WO2015193229A1 - Bet-protein inhibiting 1,4-dihydropyrido[3,4-b]pyrazinones with meta-substituted aromatic amino- or ether groups - Google Patents

Abstract

The invention relates to BET-protein-inhibiting 1,4-dihydropyrido[3,4-b]pyrazinones with meta-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 l, 4-dihydropyrido [3,4-b] pyrazinones having mefa-substituted aromatic amino or ether group

The present invention relates to BET protein-inhibiting, in particular BRD4-inhibitory l, 4-dihydropyrido [3,4-b] pyrazinones with meto-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 the expression of several genes important during and after meiosis (Shang et al., Development, 2007, 134: 3507-3515; Matzuk et al., Cell, 2012, 150: 673-684).

Furthermore, BRDT is involved in the post-meiotic organization of chromatin (Dhar et al., J. Biol. Chem., 2012, 287: 6387-6405). In vivo experiments in 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 is particularly desirable to provide selective agents to minimize undesirable effects.

It has now been found that substituted l, 4-dihydropyrido [3,4-b] pyrazinones with meta-substituted aromatic amino or ether group having the desired properties, i. E. show a BET protein, in particular a BRD4 protein inhibitory effect with high selectivity against PLK-1. The compounds of the invention thus represent valuable active ingredients for prophylactic and therapeutic use in hyper-proliferative diseases, especially in tumor diseases

Compounds according to the invention are used in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.

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-dihydroquinoxaline-2 (1H) -one 7,8-dihydropteridine-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-diazepine (4-phenyl-6i thieno [3, 2-f [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-rsoxazolo [3,4-of] [2] benzazepines, including those compounds which have optionally substituted phenyl at position 6 and also analogs with alternative heterocyclic fusion partners instead of the benzo moiety, such as 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.

Further BRD4 inhibitors of the Applicant are also described in the following applications:

WO2013 / 030150 - 6H-thieno [3,2-f] [1, 2,4] triazolo [4,3-a] [4,3-a] [1,4] 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).

By contrast, the compounds according to the invention are substituted 1,4-dihydropyrido [3,4-b] pyrazinones having a meto-substituted aromatic amino or ether group which differ structurally in manifold 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. With regard to the in WO 2006/005510 respectively. US2006 / 0009457 disclosed 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives and their activity data was also not to assume that the substances of the present invention have a high selectivity against PLK-1 , It is therefore surprising that the compounds according to the invention have a good BRD4-inhibitory action with high selectivity against PLK-1 despite the considerable structural differences to known BRD4 inhibitors.

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 2006/005510 or US2006 / 0009457 (Boehringer Ingelheim) describes 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives as inhibitors of PLK-1 for the treatment of hyperproliferative diseases. These differ from the compounds of the present invention, inter alia, by the position of the substituent (meta in the present invention with respect to para in the document cited here) on the aromatic group bonded via a heteroatom to C-7.

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

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

WO 2006/050054, WO 2007/134169 and US 2009/0264384 (Nuada LLC) describe a number of bicyclic chemotypes as inhibitors of tumor necrosis factor alpha (TNF-α) as well as 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-ethyl-1-methyl-2-oxo-1,2] , 3,4-tetrahydroquinoxalin-6-yl] amino} -3-methoxy- / V- [2-methyl-1- (pyrrolidin-1-yl) -propan-2-yl] -benzamide, CAS Registry-No. 1026451-60-4, / V- (1-Benzylpiperidin-4-yl) -4- {[(3R) -4-cyclopentyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline -6-yl] amino} -3-methoxybenzamide, CAS registry no. 1026961-36-3, 4- {[(3R) -4-cyclohexyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl] amino} - / V- [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 selectively 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 formulas (I) and (Ia)

 (I) and in those

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 for halogen or cyano,

or -C (= 0) NR ⁷ R ^8, -S (= 0) ₂ NR ⁷ R ^8, -S (= 0) ₂ R ^9, -S (= O) (= NR ¹⁰⁾ R ^u, -C (= 0) R ⁹ or

-NR ¹² R ¹³ stands,

or

represents phenyl- or 5- to 6-membered monocyclic heteroaryl- which are 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, halogen-C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, halogeno-C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkylthio, halogeno-C 1 -C ₄ -alkyl, C ₄ alkylthio, -NR ¹² R ¹³ , -C (= O) OR ¹⁴ ,

-C (= O) NR ¹² R ¹³ , -C (= O) R ¹⁴ , -S (= O) ₂ R ¹⁴ or -S (= O) ₂ NR ¹² R ¹³ ,

or

is oxazolin-2-yl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl-,

is hydrogen, hydroxy, halogen, cyano, Ci-C ₃ alkyl, C ₂ -C 4 alkenyl, C ₂ -C ₄ alkynyl, _{halo-Ci-C4-alkyl,} Ci-C ₄ alkoxy -, halogen-C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkylthio or halogen-C 1 -C ₄ -alkylthio, and if n is 2, R ² may be identical or different,

or

together for a group * -S (= O) ₂ -CH ₂ -CH ₂ - **, * -S (= O) ₂ -CH ₂ -CH ₂ -CH ₂ - **,

* -C (= O) -CH ₂ -CH ₂ - **, * -C (= O) -CH ₂ -CH ₂ -CH ₂ - **, * -S (= O) ₂ -N (R ¹⁴ ) -CH ₂ - **,

* -S (= O) ₂ -N (R ¹⁴ ) -CH ₂ -CH ₂ - **, * -C (= O) -N (R ¹⁴ ) -CH ₂ - ** or

* -C (= O) -N (R ¹⁴ ) -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 "**" is a carbon atom adjacent to this point of attachment

Ringes means

represents methyl or ethyl,

represents hydrogen or C ₁ -C ₃ -alkyl,

represents 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-C ₃ 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, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl-, C 1 -C ₄ -alkoxy, halogeno-C 1 -C ₄ -alkyl or halogeno-C 1 -C ₄ -alkoxy-, and

wherein Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl- in turn are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-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,

Ci-C3-alkyl or 4- to 8-membered heterocycloalkyl,

 in which 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-,

stands for hydrogen,

or

is Ci-Cö-alkyl- which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with hydroxy, oxo, fluorine, cyano, Ci-C / t-alkoxy, halo-Ci-C _4- alkoxy, -NR ¹² R ¹³ , Cs-Cs-cycloalkyl, C ₄ -C ₈ -cycloalkenyl, 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, Cs-Cii-spirocycloalkyl , Cs-Cn heterospirocycloalkyl, bridged

C6-C12-cycloalkyl, bridged C6-C12-heterocycloalkyl, C6-C12-bicycloalkyl, C6-C12-heterobicycloalkyl, phenyl or 5- to 6-membered heteroaryl-,

 wherein Cs-Cs-cycloalkyl, C / t-Cs-cycloalkenyl, 4- to 8-membered

 Heterocycloalkyl, 4- to 8-membered heterocycloalkenyl,

Cs-Cii-spirocycloalkyl, Cs-Cn-heterospirocycloalkyl, bridged C6-C12-cycloalkyl, bridged C6-Cn-heterocycloalkyl, C6-Ci2-bicycloalkyl, C6-Ci2-Heterobicycloalkyl- are in turn unsubstituted or one or are substituted twice, identically or differently with hydroxy, fluorine, oxo, cyano, C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, C ₃ -C ₆ -cycloalkyl-,

Cyclopropylmethyl, Ci-C3-alkylcarbonyl, Ci-C / t-alkoxycarbonyl or -NR ¹² R ¹³ , and

 wherein phenyl and 5- to 6-membered heteroaryl are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, trifluoromethyl, Ci-C3-alkyl or Ci-C3-alkoxy,

or

is C3-C6-alkenyl or C3-C6-alkynyl-,

or ₂ cycloalkyl or C6-Ci ₂ is bicycloalkyl for Cs-Cs-cycloalkyl, Cs-C t-cycloalkenyl, Cs-Cn-Spirocycloalkyl-, bridged C6-C, which are unsubstituted or mono- or disubstituted by are identical or different substituted with: hydroxy, oxo, cyano, fluoro, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl or -NR ¹² R ¹³ , or

for 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C-CII Heterospirocycloalkyl-, bridged _C6-Ci2 heterocycloalkyl or C6-Ci ₂ is -Heterobicycloalkyl- which are unsusbstituiert or mono- or doubly, identically or differently substituted with hydroxy, fluorine, oxo, cyano, C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, C ₃ -C ₆ -cycloalkyl, cyclopropylmethyl, C ₁ -C ₄ -alkyl _3- alkylcarbonyl, C 1 -C ₄ -alkoxycarbonyl or -NR ¹² R ¹³ ,

or

for phenyl or 5- to 6-membered heteroaryl group which are unsubstituted or mono- or disubstituted by identical or different substituents selected from halogen, cyano, Ci-C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ -alkynyl, halo-C ₁ -C ₄ -alkyl,

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

Halogen-C 1 -C ₄ -alkylthio, -NR ¹² R ¹³ , -N (R ¹⁴ ) -S (= O) ₂ -R ¹⁵ , -N (R ¹⁴ ) -C (= O) -R ¹⁵ 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 C ₁ -C ₄ -alkoxycarbonyl-,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, oxo, C ₁ -C ₃ -alkyl-,

C ₁ -C ₃ -alkoxy- or trifluoromethyl-,

represents hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxy, oxo or Ci-C ₃ alkoxy-substituted Ci-C ₃ -alkyl-, or fluoro-C ₁ -C ₃ -alkyl- stands,

or

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

4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, Cs-Cii heterospirocycloalkyl, bridged C6-Cn heterocycloalkyl or C6-Ci2 heterobicycloalkyl- are unsubstituted or once or twice, are substituted identically or differently with hydroxy, 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 C 1 -C ₄ -alkoxycarbonyl, -S (= O) ₂ R ¹⁵ , -NR ¹² R ¹³ or unsubstituted or C ₁ -C ₃ -alkyl-substituted 5 to 6-membered heterocycloalkyl-, in which C ₁ -C ₃ -alkyl, in turn, is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by fluorine, cyano, oxo, hydroxy, C ₁ -C ₃ -alkoxy or -NR ¹² R ¹³ ,

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 ₁ -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

 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

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 that

4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl or sulfonyl group in R ¹ ,

is cyano, Ci-Ce-alkyl, Cs-Cs-cycloalkyl or -C (= 0) OR ¹⁴ ,

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

C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, C ₃ -C ₆ -cycloalkyl, cyclopropylmethyl-,

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

is hydrogen, Ci-Cö-alkyl or phenyl-Ci-C ₃ alkyl-, and R is C ₁ -C ₆ -alkyl-, C ₃ -C ₈ -cycloalkyl- or phenyl-C ₁ -C ₃ -alkyl-, and their racemates, diastereomers, (R) -enantiomers and isomeric mixtures in which the (R) - Form predominates, as well as their polymorphs and physiologically acceptable salts,

Surprisingly, the interaction between BRD4 and an acetylated histone 4 peptide with high selectivity against PLK-1 inhibit and thus inhibit the growth of cancer and tumor cells.

Preference is given to those compounds of the general formulas (I) and (Ia) 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} -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -S (= O) ₂ R ⁹ , -C (= O) R ⁹ or -NR ¹² R ¹³ stands, or

is phenyl or oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, Ci-C3-alkyl, trifluoromethyl, Ci-C3 Alkoxy, trifluoromethoxy or -NR ¹² R ¹³ ,

 or

 is oxazolin-2-yl- which is unsubstituted or monosubstituted or disubstituted by methyl,

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

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

R ¹ and R ² together represent a group * -S (= O) ₂ -CH ₂ -CH ₂ - **, * -S (= O) ₂ -CH ₂ -CH ₂ -CH ₂ - **,

* -S (= O) ₂ -N (H) -CH ₂ - **, * -S (= O) ₂ -N (H) -CH ₂ -CH ₂ - **, * -C (= 0) -N (H) -CH ₂ - ** or * -C (= O) -N (H) -CH ₂ -CH ₂ - **, in which "*" is the point of attachment of R ¹ to the phenyl or 6 heteroaryl ring to which R ^{1 is} attached and in which "**" denotes a carbon atom of this ring adjacent to this point of attachment,

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

or is methyl or ethyl which are monosubstituted by 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 or methyl,

stands for hydrogen,

or

is Ci-Cö-alkyl- which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents with hydroxy, oxo, fluoro, cyano, C ₁ -C ₃ -alkoxy, fluoro-Ci-C ₃ Alkoxy, -NR ¹² R ¹³ , C ₃ -C ₈ cycloalkyl, 4- to 8-membered

Heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl,

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

Fluoro-C ₁ -C ₃ -alkyl, cyclopropyl, cyclopropylmethyl, acetyl or ieri-butoxycarbonyl, and

 wherein phenyl and 5- to 6-membered heteroaryl are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy,

or

is Cs-Cö-cycloalkyl-, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, cyano, fluorine, -NR ¹² R ¹³ , or

₂ heterocycloalkyl or C6-Ci ₂ is -Heterobicycloalkyl- for 4- to 8-membered heterocycloalkyl, Cs-Cn-Heterospirocycloalkyl-, bridged C6-C, which are unsusbstituiert or mono- or disubstituted by identical or different substituents Hydroxy, oxo, C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, cyclopropyl, Cyclopropylmethyl, acetyl or ieri-butoxycarbonyl,

or

represents phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl-, fluoro-C ₁ -C ₃ -alkyl- , C ₁ -C ₃ -alkoxy, fluoro-C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylthio, fluoro-C ₁ -C ₃ -alkylthio, -NR ¹² R ¹³ , -N (H) -S (= 0) ₂ -R ¹⁵ or -N (H) -C (= 0) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, oxo, methyl, methoxy or trifluoromethyl,

is hydrogen or C ₁ -C ₃ -alkyl-,

or

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

4- to 8-membered heterocycloalkyl, Cs-Cn-Heterospirocycloalkyl-, bridged _C6-Ci2 heterocycloalkyl or C6-Ci ₂ are -Heterobicycloalkyl- that

are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, C ₃ -C 6 -cycloalkyl, cyclopropylmethyl , C ₁ -C ₃ -alkylcarbonyl-,

Ci-C t-alkoxycarbonyl, -S (= 0) ₂ R ¹⁵ , -NR ¹² R ¹³ or 5- or 6-membered heterocycloalkyl which is unsubstituted or monosubstituted with C ₁ -C ₃ -alkyl,

wherein C ₁ -C ₃ -alkyl, in turn, is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents with fluoro, cyano, oxo, hydroxy, methoxy or -NR ¹² R ¹³ ,

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 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 identical or different substituents with d-Cs-alkyl-,

or

represents fluoro-C 1 -C 8 -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-C4-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 ¹² and R ^{13 are} independently hydrogen or unsubstituted or simply with

 Hydroxy or oxo substituted Ci-C3-alkyl or 5- to 6-membered

Heterocycloalkyl stand,

 wherein the 5- to 6-membered heterocycloalkyl is in turn unsubstituted or substituted once or twice, identically or differently with d-Cs-alkyl-,

 or

R ¹² and R ¹³ 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, Ci-C ₃ alkyl, fluoro-Ci-C ₃ alkyl, cyclopropyl -, cyclopropylmethyl, acetyl or ieri-butoxycarbonyl-, and

R ^{15 is} C 1 -C ₄ -alkyl-, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which the (R) - form predominates, as well as their polymorphs and physiologically acceptable salts.

Particular preference is given to those compounds of the general formulas (I) and (Ia) in which A is -NH-,

X stands for -CH-,

 Y stands for -CH-,

n is 0 or 1,

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

 or

is phenyl or oxazolyl or oxadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C ₁ -C ₃ -alkyl, R ^{2 is} hydrogen, fluorine, chlorine, methyl or methoxy,

 or

R ¹ and R ² together represent a group * -S (= O) ₂ -N (H) -CH ₂ - ** or * -C (= O) -N (H) -CH ₂ - ** in which "*" means the point of attachment of R ¹ to the phenyl ring to which R ^{1 is} attached, and wherein "**" is adjacent to this point of attachment

Carbon atom of this ring means

R ^{3 is} methyl, represents methyl or ethyl,

stands for hydrogen,

represents Cs-Cs-alkyl,

or

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

heterocycloalkyl,

 wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, and

 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,

stands for hydrogen,

or

is C 1 -C 6 -alkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, C 1 -C 3 -alkoxy-, -NR ¹² R ¹³ , Cs-C 6 -cycloalkyl-, to 6-membered heterocycloalkyl or phenyl,

wherein C3-C6-cycloalkyl and 4- to 6-membered heterocycloalkyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, Ci-C ₃ alkyl, trifluoromethyl, acetyl or ieri Butoxycarbonyl, and

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

is Cs-Cö-cycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, -NR ¹² R ¹³ ,

or

represents 4- to 6-membered heterocycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, C ₁ -C ₃ -alkyl-, trifluoromethyl-, acetyl- or ieri-butoxycarbonyl-,

or represents phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, C 1 -C 3 -alkyl-, trifluoromethyl-, C 1 -C 3 -alkoxy -, trifluoromethoxy, - NR ¹² R ¹³ , -N (H) -S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with

Fluorine, chlorine, oxo or methyl,

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

or

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

4- to 8-membered heterocycloalkyl, Cö-Cio-Heterospirocycloalkyl- or bridged Cö-Cio-Heterocycloalkyl- stand, which are unsubstituted or mono- or disubstituted by identical or different substituents with oxo, Ci-C3-alkyl, fluorine -Ci-C3-alkyl, cyclopropyl, Ci-C3-alkylcarbonyl, Ci-C t-alkoxycarbonyl, -S (= 0) ₂ R ¹⁵ , -NR ¹² R ¹³ or unsubstituted or simply with Ci-C ₃ Alkyl substituted piperidinyl,

wherein C 1 -C 3 -alkyl is in turn unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by oxo or -NR ¹² R ¹³ , is OC t -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 C3-C6-cycloalkyl-,

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

or

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

 5- to 6-membered heterocycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, C 1 -C 3 -alkyl-,

Trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl,

Cyclopropylmethyl or ieri-butoxycarbonyl, and

represents C ₁ -C ₃ -alkyl-, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers in which the (R) - form predominates, as well as their polymorphs and physiologically acceptable salts.

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

 A stands for -NH-,

 X stands for -CH-,

 Y stands for -CH-,

n is 0 or 1,

R ^{1 represents} -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ or represents -S (= O) ₂ R ⁹ ,

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

R ^{3 is} methyl,

R ^{4 is} methyl,

R ⁵ represents hydrogen,

R ^{6 is} isopropyl,

 or

 stands for benzyl,

 or

 represents cyclopentyl,

 or

 represents tetrahydropyranyl,

 or is piperidinyl which is unsubstituted or monosubstituted with ferric butoxycarbonyl,

R ^{7 is} C ₁ -C ₃ -alkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl,

 wherein phenyl is unsubstituted or monosubstituted by identical or different substituents with methyl,

 or

 is cyclopropyl or cyclohexyl,

 wherein cyclohexyl is unsubstituted or monosubstituted with

-NR ¹² R ¹³ ,

 or

are piperidinyl or Azetidinyl- which are unsubstituted or monosubstituted with oxo, methyl, acetyl or ieri-butoxycarbonyl, or is phenyl, pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl, methoxy, -N (H -S-S (= O) 2-R ¹⁵ or -N (H) -C (= O) -R ¹⁵ ,

 or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with oxo,

 is hydrogen or methyl,

 or

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

Pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, 2-oxa-6-azaspiro [3.3] heptyl or 3-oxa-8-azabicyclo [3.2.1] octyl; are unsubstituted or monosubstituted with methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl, -NR ¹² R ¹³ , / V -methylpiperidin-4-yl or 2-oxo -2- (pyrrolidin-l-yl) ethyl,

represents C ₁ -C ₃ -alkyl-,

 or

 represents cyclopropyl,

 independently of one another represent hydrogen or methyl,

 or

 together with the nitrogen atom to which they are attached represent pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl or piperazinyl, which are unsubstituted or monosubstituted by oxo, methyl or

 cyclopropylmethyl,

 represents methyl, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which outweighs the (R) - form, and their polymorphs and physiologically acceptable salts.

Most preferred are those compounds of the general formula (I) and (Ia). in which

A stands for -NH-,

 X stands for -CH-,

 Y stands for -CH-,

n is 0 or 1,

R ^{1 represents} -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ or represents -S (= O) ₂ R ⁹ ,

R ^{2 is} hydrogen or methoxy,

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

R ⁵ represents hydrogen,

R ^{6 is} isopropyl,

 or

 stands for benzyl,

 or

 represents cyclopentyl,

 or

 for tetrahydropyran-4-yl or

 represents piperidin-4-yl-,

 or for

 stands,

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

R ⁷ for

, OH .0. sChL CH, CH,

steht,

stands,

or for

 stands,

 or for

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

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

R is hydrogen or methyl,

 or

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, for

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

R ^{9 is} methyl, isopropyl or cyclopropyl, and

R ^{16 is} methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl,

 Methylsulfonyl, / V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl, and their racemates, diastereomers, (R) -enantiomers and isomeric mixtures in which the (R) - Form predominates, as well as their polymorphs and physiologically acceptable salts.

