -C ₃ -alkyl, with the proviso that the 5- to 6-membered heterocycloalkyl does not have a nitrogen atom on the carbonyl, Sulfinyl or sulfonyl group is bound in R ¹ , and R ¹⁰ and R ^{11 are} independently hydrogen or Ci-C ₃ alkyl or  Acetyl stand,  or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached, for 5- to 6-membered heterocycloalkyl, heterospirocycloalkyl or bridged heterocycloalkyl groups which are unsubstituted or monosubstituted by C ₁ -C ₃ -alkyl-, trifluoromethyl-, difluoromethyl-,  2,2,2-trifluoroethyl, acetyl, ieri-butoxycarbonyl or  2- (N, N-dimethylamino) ethyl, as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts. Compounds of the general formula (I) according to Claims 1 to 3, in which  A stands for -NH-,  X is -N- or -CH-,  Y stands for -CH-, n is 0 or 1, R ^{1 is} halogen, cyano, -S (= O) R ⁷ , -S (= O) ₂ R ⁷ or -NR ¹⁰ R ^U , or  is isoxazolyl, which is unsubstituted or monosubstituted or disubstituted by methyl,  or  is piperidinyl which is unsubstituted or monosubstituted with Methyl, provided that the piperidinyl is not linked to the rest of the molecule via a nitrogen atom, R ^{2 is} hydrogen, fluorine, methyl, trifluoromethyl or methoxy, R ^{3 is} methyl, R ^{4 is} methyl, R ⁵ represents hydrogen, R ^{6 is} isopropyl,  or  represents cycloheptyl,  or  is tetrahydropyranyl or piperidinyl, which are unsubstituted or monosubstituted with methyl, R ^{7 is} C 1 -C ³ -alkyl which is unsubstituted or monosubstituted with  cyano,  or  represents difluoromethyl,  or is piperidinyl, which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl is not linked via a nitrogen atom via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R ¹ , and R ¹⁰ and R ¹¹ independently of one another represent C 1 -C 3 -alkyl or acetyl,  or R ¹⁰ and R ¹¹ are together with the nitrogen atom to which they are attached to 6- membered heterocycloalkyl, which is unsubstituted or monosubstituted with Ci-C3 alkyl, 2,2,2-trifluoroethyl, acetyl or 2- (N, N-dimethylamino) ethyl,  or for 2-azaspiro [3.3] heptyl, 2-oxa-6-azaspiro [3.3] heptyl, or 8-oxa 3-azabicyclo [3.2.1] octyl, as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts. Compounds of the general formula (I) according to Claims 1 to 4,  A stands for -NH-,  X is -N- or -CH-,  Y stands for -CH-, n is 0 or 1, R ¹ for bromine, cyano or for

where "*" is the point of attachment to the rest of the molecule, R ^{2 is} hydrogen, fluorine, methyl, trifluoromethyl or methoxy, R ^{3 is} methyl, R ^{4 is} methyl, R ⁵ represents hydrogen, R ^{6 is} isopropyl, or  represents cycloheptyl,  or  for tetrahydropyran-4-yl or / V-methyl-piperidin-4-yl-, and their diastereomers, racemates, polymorphs and physiologically acceptable salts. Compounds of the general formula (I) according to Claim 1: (3R) -l, 3-dimethyl-6- {[4- (propan-2-ylsulphonyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazin-2 (lH) -one; (3R) - 1, 3-Dimethyl-6- {[4- (methylsulfonyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one; (3R) -6 - [(4-Bromophenyl) amino] -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3-b] pyrazine-2 (lH) -one; (3R) -6- {[4- (3,5-dimethyl-1,2-oxazol-4-yl) -phenyl] -amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl ) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -6- {[4- (4-Ethyl-piperazin-1-yl) -phenyl] -amino} -l, 3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one; (3R) -1,3-Dimethyl-6- ({4- [4- (propan-2-yl) -piperazine-1-yl-phenyl} -amino) -4- (tetrahydro-2H-pyran-4-yl) -3 , 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; (3R) - 1, 3-Dimethyl-4- (tetrahydro-2H-pyran-4-yl) -6- ({4- [4- (2,2,2-trifluoroethyl) piperazin-1-yl] -phenyl} amino) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; 5- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3-b] pyrazine 6-yl] amino} pyridine-2-carbonitrile (3R) -4-Cycloheptyl-1,3-dimethyl-6- {[4- (methylsulfonyl) phenyl] amino} -3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one; (R) -1,3-Dimethyl-4- (1-methylpiperidin-4-yl) -6- {[4- (methylsulfonyl) phenyl] amino} -3,4- dihydropyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -6- {[2-Methoxy-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydropyran-4-yl) -3,4-dihydropyrido [2,3-b ] pyrazin-2 (lH) -one; (3R) -4-isopropyl-6- {[4- (isopropylsulfonyl) phenyl] amino} -1,3-dimethyl-3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one; (3R) -6- ({4- [(difluoromethyl) sulfonyl] phenyl} amino) -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3- b] pyrazin-2 (lH) -one; 2 - [(4- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3- b] pyrazine-6-yl] amino} phenyl) sulfonyl] propanenitrile; [(4- {[(3R) -1,3-Dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydropyrido [2,3b] pyrazine -6-yl] amino} phenyl) sulfonyl] acetonitrile; (3R) -4-Cycloheptyl-1,3-dimethyl-6- ({4 - [(1-methylpiperidin-4-yl) sulfonyl] phenyl} amino) -3,4-dihydropyrido [2,3-b] pyrazine -2 (lH) -one; (3R) -6- {[4- (2-azaspiro [3.3] hept-2-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -l, 3-dimethyl-6- {[4- (2-oxa-6-azaspiro [3.3] hept-6-yl) -phenyl] -amino} -4- (tetrahydro-2H-pyran-4-yl ) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -l, 3-dimethyl-6 - ({4 - [(lR, 5S) -8-oxa-3-azabicyclo [3.2.1] oct-3-yl] -phenyl} -amino) -4- (tetrahydro -2H-pyran-4-yl) -3,4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -1,3-Dimethyl-6- ({4- [(1-methylpiperidin-4-yl) sulfonyl] phenyl} amino) -4- (tetrahydro-2H-pyran-4-yl) -3,4 -dihydropyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -l, 3-dimethyl-6 - ({4 - [(1-methylpiperidin-4-yl) sulfinyl] phenyl} amino) -4- (tetrahydro-2H-pyran-4-yl) -3,4 -dihydropyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -1,3-dimethyl-6- {[2-methyl-4- (4-methyl-piperazin-1-yl) -phenyl] -amino} -4- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; (3R) -1,3-dimethyl-6- {[4- (morpholin-4-yl) -2- (trifluoromethyl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3, 4-dihydro-pyrido [2,3-b] pyrazin-2 (lH) -one; / V- (4- {[(3R) -l, 3-dimethyl-2-oxo-4- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [2,3- b] pyrazine-6-yl] amino} phenyl) - / V-methylacetamide; 6- [(4- {4- [2- (Dimethylamino) ethyl] piperazine-1-ylphenyl) -amino] -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4 -dihydropyrido [2,3-b] pyrazin-2 (lH) -one; 6- {[2-Methoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one; 1,3-Dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) - 3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one; 6- {[4- (4-acetylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2,3- b] pyrazin-2 (lH) -one; (3R) - 1, 3-Dimethyl-6- {[4- (1-methylpiperidin-4-yl) -phenyl] -amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one; (35) - 1,3-Dimethyl-6- {[4- (1-methylpiperidin-4-yl) phenyl] amino} -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one; (3R) -6- {[4- (4-Acetyl-piperazin-1-yl) -phenyl] -amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one; (35) -6- {[4- (4-Acetylpiperazin-1-yl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [ 2,3-b] pyrazin-2 (lH) -one; (3R) -6- {[2-Fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazine-2 (1H) -one, and (35) -6- {[2-Fluoro-4- (methylsulfonyl) phenyl] amino} -1,3-dimethyl-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrido [2, 3-b] pyrazin-2 (lH) -one; as well as their diastereomers, racemates, polymorphs and physiologically tolerated salts. Use of the compounds according to claims 1 to 6 as medicaments. Use according to claim 7, for the prophylaxis and / or therapy of  Tumor diseases. 9. Use of the compounds according to claims 1 to 6, for the preparation of a medicament. 10. Use of the compounds according to claims 1 to 6 for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases. Use of the compounds according to claims 1 to 6, for the prophylaxis and / or therapy of hyperproliferative diseases. Use of the compounds according to claims 1 to 6 for the prophylaxis and / or therapy of viral infections, neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases and in the male  Fertility control. Use of the compounds according to claims 1 to 6 for the preparation of a medicament for the prophylaxis and / or therapy of viral infections,  neurodegenerative diseases, inflammatory diseases, atherosclerotic diseases and in male fertility control. 14. Compounds according to claims 1 to 6 in combination with one or more further pharmacologically active substances. 15. Compounds in combination according to claim 14, for the prophylaxis and / or therapy of hyperproliferative diseases. 16. Compounds in combination according to claim 14, for the prophylaxis and / or therapy of tumor diseases. 17. Compounds in combination according to claim 14, for the prophylaxis and / or therapy of viral infections, neurodegenerative diseases, inflammatory  Diseases, atherosclerotic diseases and in the male  Fertility control.