The present invention further relates to compounds of the general formulas (I) and (Ia)

in denen

in which

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} -C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ ,

 or

is halogen, cyano, -S (= O) ₂ R ⁹ , -S (= O) (= NR ¹⁰ ) R ^u , -C (= O) R ⁹ or -NR ¹² R ¹³ , or

is phenyl or 5- to 6-membered monocyclic heteroaryl, which 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 t-alkyl, C ¹ -C ₄ -alkoxy, halogeno-C ¹ -C ₄ -alkoxy, C ¹ -C ₄ -alkylthio, halogeno-C ¹ -C ₄ -alkylthio, -NR ¹² R ¹³ , -C (= 0) OR ¹⁴ , -C (= O) N ¹² R ¹³ , -C (= O) R ¹⁴ , -S (= O) ₂ R ¹⁴ , -S (= O) ₂ NR ¹² R ¹³ ,

or

is oxazolin-2-yl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl-,

alkyl, hydrogen, hydroxy, halogen, cyano, Ci-C3-alkyl, C2-C4-alkenyl, C2-C4 alkynyl, halo-Ci-C _4, C ₄ alkoxy, halogen 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 (= O) ₂ -CH ₂ -CH ₂ - **, * -S (= O) ₂ -CH ₂ -CH ₂ -CH ₂ - **,

* -C (= O) -CH ₂ -CH ₂ - **, * -C (= O) -CH ₂ -CH ₂ -CH ₂ - **, * -S (= O) ₂ -N (R ¹⁴ ) -CH ₂ - **,

* -S (= O) ₂ -N (R ¹⁴ ) -CH ₂ -CH ₂ - **, * -C (= O) -N (R ¹⁴ ) -CH ₂ - ** or * -C (= 0 ) -N (R ¹⁴ ) -

CH ₂ -CH ₂ - **, where "*" is the point of attachment of R ¹ to the phenyl or

6-membered heteroaryl ring to which R ^{1 is} bonded, and in which "**" denotes a carbon atom of this ring adjacent to this attachment point, represents methyl or ethyl,

represents 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 C ₁ -C 3 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, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy -, halogen-C 1 -C ₄ -alkyl or halogen-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

represents phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or mono- 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-,

stands for hydrogen,

or

is Ci-Cö-alkyl-, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents with hydroxy, oxo, fluorine, cyano, Ci-C t-alkoxy, halo-Ci-C ₄ alkoxy, -NR ¹² R ¹³ , Cs-Cs-cycloalkyl, C ₄ -C ₈ -cycloalkenyl, 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C 5 -C 11 -spirocycloalkyl- , Cs-Cn-heterospirocycloalkyl, bridged C6-C12-cycloalkyl, bridged C6-C12-heterocycloalkyl, C6-C12-bicycloalkyl, C6-C12-heterobicycloalkyl, phenyl or 5- to 6-membered heteroaryl-,

 wherein Cs-Cs-cycloalkyl, C4-C8-cycloalkenyl, 4- to 8-membered

Heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-C11 spirocycloalkyl, Cs-Cn heterospirocycloalkyl, bridged C6-C12 cycloalkyl, bridged C6-Cn heterocycloalkyl, C6-Ci2 bicycloalkyl, C6 -Ci2-Heterobicycloalkyl- in turn are unsubstituted or mono- or di-substituted by identical or different hydroxy, fluoro, oxo, cyano, Ci-C ₃ alkyl, fluoro-Ci-C ₃ alkyl, C ₃ -C ₆ -cycloalkyl-,

Cyclopropylmethyl, Ci-C3-alkylcarbonyl, Ci-C-t-alkoxycarbonyl or -NR ¹² R ¹³ , and

 wherein phenyl and 5- to 6-membered heteroaryl are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, trifluoromethyl, Ci-C3-alkyl or Ci-C3-alkoxy,

or

is C ₃ -C 6 alkenyl or C ₃ -C 6 alkynyl,

or

is Cs-Cs-cycloalkyl, C t -Cs -cycloalkenyl, Cs-Cn-spirocycloalkyl, bridged C 6 -C 12 -cycloalkyl or C 6 -C 12 -cycloalkyl-, which are unsubstituted or mono- or disubstituted, the same or variously substituted with: hydroxy, oxo, cyano, fluoro, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl or -NR ¹² R ¹³ , or

for 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-Cn-Heterospirocycloalkyl-, bridged Coe-Cn-heterocycloalkyl or C6-C ₁₂ - Heterobicycloalkyl- stands which are unsusbstituiert or mono- or disubstituted by identical or different substituted with hydroxy, fluoro, oxo, cyano, Ci-C3 Alkyl, fluoro-C ₁ -C ₃ -alkyl, C ₃ -C 6 -cycloalkyl, cyclopropylmethyl-,

C ₁ -C ₃ -alkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl or -NR ¹² R ¹³ ,

or

is phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C ₄ -alkyl-, C ₂ -C ₄ -alkenyl-, C _{2-C4-alkynyl,} halo-Ci-C4-alkyl-, C1-C4 alkoxy, _{halo-Ci-C4-alkoxy,} Ci-C ₄ alkylthio, halo-Ci-C ₄ alkylthio , -NR ¹² R ¹³ , -N (R ¹⁴ ) -S (= O) ₂ -R ¹⁵ , -N (R ¹⁴ ) -C (= O) -R ¹⁵ 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-,

or 2,3-dihydroindenyl, which is unsubstituted or mono- or disubstituted by identical or different substituents from Ci-C with halo, cyano, oxo, ₃ alkyl, C ₁ -C ₃ - alkoxy or trifluoromethyl,

represents hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxy, oxo or Ci-C ₃ alkoxy-substituted Ci-C ₃ -alkyl-, or fluoro-C ₁ -C ₃ -alkyl- stands,

or

together with the nitrogen atom to which they are attached form 4- to 8-membered for heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-C11 Heterospirocycloalkyl-, bridged _C6-Ci2 heterocycloalkyl or C6-C ₁₂ - Heterobicycloalkyl- are unsubstituted or mono- or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, Ci-C ₃ alkyl, fluoro-Ci-C3-alkyl, C3-C6-cycloalkyl -, Cyclopropylmethyl-, Ci-C3-Alkylcarbo- nyl-, Ci-C ₄ alkoxycarbonyl, -S (= 0) ₂ R ¹⁴ , -NR ¹² R ¹³ or unsubstituted or monosubstituted by Ci-C ₃ alkyl 5- to 6-membered heterocycloalkyl-, in which C ₁ -C ₃ -alkyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluoro, cyano, oxo,

Hydroxy, C ₁ -C ₃ -alkoxy- or -NR ¹² R ¹³ ,

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 is in turn unsubstituted or mono-, di- or trisubstituted, the same or different substituted Ci-C C-C with halo, cyano, ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, ₄ alkoxy, halogen-Ci-C ₄ Alkyl or halo-C 1 -C ₄ alkoxy, and

in which C ₃ -C 8 -cycloalkyl- and 4- to 8-membered heterocycloalkyl- are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with 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 or sulfonyl group in R ¹ ,

is cyano, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl or -C (= O) OR ¹⁴ , 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 hydroxy, oxo or Ci-C ₃ alkoxy-substituted Ci-C3-alkyl-, or fluoro-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 with C1-C3-alkyl-,

 or

 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,

Ci-Cs-alkyl, fluoro-Ci-C ₃ alkyl, Cs-Ce-cycloalkyl, cyclopropylmethyl, C1-C3

Alkylcarbonyl or C 1 -C ₄ -alkoxycarbonyl,

is C ₁ -C 6 -alkyl- or phenyl-C ₁ -C ₃ -alkyl-,

represents C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl or phenyl-C ₁ -C ₃ -alkyl, and their racemates, diastereomers, (R) -enantiomers and isomeric mixtures in which the (R) form predominates as well as polymorphs and physiologically tolerated salts. Also of great interest are compounds of the general formulas (I) and (Ia) 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} -C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ ,

 or

is -S (= O) ₂ R ⁹ , -C (= O) R ⁹ or -NR ¹² R ¹³ ,

 or

is phenyl or oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, Ci-C3-alkyl, trifluoromethyl, Ci-C3 Alkoxy, trifluoromethoxy or -NR ¹² R ¹³ ,

 or

 is oxazolin-2-yl- which is unsubstituted or monosubstituted or disubstituted by methyl,

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, or

R ¹ and R ² together represent a group * -S (= O) ₂ -CH ₂ -CH ₂ - **, * -S (= O) ₂ -CH ₂ -CH ₂ -CH ₂ - **,

* -S (= O) ₂ -N (H) -CH ₂ - **, * -S (= O) ₂ -N (H) -CH ₂ -CH ₂ - **, * -C (= 0) -N (H) -CH ₂ - ** or * -C (= O) -N (H) -CH ₂ -CH ₂ - **, in which "*" is the point of attachment of R ¹ to the phenyl or 6 heteroaryl ring to which R ^{1 is} attached and in which "**" denotes a carbon atom of this ring adjacent to this attachment point,

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

 or

 is methyl or ethyl which are unsubstituted or monosubstituted by 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 or methyl,

stands for hydrogen,

or

is C 1 -C 6 -alkyl- which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with hydroxyl, oxo, fluorine, cyano, C ₁ -C ₃ -alkoxy-, fluoro-C ₁ -C ₃ - alkoxy, -NR ¹² R ¹³ , Cs-Cs-cycloalkyl, 4- to 8-membered

Heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl,

 in which Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by hydroxy, oxo, cyano, C 1 -C 3 -alkyl-, fluoro-C 1 -C 3 -cycloalkyl- Alkyl, cyclopropyl, cyclopropylmethyl, acetyl or tert-butoxycarbonyl, and

 wherein phenyl and 5- to 6-membered heteroaryl are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy,

or

is C3-C6-cycloalkyl-, which may optionally be monosubstituted or disubstituted by identical or different substituents with: hydroxy, oxo, cyano, fluorine, -NR ¹² R ¹³ , or

represents 4- to 8-membered heterocycloalkyl, Cs-Cn-heterospirocycloalkyl, bridged C6-C12-heterocycloalkyl or C6-C12-heterobicycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, Oxo, C ₁ -C ₃ -alkyl, fluoro-C ₁ -C ₃ -alkyl, cyclopropyl, cyclopropylmethyl, acetyl or ieri-butoxycarbonyl-,

or

represents phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C ₁ -C ₃ -alkyl-, fluoro-C ₁ -C ₃ -alkyl- , C ₃ alkoxy alkoxy, fluoro-C -C _3, C ₁ -C ₃ - alkylthio, fluoro-C -C ₃ alkylthio, -NR ¹² R ^13, -N (H) - S (= 0) ₂ -R ¹⁵ or -N (H) -C (= 0) -R ¹⁵ , or is unsubstituted 2,3-Difiydroindenyl-, d _as or mono- or disubstituted by identical or different substituents selected from fluorine, chlorine, cyano, oxo, methyl, Mefhoxy- or trifluoromethyl,

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

or

together with the nitrogen atom to which they are bonded represent 4- to 8-membered heterocycloalkyl, Cs-Cn-heterospirocycloalkyl, bridged C6-C12 heterocycloalkyl or C6-C12 heterobicycloalkyl groups which are unsubstituted or or disubstituted by identical or different substituted with hydroxy, fluoro, oxo, cyano, Ci-C ₃ alkyl, fluoro-Ci-C ₃ alkyl, C ₃ -C ₆ cycloalkyl, cyclopropylmethyl, Ci-C3 Alkylcarbonyl, Ci-C t-alkoxycarbonyl,

-S (= O) 2R ¹⁴ , -NR ¹² R ¹³ or unsubstituted or C 1 -C 3 -alkyl-substituted 5- to 6-membered heterocycloalkyl-,

wherein C 1 -C 3 -alkyl, in turn, is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents with fluoro, cyano, oxo, hydroxy, methoxy or -NR ¹² R ¹³ ,

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 ,

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

R ¹² and R ¹³ 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,

R ^{14 is} C 1 -C ₄ -alkyl-,

R ^{15 is} C 1 -C ₄ -alkyl-, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers in which outweighs the (R) - form as well as polymorphs and physiologically acceptable salts.

Also of particular interest are those compounds of the general formulas (I) and (Ia) in which

 A stands for -NH-,

X stands for -CH-,

 Y stands for -CH-,

n is 0 or 1,

R ^{1 is} -C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ ,

 or

stands for -S (= 0) ₂ R ⁹ ,

 or

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

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

 or

R ¹ and R ² together represent a group * -S (= O) ₂ -N (H) -CH ₂ - ** or * -C (= O) -N (H) -CH ₂ - ** in which "*" denotes the point of attachment of R ¹ to the phenyl ring to which R ^{1 is} attached, and in which "**" denotes a carbon atom of this ring adjacent to this point of attachment,

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 phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, and

 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,

stands for hydrogen,

or

is C ₁ -C 6 -alkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, C ₁ -C ₃ -alkoxy, -NR ¹² R ¹³ , C ₃ -C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl or phenyl,

wherein C ₃ -C 6 -cycloalkyl and 4- to 6-membered heterocycloalkyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, Ci-C ₃ alkyl, trifluoromethyl, acetyl or ieri-butoxycarbonyl, and

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

is C3-C6-cycloalkyl- which may optionally be monosubstituted or disubstituted by identical or different substituents with: hydroxy, oxo, -NR ¹² R ¹³ ,

or

represents 4- to 6-membered heterocycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, C 1 -C 3 -alkyl-, trifluoromethyl-, acetyl- or ieri-butoxycarbonyl-,

or

represents phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, C ₁ -C ₃ -alkyl-, trifluoromethyl-, C ₁ -C ₃ Alkoxy, trifluoromethoxy, - NR ¹² R ¹³ , -N (H) -S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ ,

 or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with

Fluorine, chlorine, oxo or methyl,

is hydrogen or C ₁ -C ₃ -alkyl-,

 or

together with the nitrogen atom to which they are attached represent 4- to 8-membered heterocycloalkyl, C 10-Cio-heterospirocycloalkyl or bridged C 12 -C 20 heterocycloalkyl groups which are unsubstituted or monosubstituted or disubstituted by identical or different substituents are oxo, C ₁ -C ₃ -alkyl-, fluoro-C ₁ -C ₃ -alkyl-, cyclopropyl-, C ₁ -C ₃ -alkylcarbonyl-, C ₁ -C 4 -alkoxycarbonyl-, -S (= O) ₂ R ¹⁴ , - NR ¹² R ¹³ or unsubstituted or C ₁ -C ₃ -alkyl-substituted piperidinyl,

in which C ₁ -C ₃ -alkyl, in turn, is unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by oxo or -NR ¹² R ¹³ , C 1 -C 4 -alkyl-, which is unsubstituted or monosubstituted is 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

 stands for trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl, independently of one another represent hydrogen or C 1 -C 3 -alkyl, or

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

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

 Trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or ieri-butoxycarbonyl,

represents C ₁ -C ₃ -alkyl-,

represents Ci-Cs-alkyl-, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which outweighs the (R) form and polymorphs and physiologically acceptable salts. Also of particular interest are those compounds of the general formulas (I) and (Ia) in which

 A stands for -NH-,

 X stands for -CH-,

Y stands for -CH-,

n is 0 or 1,

R ^{1 is} -C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ ,

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

R ^{3 is} methyl,

R ^{4 is} methyl or ethyl,

R ⁵ represents hydrogen,

R ^{6 is} isopropyl,

 or

 stands for benzyl,

 or

 represents cyclopentyl,

 or

 represents tetrahydropyranyl,

R ^{7 is} C 1 -C 4 -alkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl,

 wherein phenyl is unsubstituted or monosubstituted by identical or different substituents with methyl,

 or

 is cyclopropyl or cyclohexyl,

wherein cyclohexyl is unsubstituted or monosubstituted with hydroxy or -NR ¹² R ¹³ ,

 or

 is piperidinyl or azetidinyl which is unsubstituted or monosubstituted by oxo, methyl or ieri-butoxycarbonyl,

 or

is phenyl, pyrazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl, methoxy, -N (H) -S (= 0) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ , or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with

oxo,

R ^{8 is} hydrogen or methyl, or

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, for

 Pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, 2-oxa-6-azaspiro [3.3] heptyl or 3-oxa-8-azabicyclo [3.2.1] octyl; unsubstituted or monosubstituted with methyl, ethyl, 2,2,2-

Trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl, -NR ¹² R ¹³ , N-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl,

R ¹² and R ¹³ independently of one another represent hydrogen or methyl,

 or

R ¹² and R ¹³ together with the nitrogen atom to which they are attached, for pyrrolidinyl,

 Imidazolidinyl, piperidinyl, morpholinyl or piperazinyl, which are unsubstituted or monosubstituted with oxo, methyl or

 cyclopropylmethyl,

R ^{14 is} methyl,

R ^{15 is} methyl, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which outweighs the (R) form and polymorphs and physiologically acceptable salts.

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

 A stands for -NH-,

 X stands for -CH-,

Y stands for -CH-,

n is 0,

R ^{1 is} -C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ ,

R ^{3 is} methyl,

R ^{4 is} methyl or ethyl,

R ⁵ represents hydrogen,

R ^{6 is} isopropyl,

 or

 stands for benzyl,

 or

 represents cyclopentyl,

 or

represents tetrahydropyran-4-yl-,

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

 or

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

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

R is methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl,

Methylsulfonyl, / V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl, and their racemates, diastereomers, (R) -enantiomers and isomeric mixtures in which the (R) - Form predominates as well as polymorphs and physiologically tolerated salts. Preference is given to compounds of the general formula (I) in which A is -NH-.

Particular preference is given to compounds of the general formula (Ia) 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 for

-N (C ₁ -C ₃ -alkyl) - stands.

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 for

-N (methyl) - stands.

Particular preference is given to compounds of the general formula (Ia) 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 (Ia) 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-.

Particular preference is given to compounds of the general formula (Ia) 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-. Particular preference is given to compounds of the general formula (Ia) 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.

Particular preference is given to compounds of the general formula (Ia) in which n is the number 0.

Particular preference is given to compounds of the general formula (Ia) in which n is the number 1.

Particular preference is given to compounds of the general formula (Ia) in which R ^{1 is}

-C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ ,

or

stands for -S (= 0) ₂ R ⁹ ,

or

represents phenyl or 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 (Ia) in which R ^{1 is}

-C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ or -S (= O) ₂ R ⁹ .

Particular preference is given to compounds of the general formula (Ia) in which R ^{1 is}

-C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ .

Particular preference is given to compounds of the general formula (Ia) in which R ^{1 is}

-S (= 0) ₂ R ⁹ stands.

Particular preference is given to compounds of the general formula (Ia) in which R ^{1 is} phenyl- or 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 (Ia) in which R ^{2 is} hydrogen, fluorine, chlorine, methyl or methoxy.

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

Very particular preference is given to compounds of the general formula (Ia) in which R ^{2 is} hydrogen or methoxy. Particular preference is given to compounds of the general formula (Ia) in which R ¹ and R ² together are a group * -S (= O) ₂ -N (H) -CH ₂ - ** or * -C (= 0) - N (H) -CH ₂ - ** wherein "*" represents the point of attachment of R ¹ to the phenyl ring to which R ^{1 is} attached, and wherein "**" represents a carbon atom adjacent to this point of attachment of that ring. Particular preference is given to compounds of the general formula (Ia) in which R ^{1 is}

-C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ ,

or

stands for -S (= 0) ₂ R ⁹ ,

or

represents phenyl or oxazolyl or oxadiazolyl which are unsubstituted or mono- or disubstituted by identical or different substituents with C 1 -C 3 -alkyl-,

and in those

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

or in those

R ¹ and R ² together represent a group * -S (= O) ₂ -N (H) -CH ₂ - ** or * -C (= O) -N (H) -CH ₂ - ** in which "*" means the point of attachment of R ¹ to the phenyl ring to which R ^{1 is} attached, and wherein "**" represents a carbon atom of this ring adjacent to this point of attachment.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{1 is} -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ or -S (= O) ₂ R ⁹ .

and in those

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

Very particular preference is given to compounds of the general formula (Ia) in which R ^{1 is} -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ or -S (= O) ₂ R ⁹ .

and in those

R ^{2 is} hydrogen or or methoxy. Very particular preference is given to compounds of the general formula (Ia) in which R ^{1 is} -C (= O) NR ⁷ R ⁸ or -S (= O) ₂ NR ⁷ R ⁸ ,

and in those

R ^{2 is} hydrogen, methyl 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.

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

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

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

Preference is given to compounds of the general formula (Ia) 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. Particular preference is given to compounds of the general formula (Ia) in which one substituent each of R ⁴ and R ^{5 is} methyl and one is hydrogen, so that with respect to that of R ⁴ , R ⁵ and that 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.

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

Particular preference is given to compounds of the general formula (Ia) 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 mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, and

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

or

is C3-C8-cycloalkyl- or 4- to 6-membered heterocycloalkyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl or Ci-C4-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 (Ia) in which R ^{6 is} C ₃ -C ₅ -alkyl.

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

 wherein phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, 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 (Ia) 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 (Ia) in which R ^{6 is}

C ₁ -C 6 -cycloalkyl- or 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-. Particular preference is given to compounds of the general formula (Ia) 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 (Ia) in which R ^{6 is} isopropyl,

or

stands for benzyl,

or

represents cyclopentyl,

or

represents tetrahydropyranyl. or

is piperidinyl which is unsubstituted or monosubstituted with ieri-butoxycarbonyl-.

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

or

stands for benzyl,

or

represents cyclopentyl,

or

represents tetrahydropyranyl.

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

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

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

Very particular preference is given to compounds of the general formula (Ia) in which R ^{6 is} tetrahydropyranyl. Very particular preference is given to compounds of the general formula (Ia) in which R ^{6 is} piperidinyl which is unsubstituted or monosubstituted by ieri-butoxycarbonyl-.

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

Isopropyl stands,

or

stands for benzyl,

or

represents cyclopentyl,

or

represents tetrahydropyran-4-yl-,

or

represents piperidin-4-yl-, or for

 it is not, there is no point of reference

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

Tetrahydropyran-4-yl, piperidin-4-yl or for

steht, worin "*" den Anknüpfungspunkt an den Rest des Moleküls bedeutet.

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

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

Piperidine -4-yl.

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

Tetrahydropyran-4-yl is. Particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} hydrogen,

or

is C 1 -C 6 -alkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, C 1 -C 3 -alkoxy-, -NR ¹² R ¹³ , C 3 -C 6 -cycloalkyl-, to 6-membered heterocycloalkyl or phenyl,

 in which C 3 -C 6 -cycloalkyl and 4- to 6-membered heterocycloalkyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, C 1 -C 3 -alkyl, trifluoromethyl, acetyl or trimeric Butoxycarbonyl, and

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

is Cs-Cö-cycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, -NR ¹² R ¹³ ,

or

represents 4- to 6-membered heterocycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, C 1 -C 3 -alkyl-, trifluoromethyl-, acetyl- or ieri-butoxycarbonyl-,

or

is phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, C ₁ -C ₃ -alkyl-, trifluoromethyl-, C ₁ -C ₃ - Alkoxy, trifluoromethoxy, -NR ¹² R ¹³ , -N (H) -S (= O) ₂ -R ¹⁵ or

-N (H) -C (= O) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with fluoro, chloro, oxo or methyl.

Particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} hydrogen,

or

is Ci-Cö-alkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, Ci-C ₃ alkoxy, -NR ¹² R ¹³ , Cs-Cö-cycloalkyl, 4 to 6-membered heterocycloalkyl or phenyl,

 in which C 5 -C 6 -cycloalkyl and 4- to 6-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by hydroxy, oxo, C 1 -C 3 -alkyl-, trifluoromethyl-, acetyl- or tricyclic Butoxycarbonyl, and

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

or

is Cs-Cö-cycloalkyl-, which may optionally be monosubstituted or disubstituted by identical or different substituents with: hydroxy, oxo, -NR ¹² R ¹³ ,

or

represents 4- to 6-membered heterocycloalkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, C 1 -C 3 -alkyl-, trifluoromethyl-, acetyl- or ieri-butoxycarbonyl-,

or

is phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, C ₁ -C ₃ -alkyl-, trifluoromethyl-, C ₁ -C ₃ - Alkoxy, trifluoromethoxy, -NR ¹² R ¹³ , -N (H) -S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with fluoro, chloro, oxo or methyl. Particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} hydrogen,

or

is C ₁ -C 6 -alkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, C ₁ -C ₃ -alkoxy-, -NR ¹² R ¹³ , C ₃ -C 6 -cycloalkyl-, 4- to 6-membered heterocycloalkyl or phenyl,

wherein C ₃ -C 6 -cycloalkyl and 4- to 6-membered heterocycloalkyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, Ci-C ₃ alkyl, trifluoromethyl, acetyl or ieri-butoxycarbonyl, and

 wherein phenyl is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy.

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

Cs-Cö-cycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, -NR ¹² R ¹³ .

Particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} C 3 -C 6 -cycloalkyl- which may optionally be monosubstituted or disubstituted by identical or different substituents: hydroxyl, oxo, -NR ¹² R ¹³ . Particular preference is given to compounds of the general formula (Ia) in which R ^{7 represents}

4- to 6-membered heterocycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, Ci-C ₃ alkyl, trifluoromethyl, acetyl or ieri-butoxycarbonyl-. Particularly preferred are compounds of general formula (Ia) in which R ^{7 is} phenyl or

5- to 6-membered heteroaryl radicals which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, C 1 -C 3 -alkyl-, trifluoromethyl-,

C ₁ -C ₃ alkoxy, trifluoromethoxy, -NR ¹² R ¹³ , -N (H) -S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ , or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted by fluorine, chlorine, oxo or methyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} C ₁ -C ₃ -alkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl,

 wherein phenyl is unsubstituted or monosubstituted by identical or different substituents

Methyl-,

or

is cyclopropyl or cyclohexyl,

wherein cyclohexyl is unsubstituted or monosubstituted with -NR ¹² R ¹³ , or

is piperidinyl or azetidinyl, which are unsubstituted or monosubstituted by oxo, methyl, acetyl or ieri-butoxycarbonyl,

or

is phenyl, pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl, methoxy, -N (H -S-S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with oxo,

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} C 1 -C 4 -alkyl, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl,

 wherein phenyl is unsubstituted or monosubstituted by identical or different substituents

Methyl-,

or

is cyclopropyl or cyclohexyl,

wherein cyclohexyl is unsubstituted or monosubstituted with hydroxy or -NR ¹² R ¹³ ,

or

is piperidinyl or azetidinyl, which is unsubstituted or monosubstituted with oxo,

Methyl or ieri-butoxycarbonyl,

or

is phenyl, pyrazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl, methoxy, -N (H) -S (= 0) ₂ -R ¹⁵ or -N (H) -C (= 0) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with oxo, Very particular preference is given to compounds of the general formula (Ia) in which R ⁷ is C 1 -C 3 -alkyl- which is unsubstituted or or doubly, identically or differently substituted by hydroxy, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl-, wherein phenyl is unsubstituted or monosubstituted by identical or different substituents with methyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} C 1 -C 4 -alkyl, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl,

 wherein phenyl is unsubstituted or monosubstituted by identical or different substituents

Methyl-.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} cyclopropyl or cyclohexyl,

wherein cyclohexyl is unsubstituted or monosubstituted with -NR ¹² R ¹³ .

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} cyclopropyl or cyclohexyl,

 wherein cyclohexyl is unsubstituted or monosubstituted with hydroxy or

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} piperidinyl or azetidinyl, which is unsubstituted or monosubstituted by oxo, methyl, acetyl or ieri-butoxycarbonyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} piperidinyl or azetidinyl, which is unsubstituted or monosubstituted by oxo, methyl or acetyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} piperidinyl or azetidinyl, which is unsubstituted or monosubstituted by oxo, methyl or ieri-butoxycarbonyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} phenyl, pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl, which are unsubstituted or mono- or disubstituted, identical or are variously substituted with cyano, methyl, methoxy, -N (H) -S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with oxo.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} Phenyl, pyrazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl-, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl, methoxy, -N (H) -S ( = 0) ₂ -R ¹⁵ or -N (H) -C (= 0) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with oxo.

Particular preference is given to compounds of the general formula (Ia) in which R ^{8 is} hydrogen or C ₁ -C ₃ -alkyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{8 is} hydrogen or methyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ⁷ and R ⁸ , together with the nitrogen atom to which they are bonded, represent pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl , 2-oxa-6-azaspiro [3.3] heptyl or

3-oxa-8-azabicyclo [3.2.1] octyl which are unsubstituted or monosubstituted with methyl, ethyl, 2,2,2-trifluorofhyl, acetyl, methoxycarbonyl, methylsulfonyl, -NR ¹² R ¹³ , / V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} C ₁ -C ₃ -alkyl, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl,

 wherein phenyl is unsubstituted or monosubstituted by identical or different substituents

Methyl-,

or

is cyclopropyl or cyclohexyl,

wherein cyclohexyl is unsubstituted or monosubstituted with -NR ¹² R ¹³ , or

is piperidinyl or azetidinyl, which are unsubstituted or monosubstituted by oxo, methyl, acetyl or ieri-butoxycarbonyl,

or

is phenyl, pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl, methoxy, -N (H -S-S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with oxo and in which

R ^{8 is} hydrogen or methyl,

or in those R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, for pyrrohdinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, 2-oxa-6-azaspiro [3.3] heptyl or 3-oxa-8-azabicyclo [3.2.1] octyl which are unsubstituted or monosubstituted with methyl, ethyl, 2,2,2-trifluorofhyl, acetyl, methoxycarbonyl, methylsulfonyl, -NR ¹² R ¹³ , / V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 is} C 1 -C 4 -alkyl, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl,

 wherein phenyl is unsubstituted or monosubstituted by identical or different substituents

Methyl-,

or

is cyclopropyl or cyclohexyl,

wherein cyclohexyl is unsubstituted or monosubstituted with hydroxy or -NR ¹² R ¹³ ,

or

is piperidinyl or azetidinyl, which is unsubstituted or monosubstituted with oxo,

Methyl or ieri-butoxycarbonyl,

or

is phenyl, pyrazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl, methoxy, -N (H) -S (= 0) ₂ -R ¹⁵ or -N (H) -C (= 0) -R ¹⁵ ,

or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with oxo and in which

R ^{8 is} hydrogen or methyl,

or in those

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, for pyrrohdinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, 2-oxa-6-azaspiro [3.3] heptyl or 3-oxa-8-azabicyclo [3.2.1] octyl which are unsubstituted or monosubstituted with methyl, ethyl, 2,2,2-trifluorofhyl, acetyl, methoxycarbonyl, methylsulfonyl, -NR ¹² R ¹³ , / V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl.

steht, worin "*" den Anknüpfungspunkt an den Rest des Moleküls bedeutet. Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 represents}

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

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

.0.

 OL CH,

stands,

or for

stands,

or for

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

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

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

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

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

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

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

Very particular preference is given to compounds of the general formula (Ia) in which R ⁷ and R ^8, together with the nitrogen atom to which they are bonded,

stehen, worin "*" den Anknüpfungspunkt an den Rest des Moleküls bedeutet, und

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

wherein R ^{16 is} methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl,

/ V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl. Very particular preference is given to compounds of the general formula (Ia) in which R ^{7 represents}

.0.

 OL CH,

stands,

or for

stands,

or for

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

and in those

R ^{8 is} hydrogen or methyl,

or in those

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, for

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

wherein R ^{16 is} methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl

/ V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl.

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

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

R ^{8 is} hydrogen or methyl,

or in those

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached,

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

wherein R ^{16 is} methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl,

/ V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl.

Particular preference is given to compounds of the general formula (Ia) in which R ^{9 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

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

Particular preference is given to compounds of the general formula (Ia) in which R ^{9 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 (Ia) in which R ^{9 is}

Trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl stands. Very particular preference is given to compounds of the general formula (Ia) in which R ^{9 is} C 1 -C ³ -alkyl, or is cyclopropyl. Very particular preference is given to compounds of the general formula (Ia) in which R ^{9 is} C ₁ -C ₃ -alkyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{9 is} cyclopropyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{9 is} methyl, isopropyl or cyclopropyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ^{9 is} methyl or isopropyl.

Highly preferred are compounds of the general formula (Ia) in which R ^{9 is} methyl.

Highly preferred are compounds of the general formula (Ia) in which R ^{9 is} isopropyl.

Particular preference is given to compounds of the general formula (Ia) in which R ¹² and R ^13, independently of one another, are hydrogen or C ₁ -C ₃ -alkyl,

or

together with the nitrogen atom to which they are attached, for 5- to 6-membered

Heterocycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, Ci-C ₃ alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or ieri-butoxycarbonyl. Particular preference is given to compounds of the general formula (Ia) in which R ¹² and R ¹³ independently of one another are hydrogen or C ₁ -C ₃ -alkyl.

Particular preference is given to compounds of the general formula (Ia) in which R ¹² and R ^13, together with the nitrogen atom to which they are bonded, are 5- to 6-membered

Heterocycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, Ci-C3-alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, Cyclopropyl, cyclopropylmethyl or ieri-butoxycarbonyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ¹² and R ^13, independently of one another, are hydrogen or methyl,

or

together with the nitrogen atom to which they are attached represent pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl or piperazinyl, which are unsubstituted or monosubstituted by oxo, methyl or cyclopropylmethyl. Very particular preference is given to compounds of the general formula (Ia) in which R ¹² and R ^13, independently of one another, are hydrogen or methyl.

Very particular preference is given to compounds of the general formula (Ia) in which R ¹² and R ^13, together with the nitrogen atom to which they are attached, represent pyrroldinyl, imidazolidinyl, piperidinyl, morpholinyl or piperazinyl, which are unsubstituted or simply substituted with oxo, methyl or cyclopropylmethyl.

Preference is given to compounds of the general formula (Ia) in which R ^{14 is} hydrogen. Particular preference is given to compounds of the general formula (Ia) in which R ^{15 is}

Ci-Cs-alkyl.

Particular preference is given to compounds of the general formula (Ia) in which R ^{15 is} methyl.

Particular preference is given to compounds of the general formula (Ia) in which A is -NH-, X is -CH- or -N-, 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. Particular preference is given to compounds of the general formula (Ia) 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. Very particular preference is given to the following compounds of the general formulas (I) and (Ia):

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1-methylpiperidin-4-yl) benzenesulfonamide;

3- {[(2R) -2,4-Dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine 7-yl] amino} -N- (1-methylpiperidin-4-yl) benzenesulfonamide;

2,4-Dimethyl-7- ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one;

2,4-Dimethyl-1- (tetrahydro-2H-pyran-4-yl) -7 - [(3- {[4- (2,2,2-trifluoroethyl) -piperazin-1-yl] -sulfonyl} -phenyl) -amino ] -l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one; / V- [2- (dimethylamino) ethyl] -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [ 3,4-b] pyrazine-7-yl] amino} benzenesulfonamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide;

1-Benzyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one;

(2R) - 1-Benzyl-2,4-dimethyl-7- ({3 - [(4-methylpiperazin-1-yl) -sulfonyl] -phenyl} -amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one;

1-Benzyl-2,4-dimethyl-7- [(3- {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] sulfonyl} phenyl) amino] -1,4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methylpiperidine benzenesulfonamide -4-yl); 3- {[(2R) -l-benzyl-2,4-dimethyl-3-oxo-l, 23,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (l - methylpiperidin-4-yl) benzenesulfonamide;

4- {[2,4-Dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide;

3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] - / V- [2- (2- dimethylamino) ethyl] benzenesulfonamide; A ⁱ 2- (dimethylamino) ethyl] -3- {[2,4-dimethyl-3-oxo - (propan-2-yl), 23,4-etrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzolsulfonamid;

2,4-Dimethyl-1 - (propan-2-yl) -7- [(3- {[4- (2,2,2-trifluoroethyl) piperazine-1-yl] sulfonyl] -phenyl) -amino] -l, 4 -dihydropyrido [3,4-b] pyrazin-3 (2H) -one;

2,4-Dimethyl-7- ({3- [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1- (propan-2-yl) -1,4-dihydropyrido [3,4-b ] pyrazin-3 (2H) -one;

3- {[2,4-dimethyl-3-oxo-1- (propan-2-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (1-methylpiperidin-4-yl) benzenesulfonamide;

3- {[(2R) -2,4-Dimethyl-3-oxo-1 - (propan-2-yl) -1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (1-methylpiperidin-4-yl) benzenesulfonamide; 3- {[2,4-dimethyl-3-oxo-1- (propan-2-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide;

(2R) -1-cyclopentyl-2,4-dimethyl-7 - ({3- [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one;

1-cyclopentyl-2,4-dimethyl-7- ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one;

(2R) -1-cyclopentyl-2,4-dimethyl-7 - ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one;

3 - [(l-benzyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-7-yl) amino] - / V- cyclopropylbenzamid;

1-Benzyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one;

3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methylpiperidine benzamide -4-yl);

3 - [(l-benzyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-7-yl) amino] - / V- {cis-4 - [4- (cyclopropylmethyl) piperazine-1-yl] cyclohexylbenzamide;

1-Benzyl-2,4-dimethyl-7- {[3- (2-oxa-6-azaspiro [3.3] hept-6-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one; 1-Benzyl-2,4-dimethyl-7- {[3- (8-oxa-3-azabicyclo [3.2.1] oct-3-ylcarbonyl) -phenyl] -amino} -l, 4-dihydropyrido [3,4- b] pyrazin-3 (2H) -one;

3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] - / V- [2- (2- dimethylamino) ethyl] benzamide;

/ V- (1-acetylpiperidin-4-yl) -3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7 -yl) amino] benzamide;

3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (cyclopropylmethyl) benzamide ;

1-Benzyl-2,4-dimethyl-7 - [(3- {[4- (2,2,2-trifluoroethyl) piperazine-1-yl] carbonyl] -phenyl) -amino] -1,4-dihydropyrido [3,4 -b] pyrazin-3 (2H) -one; 3 - [(l-benzyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-7-yl) amino] - / V- [2- ( 4-methylpiperazin-1-yl) ethyl] benzamide;

3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methylazetidine -3-yl) benzamide;

2,4-Dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one; (2R) -2,4-dimethyl-7- ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1,4 -dihydropyrido [3,4-b] pyrazin-3 (2H) -one; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1-methyl-1H-pyrazol-3-yl) -benzamide;

2,4-Dimethyl-7 - [(3- {[4- (1-methylpiperidin-4-yl) piperazine-1-yl] carbonyl} phenyl) amino] -1- (tetrahydro-2H-pyran-4-yl ) -l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one;

A ^r - (3-Cyanophenyl) -3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2 H -pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4 -b] pyrazine-7-yl] amino} benzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (2-hydroxyethyl) -N-methylbenzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - ethylbenzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (3-methoxyphenyl) benzamide;

2,4-Dimethyl-7- ({3 - [(3-methylpiperidin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one;

2,4-Dimethyl-7 - [(3- {[4- (methylsulfonyl) piperazin-1-yl] carbonyl] -phenyl) -amino] -1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one;

A ^r - [3- (dimethylamino) propyl] -3- {[2,4-dimethyl-3-oxo-l- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [ 3,4-b] pyrazine-7-yl] amino-jbenzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1H-pyrazol-3-yl) benzamide; 7 - ({3 - [(4-acetylpiperazin-1-yl) carbonyl] phenyl} amino) -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (4-methoxyphenyl) benzamide;

/ V- [2- (dimethylamino) -2-oxoethyl] -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4 tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V-methylbenzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (pyridazin-4-yl) benzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V-methyl- / V- (3-methylbenzyl) -benzamide;

Methyl 4- (3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine -7-yl] amino} benzoyl) piperazine-1-carboxylate;

N- [3- (dimethylamino) propyl] -3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3 , 4-b] pyrazin-7-yl] amino} - / V-methylbenzamide;

/ V- [2- (dimethylamino) ethyl] -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [ 3,4-b] pyrazine-7-yl] amino-jbenzamide;

2,4-Dimethyl-7- ({3 - [(4-methyl-1,4-diazepan-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1 , 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (pyridin-4-yl) benzamide;

7- ({3 - [(4-Ethylpiperazin-1-yl) carbonyl] phenyl} amino) -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (3-methoxypropyl) benzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (l, 3-oxazol-2-yl) benzamide;

2,4-Dimethyl-7- {[3- ({4- [2-oxo-2- (pyrrolidin-1-yl) ethyl] piperazine-1-yl} carbonyl) phenyl] amino} - 1 - (Tetrahydro-2H-pyran-4-yl) -l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [3- (pyrrolidin-1-yl) propyl] benzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- {3 - [(methylsulfonyl) amino] phenyl} benzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1-oxo-2,3-dihydro-1H-inden-5-yl) benzamide;

/ V- (4-acetamidophenyl) -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4 -b] pyrazine-7-yl] amino} benzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1-methyl-1H-pyrazol-5-yl) benzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1,2-oxazol-3-yl) benzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [2- (2-oxoimidazolidin-1-yl) ethyl] benzamide;

3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (1H-imidazol-2-yl) benzamide;

1-cyclopentyl-2,4-dimethyl-7- {[3- (morpholin-4-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; / V- (3-cyanophenyl) -3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzamid;

7- ({3 - [(4-Acetylpiperazin-1-yl) carbonyl] phenyl} amino) -1-cyclopentyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one;

3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (3-methoxyphenyl) benzamide; 3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (1-methyl- benzamide lH-pyrazol-5-yl); 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (3-methoxypropyl) benzamide;

Methyl 4- (3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} benzoyl) piperazine - 1-carboxylate; 1-isopropyl-2,4-dimethyl-7- {[3- (morpholin-4-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one;

A ^r - (4-cyanophenyl) -3- {[1-isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino } benzamide;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- (4-methoxyphenyl) benzamide; / V- (cyclopropylmethyl) -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b ] pyrazine-7-yl] amino} benzamide;

1-Isopropyl-2,4-dimethyl-7- ({3- [(4-methyl-1,4-diazepan-1-yl) carbonyl] -phenyl} -amino) -1,4-dihydropyrido [3,4-b ] pyrazin-3 (2H) -one;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- (3-methoxypropyl) benzamide;

3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [2- (2 -oxoimidazolidin-l-yl) ethyl] benzamide;

3 - [(1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] - / V-methyl-N- ( 3-methylbenzyl) benzamides; 3 - [(1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methyl -lH-pyrazol-3-yl) benzamide; 3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} -N- (1H-pyrazole) 3-yl) benzamide;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [3- (pyrrolidine - 1 -yl) propyl] benzamide;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- [2- (2 - oxoimidazolidin-1-yl) ethyl] benzamide; 3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- [2- (dimethylamino ) ethyl] - methylbenzamide;

3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- (2-methoxyethyl) benzamide;

3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- (4-methoxyphenyl) benzamide;

1-cyclopentyl-2,4-dimethyl-7- ({3 - [(3-methylpiperidinediyl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one;

7 - ({3 - [(4-Acetylpiperazin-1-yl) carbonyl] phenyl} amino) -1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; / V- (4-acetamidophenyl) -3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino } benzamide;

A ^r - [2- (dimethylamino) ethyl] -3- {[l-isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7 yl] amino} benzamide;

Methyl 4- (3- {[l-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} benzoyl) -piperazine - 1-carboxylate;

3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (1, 3) oxazol-2-yl) benzamide;

3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (2- hydroxyethyl) - / V-methylbenzamide;

3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1H-pyrazole) 3-yl) benzamide;

1-cyclopentyl-2,4-dimethyl-7- {[3- ({4- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -piperazin-1-yl} carbonyl) -phenyl] -amino} -1 , 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one;

3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [3- (dimethylamino ) propyl] benzamide;

3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [3- (pyrrolidine - 1 -yl) propyl] benzamide; 1-Cyclopentyl-2,4-dimethyl-7 - [(3- {[4- (methylsulfonyl) piperazin-1-yl] carbonyl} phenyl) amino] -1,4-dihydropyrido [3,4-b] pyrazine 3 (2H) -one;

1-Isopropyl-2,4-dimethyl-7- {[3- ({4- [2-oxo-2- (pyrrolidin-1-yl) -ethyl] -piperazin-1-yl} -carbonyl) -phenyl] -amino} - 1 , 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one;

1-isopropyl-2,4-dimethyl-7- [(3- {[4- (1-methylpiperidin-4-yl) piperazin-1-yl] carbonyl} phenyl) amino] -l, 4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one;

3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N-ethylbenzamide;

3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [3- (dimethylamino ) propyl] - methylbenzamide; 1-cyclopentyl-2,4-dimethyl-7- {[3- (pyrrolidin-1-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one;

3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1,3-) oxazol-2-yl) benzamide;

/ V- (2-Hydroxyethyl) -3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino } - / V-methylbenzamide; / V- [3- (dimethylamino) propyl] -3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7 yl] amino} benzamide; / V- [3- (dimethylamino) propyl] -3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7 yl] amino} - methylbenzamide;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} - / V- (pyridazine-4 -yl) benzamide;

3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- (cyclopropylmethyl) benzamide;

/ V- (4-acetamidophenyl) -3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzamid;

3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- [2- (dimethylamino ) ethyl] benzamide; 1-cyclopentyl-7- ({3- [(4-ethylpiperazin-1-yl) carbonyl] phenyl} amino) -2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one;

3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- [2- (dimethylamino ) -2-oxoethyl] - / V-methylbenzamide;

3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] -amino} -N- (1-methyl- benzamide lH-pyrazol-5-yl);

3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] -amino} -N- {3- [( methylsulfonyl) amino] phenyl} benzamide;

2,4-Dimethyl-7- {[3- (morpholin-4-ylcarbonyl) phenyl] amino} -1- (tetr-ahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3,4-b ] pyrazin-3 (2H) -one; / V- (4-cyanophenyl) -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydropyrido [3,4 -b] pyrazine-7-yl] amino} benzamide; 3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- {3- [( methylsulfonyl) amino] phenyl Jbenzamide;

3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (pyridazine-4-) yl) benzamide;

1-cyclopentyl-2,4-dimethyl-7- [(3- {[4- (1-methylpiperidin-4-yl) piperazin-1-yl] carbonyl} phenyl) amino] -l, 4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one; 1-Isopropyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (3-methoxyphenyl) benzamide;

1-Isopropyl-2,4-dimethyl-7- {[3- (pyrrolidin-1-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one;

3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (1-methyl- lH-pyrazol-3-yl) benzamide;

1-Isopropyl-2,4-dimethyl-7- [(3- {[4- (methylsulfonyl) piperazine-1-yl] carbonyl} phenyl) amino] -1,4-dihydropyrido [3,4-b] pyrazine 3 (2H) -one; 3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} -N- (1-oxo) 2, 3-dihydro-1H-inden-5-yl) benzamide;

A ^r - (3-cyanophenyl) -3- {[1-isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzamid;

/ V-ethyl-3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino-jbenzamide;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (pyridine-4-) yl) benzamide;

7- ({3- [(4-ethylpiperazin-1-yl) carbonyl] phenyl} amino) -1-isopropyl-2,4-dimethyl-1,4 dihydropyrido [3,4-b] pyrazin-3 (2H) -one;

A ^r - [2- (dimethylamino) -2-oxoethyl] -3- {[l-isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine -7-yl] amino} - / V-methylbenzamide;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} - / V- (1-oxo 2,3-dihydro-1H-inden-5-yl) benzamide;

3- {[l-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} - / V-methyl-N- ( 3-methylbenzyl) benzamide;

3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} -N- [3- (morpholine -4-yl) propyl] benzamide; 1-cyclopentyl-2,4-dimethyl-7- ({3- [(4-methyl-1,4-diazepan-1-yl) carbonyl] -phenyl} -amino) -1,4-dihydropyrido [3,4-b ] pyrazin-3 (2H) -one;

1-Isopropyl-2,4-dimethyl-7- ({3 - [(3-methylpiperidin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one;

3- {[(2R) -1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (l-methylpiperidin-4-yl) benzenesulfonamide;

3- {[(2S) -1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (l-methylpiperidin-4-yl) benzenesulfonamide;

(2R) -7- {[2-methoxy-5- (morpholin-4-ylsulphonyl) phenyl] amino} -2,4-dimethyl-1 - (tetrahydro-2H-pyran-4-yl) -1,4 dihydropyrido [3,4- b] pyrazin-3 (2H) -one; (2R) -7- {[5- (isopropylsulfonyl) -2-methoxyphenyl] amino} -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4 -b] pyrazin-3 (2H) -one;

(2R) -7- {[5- (cyclopropylsulfonyl) -2-methoxyphenyl] amino} -2,4-dimethyl-1- (tetrahydro-2H-pyranyl)

4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; ieri-butyl-4- [7- {[2-methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-3-oxo-3,4-dihydropyrido [3,4-b] pyrazine-1 (2H) -yl] piperidine-1-carboxylate; 7- {[2-Methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-1- (piperidin-4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 ( 2H) -one; (2R) -1-Benzyl-7- {[2-methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one;

3- {[(2S) -1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- ( 1-methylpiperidin-4-yl) benzenesulfonamide;

(2S) -1-Benzyl-2,4-dimethyl-7- ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one;

3- {[(2 _L S ') - 1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} - / V- (1-methylpiperidin-4-yl) benzenesulfonamide;

(2S) -1-cyclopentyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one and

(2 _{l of} S ') - 2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) - l, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers in which outweighs the (R) form, as well as their polymorphs and physiologically compatible salts.

Definitions: By Ci-Cö-alkyl, or a Ci-Cö-alkyl group is meant a linear or branched, saturated, monovalent hydrocarbon radical, such as. 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, C ₁ -C 6 -alkyl or a C ₁ -C 6 -alkyl group is C ₁ -C 4 -alkyl, C ₂ -C 4 -alkyl or C ₂ -C 5 -alkyl, particularly preferably C ₁ -C 3 -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, tert-butylene, where-pentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropylene, 1,2-dimethylpropylene, eo-pentylene or 1 , 1-dimethylpropylene residue.

C ₂ -C 6 -alkenyl, or a C ₂ -C 6 -alkenyl group, is to be understood as meaning a linear or branched monovalent hydrocarbon radical having one or two C =C double bonds, such as, for example, an ethenyl, (II) prop -2-enyl, (Z) -prop-2-enyl, allyl (prop-l-enyl), allenyl-buten-1-yl, or buta-l, 3-dienyl radical. Preference is given to C3-C6-alkenyl or C ₂ -C4-alkenyl, particular preference to ethenyl and allyl.

C ₂ -C 6 -alkynyl, or a C ₂ -C 6 -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. C3-C6-alkynyl or C ₂ -C4 -alkynyl is preferred, ethinyl and propargyl are particularly preferred.

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 ferric 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. By Ci-C3-alkylamino, or a Ci-C3-alkylamino group is meant 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, N-ethyl-N-methylamino, -methyl-Nn-propylamino and -isopropyl-n-propylamino -.

By Ci-C t-alkylthio, or a Ci-C4-alkylthio group is meant a linear or branched, saturated Alkylthioetherrest -S-alkyl, such as. a methylthio, ethylthio, n-propylthio, isopropylthio, or heptylbutyl radical.

Preferably, Ci-C / t-alkylthio, or a Ci-C4-alkylthio group Ci-C ₃ -alkylthio, particularly preferably a methylthio or ethylthio radical to understand.

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 = NH of the above sulphoximine may be optionally substituted with _Ci-C3 alkyl, Ci-C ₃ alkylcarbonyl, C ₁ -C4- alkoxy carbonyl.

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 also the binding of two double-bonded oxygen atoms to sulfur to form 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 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.

 Particularly preferred are perfluorinated alkyl radicals such as trifluoromethyl 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 halogeno-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 or 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, or ieri.-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 and ethoxyethyl.

Aryl is understood as meaning an unsaturated fully conjugated system composed of carbon atoms which has 3, 5 or 7 conjugated double bonds, such as, for example, phenyl, naphthyl or phenantryl. Preference is given to phenyl. By 2,3-dihydro-indenyl is meant a bicyclic ring system according to the structures shown below,

 or where "*" represents the point of attachment to the rest of the molecule. Preferably, 2,3-dihydroindenyl is attached to the remainder of the molecule via the phenyl moiety.

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 which may be mentioned are 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, Isochinohnyl, Cinnolinyl, Chinazohnyl, Chinoxahnyl, Imidazopyridinyl or benzoxazinyl.

 Preferred is 5- to 6-membered monocyclic heteroaryl, for example, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl.

C3-C6-Cycloalkyl, C3-C5-cycloalkyl or Cs-Cs-cycloalkyl is to be understood as meaning a monocyclic saturated ring system composed exclusively of carbon atoms and having 3 to 6, 3 to 8 atoms or 5 to 8 atoms. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Under C t-Cö-cycloalkenyl, C t-Cs-cycloalkenyl, or Cs-Cs-cycloalkenyl is a monocyclic, built up exclusively from carbon atoms, mono- or polyunsaturated, non-aromatic ring system with 4 to 6, 4 to 8 atoms, respectively To understand 5 to 8 atoms. Examples are cyclobuten-1-yl, cyclopenten-1-yl, cyclohexen-2-yl, cyclohexene-1-yl or cycloocta-2,5-dienyl.

By heterocycloalkyl is meant a 4- to 8-membered monocyclic saturated ring system having from 1 to 3 heteroatoms as defined above, in any combination. Preference is given to 4- to 7-membered heterocycloalkyl groups, particular preference is given to 5- to 6-membered heterocycloalkyl groups. By way of example, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, azepanyl, morpholinyl,

Thiomorpholinyl or piperazinyl. 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, or 4H- [1,4] thiazinyl.

By C5-C11 -spirocycloalkyl or Cs-Cn-heterospirocycloalkyl with a replacement of 1-4 carbon atoms by heteroatoms as defined above in any combination, is meant a fusion of two saturated ring systems sharing a common atom. Examples are spiro [2.2] pentyl, spiro [2.3] hexyl, azaspiro [2.3] hexyl, spiro [3.3] heptyl,

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, and the other homologous spiro [3.4] -, spiro [4.4] -, spiro [5.5] -, spiro [6.6] -, spiro [2.4] -, Spiro [2.5], spiro [2.6], spiro [3.5], spiro [3.6], spiro [4.5], spiro [4.6] and spiro [5.6] systems, including variants modified by heteroatoms as defined , Cö-Cs-heterospirocycloalkyl is preferred.

Under C6-Ci2-bicycloalkyl or C6-Ci2-Heterobicycloalkyl with a replacement of 1-4

Carbon atoms through heteroatoms as defined above in any combination is to be understood as meaning a fusion of two saturated ring systems sharing in common two directly neighboring atoms. Examples are bicyclo [2.2.0] hexyl, bicyclo [3.3.0] octyl,

Bicyclo [4.4.0] decyl, bicyclo [5.4.0] undecyl, bicyclo [3.2.0] heptyl, bicyclo [4.2.0] octyl,

Bicyclo [5.2.0] nonyl, bicyclo [6.2.0] decyl, bicyclo [4.3.0] nonyl, bicyclo [5.3.0] decyl,

Bicyclo [6.3.0] undecyl and bicyclo [5.4.0] undecyl, including heteroatom-modified variants such as 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 and the other possible combinations as defined. Cö-Cio-Heterobicycloalkyl is preferred. A bridged C6-C12 ring system such as bridged C6-Cn-cycloalkyl or bridged C6-C12 heterocycloalkyl is understood to mean a fusion of at least two saturated rings which share two atoms which are not directly adjacent to one another. It can both a bridged carbocycle (bridged cycloalkyl) arise as well as a bridged heterocycle (bridged heterocycloalkyl) with a replacement of 1-4 carbon atoms by heteroatoms as defined above in any combination. Examples are bicyclo [2.2.1] heptyl, azabicyclo [2.2. l] heptyl, oxazabicyclo [2.2. l] heptyl, thiazabicyclo [2.2. l] heptyl,

Diazabicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, azabicyclo [2.2.2] octyl, diazabicyclo [2.2.2] octyl, oxazabicyclo [2.2.2] octyl, thiazabicyclo [2.2.2] octyl, bicyclo 3.2.1] octyl, azabicyclo [3.2.1] octyl, diazabicyclo [3.2.1] octyl, oxazabicyclo [3.2.1] octyl, thiazabicyclo [3.2.1] octyl,

Bicyclo [3.3.1] nony 1, azabicyclo [3.3.1] nonyl, diazabicyclo [3.3.1] nonyl,

Oxazabicyclo [3.3.1] nonyl, thiazabicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl,

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

Thiazabicyclo [4.2.1] nonyl, bicyclo [3.3.2] decyl, 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 and the other possible combinations as defined. Preferred is bridged C _Ö -C _IO - Heterocy clo alky. 1

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 of the compounds of the invention.

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

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, 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-2), 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 can be isolated in a known manner; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on chiral or achiral phase.

As a rule, the enantiomers according to the invention inhibit the 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 (2R) - configured compounds of the invention with their (2S) enantiomers, in particular the corresponding racemates and mixtures of enantiomers in which outweighs the (2R) form.

If the compounds according to the invention can occur in tautomeric forms, the present invention 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 (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings that control the release of the compound of the invention), rapidly disintegrating tablets in the oral cavity, in films / wafers, in films / lyophilisates, in capsules (eg hard or soft gelatin capsules), in coated tablets, 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 adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulfate, polyoxysorbitanoleate), 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 to pharmaceutical preparations takes place in the person skilled in the known manner by converted to the active compound or compounds with the ^{'conventional} galenic excipients in the desired form of administration.

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

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

For example, tumors of the male reproductive organs are treatable

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

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

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

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

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

For example, soft-tissue sarcomas and osteosarcomas are treatable as sarcomas. For example, non-Hodgkin's lymphomas, Hodgkin's, can be treated as lymphomas. Lymphomas, cutaneous lymphomas, central nervous system lymphomas and AIDS-associated 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 associated with inflammatory, allergic and / or proliferative processes: chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatoses, especially Boeck's disease,

Rheumatic diseases / autoimmune diseases / joint diseases 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 irritants 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 in inflammatory genesis, eg 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, in particular 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. 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, in particular 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.

Another object of the present invention relates to pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for prophylaxis and / or therapy of leukemias, especially 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 compound of the invention and one or more other active ingredients, in particular for the prophylaxis and / or therapy of the aforementioned diseases.

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

As suitable combination active ingredients may be mentioned by way of example, without this enumeration being conclusive: Abiraterone acetate, abraxane, acolbifen, actimmun, actinomycin D (dactinomycin), afatinib, affinitak, afinitor, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, alpharadine, altretamine, aminoglutethimide, 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 , Cefesone, celebrex, celmoleukin, cerubidine, cediranib, chlorambucil, cisplatin, cladribine, clodronic acid, clofarabine, colaspase, copanlisib, corixa, crisnatol, crizotinib, cyclophosphamide, cyproterone acetate, cytarabine, D acarbazin, Dactinomycin, Dasatinib, Daunorubicin, DaunoXome, Decadron, Decadron Phosphate, Decitabine, Degarelix, Delestrogen, Denileukin Diftitox, Depomedrol, Deslorelin, Dexrazoxane,

Diethylstilbestrol, diflucan, 2 ', 2'-difluorodoxycytidine, DN-101, docetaxel, doxifluridine, doxorubicin (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), fluoxymesterone, flutamide, folotin, formestane, fosteabin, fotemustine, fulvestrant, gammagard, gefitinib, gemcitabine, gemtuzumab , Gleevec, gliadel, goserelin, gossypol, granisetron hydrochloride, hexamethylmelamine, histamine dihydrochloride, histrelin, holmium-166-DOTPM, hycamtine, 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-ΐα, interleukin 2, intron A, Iressa, irinotecan, ixabepilone, keyhole limpet hemocyanin, cytril, lanreotide, lapatinib, lasofoxifene, 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, Nilotimibe, Nilutamide, Nimustin, Nolatrexed, Nolvadex, NSC-631570 , Obatoclax, Oblimersen, OCT-43, Octreotide, Olapa rib, ondansetron hydrochloride, onco-TCS, Orapred, Osidem, oxaliplatin, paclitaxel, pamidronate disodium, Pazopanib, pediapred, pegaspargase, pegasys, pemetrexed, pentostatin, N-phosphonoacetyl-L-aspartate, picibanil, pilocarpine hydrochloride, pirarubicin, plerixafor, plicamycin, PN-401, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, Procarbitol, 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,

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

In particular, the compounds of the invention may be used in combination with angiogenesis-directed therapies, such as e.g. Bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib, lenalidomide, copanlisib or thalidomide are used. 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 of using the chemotherapeutic agents used in lower doses than in monotherapy;

• the possibility of a more tolerable therapy with fewer side effects compared to a single dose; · The ability to treat a wider range of tumors;

• achieving a higher response rate to therapy;

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

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

Preparation of the compounds according to the invention:

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 of the signals (δ) are given in ppm (parts per million). ACN acetonitrile

out. Selected

 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

 DMF V, V-Dimethylformamide

 DMSO-d6 deuterated dimethyl sulfoxide

 DMSO dimethyl sulfoxide

EE ethyl acetate

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

 hexafluorophosphate

 HEPES 2- {4- (2-hydroxyethyl) -1-piperazinyl} -ethanesulfonic acid

 KOtBu potassium ferric butoxide

LCMS liquid chromatography coupled with mass spectrometry

 PyBOB benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

RP-HPLC Reversed Phase High Pressure Liquid Chromatography

 RT room temperature

 T3P 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide

TB TU (benzotriazol-1-yloxy) bis-dimethylaminomethylium fluoroborate

 THF tetrahydrofuran

TFA trifluoroacetic acid UPLC Ultra high performance chromatography

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

General description of the preparation of the compounds of the general formulas (I) and (II) according to the invention The compounds of the formulas (Ib), (Ic) and (Id) shown in Scheme 1 can be prepared by synthetic routes which are described below. The abovementioned formulas represent various subsets of the general formula (I) in which A, X, Y, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and n are defined as for the general Formula (I). In carboxamides of the formula (Ib), a group -C (= O) NR ⁷ R ^{8 is} in the position of R ¹ ; in sulfonamides of the formula (Ic) -S (= O) ₂ NR ⁷ R ⁸ in the position of R ¹ , and in compounds (Id) finally HetAr, the 5-membered monocyclic heteroaryl- as in formula (I) for R ¹ , at the location of R ¹ . The methods described below are suitable in the same way for the preparation of compounds which can be represented by the analogous to (Ib), (Ic) and (Id) subsets of the general formula (Ia).

Scheme 1: Compounds of general formula (I) and their subgroups (Ib), (Ic) and (Id).

In addition to the synthesis sequences discussed below, further synthetic routes for the synthesis of compounds of the general formula (I) according to the invention can be carried out in accordance with the general knowledge of those skilled in organic chemistry become. 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, for example, the substituents R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ 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 Croups in Organic Synthesis, 3rd Ed., 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).

The preparation of intermediates of the formula (VI) in which R ⁴ , R ⁵ and R ^{6 are} defined as in the general formula (I) is described in Scheme 2.

3-Amino-4,6-dichloropyridine ((II), CAS No. 7321-93-9) is reacted with compounds of the formula (III) 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 the person skilled in the art, reaction is carried out with a common solvent such as dichloromethane, THF or methyl isopropyl ether, and with the addition of a base such as triethylamine, V-diisopropylethylamine or pyridine. The base can also be used as a solvent. In this case, compounds of the formula (IV) are obtained. These intermediates (IV) are reacted with amines of the formula R ⁶ -NH ₂ , in which R ^{6 is} defined as in the general formula (I), to give compounds of the formula (V). This reaction can be carried out by reaction in various solvents such as toluene or acetonitrile and with addition of a base such as potassium carbonate, N, N-diisopropylethylamine or triethylamine at elevated temperature (Org. Lett. (2008), 10, p 2905 ff, SP Marsden et al.). Dihydropyridopyrazinones of formula (VI) are subsequently obtained by cyclization of the compounds of formula (V) in the presence of a suitable base such as triethylamine, diisopropylethylamine or potassium carbonate at elevated temperature in solvents such as A 1 -dimethylformamide, N, N-dimethylacetamide , Methylpyrrolidone or dimethyl sulfoxide (see also

WO2010 / 96426 A2, Example 16).

The Racemates (if R ⁴ and R ⁵ are different from each other) are intermediates of the formula (VI) and the derivatives thereof prepared according to Schemes 3, 4, 5 and 6, including the compounds of the formula (Ib), (Ic) and (Id) according to the invention, if appropriate, 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.

Scheme 2: Preparation of intermediates of formula (VI) from 3-amino-4,6-dichloropyridine (II).

Scheme 2a illustrates the alternative construction of intermediates of formula (V) in which the stray chemistry of the stereocenter formed when R ⁴ and R ⁵ are different from each other can be defined from R ⁴ and R ⁵ and the carbon atom attached to them. For this purpose, nitrogen atom-protected amino acids of the formula (VII) 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-4,6-dichloropyridine ((II), CAS No. 7321-93-9). These are known to the skilled person

Coupling reagents such as T3P, TBTU, HATU or DCC used. Conversion of the carboxylic acids to their amides is generally described in reference books such as "Compendium of Organic Synthetic Methods," Volume I-VI (Wiley Interscience) or "The Practice of Peptide Synthesis," Bodansky (Springer Verlag). Compounds of the formula (VII) are known to the person skilled in the art and are commercially available. The compounds of the formula (VIII) obtained are then converted by deprotection of the protective group PG on the amine by suitable methods to give the compounds of the formula (IX). 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 reaction to give compounds of the formula (VIa) 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. 1010/105906 AI). In this case, the primary amine (I), as a free base or in salt form, is reacted with an aldehyde or ketone suitable for the introduction of R ⁶ in situ to give an imine and this is then added by addition of a suitable

Reductant such as sodium triacetoxyborohydride to the secondary amine of formula (X) transformed. The secondary amines of formula (X) can be cyclized to Dihydropyridopyrazinonen the formula (Via) implement. For this purpose, it is possible to react compounds of the formula (X) in the presence of a suitable base, for example a trialkylamine such as triethylamine or / V, / V-diisopropylethylamine, in a solvent such as N, N-dimethylformamide or dimethylacetamide under elevated temperature (see also WO2010 / 96426 A2, Example 16). The reaction is also possible in the absence of a base and without solvent.

The optionally stereoisomerically pure Dihydropyridopyrazinone of formula (Via) can in the same manner as the analogous, optionally racemic compounds of formula (VI) in the sense of Schemes 3, 4, 5 and 6 to the compounds of the invention (Ib), (Ic) and (Id) continue to be implemented. The described reaction routes make it possible, when using an enantiomerically pure protected amino acid of the formula (VII) at the beginning of the sequence, to substantially suppress epimerization or racemization of the stereogenic center on the carbon atom which is bonded to R ⁴ and R ⁵ .

Schema 2a: Stereospezifische Synthese von Zwischenprodukten der Formel (VIII) aus 3-Amino- 4,6-dichlorpyridin (II). Schema 3 illustriert die Umsetzung von der wie in Schema 2 gezeigt erhaltenen Zwischenprodukte der Formel (VI), in denen R⁴, R⁵ und R⁶ definiert wie in der allgemeinen Formel (I), zu

Scheme 2a: Stereospecific synthesis of intermediates of formula (VIII) from 3-amino-4,6-dichloropyridine (II). Scheme 3 illustrates the reaction of the intermediates of formula (VI) as shown in Scheme 2 in which R ⁴ , R ⁵ and R ^{6 are} defined as in general formula (I)

Carboxylic esters of the formula (XIII). The alkylation to compounds of formula (XI) can be carried out by reaction with R ³ -LG wherein R ^{3 is} defined as in the general formula (I) and LG is a leaving group, preferably iodide, in the presence of a suitable base such as sodium hydride , according to conditions known to those skilled in the art. This alkylation can also be carried out at an earlier stage, for example by alkylation of compounds of the formula (VIII) in Scheme 2a, as in the protocols for the preparation of the intermediates 47 to 50 im

Experimental part described in detail. The further reaction of the resulting compounds of the formula (XI) to give the ester derivatives (XIII) can be carried out by reaction with compounds of the formula (XII) in which A, X, Y, R ² and n are defined as in the general formula I, and in which R ^{E is} C 1 -C 6 -alkyl, for example in a palladium-catalyzed coupling reaction according to Buchwald and Hartwig (for A = -NH- or -N (C 1 -C 3 -alkyl) -; see, for example, J. Chem.

Organomet. Chem. (1999), 576, pl25ff), or, for example, by an aromatic nucleophilic substitution reaction known to the skilled worker with a hydroxyarene, for example a phenol (for A = -O-). Suitable palladium sources are, for example, palladium acetate or palladium (dba) complexes, such as, for example, Pd ₂ (dba) ₃ (CAS No. 51364-51-3 or 52409-22-0). The conversion depends strongly on the ligands used. The examples listed in the experimental section could thus be obtained, for example, by the use of (+) - BINAP (cf also US2006 / 009457 Al). The compounds of formula (XII) are partially commercially available or can be prepared using methods known to those skilled in the art.

In the same way can be obtained as shown in Scheme 2a intermediates of the formula (Via) in which R ⁴ , R ⁵ and R ^{6 are} defined as in the general formula (I), with the optionally described as described there stereochemistry, im Implement the meaning of Scheme 3.

Scheme 3: Reaction of compounds of the formula (VI) to give carboxylic acid esters of the formula (XIII) The preparation of carboxamides of the general formula (Ib) can be carried out in accordance with Scheme 4 by hydrolysis of the respective esters of the formula (XIII) to give the corresponding carboxylic acids of the formula (XIV ) carried out by methods known to those skilled in the art. These reactions are preferably carried out using alkali hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide in aqueous alcoholic solutions.

The carboxylic acids (XIV) thus obtained can be converted into the carboxamides of the general formula (Ib) according to the invention by reaction with the generally commercially available, for example with the specified in the embodiments, amines of the formula R ⁷ R ⁸ NH, in which R ⁷ and R ⁸ are as defined for general formula (I), with additional activation by a method well known to those skilled in the art. Possible methods mentioned here are the use of HATU, HBTU, PyBOB or T3P with addition of a suitable base. Conversion of the carboxylic acids to their amides is generally described in reference books such as "Compendium of Organic Synthetic Methods," Volume I-VI (Wiley Interscience) or "The Practice of Peptide Synthesis," Bodansky (Springer Verlag).

Schema 4: Umsetzung von Ester-Derivaten der Formel (XIII) zu erfindungsgemäßen

Scheme 4: Reaction of ester derivatives of the formula (XIII) to give inventive

Carboxamides of the formula (Ib). The compounds of the formula (Ic) according to the invention having a sulfonamide group at the site of R ¹ can be prepared according to Scheme 5. Here, compounds of the formula (XI) in which the chlorine may also be replaced by bromine or another leaving group in a manner similar to that discussed in Scheme 3 for the reaction of (XI) to (XIII) with compounds of formula (XV) in which A, X, Y, R ² , R ⁷ , R ⁸ and n are as defined in the general formula (I), in a palladium-catalyzed coupling reaction according to Buchwald and Hartwig, or an aryl ether synthesis, for example by nucleophilic aromatic substitution, directly to the compounds of the formula (Ic) are reacted, (see, for example, J. Med Chem. (1996), 39, p904ff., TR Jones et al.). Compounds of formula (XV) are commercially available or may be prepared by methods known to those skilled in the art.

Scheme 5: Preparation of the compounds of the formula (Ic) according to the invention from compounds of the formula (XI).

Furthermore, in analogous manner from the halogenated intermediates such as (XI) by reaction with compounds of formula (XVI), in which A, X, Y, R ² and n are defined as in the general formula (I), and in which HetAr for 5-membered monocyclic

Heteroraryl, as defined for R ¹ in formula (I), compounds of the formula (Id) according to the invention are obtained, as shown in Scheme 6:

Scheme 6: Preparation of the compounds of the formula (Id) according to the invention from compounds of the formula (XI).

Compounds of the formula (Id) analogous phenyl derivatives in which optionally substituted phenyl as defined in formula (I) for R ¹ at the site of HetAr in Scheme 6 can be obtained in an analogous manner. In addition, the compounds of the formula (Id) according to the invention can also be prepared from the ester intermediates of the formula (XIII) shown in scheme 4 and

Carboxylic acids of the formula (XIV) can be constructed by the skilled person known manner.

Compounds of the formula (XVI), as well as the abovementioned phenyl analogs, are optionally commercially available or known to the person skilled in the art.

Compounds of the invention of the general formulas (I) and (Ia) with other groups R ¹ as defined in the general formula (I), for example halogen, cyano, -S (= O) ₂ R ⁹ , -S (= O) (= NR ¹⁰ ) R ^u , -C (= O) R ⁹ or -NR ¹² R ¹³ can be prepared using synthetic methods analogous to the procedures described above, or optionally further, known in the art synthetic routes can be followed become.

embodiments

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

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

IUPAC names were created using the nomenclature software ACD Name batch, version 12.01, from Advanced Chemical Development, Inc., and adapted as needed, for example, to the German-language nomenclature.

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

The following examples illustrate the preparation of the intermediates used for preparing compounds of the invention.

Intermediate 1:

 2-bromo-N- (4,6-dichloropyridin-3-yl) propanamide

A suspension of 110 g of 3-amino-4,6-dichloropyridine and 214 g of potassium carbonate in 2.2 L methyl-ieri-butyl ether was slowly added at 0 ° C with 204 g of 2-Brompropionsäurebromid and stirred for complete addition with heating to RT 17 hours , The reaction was diluted with ethyl acetate and the solid was filtered off with suction. The solid was suspended in dichloromethane and extracted twice with water. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. 127.7 g of 2-bromo / V- (4,6-dichloropyridin-3-yl) propanamide were obtained. ^ -NMR: (300 MHz, 25 ° C, CDCL): δ = 1.76 (d, 3H); 4.88 (q, 1H); 7.91 (s, 1H); 8.64 (s, 1H); 10.27 (bs, 1H).

Intermediate 2:

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

A solution of 30 g of intermediate 2, 25.5 g of tetrahydro-2H-pyran-4-amine and 52.6 ml of N, N-Oi-iso-propylethylamine in 150 ml of acetonitrile was stirred at RT for 68 hours. The approach was with Ethyl acetate, washed twice with water and once with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. This gave 31.5 g of A ⁱ - (4,6-Dichloro-pyridin-3-yl) -A ^r2 - (tetrahydro-2H-pyran-4-yl) alaninamide as an oil which crystallized gradually.

Ή-NMR: (300 MHz, 25 ° C, CDCl ₃ ): δ = 0.89-0.97 (m, 1H); 1.21-1.42 (m, 5H); 1.65-1.76 (m, 1H); 1.81-1.92 (m, 1H); 2.64 (tt, 1H); 3.20-3.35 (m, 3H); 3.43 (q, 1H); 3.76-3.89 (m, 2H); 7.87 (s, 1H); 9.11 (s, 1H).

Intermediate 3:

 7-Chloro-2-methyl-1- (tetrahydro-2H-yran-4-yl), 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

A solution of 31 g of Intermediate 2 and 136 ml of A ^ -Di-w-propylethylamine in 199 ml of DMA was stirred in a sealed steel autoclave for 96 hours at 165 ° C internal temperature. After cooling to RT, the reaction was taken up in water and extracted twice with ethyl acetate. The combined organic phases were washed three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. 32 g of 7-chloro-2-methyl-1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one were obtained as crude product. The purity was sufficient for further implementation.

Ή-NMR: (400 MHz, 25 ° C, CDCl ₃ ): δ = 1.30 (d, 3H); 1.67-1.77 (m, 1H); 1.88 (qd, 1H); 1.95-2.08 (m, 2H); 3.48-3.60 (m, 2H); 3.75 (tt, 1H); 4.08-4.19 (m, 2H); 4.22 (q, 1H); 6.68 (s, 1H); 7.74 (s, 1H); 8.30 (bs, 1H). Intermediate 4:

 7-Chloro-2,4-dimethyl - (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

A solution of 32 g of intermediate 3 and 14.1 ml of methyl iodide in 500 ml of DMF was added slowly with 9.1 g of sodium hydride (60% in white oil) at 0 ° C in portions. After complete addition, stirring was continued for a further hour at 0 ° C. The batch was poured into water, the pH was made neutral with saturated ammonium chloride solution and extracted three times with ethyl acetate. 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 to 50% ethyl acetate content). 11.4 g of 7-chloro-2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one were obtained.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.07 (d, 3H); 1.48-1.58 (m, 1H); 1.66-1.94 (m, 3H); 3.28 (s, 3H); 3.39-3.59 (m, 2H); 3.85-4.00 (m, 3H); 4.27 (q, 1H); 7.04 (s, 1H); 7.93 (s, 1H).

Intermediate 5:

tert -Butyl {(2 f) -1 - [(4,6-dichloropyridin-3-yl) amino] -1-oxopropan-2-yl} carbamate

A solution of 47.4 g of 3-amino-4,6-dichloropyridine (CAS 7321-93-9) and 50.0 g of D-Boc-alanine ^' 150 ml of pyridine was slowly added at 0 ° C with 361 ml of a 50% solution of T3P ( in ethyl acetate). It was allowed to stir for a further 2.5 hours at 0 ° C. It became cautious on saturated

Given potassium carbonate solution. The mixture was extracted twice with ethyl acetate, the washed organic phase with saturated sodium chloride solution, dried over sodium sulfate and concentrated completely in vacuo. This gave 39.4 g of ieri-butyl {(2R) -1 - [(4,6-dichloropyridin-3-yl) amino] -1-oxopropan-2-yl} carbamate as crude product, which was stirred with about 200 ml of diethyl ether , This gave 31.7 g of the desired product ieri-butyl {(2R) -1 - [(4,6-dichloropyridin-3-yl) amino] -1-oxopropan-2-yl} carbamate.

H-NMR: (400 MHz, 25 ° C, CDCl ₃ ): δ = 1.45-1.51 (m, 12H); 4.31-4.44 (m, 1H); 4.85-4.98 (bs, 1H); 7.39 (s, 1H); 8.87 (bs, 1H); 9.39 (s, 1H).

Intermediate 6:

N- (4,6-dichloropyridin-3-yl) -D-alaninamide, hydrochloride

A solution of 30 g of intermediate 5 in 124 ml of dioxane was incubated at RT with 38.4 ml of conc. Hydrochloric acid added. It was stirred for 3 hours at RT. The mixture was then concentrated completely under reduced pressure and the residue was stirred at 0 ° C. with diethyl ether. The precipitate was filtered off with suction and washed twice with cold diethyl ether. 27.2 g of N- (2,6-dichloropyridin-3-yl) -D-alaninamide, hydrochloride were obtained.

H-NMR: (500 MHz, 25 ° C, DMSO-d6): δ = 1.52 (d, 3H); 4.18-4.27 (m, 1H); 7.92 (s, 1H); 8.40-8.52 (m, 3H); 8.60 (s, 1H); 10.72 (s, 1H).

Intermediate 7:

 Λ ^ - (4,6-ΒϊοΗ1θΓ γπΰϊη-3-γ1) -ΛΛ - (ί6ίΓ3ΗγΰΓθ-2Η-γΓ3η-4-γ1) -Β-3ΐ3ηϊη3ηιϊΰ

A solution of 16.6 g of intermediate 6, 7.7 g of tetrahydro-4H-pyran-4-one and 9.7 g of sodium acetate in 400 ml of dichloromethane was added at 0 ° C with 37.5 g Natriumtriacetoxyborhydrid and stirred at 0 ° C for 2.5 hours. It was stirred for a further 17 hours at RT. The mixture was poured carefully onto saturated sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted three more times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was triturated with di-propyl ether and the residue was filtered off with suction. 12.4 g was obtained N- (4,6-Dichloro-pyridin-3-yl) -A ^r2 - (tetrahydro-2H-pyran-4-yl) -D-alaninamide.

Ή-NMR: (500 MHz, 25 ° C, CDCl ₃ ): δ = 0.89-0.97 (m, 1H); 1.21-1.42 (m, 5H); 1.65-1.76 (m, 1H); 1.81-1.92 (m, 1H); 2.64 (tt, 1H); 3.20-3.35 (m, 3H); 3.43 (q, 1H); 3.76-3.89 (m, 2H); 7.87 (s, 1H); 9.11 (s, 1H).

Intermediate 8:

 (2A) -7-chloro-2-methyl- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

A solution of 11.5 g of intermediate 7 and 31 ml of di-bis-propyl-ethylamine in 230 ml of DMA was stirred in a sealed steel autoclave for 2 hours at an internal temperature of 230 ° C. After cooling to RT, the reaction was taken up in water and extracted three times with dichloromethane. The combined organic phases were completely evaporated in vacuo. The residue was stirred with diethyl ether. 6.5 g of (2R) -7-chloro-2-methyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one were obtained as crude haul.

Ή-NMR: (400 MHz, 25 ° C, CDCl ₃ ): δ = 1.30 (d, 3H); 1.67-1.77 (m, 1H); 1.88 (qd, 1H); 1.95-2.08 (m, 2H); 3.48-3.60 (m, 2H); 3.75 (tt, 1H); 4.08-4.19 (m, 2H); 4.22 (q, 1H); 6.68 (s, 1H); 7.74 (s, 1H); 8.30 (bs, 1H).

Opt. Rotation: [α _D ] = -204 ° (methanol, c = 1 g / 100 ml).

Intermediate 9:

 (3 f) -7-Chloro-2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl), 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

1.1 g of 7-chloro-2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (Intermediate 4) were separated by chiral HPLC (Chiralpak AS-H 5μιη 250x20 mm, hexane / ethanol 70:30 (v / v)) into the enantiomers. 465 mg of (3R) -7-chloro-2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) were obtained. -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.07 (d, 3H); 1.48-1.58 (m, 1H); 1.66-1.94 (m, 3H); 3.28 (s, 3H); 3.39-3.59 (m, 2H); 3.85-4.00 (m, 3H); 4.27 (q, 1H); 7.04 (s, 1H); 7.93 (s, 1H).

Chiral HPLC: Rt = 4.03 min

 Instrument: Waters Alliance 2695; Column: Chiralpak AS-H 5μιη 150x4.6 mm; eluent:

Hexane / ethanol 70:30 (v / v); Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (lmg / ml

Ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Opt. Rotation: [a _D ] = -261 ° (methanol, c = 1 g / 100 ml). Intermediate 10:

 A ^ -Benzyl-N- (4,6-dichloropyridin-3-yl) alaninamide

A solution of 30 g of Intermediate 1, 26.97 g of benzylamine and 52.6 ml of di-o-propyl-propylamine in 150 ml of acetonitrile was stirred for 168 hours at RT. The reaction was diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. 41.1 g / V ² -benzyl / V- (4,6-dichloropyridin-3-yl) alaninamide was obtained.

1H-NMR: (300 MHz, 25 ° C, DMSO-d6)

(m, 7H); 7.87 (s, 1H); 9.01 (s, 1H).

Intermediate 11:

l-benzyl-7-chloro-2-methyl-l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one

A solution of 41.1 g Intermediate 10 and 176 ml di-1-propylpropylamine in 259 ml DMA was stirred in a sealed steel autoclave for 25 hours at 165 ° C internal temperature. After cooling to RT, the reaction was evaporated completely and the residue was taken up in ethyl acetate. The organic phase was washed three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. This gave 29.9 g of 1-benzyl-7-chloro-2-methyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one. H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.21 (d, 3H); 4.02 (q, 1H); 4.42 (d, 1H); 4.73 (d, 1H); 6.66) s, 1H); 7.19-7.42 (m, 5H); 7.66 (s, 1H); 10.78 (s, 1H). Intermediate 12:

l-benzyl-7-chloro-2,4-dimethyl-l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one

A solution of 29 g of intermediate 11 and 18.8 ml of methyl iodide in 290 ml of DMF was slowly added in portions with 12.1 g of sodium hydride (60% in white oil) at 0 ° C. After complete addition, stirring was continued for a further hour at 0 ° C. The batch was poured into water, the pH was made neutral with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were washed three times with water and once with saturated

Washed sodium chloride solution, dried over sodium sulfate and the solvent completely removed in vacuo. The residue was taken up in dichloromethane and the precipitate was filtered off with suction: 5.1 g of the desired product. The solution was again completely evaporated and the residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 50% ethyl acetate content): an additional 9 g of the desired product. A total of 14.1 g of 1-benzyl-7-chloro-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one was obtained. H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.17 (d, 3H); 3.31 (s, 3H); 4.14 (q, 1H); 4.42 (d, 1H); 4.74 (d, 1H); 6.70 (s, 1H); 7.26-7.41 (m, 5H); 7.91 (s, 1H).

Intermediate 13:

 (3E) -l-benzyl-7-chloro-2,4-dimethyl-l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one

4.2 g of 1-benzyl-7-chloro-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (Intermediate 12) were purified by chiral HPLC (Chiralpak IB 5μιη 250x50 mm , Hexane / 2-propanol 70:30 (v / v)) in the Enantiomers separated. 1.75 g of (3R) -1-benzyl-7-chloro-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one were obtained.

Chiral HPLC: Rt = 3.68 min

Instrument: Waters Alliance 2695; Column: Chiralpak IB 5μιη 150x4.6 mm; Eluent: hexane / 2-propanol 70:30 (v / v); Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (lmg / ml

Ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Intermediate 14:

 3 - {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} benzoate

A suspension of 8.1 g of Intermediate 4, 7.87 g of 3-aminobenzoic acid methyl ester (CAS 4518-10- 9), 1.17 g of palladium (II) acetate, 25.43 g of cesium carbonate and 3.24 g of (+) - BINAP in 324 ml of toluene for 11 hours under a Argon atmosphere stirred at 130 ° C. The reaction solution was added to water, extracted twice with ethyl acetate, the combined organic phases dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol gradient to 1% methanol content). 6 g of 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine] were obtained. 7-yl] amino} benzoic acid methyl ester.

1H-NMR: (300 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.60-1.70 (m, 1H); 1.78 (qd, 1H); 1.87-2.00 (m, 2H); 3.27 (s, 3H); 3.38-3.52 (m, 2H); 3.70 (tt, 1H); 3.84 (s, 3H); 3.92-4.05 (m, 2H); 4.19 (q, 1H); 6.37 (s, 1H); 7.30-7.43 (m, 2H); 7.82 (s, 1H); 7.88-7.96 (m, 1H); 8.31 (t, 1H); 9.02 (s, 1H). Intermediate 15:

 3 - {[2,4-Dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino } benzoic acid

A solution of 6.7 mg of intermediate 14 in 55 ml of THF and 370 ml of methanol was added at RT with 163 ml of IN lithium hydroxide solution and stirred at 60 ° C for 7 hours. It was adjusted to pH = 7 with 1N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed completely in vacuo. In addition, the aqueous phase was concentrated until a precipitate formed. This was filtered off with suction and combined with the residue from the organic phase. 6.0 g of 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine] were obtained. 7- yl] amino jbenzoic acid.

H-NMR: (500 MHz, 25 ° C, DMSO-d6): δ = 1.25 (d, 3H); 1.65-1.72 (m, 1H); 1.83 (qd, 1H); 1.91- 2.03 (m, 2H); 3.27 (s, 3H); 3.36 (dt, 1H); 3.42 (dt, 1H); 3.86-3.98 (m, 3H); 4.40 (q, 1H); 6.65 (s, 1H); 7.51-7.57 (m, 2H); 7.64 (s, 1H); 7.69-7.75 (m, 1H); 7.88 (s, 1H); 10.21 (bs, 1H); 13.10 (bs, 1H).

Intermediate 16:

 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] -benzoic acid methyl ester

A suspension of 6.0 g of Intermediate 12, 5.7 g of 3-aminobenzoic acid methyl ester (CAS 4518-10- 9), 848 mg of palladium (II) acetate, 30.77 g of cesium carbonate and 2.34 g of (+) - BINAP in 471 ml of toluene was added under a 27 hours Argon atmosphere stirred at 130 ° C. The reaction solution was added to water, extracted twice with ethyl acetate, the combined organic phases 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). 1.98 g of methyl 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] benzoate were obtained.

1H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 1H); 3.83 (s, 3H); 4.10 (q, 1H); 4.42 (d, 1H); 4.51 (d, 1H); 6.11 (s, 1H); 7.26-7.33 (m, 2H); 7.33-7.41 (m, 5H); 7.80 (s, 1H); 7.82-7.86 (m, 1H); 8.23 (t, 1H); 8.95 (s, 1H).

Intermediate 17:

 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) amino] benzoic acid

A solution of 1.9 mg of intermediate 16 in 15.5 ml of THF and 103 ml of methanol was added at RT with 45.6 ml of IN lithium hydroxide solution and stirred at 60 ° C for 7 hours. It was adjusted to pH = 7 with 1N hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed completely in vacuo. 1.1 g of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] benzoic acid were obtained.

^ -NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 3H); 3.31 (s, 3H); 4.09 (q, IH); 4.40 (d, IH); 4.50 (d, IH); 6.11 (s, IH); 7.21-7.31 (m, 2H); 7.31-7.41 (m, 5H); 7.73-7.79 (m, IH); 7.80 (s, IH); 8.18 (t, IH); 8.90 (s, IH).

Intermediate 18:

3 - [(1-Cyclopentyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] -benzoic acid methyl ester

A suspension of 6.0 g of 7-chloro-1-cyclopentyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] py] -3 (2H) -one (preparation described in US20060009457, Compound X6j), 6.16 g 3-aminobenzoic acid methyl ester (CAS 4518-10-9), 914 mg palladium (II) acetate, 33.2 g

Cesium carbonate and 2.54 g of (+) - BINAP in 508 ml of toluene was added under a Argon atmosphere stirred at 130 ° C. The reaction solution was added to water, extracted twice with ethyl acetate, the combined organic phases 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). 6.5 g of methyl 3 - [(1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) amino] benzoate were obtained.

1 H NMR: (400 MHz, 25 ° C, DMSO-d 6): δ = 1.06 (d, 3H); 1.56-1.80 (m, 6H); 1.97-2.08 (m, 2H); 3.27 (s, 3H); 3.75-3.83 (m, 1H); 3.84 (s, 3H); 4.14 (q, 1H); 6.30 (s, 1H); 7.35 (t, 1H); 7.41 (td, 1H); 7.81 (s, 1H); 7.90-7.96 (m, 1H); 8.30 (t, 1H); 9.02 (s, 1H).

Intermediate 19:

 3 - [(1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) amino] benzoic acid

A solution of 6.3 mg of intermediate 18 in 54 ml of THF and 360 ml of methanol was added at RT with 160 ml of IN lithium hydroxide solution and stirred at 60 ° C for 7 hours. It was with IN

Hydrochloric acid adjusted to pH = 7 and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed completely in vacuo. In addition, the aqueous phase was almost completely concentrated and washed twice with

Extracted dichloromethane. The combined dichloromethane phases were also over

Dried sodium sulfate and completely concentrated in vacuo. This residue was combined with the residue from the first extraction. This gave 2.75 g of 3 - [(1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] benzoic acid.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.22 (d, 3H); 1.46-1.82 (m, 6H); 1.89-2.06 (m, 2H); 3.26 (s, 3H); 3.89-4.03 (m, 1H); 4.34 (q, 1H); 6.33 (s, 1H); 7.52 (t, 1H); 7.56-7.66 (m, 2H); 7.70 (d, 1H); 7.91 (bs, 1H); 9.98 (bs, 1H). Intermediate 20:

 3 - [(1-Isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] -benzoic acid methyl ester

A mixture of 6.7 g of 7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (preparation described in US20060009457, compound X6h), 7.58 g of 3-aminobenzoic acid methyl ester (CAS 4518-10-9), 987 mg of (2'-aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl [2 ', 4', 6'-tri (propan-2-yl) biphenyl-2-yl] phosphine (1: 1) (CAS 1310584-14-5, commercially available) and 3.38 g of sodium ieri-butoxide in 33.5 ml of toluene was stirred at 80 ° C for 8 hours under argon atmosphere. The reaction solution was added to water, extracted twice with ethyl acetate, the combined organic phases dried over sodium sulfate and the solvent removed in vacuo. The residue was through

Chromatography on silica gel (dichloromethane / methanol gradient to 1% methanol content). This gave 4.3 g of methyl 3 - [(1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] benzoate. 1H NMR: (300 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.24-1.35 (m, 6H); 3.27 (s, 3H); 3.80- 3.94 (m + s, 4H); 4.20 (q, 1H); 6.30 (s, 1H); 7.30-7.44 (m, 2H); 7.80 (s, 1H); 7.88-7.96 (m, 1H); 8.32 (bs, 1H); 9.02 (s, 1H).

Intermediate 21:

 3 - [(1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) amino] benzoic acid

A solution of 5 g of intermediate 20 in 46 ml of THF and 307 ml of methanol was added at RT with 136 ml of IN lithium hydroxide solution and stirred at 60 ° C for 6 hours. It was with IN

Hydrochloric acid adjusted to pH = 7 and extracted twice with ethyl acetate. The resulting solid was filtered off and dried in vacuo. 4.4 g of 3 - [(1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] benzoic acid were obtained.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.25-1.34 (m, 6H); 3.27 (s, 3H); 3.87 (sept, 1H); 4.20 (q, 1H); 6.30 (s, 1H); 7.31 (t, 1H); 6.35-7.41 (m, 1H); 7.80 (s, 1H); 7.84-7.91 (m, 1H); 8.30 (bs, 1H); 8.97 (s, 1H).

Intermediate 22:

N ² -cyclopentyl-N- (4,6-dichloropyridin-3-yl) -D-alaninamide

A solution of 4.9 g of Intermediate 6, 1.98 mg of cyclopentanone and 2.97 g of sodium acetate in 200 ml of dichloromethane was added at 0 ° C with 11.52 g Natriumtriacetoxyborhydrid and after

Warm to RT for 14 hours. The approach was carefully saturated

Sodium bicarbonate solution, the phases were separated and the aqueous phase extracted three times with dichloromethane. The combined organic phases were over

Dried sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 25% ethyl acetate content). 4.85 mg / V ² -cyclopentyl- / V- (4,6-dichloropyridin-3-yl) -D-alaninamide were obtained.

H-NMR: (300 MHz, 25 ° C, DMSO-d6): δ = 1.27 (d, 3H); 1.28-1.85 (3m, 8H); 3.05 (qi, 1H); 3.29 (q, lH); 7.90 (s, lH); 9.12 (s, 1H).

Intermediate 23:

 (-) - (2E) -7-chloro-l-cyclopentyl-2-methyl-l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one

A solution of 4.85 g of Intermediate 22 and 21.8 ml of di-o-propylethylamine in 80 ml of DMF was stirred in a sealed glass pressure vessel for 56 hours at 170 ° C internal temperature. After cooling to RT, the reaction was taken up in water and extracted three times with dichloromethane. The combined organic phases were completely evaporated in vacuo. The residue was purified by chromatography on silica gel (hexane / ethyl acetate gradient to 85% ethyl acetate content). This gave 3.1 g of (-) - (2R) -7-chloro-1-cyclopentyl-2-methyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one.

H-NMR: (300 MHz, 25 ° C, DMSO-d6): δ = 1.10 (d, 3H); 1.52-1.76 (m, 6H); 1.83-1.95 (m, 1H); 1.95-2.07 (m, 1H); 3.93-4.13 (m, 2H); 6.80 (s, 1H); 7.64 (s, 1H); 10.70 (bs, 1H).

Opt. Rotation: [α _D ] = -174 ° (DMSO, c = 1.08 g / 100 ml).

Intermediate 24:

 (2A) -7-chloro-l-cyclopentyl-2,4-dimethyl-l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one

A solution of 3.1 g of intermediate 23 and 1.1 ml of methyl iodide in 70 ml of DMF was added slowly with 700 mg of sodium hydride (60% in white oil) at 0 ° C in portions. After complete addition, stirring was continued for a further hour at 0 ° C. The batch was poured into water, the pH was made neutral with saturated ammonium chloride solution and extracted three times with ethyl acetate. 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 3: 2). 3.0 g of (2R) -7-chloro-1-cyclopentyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one were obtained. ^ -NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.06 (d, 3H); 1.51-1.74 (m, 6H); 1.87-1.97 (m, 1H); 1.97-2.05 (m, 1H); 3.28 (s, 3H); 4.00 (qi, 1H); 4.22 (q, 1H); 6.86 (s, 1H); 7.92 (s, 1H).

Intermediate 25:

3 - {[(2A) -1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -benzoic acid methyl ester

A suspension of 400 mg of Intermediate 24, 411 mg of 3-aminobenzoic acid methyl ester (CAS 4518- 10-9), 61 mg of palladium (II) acetate, 2.21 g of cesium carbonate and 169 mg of (+) - BINAP in 30.4 ml of toluene was stirred for 5 hours under a Argon atmosphere stirred at 120 ° C. The reaction solution was added to water, extracted twice with ethyl acetate, the combined organic phases dried over sodium sulfate and the solvent removed in vacuo. The residue became purified by chromatography on silica gel (dichloromethane / methanol gradient to 1% methanol content). 240 mg of 3- {[(2R) -l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} were obtained. benzoate. 1H-NMR: (300 MHz, 25 ° C, DMSO-d6): δ = 1.06 (d, 3H); 1.53-1.81 (m, 6H); 1.95-2.09 (m, 2H); 3.27 (s, 3H); 3.73-3.88 (m + s, 4H); 4.14 (q, 1H); 6.29 (s, 1H); 7.35 (t, 1H); 7.38-7.44 (m, 1H); 7.81 (s, 1H); 7.89-7.96 (m, 1H); 8.30 (bs, 1H); 9.04 (s, 1H).

Intermediate 26:

 3 - {[(2A) -1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} benzoic acid

A solution of 200 mg of intermediate 25 in 1.6 ml of THF and 12 ml of methanol was added at RT with 5.1 ml of IN lithium hydroxide solution and stirred at 60 ° C for 5 hours. It was adjusted to pH = 7 with 1N hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed completely in vacuo. 120 mg of 3- {[(2R) -l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} were obtained. benzoic acid.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.22 (d, 3H); 1.46-1.82 (m, 6H); 1.89-2.06 (m, 2H); 3.26 (s, 3H); 3.89-4.03 (m, 1H); 4.34 (q, 1H); 6.33 (s, 1H); 7.52 (t, 1H); 7.56-7.66 (m, 2H); 7.70 (d, 1H); 7.91 (bs, 1H); 9.98 (bs, 1H). Intermediate 27:

 N- (l-methylpiperidin-4-yl) -3-nitrobenzenesulfonamide

A solution of 3 g of 3-nitrobenzenesulfonyl chloride (CAS 121-51-7) and 1.62 g of 4-amino-1-methylpiperidine (CAS 41838-46-4) in 75 ml of dichloromethane was added at 0 ° C with 7.2 ml

Triethylamine and stirred for 16 hours, the temperature was raised slowly to RT. The reaction was diluted with dichloromethane and washed with water and saturated

Washed sodium chloride solution, dried over sodium sulfate and concentrated completely in vacuo. The remaining residue was purified by chromatography on silica gel

(Dichloromethane / methanol gradient to 1% methanol content). 3.5 g of N- (1-methylpiperidin-4-yl) -3-nitrobenzenesulphonamide were obtained. H-NMR: (400 MHz, 25 ° C, CDCh): δ = 1.51-1.63 (m, 2H); 1.79-1.89 (m, 2H); 2.02-2.13 (m, 2H); 2.27 (s, 3H); 2.70-2.80 (m, 2H); 3.23-3.32 (m, 1H); 7.75 (t, 1H); 8.20-8.26 (m, 1H); 8.42-8.47 (m, 1H); 8.74 (t, 1H).

Intermediate 28:

 3-Amino-N- (l-methylpiperidin-4-yl) benzenesulfonamide

A suspension of 3.5 g of intermediate 27 and 350 mg of palladium (10% on charcoal) in 100 ml of methanol was shaken under a hydrogen atmosphere at RT for 8 hours. It was filtered through diatomaceous earth and the solution was completely concentrated in vacuo. 2.8 g of 3-amino- / V- (1-methylpiperidin-4-yl) benzenesulfonamide were obtained. Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.27-1.43 (m, 2H); 1.46-1.58 (m, 2H); 1.71-1.84 (m, 2H); 2.06 (s, 3H); 2.54-2.64 (m, 2H); 2.76-2.90 (m, 1H); 5.54 (bs, 1H); 6.68-6.75 (m, 1H); 6.88 (bd, 1H); 6.98 (t, 1H); 7.17 (t, 1H); 7.46 (d, 1H).

Intermediate 29:

l-methyl-4 - [(3-nitrophenyl) sulfonyl] piperazine

A solution of 3 g of 3-nitrobenzenesulfonyl chloride (CAS 121-51-7) and 1.42 g of 1-methylpiperazine (CAS 109-01-3) in 75 ml of dichloromethane was treated at 0 ° C with 7.2 ml of triethylamine and stirred for 16 hours, the temperature was slowly raised to RT. Of the

The mixture was diluted with dichloromethane and washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated completely in vacuo. The remaining residue was purified by chromatography on silica gel (dichloromethane / methanol gradient to 1% methanol content). 3.6 g of 1-methyl-4 - [(3-nitrophenyl) sulfonyl] -piperazine were obtained.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 2.14 (s, 3H); 2.33-2.40 (m, 4H); 2.95-3.01 (m, 4H); 7.96 (t, 1H); 8.17 (ddd, 1H); 8.37 (t, 1H); 8.55 (ddd, 1H).

Intermediate 30:

 3 - aniline [(4-methylpiperazin-l-yl) sulfonyl]

A suspension of 3.2 g of intermediate 29 and 350 mg of palladium (10% on charcoal) in 100 ml of methanol was shaken under a hydrogen atmosphere at RT for 7 hours. It was filtered through diatomaceous earth and the solution was completely concentrated in vacuo. 2.8 g of 3- [(4-methylpiperazin-1-yl) sulfonyl] aniline were obtained.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 2.14 (s, 3H); 2.31-2.38 (m, 4H); 2.82-2.89 (i

5.62 (bs, 2H); 6.76-6.80 (m, 1H); 6.82 (ddd, 1H); 6.90 (t, 1H); 7.24 (t, 1H).

Intermediate 31:

l - [(3-nitrophenyl) sulfonyl] -4- (2,2,2-trifluoroethyl) piperazine

A solution of 2 g of 3-nitrobenzenesulfonyl chloride (CAS 121-51-7) and 1.59 g of 1- (2,2,2-trifluoroethyl) piperazine (CAS 13349-90-1) in 50 ml of dichloromethane at 4.8 ° C ml of triethylamine and stirred for 16 hours, the temperature was raised slowly to RT. The reaction was diluted with dichloromethane and washed with water and saturated

Washed sodium chloride solution, dried over sodium sulfate and concentrated completely in vacuo. This gave 3.1 g of l - [(3-nitrophenyl) sulfonyl] -4- (2,2,2-trifluoroethyl) piperazine.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 2.65-2.72 (m, 4H); 2.95-3.02 (m, 4H); 3.19 (q, 2H); 7.96 (t, 1H); 8.17 (ddd, 1H); 8.36 (t, 1H); 8.56 (ddd, 1H). Intermediate 32:

 3 - {[4- (2,2,2-trifluoroethyl) piperazin-l-yl] sulfonyl} aniline

A suspension of 3.1 g of Intermediate 31 and 310 mg of palladium (10% on charcoal) in 200 ml of methanol was shaken under a hydrogen atmosphere at RT for 7 hours. It was filtered through diatomaceous earth and the solution was completely concentrated in vacuo. 2.8 g of 3- {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] sulfonyl} aniline were obtained.

'H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 2.64-2.71 (m, 4H); 2.82-2.89 (m, 4H); 3.18 (q, 2H); 5.64 (bs, 2H); 6.78 (ddd, 1H); 6.83 (ddd, 1H); 6.89 (t, 1H); 7.25 (t, 1H).

Intermediate 33:

 N- [2- (dimethylamino) ethyl] -3-nitrobenzenesulfonamide

A solution of 3 g of 3-nitrobenzenesulfonyl chloride (CAS 121-51-7) and 1.59 g of N, N-dimethylethane-1,2-diamine (CAS 108-00-9) in 75 ml of dichloromethane was added at 0 ° C with 7.2 ml Triethylamine and stirred for 16 hours, the temperature was raised slowly to RT. The reaction was diluted with dichloromethane and washed with water and saturated

Washed sodium chloride solution, dried over sodium sulfate and concentrated completely in vacuo. , The remaining residue was purified by chromatography on silica gel

(Dichloromethane / methanol gradient to 1% methanol content). One received

3.3 g / V- [2- (dimethylamino) ethyl] -3-nitrobenzenesulfonamide.

H-NMR: (400 MHz, 25 ° C, CDCl ₃ ): δ = 2.13 (s, 6H); 2.37-2.44 (m, 2H); 3.02-3.10 (m, 2H); 7.76 (t, 1H); 8.20-8.26 (m, 1H); 8.41-8.48 (m, 1H); 8.73 (t, 1H). Intermediate 34:

 3-Amino-N- [2- (dimethylamino) ethyl] benzenesulfonamide

A suspension of 3.3 g of Intermediate 33 and 330 mg of palladium (10% on charcoal) in 200 ml of methanol was shaken under a hydrogen atmosphere at RT for 7 hours. It was filtered through diatomaceous earth and the solution was completely concentrated in vacuo. 2.8 g of 3-amino- / V- [2- (dimethylamino) ethyl] benzenesulfonamide were obtained.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 2.06 (s, 6H); 2.23 (t, 2H); 2.78 (t, 2H); 5.54 (bs, 2H); 6.74 (ddd, 1H); 6.85-6.90 (m, 1H); 6.98 (t, 1H); 7.18 (t, 1H); 7.24 (bs, 1H).

Intermediate 35:

 N- [2- (4-methylpiperazin-l-yl) ethyl] -3-nitrobenzenesulfonamide

A solution of 1.55 g of 3-nitrobenzenesulfonyl chloride (CAS 121-51-7) and 1.05 g of 2- (4-methylpiperazin-1-yl) ethanamine (CAS 934-98-5) in 155 ml of dichloromethane were added at 0 ° C with 3.7 ml of triethylamine and stirred for 16 hours, the temperature was raised slowly to RT. The reaction was diluted with dichloromethane and washed with water and saturated sodium chloride solution, dried over sodium sulfate and completely concentrated in vacuo. 2.1 g / V- [2- (4-methylpiperazin-1-yl) ethyl] -3-nitrobenzenesulfonamide was obtained.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 2.08 (s, 3H); 2.10-2.31 (m, 10H); 2.93 (t, 2H); 7.89 (t, 1H); 7.93 (bs, 1H); 8.20-8.25 (m, 1H); 8.46 (ddd, 1H); 8.54 (t, 1H). Intermediate 36:

 3-Amino-N- [2- (4-methylpiperazin-l-yl) ethyl] benzenesulfonamide

A suspension of 2.05 g of intermediate 35 and 220 mg of palladium (10% on charcoal) in 140 ml of methanol was shaken under a hydrogen atmosphere at RT for 7 hours. It was filtered through diatomaceous earth and the solution was completely concentrated in vacuo. 1.7 g of 3-amino- / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide were obtained.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 2.11 (s, 3H); 2.15-2.37 (m, 10H); 2.77-2.85 (m, 2H); 5.54 (bs, 2H); 6.74 (ddd, 1H); 6.87 (ddd, 1H); 6.97 (t, 1H); 7.18 (t, 1H); 7.22 (bt, 1H).

Intermediate 37:

 (2A) -7-chloro-2,4-dimethyl-l- (propan-2-yl) -l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one

1.15 g of 7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (preparation described in US20060009457, compound X6h) were purified by chiral HPLC ( Chiralpak IC 5μιη 250x30 mm, hexane / ethanol 70:30 (v / v)) separated into the enantiomers. 500 mg of (2R) -1-chloro-2,4-dimethyl-1- (propan-2-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one were obtained, as well as (S) - enantiomer, see Intermediate 51.

Chiral HPLC: Rt = 5.29 min

Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: hexane / ethnaol 70:30; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.20-1.30 (m, 6H); 3.28 (s, 3H); 4.05 (sept, 1H); 4.28 (q, 1H); 6.87 (s, 1H); 7.91 (s, 1H).

Intermediate 38:

 l- (isopropylsulfanyl) -4-methoxybenzene

A suspension of 20 g of 4-methoxythiophenol in 100 ml of methanol was added with 38 ml

 Sodium methoxide solution in methanol (5.6 M) and 26.8 ml of 2-bromopropane and stirred for 2 hours with heating to 60 ° C. After cooling to RT, it was poured into water and extracted twice with ethyl acetate. The combined organic phases were concentrated in vacuo. The residue was purified by chromatography on silica gel (heptane / ethyl acetate gradient to 10% ethyl acetate content). 24.2 g of 1- (isopropylsulfanyl) -4-methoxybenzene were obtained.

H-NMR (300 MHz, 25 ° C, CDCl ₃ ): δ = 1.24 (d, 6H); 3.19 (sept, 1H); 3.81 (s, 3H); 6.85 (d, 2H); 7.40 (d, 2H).

Intermediate 39:

 Isopropyl-4-methoxyphenylsulfon

A solution of 24 g of intermediate 38 in 240 ml of acetone, 24 ml of water and 24 ml of methanol was added at RT in portions with a total of 64.8 g of potassium peroxymonosulfate (Oxone®, CAS 10361-76-9) and then stirred for 1 hour at RT. Then another 32.4 g

 Kaliumperoxymonosulfat (Oxone®, CAS 70693-62-8) was added and stirred for 16 hours at RT. It was diluted with ethyl acetate, the solid was filtered off and the precipitate was washed with ethyl acetate. The combined organic phases were completely concentrated in vacuo and the residue taken up in ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed completely in vacuo. 27.2 g of isopropyl 4-methoxyphenylsulfone were obtained.

H NMR (300 MHz, 25 ° C, CDCL): δ = 1.28 (d, 6H); 3.15 (sept, 1H); 3.88 (s, 3H); 7.02 (d, 2H); 7.79 (d, 2H).

Intermediate 40:

 Isopropyl-4-methoxy-3-nitrophenyl sulfone

A solution of 21 g of intermediate 39 in 105 ml of concentrated sulfuric acid was added dropwise with 4.9 ml of concentrated nitric acid, so that the temperature remained between 20-30 ° C. After another 15 min. Stirring at RT was added to ice-water and extracted twice with ethyl acetate. The combined organic phases were concentrated completely in vacuo. The residue was purified by chromatography on silica gel (heptane / ethyl acetate gradient to 50% ethyl acetate content). 23.3 g of isopropyl 4-methoxy-3-nitrophenylsulfone were obtained.

H-NMR (300 MHz, 25 ° C, CDCl ₃ ): δ = 1.33 (d, 6H); 3.22 (sept, 1H); 4.08 (s, 3H); 7.27 (d, 1H); 8.05 (dd, 1H); 8.34 (d, 1H).

Intermediate 41:

 5- (isopropylsulfonyl) -2-methoxyaniline

A suspension of 22.2 g of Intermediate 40 and 23.9 g of iron powder in 222 ml of ethanol and 61.2 ml of saturated aqueous ammonium chloride solution was stirred for 2 hours while heating to reflux. The reaction was filtered through diatomaceous earth and washed with ethanol. The organic solvent was removed in vacuo. The remaining aqueous solution was diluted with water, extracted twice with ethyl acetate, the combined organic phases with washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was completely removed in vacuo. The residue was crystallized from heptane / ethyl acetate 1: 1. 13.7 g of 5- (isopropylsulfonyl) -2-methoxyaniline were obtained. Ή-NMR (300 MHz, 25 ° C, CDCl ₃ ): δ = 1.28 (d, 6H); 3.15 (sept, 1H); 3.93 (s, 3H); 4.04 (bs, 2H); 6.87 (d, 1H); 7.15 (d, 1H); 7.25 (dd, 1H).

Intermediate 42:

l- (Cyclopropylsulfanyl) -4-methoxybenzene

A suspension of 15 g of 4-methoxythiophenol and 52.3 g of cesium carbonate in 105 ml of N, N-dimethylformamide was mixed with 25.9 g of cyclopropyl bromide and stirred for 16 hours while heating to 60 ° C. After cooling to RT, it was poured into water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous

Washed sodium chloride solution and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (heptane / ethyl acetate gradient to 10% ethyl acetate content). 19.2 g of 1- (cyclopropylsulfanyl) -4-methoxybenzene were obtained.

H NMR (300 MHz, 25 ° C, CDCl ₃ ): δ = 0.66-0.71 (m, 2H); 0.96-1.02 (m, 2H); 2.15-2.23 (m, 1H); 3.81 (s, 3H); 6.87 (d, 2H); 7.35 (d, 2H). Intermediate 43:

 Cyclopropyl-4-methoxyphenylsulfon

A solution of 19.2 g of Intermediate 42 in 192 ml of acetone, 19.2 ml of water and 19.2 ml of methanol was added in portions at 0-5 ° C with a total of 52.38 g of potassium peroxymonosulfate (Oxone®, CAS 70693-62-8) and then at RT for 16 Hours stirred. It was diluted with ethyl acetate, the solid was filtered off and the precipitate was washed with ethyl acetate. The combined organic phases were completely concentrated in vacuo and the residue taken up in ethyl acetate. The organic phase was washed with saturated aqueous

Washed sodium chloride solution, dried over magnesium sulfate and the solvent was completely removed in vacuo. 16.7 g of cyclopropyl-4-methoxyphenylsulfone were obtained.

H-NMR (300 MHz, 25 ° C, CDCl ₃ ): δ = 0.97-1.04 (m, 2H); 1.29-1.35 (m, 2H); 2.40-2.48 (m, 1H); 3.89 (s, 3H); 7.01 (d, 2H); 7.82 (d, 2H).

Intermediate 44:

 Cyclopropyl-4-methoxy-3-nitrophenyl sulfone

A solution of 20 g of Intermediate 43 (prepared from two reactions to give Intermediate 43) in 100 ml of concentrated sulfuric acid was added dropwise with 2.3 ml of concentrated nitric acid so that the temperature remained between 20-30 ° C. After another 15 min. Stirring at RT was in Ice water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed completely in vacuo. This approach was repeated again with 10 g of intermediate 43. The combined residues of the two batches were taken up with 200 ml of heptane and it was concentrated again in vacuo to about 100 ml. This formed a crystals. It was allowed to stand at RT and it formed more crystals. This was filtered off with suction and washed with heptane. 15.8 g of cyclopropyl-4-methoxy-3-nitrophenylsulfone were obtained. H-NMR (300 MHz, 25 ° C, CDCl ₃ ): δ = 1.06-1.13 (m, 2H); 1.35-1.42 (m, 2H); 2.44-2.53 (m, 1H); 4.08 (s, 3H); 7.26 (d, 1H); 8.07 (dd, 1H); 8.37 (d, 1H).

Intermediate 45:

5- (cyclopropylsulfonyl) -2-methoxyaniline

A suspension of 10 g of Intermediate 44 and 10.85 g of iron powder in 100 ml of ethanol and 27.7 ml of saturated aqueous ammonium chloride solution was stirred for 2 hours while heating to reflux. The reaction was filtered through diatomaceous earth and washed with ethanol. The organic solvent was removed in vacuo. The residual aqueous solution was diluted with water, extracted twice with ethyl acetate, the combined organic phases washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed completely in vacuo. The residue was crystallized from heptane / ethyl acetate 1: 1. 6.3 g of 5- (cyclopropylsulfonyl) -2-methoxyaniline were obtained.

H-NMR (300 MHz, 25 ° C, CDCh): δ = 0.95-1.03 (m, 2H); 1.27-1.34 (m, 2H); 2.40-2.48 (m, 1H); 3.93 (s, 3H); 4.05 (bs, 2H); 6.87 (d, 1H); 7.18 (d, 1H); 7.27 (dd, 1H). Intermediate 46:

 (2S) -7-Chloro-cyclopentyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

9.8 g of 7-chloro-1-cyclopentyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -ori (preparation described in US20060009457, Compound X6j) were purified by chiral HPLC (Chiralpak IB 5μηι 250x50 mm, hexane / 2-propanol 90:10 (v / v)) separated into the enantiomers. 4.21 g of (2S) -7-chloro-1-cyclopentyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one were obtained. The (R) -enantiomer was also obtained (see also Intermediate 24).

Chiral HPLC: Rt = 3.8 min

 Instrument: Waters Alliance 2695; Column: Chiralpak IB 5μιη 150x4.6 mm; Eluent: hexane / 2-propanol / 90:10; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Optical rotation: [a] _D ²⁰ = 229.3 ° +/- 0.43 ° (c = 7.0 mg / ml, methanol).

Intermediate 47:

Butyl - {(2 f) ^ (4,6-dichloropyridin-3-yl) (methyl) aynino] -1-oxopropan-2-yl} carbamate

A suspension of 1.0 g of intermediate 5 in 10 ml of DMF under an argon atmosphere at 0 ° C bath temperature with 0.29 ml of methyl iodide and 0.144 g of sodium hydride (60% in oil over 1 hour in 6 portions) and 4 hours together at 0 ° C. Bath temperature stirred. For work-up, the mixture was poured into ice-water, extracted twice with ethyl acetate, dried over sodium sulfate and concentrated in vacuo and purified by chromatography on silica gel

(Hexane / ethyl acetate gradient to 60% ethyl acetate content). This gave 0.92 g of ieri-butyl {(2R) -1 - [(4,6-dichloropyridin-3-yl) (methyl) amino] -1-oxopropan-2-yl} carbamate as an almost colorless resin. Ή-NMR (500 MHz, DMSO-d ₆ ): δ = a) 1.01 (d, 3H); 1.34 (s, 9H); 3.10 (s, 3H); 3.85 (quin, 1H); 7.19 (brd d, 1H); 8.02 (s, 1H); 8.53 (s, 1H); b) 1.08 (d, 3H); 1.28 (s, 9H); 3.08 (s, 3H); 4.01 (quin, 1H); 6.92 (brd d, 1H); 7.95 (s, 1H); 8.63 (s, 1H). (Rotamer a: b = 3: 2)

Optical rotation: [a] _D ²⁰ = -26.8 ° +/- 0.13 ° (methanol)

Intermediate 48:

 N- (4,6-Dichloro-pyridin-3-yl) -N-methyl-D-alaninamide

A solution of 0.68 g of Intermediats 47 in 2.7 ml of dioxane was added at room temperature with concentrated hydrochloric acid (0.75 ml) and stirred for 3 hours. For workup, the mixture was concentrated to dryness in vacuo, stirred with diethyl ether (5 ml) at 0 ° C bath temperature, filtered off with suction and washed twice with cold diethyl ether. 0.39 g of N- (4,6- Dichloropyridine ^ -y ^ - methyl-δ-alanineamide as a fine, almost colorless dihydrochloride.

H-NMR (400MHz, DMSO-d _6): δ = a) 1.11 (d, 3H); 3.16 (s, 3H); 3.55 (brs, 3H); 3.83 (quin, 1H); 8.12 - 8.13 (m, 1H); 8.48 (brs., 1H); 8.73 (s, 1H); b) 1.22 (d, 3H); 3.17 (s, 3H); 3.55 (brs, 3H); 4.57 - 4.65 (m, 1H); 8.02 (s, 1H); 8.78 (s, 1H) (rotamer a: b = 3: 2).

Intermediate 49:

ieri-butyl-4 - ({(2 f) -1 - [(4,6-dichloropyridin-3-yl) (methyl) amino] -1-oxopropan-2-yl} amino) piperidine-1-carboxylate

A solution of 1.89 g of intermediate 48 in 19 ml of dichloromethane was treated at 0 ° C bath temperature with 0.74 g of sodium acetate, 1.11 g of l-Boc-4-piperidone and 1.8 g Natriumtriacetoxyborhydrid and stirred for 2 hours on the ice bath, then allowed to warm to room temperature and stirred together for 4 hours. For work up was in saturated

Sodium bicarbonate solution, shaken carefully until the evolution of gas, the organic phase separated, extracted with dichloromethane, dried with sodium sulfate and concentrated to dryness in vacuo, with cold hexane (2 x 6 g) stirred, decanted and concentrated again in vacuo to dryness. 2.01 g of ieri-butyl-4 - ({(2R) -1 - [(4,6-dichloropyridin-3-yl) (methyl) amino] -1-oxopropan-2-yl} amino) piperidine 1 - Carboxylate as almost colorless resin. H NMR (400MHz, CDCL): δ = a) 1.19 (d, 3H); 1.46 (s, 9H); 1.50 - 1.65 (m, 2H); 1.70 (d, 2H); 1.83-1.92 (m, 1H); 2.51 (br., 1H); 2.81 (brs., 1H); 3.08 (q, 1H); 3.27 (s, 3H); 3.86 (brs, 1H); 3.99 (br., 2H); 7.61 (s, 1H); 8.36 (s, 1H) ;. b) 1.11 - 1.15 (m, 3H); 1.47 (s, 9H); 1.50 - 1.65 (m, 2H); 1.70 (d, 2H); 1.83-1.92 (m, 1H); 2.51 (br., 1H); 2.81 (brs., 1H); 3.24 (q, 1H); 3.25 - 3.28 (m, 3H); 3.86 (brs, 1H); 3.99 (br., 2H); 7.59 (s, 1H); 8.31 (s, 1H). (Rotamer a: b = 3: 2). Intermediate 50:

 te ^ Butyl-4 (2A) -7-chloro-2,4-dimethyl-3-oxo-3,4-dm ^^

 yl] piperidine-l-carboxylate

2.0 g of intermediate 49 were heated for 1 hour at 150 ° C bath temperature, cooled, taken up with 20 ml of dichloromethane, extracted with water, the organic phase over

 Dried over sodium sulfate, concentrated in vacuo and the residue purified by chromatography on silica gel (dichloromethane / ethanol gradient to 6% ethanol content). 0.65 g of tert-butyl-4 - [(2R) -7-chloro-2,4-dimethyl-3-oxo-3,4-dihydropyrido [3,4-b] pyrazine-1 (2H) -yl] was obtained. piperidine-1-carboxylate as a beige oil.

Ή-NMR (400MHz, CDC1 ₃ ): δ [ppm] = 1.21 (d, 3H); 1.50 (s, 9H); 1.68 (qd, 1H); 1.61 - 1.76 (m, 1H); 1.76 (br., 1H); 2.02 (br., 1H); 2.78 - 2.91 (m, 2H); 3.40 (s, 3H); 3.64 (tt, 1H); 4.24 (q, 1H); 4.27 - 4.41 (m, 2H); 6.67 (s, 1H); 7.87 (s, 1H).

Optical rotation: [a] _D ²⁰ -176.2 ° +/- 0.13 ° (methanol), ee> 99.

Intermediate 51:

 (2S) -7-chloro-l-isopropyl-2,4-dimethyl-l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one

1.15 g of 7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (preparation described in US20060009457, compound X6h) were separated by chiral HPLC (Chiralpak IC 5μηι 250x30 mm, hexane / ethanol 70:30 (v / v)) into the enantiomers. 475 mg of (2S) -7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one and the (R) -enantiomer were obtained, see Intermediate 37.

Chiral HPLC: Rt = 4.47 min

 Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: hexane / ethanol / 70:30; Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 1: 1); DAD 996 scan: 280 nm.

Optical rotation: [a] _D ²⁰ = 271.2 ° +/- 0.1 ° (c = 10 mg / ml, methanol).

Compounds of the invention

The following examples illustrate the preparation of the compounds of the invention.

Example 1:

 3 - {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (l-methylpiperidin-4-yl) benzolsulfonaniid

A mixture of 150 mg Intermediate 4, 195 mg Intermediate 28, 8.8 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 235 mg of cesium carbonate and 11 mg of xanthphos (CAS 161265-03-8) in 10 ml of dioxane was stirred at 120 ° C for 7 hours under argon atmosphere. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated 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 5μηι 100x30mm, mobile phase: acetonitrile / water (0.2 vol% ammonia) gradient). 70 mg of 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine] were obtained. 7-yl] amino} - / V- (1-methylpiperidin-4-yl) benzenesulfonamide.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.32-1.45 (m, 2H); 1.52-1.60 (m, 2H); 1.61-1.68 (m, 1H); 1.73-1.86 (m, 3H); 1.87-1.99 (m, 2H); 2.06 (s, 3H); 2.56-2.64 (m, 2H); 2.86-2.97 (m, 1H); 3.28 (s, 3H); 3.40-3.50 (m, 2H); 3.71 (tt, 1H); 3.93-4.04 (m, 2H); 4.20 (q, 1H); 6.38 (s, 1H); 7.20-7.25 (m, 1H); 7.40 (t, 1H); 7.57 (d, 1H); 7.77-7.82 (m + s, 2H); 8.23 (t, 1H); 9.10 (s, 1H). Example 2:

 3 - {[(2A) -2,4-Dimethyl-3-oxo-1-tetrahydro-2H-yran-4-yl] -1,3,3,4-tetrahydropyrido [3,4-b] pyrazine-7 -yl] amino} -N- (l-methylpiperidin-4-yl) benzenesulfonamide

A mixture of 120 mg Intermediate 9, 156 mg Intermediate 28, 7 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 188 mg of cesium carbonate and 9 mg of xanthphos (CAS 161265-03-8) in 8 ml of dioxane was stirred for 9 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 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 (0.2 vol% ammonia) gradient). There were obtained 75 mg of 3- {[(2R) -2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4- b] pyrazine-7-yl] amino} -N- (1-methylpiperidin-4-yl) benzenesulfonamide.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.32- 1.45 (m, 2H); 1.52-1.60 (m, 2H); 1.61-1.68 (m, IH); 1.73-1.86 (m, 3H); 1.87-1.99 (m, 2H); 2.06 (s, 3H); 2.56-2.64 (m, 2H); 2.86-2.97 (m, IH); 3.28 (s, 3H); 3.40-3.50 (m, 2H); 3.71 (tt, IH); 3.93-4.04 (m, 2H); 4.20 (q, IH); 6.38 (s, IH); 7.20-7.25 (m, IH); 7.40 (t, IH); 7.57 (d, IH); 7.77-7.82 (m + s, 2H); 8.23 (t, IH); 9.10 (s, IH).

Example 3:

 2,4-Dimethyl-7 - ({3 (4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1- (tetrahydro-pyran-4-yl) -1,4-dihydropyrido [3,4-b ] pyrazin-3 (2H) -one

A mixture of 150 mg Intermediate 4, 184 mg Intermediate 30, 8.8 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 235 mg of cesium carbonate and 11 mg of xanthphos (CAS 161265-03-8) in 10 ml of dioxane was stirred for 9 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 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 (0.2 vol% ammonia) gradient). This gave 100 mg of 2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1,4 - dihydropyrido [3,4-b] pyrazine-3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.59-1.69 (m, 1H); 1.79 (dq, 1H); 1.86-2.00 (m, 2H); 2.13 (s, 3H); 2.31-2.40 (m, 4H); 2.85-2.96 (m, 4H); 3.28 (s, 3H); 3.36-3.52 (m, 2H); 3.71 (tt, 1H); 3.92-4.06 (m, 2H); 4.20 (q, 1H); 6.38 (s, 1H); 7.12 bd, 1H); 7.47 (t, 1H); 7.82 (s, 1H); 7.88-7.94 (m, 1H); 8.17 (t, 1H); 9.21 (s, 1H).

Example 4:

 2,4-Dimethyl - (tetrahydro-2H-yran-4-yl) -7 - [(3 - {[4- (2,2,2-trifluoroethyl) -piperazin-1-yl] -sulfonyl} -phenyl) -amino] - l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one

A mixture of 150 mg Intermediate 4, 234 mg Intermediate 32, 8.8 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 235 mg of cesium carbonate and 11 mg of xanthphos (CAS 161265-03-8) in 10 ml of dioxane was stirred for 9 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 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). 96 mg of 2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -7- [(3- {[4- (2,2,2-trifluoroethyl) -piperazin-1-yl] sulfonyl were obtained } phenyl) amino] -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.61-1.69 (m, 1H); 1.80 (qd, 1H); 1.87-1.99 (m, 2H); 2.66-2.74 (m, 4H); 2.87-2.96 (m, 4H); 3.28 (q, 2H); 3.28 (s, 3H); 3.40-3.50 (m, 2H); 3.71 (tt, 1H); 3.93-4.04 (m, 2H); 4.20 (q, 1H); 6.38 (s, 1H); 7.12 (dd, 1H); 7.48 (t, 1H); 7.82 (s, 1H); 7.92 (dd, 1H); 8.17 (t, 1H); 9.19 (s, 1H).

Example 5:

 N 2- (dimethylamino) ethyl] -3 - {[2,4-dimet ^^

tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} benzenesulfonamide

A mixture of 150 mg Intermediate 4, 176 mg Intermediate 34, 8.8 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 235 mg of cesium carbonate and 11 mg of xanthphos (CAS 161265-03-8) in 10 ml of dioxane was stirred for 10 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 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 (0.2 vol% ammonia) gradient). 94 mg / V- [2- (dimethylamino) ethyl] -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3] 4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino-jbenzenesulfonamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.59-1.70 (m, 1H); 1.79 (qd, 1H); 1.85-2.00 (m, 2H); 2.06 (s, 6H); 2.25 (t, 2H); 2.79-2.90 (m, 2H); 3.27 (s, 3H); 3.38-3.52 (m, 2H); 3.71 (tt, 1H); 3.91-4.05 (m, 2H); 4.20 (q, 1H); 6.38 (s, 1H); 7.18-7.24 (m, 1H); 7.36-7.49 (m, 2H); 7.79-7.87 (m + s, 2H); 8.20 (t, 1H); 9.13 (s, 1H).

Example 6:

 3 - {[2,4-dimethyl-3-oxo ^ - (tetrahydro-2H-pyran-4-yl), 2,3,4-etrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N - [2- (4-methylpiperazin-l-yl) ethyl] benzenesulfonamide

A mixture of 150 mg Intermediate 4, 216 mg Intermediate 36, 8.8 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 274 mg of cesium carbonate and 11 mg of xanthphos (CAS 161265-03-8) in 10 ml of dioxane was stirred for 7 hours under an argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated 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 (0.2 vol% ammonia) gradient). 161 mg of 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine] were obtained. 7-yl] amino} -N- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.59- 1.69 (m, 1H); 1.79 (dq, 1H); 1.86-2.00 (m, 2H); 2.08 (s, 3H); 2.14-2.34 (m, 10H), 2.86 (bt, 2H); 3.28 (s, 3H); 3.38-3.51 (m, 2H); 3.71 (tt, 1H); 3.91-4.05 (m, 2H); 4.20 (q, 1H); 6.38 (s, 1H); 7.21 (bd, 1H); 7.36 (bs, 1H); 7.41 (t, 1H); 7.77-7.84 (m, 2H); 8.23 (t, 1H); 9.13 (s, 1H).

Example 7:

1-Benzyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one

A mixture of 150 mg Intermediate 12, 241 mg Intermediate 30, 18.6 mg (2'-Aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl [2 ', 4', 6'-tri (propan-2-yl) biphenyl -2-yl] phosphine (1: 1) (CAS 1310584-14-5, commercially available) and 64 mg of sodium ieri-butoxide in 3.8 ml of dioxane was stirred at 80 ° C for 9 hours under argon atmosphere. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase became more saturated

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). This gave 102 mg of 1-benzyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.15 (d, 3H); 2.13 (s, 3H); 2.30-2.40 (m, 4H); 2.83-2.94 (m, 4H); 3.32 (s, 3H); 4.11 (q, 1H); 4.42 (d, 1H); 4.52 (d, 1H); 6.11 (s, 1H); 7.10 (bd, 1H); 7.25-7.40 (m, 5H); 7.42 (t, 1H); 7.80 (s, 1H); 7.84 (bd, 1H); 8.11 (t, 1H); 9.14 (s, 1H).

Example 8:

 (2 f) -1-Benzyl-2,4-dimethyl-7 - ({3 (4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine 3 (2H) -one

100 mg of 1-benzyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (Example 7) were separated by chiral HPLC (Chiralpak IA 5μιη 250x30 mm, ethanol / methanol / diethylamine 50: 50: 0.1 (v / v)) into the enantiomers. 32 mg of (2R) -1-benzyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4 -b] pyrazine-3 (2H) -one and the (S) -enantiomer, see Example 150.

Chiral HPLC: Rt = 3.48 min

Instrument: Waters Alliance 2695; Column: Chiralpak IA 3μιη 100x4.6 mm; Eluent A: ethanol / methanol / 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.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.15 (d, 3H); 2.13 (s, 3H); 2.30-2.40 (m, 4H); 2.83-2.94 (m, 4H); 3.32 (s, 3H); 4.11 (q, 1H); 4.42 (d, 1H); 4.52 (d, 1H); 6.11 (s, 1H); 7.10 (bd, 1H); 7.25-7.40 (m, 5H); 7.42 (t, 1H); 7.80 (s, 1H); 7.84 (bd, 1H); 8.11 (t, 1H); 9.14 (s, 1H).

Example 9:

1-Benzyl-2,4-dimethyl-7 (3 - {[4- (2,2,2-trifluoroethyl) -piperazine-1-yl] sulfonyl} -phenyl) -amino] -l, 4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one

A mixture of 150 mg Intermediate 12, 305 mg Intermediate 32, 18.6 mg (2'-Aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl [2 ', 4', 6'-tri (propan-2-yl) biphenyl -2-yl] phosphine (1: 1) (CAS 1310584-14-5, commercially available) and 64 mg of sodium iperi-butoxide in 3.8 ml of dioxane was stirred at 80 ° C for 8 hours under argon atmosphere. The reaction was poured onto water and extracted three times with ethyl acetate. The organic phase became more saturated

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 (0.2% by volume ammonia)).

Gradient). 42 mg of 1-benzyl-2,4-dimethyl-7 - [(3- {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] sulfonyl} phenyl) amino] -1, dihydropyrido [3,4-b] pyrazin-3 (2H) -one.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.15 (d, 1H); 2.62-2.73 (m, 4H); 2.83-2.94 (m, 4H); 3.17 (q, 1H); 3.32 (s, 3H); 4.11 (q, 1H); 4.43 (d, 1H); 4.52 (d, 1H); 6.11 (s, lH); 7.10 (bd, 1H); 7.25-7.39 (m, 5H); 7.43 (t, 1H); 7.80 (s, 1H); 7.85 (dd, 1H); 8.11 (t, 1H); 9.16 (s, 1H).

Example 10:

 3 (1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) -amino] -N- (1-methylpiperidin-4-yl ) benzenesulfonamide

A mixture of 150 mg Intermediate 12, 154 mg Intermediate 28, 18.6 mg (2'-Aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl [2 ', 4', 6'-tri (propan-2-yl) biphenyl -2-yl] phosphine (1: 1) (CAS 1310584-14-5, commercially available) and 64 mg of sodium ieri-butoxide in 3.8 ml of dioxane was stirred for 8 hours under an argon atmosphere at 80 ° C. The reaction was poured onto water and extracted three times with ethyl acetate. The organic phase became more saturated

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 5 μm 100 × 30 mm, mobile phase: acetonitrile / water (0.2% by volume formic acid) gradient). 120 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- were obtained. (l-methylpiperidin-4-yl) benzenesulfonamide.

'H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.15 (d, 3H); 1.32- 1.49 (m, 2H); 1.52-1.64 (m, 2H); 1.97 (bt, 2H); 2.15 (s, 3H); 2.64-2.74 (m, 2H); 2.87-3.02 (m, IH); 3.31 (s, 3H); 4.11 (q, IH); 4.42 (d, IH); 4.52 (d, IH); 6.12 (s, IH); 7.20 (bd, IH); 7.25-7.41 (m, 5H); 7.63 (d, IH); 7.73 (dd, IH); 7.78 (s, IH); 8.18 (t, IH); 9.08 (s, IH).

Example 11:

 3 - {[(2 / f) -Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-etrahydropyri]

(L-methylpiperidin-4-yl) benzenesulfonamide

110 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1 -methylpiperidin-4-yl) benzenesulfonamide (Example 10) were separated by chiral HPLC (Chiralpak ID 5μιη 250x20 mm, acetonitrile / diethylamine 100: 0.1 (v / v)) into the enantiomers. 40 mg of 3- {[(2R) -l-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} were obtained. - / V- (1-methylpiperidin-4-yl) benzenesulfonamide and the (S) -enantiomer, see Example 151.

Chiral HPLC: Rt = 4.89 min

Instrument: Waters Alliance 2695; Column: Chiralpak ID 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.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.15 (d, 3H); 1.32-1.49 (m, 2H); 1.52-1.64 (m, 2H); 1.97 (bt, 2H); 2.15 (s, 3H); 2.64-2.74 (m, 2H); 2.87-3.02 (m, 1H); 3.31 (s, 3H); 4.11 (q, 1H); 4.42 (d, 1H); 4.52 (d, 1H); 6.12 (s, 1H); 7.20 (bd, 1H); 7.25-7.41 (m, 5H); 7.63 (d, 1H); 7.73 (dd, 1H); 7.78 (s, 1H); 8.18 (t, 1H); 9.08 (s, 1H).

Example 12:

 4 - {[2,4-dimethyl-3-oxo ^ - (tetrahydro-2H-pyran-4-yl), 2,3,4-etrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N - [2- (4-methylpiperazin-l-yl) ethyl] benzenesulfonamide

A mixture of 150 mg Intermediate 12, 281 mg Intermediate 36, 18.6 mg (2'-aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl [2 ', 4', 6'-tri (propan-2-yl) biphenyl -2-yl] phosphine (1: 1) (CAS 1310584-14-5, commercially available) and 64 mg of sodium ieri-butoxide in 3.8 ml of dioxane was stirred for 8 hours under an argon atmosphere at 80 ° C. The reaction was poured onto water and extracted three times with ethyl acetate. The organic phase became more saturated

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 (0.2 vol% ammonia) - gradient). 20 mg of 4- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine] were obtained. 7-yl] amino} - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 3H); 2.08 (s, 3H); 2.14-2.33 (m, 10H); 2.80-2.89 (m, 2H); 3.31 (s, 3H); 4.11 (q, 1H); 4.42 (d, 1H); 4.51 (d, 1H); 6.11 (s, 1H); 7.19 (bd, 1H); 7.25-7.41 (m, 6H); 7.74 (dd, 1H); 7.79 (s, 1H); 8.15 (t, 1H); 9.08 (s, 1H).

Example 13:

 3 (1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl) -amino] -N- [2- (dimethylamino) -ethyl] benzenesulfonamide

A mixture of 300 mg Intermediate 12, 459 mg Intermediate 34, 37 mg (2'-Aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl [2 ', 4', 6'-tri (propan-2-yl) biphenyl -2-yl] phosphine (1: 1) (CAS 1310584-14-5, commercially available) and 127 mg of sodium feri-butylate in 7.5 ml of dioxane was stirred for 8 hours under argon atmosphere at 80 ° C. The reaction was poured onto water and extracted three times with ethyl acetate. The organic phase became more saturated

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 5 μm 100 × 30 mm, mobile phase: acetonitrile / water (0.2% by volume formic acid) gradient). 40 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- [2- (dimethylamino) ethyl] benzenesulfonamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.15 (d, 3H); 2.08 (s, 6H); 2.27 (t, 2H); 2.84 (t, 2H); 3.31 (s, 3H); 4.10 (q, 1H); 4.42 (d, 1H); 4.52 (d, 1H); 6.12 (s, 1H); 7.17-7.22 (m, 1H); 7.26-7.32 (m, 1H); 7.32-7.41 (m, 5H); 7.77 (dd, 1H); 7.70 (s, 1H); 8.13 (t, 1H); 9.06 (s, 1H).

Example 14:

 N- [2- (dimethylamino) ethyl] -3 - {[2,4-dimethyl-3-oxo-l- (propan-2

tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} benzenesulfonamide

A mixture of 150 mg of 7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (preparation described in US20060009457, compound X6h), 205 mg Intermediate 34, 10 mg Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 274 mg

Cesium carbonate and 13 mg of xanthphos (CAS 161265-03-8) in 2.5 ml of dioxane were stirred for 9 hours under argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase became more saturated

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 5 μm 100 × 30 mm, mobile phase: acetonitrile / water (0.2% by volume formic acid) gradient). 20 mg / V- [2- (dimethylamino) ethyl] -3- {[2,4-dimethyl-3-oxo-1- (propan-2-yl) -l, 2,3,4-tetrahydropyrido] 3,4-b] pyrazin-7-yl] amino} benzenesulfonamide. Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.26-1.33 (m, 6H); 2.08 (s, 6H); 2.28 (t, 2H); 2.86 (t, 2H); 3.27 (s, 3H); 3.87 (sept, 1H); 4.21 (q, 1H); 6.31 (s, 1H); 7.19-7.23 (m, 1H); 7.41 (t, 1H); 7.79 (s, 1H); 7.82-7.86 (m, 1H); 8.17 (bs, 1H); 8.20 (t, 1H); 9.12 (s, 1H).

Example 15:

 2,4-Dimethyl- (propan-2-yl) -7 (3 - {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] sulfonyl} phenyl) amino] -l, 4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one

A mixture of 150 mg of 7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (preparation described in US20060009457, compound X6h), 272 mg Intermediate 32, 10 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 274 mg cesium carbonate and 13 mg xanthophos (CAS 161265-03-8) in 4 ml dioxane were added under an argon atmosphere for 7 hours Stirred at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated 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 (0.2 vol% ammonia) gradient). There were obtained 36 mg of 2,4-dimethyl-1- (propan-2-yl) -7- [(3- {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] sulfonyl] phenyl] amino] -l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.27-1.33 (m, 6H); 2.65-2.73 (m, 4H); 2.88-2.95 (m, 4H); 3.18 (q, 2H); 3.27 (s, 3H); 3.88 (sept, 1H); 4.21 (q, 1H); 6.31 (s, 1H); 7.09-7.14 (m, 1H); 7.47 (t, 1H); 7.80 (s, 1H); 7.88-7.93 (m, 1H); 8.18 (t, 1H); 9.20 (s, 1H).

Example 16:

 2,4-Dimethyl-7 - ({3 (4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1- (propan-2-yl) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one

Analogously to Example 14, starting from 150 mg of 7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (preparation described in US20060009457, Compound X6h) and 215 mg of intermediate 30 after 7 hours of reaction at 120 ° C. 18 mg of 2,4-dimethyl-7 - ({3- [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1 - ( propan-2-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.27-1.33 (m, 6H); 2.14 (s, 3H); 2.34- 2.41 (m, 4H); 2.87-2.96 (m, 4H); 3.28 (s, 3H); 3.88 (sept, 1H); 4.21 (q, 1H); 6.31 (s, 1H); 7.09-7.14 (m, 1H); 7.46 (t, 1H); 7.80 (s, 1H); 7.87-7.93 (m, 1H); 8.18 (t, 1H); 9.19 (s, 1H).

Example 17:

 3 - {[2,4-dimethyl-3-oxo-1- (propan-2-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - N - (l-methylpiperidin-4-yl) benzenesulfonamide

Analogously to Example 14, starting from 150 mg of 7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (preparation described in US20060009457, Compound X6h) and 227 mg of intermediate 28 after 8 hours of reaction at 120 ° C. 30 mg of 3- {[2,4-dimethyl-3-] oxo-1 - (propan-2-yl) -1,2,3,4-tetrahydropyrido [3,4- b] pyrazine-7-yl] amino} -N- (1-methylpiperidin-4-yl) benzenesulfonamide ,

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.26- 1.32 (m, 6H); 1.32-1.46 (m, 2H); 1.50-1.62 (m, 2H); 1.74-1.88 (m, 2H); 2.07 (s, 3H); 2.55-2.66 (m, 2H); 2.84-2.99 (m, 1H); 3.27 (s, 3H); 3.88 (sept, 1H); 4.21 (q, 1H); 6.31 (s, 1H); 7.21 (bd, 1H); 7.39 (t, 1H); 7.60 (d, 1H); 7.76-7.84 (m, 2H); 8.24 (t, 1H); 9.13 (s, 1H).

Example 18:

 3 - {[(2A) -2,4-Dimethyl-3-oxo-1- (propan-2-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (l-methylpiperidin-4-yl) benzenesulfonamide

In analogy to Example 14, starting from 150 mg of intermediate 37 and 239 mg of intermediate 28 after 9 hours of reaction at 120 ° C., 101 mg of 3- {[(2R) -2,4-dimethyl-3-oxo-1 - (propane) 2-yl) -1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (1-methylpiperidin-4-yl) benzenesulfonamide.

'H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.26- 1.32 (m, 6H); 1.32-1.46 (m, 2H); 1.50-1.62 (m, 2H); 1.74-1.88 (m, 2H); 2.07 (s, 3H); 2.55-2.66 (m, 2H); 2.84-2.99 (m, 1H); 3.27 (s, 3H); 3.88 (sept, 1H); 4.21 (q, 1H); 6.31 (s, 1H); 7.21 (bd, 1H); 7.39 (t, 1H); 7.60 (d, 1H); 7.76-7.84 (m, 2H); 8.24 (t, 1H); 9.13 (s, 1H). Example 19:

 3 - {[2,4-dimethyl-3-oxo-1 - (propan-2-yl), 2,3,4-etrahydropyrido [3,4-b] pyrazine-7-yl] amino} - N- [2- (4-methylpiperazin-l-yl) ethyl] benzenesulfonamide

Analogously to Example 14, starting from 150 mg of 7-chloro-1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (preparation described in US20060009457, Compound X6h) and 251 mg of intermediate 36 after 8 hours of reaction at 120 ° C. 33 mg of 3- {[2,4-dimethyl-3-oxo-1 - (propan-2-yl)-1,2,3,4] tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.27- 1.34 (m, 6H); 2.08 (s, 3H); 2.15- 2.35 (m, 10H); 2.87 (bt, 2H); 3.27 (s, 3H); 3.87 (sept, 1H); 4.21 (q, 1H); 6.31 (s, 1H); 7.21 (bd, 1H); 7.33 (bs, 1H); 7.40 (t, 1H); 7.79 (s, 1H); 7.81 (dd, 1H); 8.23 (t, 1H); 9.12 (s, 1H).

Example 20:

 (2 f) -Cyclopentyl-2,4-dimethyl-7 - ({3 (4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 ( 2H) -one

In analogy to Example 14 starting from 200 mg of intermediate 24 and 347 mg of intermediate 30 after 3 hours of reaction at 120 ° C 130 mg (2R) -l-cyclopentyl-2,4-dimethyl-7 - ({3 - [(4 - methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one. Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.06 (d, 3H); 1.53-1.81 (m, 6H); 1.96-2.09 (m, 2H); 2.14 (s, 3H); 2.32-2.43 (m, 4H); 2.86-2.98 (m, 4H); 3.80 (qi, 1H); 4.15 (q, 1H); 6.30 (s, 1H); 7.12 (d, 1H); 7.47 (t, 1H); 7.80 (s, 1H); 7.92 (dd, 1H); 8.17 (t, 1H); 9.21 (s, 1H).

Example 21:

1-Cyclopentyl-2,4-dimethyl-7 - ({3 (4-methylpiperazin-1-yl) carbonyl] -phenyl} -amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

A solution of 220 mg Intermediate 19, 116 mg N-methylpiperazine (CAS 109-01-3), 0.32 ml triethylamine and 330 mg HATU in 8 ml DMF was stirred for 16 hours at RT. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried sodium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol gradient to 1% methanol content). 135 mg of 1-cyclopentyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine were obtained -3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.05 (d, 3H); 1.53-1.80 (m, 6H); 1.97-2.09 (m, 2H); 2.20 (s, 3H); 2.24-2.41 (m, 4H); 3.26 (s, 3H); 3.31-3.47 (m, 2H); 3.47-3.69 (m, 2H); 3.79 (qi, 1H); 4.14 (q, 1H); 6.28 (s, 1H); 6.79 (d, 1H); 7.27 (t, 1H); 7.59 (dd, 1H); 7.80 (t, 1H); 8.91 (s, 1H). Example 22:

 (2 f) -Cyclopentyl-2,4-dimethyl-7 - ({3 (4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 ( 2H) -one

A solution of 110 mg of intermediate 26, 58 mg of N-methylpiperazine (CAS 109-01-3), 0.16 ml of triethylamine and 165 mg of HATU in 12 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried 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 (0.2 vol% ammonia) gradient). 23 mg of (2R) -1-cyclopentyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4 -b] pyrazin-3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.05 (d, 3H); 1.53-1.80 (m, 6H); 1.97-2.09 (m, 2H); 2.20 (s, 3H); 2.24-2.41 (m, 4H); 3.26 (s, 3H); 3.31-3.47 (m, 2H); 3.47-3.69 (m, 2H); 3.79 (qi, 1H); 4.14 (q, 1H); 6.28 (s, 1H); 6.79 (d, 1H); 7.27 (t, 1H); 7.59 (dd, 1H); 7.80 (t, 1H); 8.91 (s, 1H).

Example 23:

 3 (1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] -N-cyclopropylbenzamide

A solution of 90 mg Intermediate 17, 25 mg cyclopropylamine (CAS 765-30-0), 0.13 ml triethylamine and 127 mg HATU in 3.1 ml DMF was stirred for 16 hours at RT. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried 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). 37 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- cyclopropylbenzamid.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 0.52-0.57 (m, 2H); 0.64-0.70 (m, 2H); 1.14 (d, 3H); 2.78-2.87 (m, IH); 3.30 (s, 3H); 4.10 (q, IH); 4.41 (d, IH); 4.49 (d, IH); 6.11 (s, IH); 7.17-7.24 (m, 2H); 7.26-7.32 (m, IH); 7.33-7.40 (m, 4H); 7.74-7.79 (m, 2H); 7.87 (bs, IH); 8.28 (d, IH); 8.83 (s, IH).

Example 24:

1-Benzyl-2,4-dimethyl-7 - ({3 (4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) - on

A solution of 90 mg Intermediate 17, 45 mg N-methylpiperazine (CAS 109-01-3), 0.13 ml triethylamine and 127 mg HATU in 3.1 ml DMF was stirred for 16 hours at RT. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried 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). This gave 23 mg of 1-benzyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine - 3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 3H); 2.20 (s, 3H); 2.24-2.41 (m, 4H); 3.30 (s, 3H); 3.34 (bs, 2H); 3.59 (bs, 2H); 4.09 (q, IH); 4.41 (d, IH); 4.51 (d, IH); 6.10 (s, IH); 6.77 (d, IH); 7.21 (t, IH); 7.26-7.32 (m, IH); 7.33-7.41 (m, 4H); 7.46-7.50 (m, IH); 7.72 (t, IH); 7.79 (s, IH); 8.85 (s, IH).

Example 25:

 3 (1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) -amino] -N- (1-methylpiperidin-4-yl ) benzamide

A solution of 90 mg of intermediate 17, 51 mg of 4-amino-N-methylpiperidine (CAS 41838-46-4), 0.13 ml of triethylamine and 127 mg of HATU in 3.1 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried 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). 14 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) -amino] - / V- (1-methylpiperidin-4-yl) benzamide.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 3H); 1.55-1.68 (m, 2H); 1.73-1.83 (m, 2H); 2.13-2.23 (m, 2H); 2.28 (s, 3H); 2.84-2.94 (m, 2H); 3.30 (s, 3H); 3.75 (qi, IH); 4.10 (q, IH); 4.41 (d, IH); 4.49 (d, IH); 6.12 (s, IH); 7.20-7.26 (m, 2H); 7.26-7.33 (m, IH); 7.32-7.40 (m, 4H); 7.77 (s, IH); 7.78-7.83 (m, IH); 7.86 (bs, IH); 8.15 (d, IH); 8.84 (s, IH).

Example 26:

 3 (1-benzyl-2,4-dimethyl-3-oxo-1, 2,3,4-etrahyto

[4- (cyclopropylmethyl) piperazin-l-yl] cyclohexyl} benzamide

A solution of 90 mg of intermediate 17, 106 mg of ris -4- [4- (cyclopropylmethyl) piperazin-1-yl] cyclohexanamine (CAS 755039-90-8, preparation described in WO2006018220), 0.13 ml of triethylamine and 127 mg of HATU in 3.1 ml of DMF was stirred at RT for 16 h. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried 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). 12 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- {cw-4- [4- (cyclopropylmethyl) piperazine-1-yl] cyclohexylbenzamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 0.03-0.08 (m, 2H); 0.41-0.48 (m, 2H); 0.76-0.85 (m, IH); 1.14 (d, 3H); 1.23-1.39 (m, IH); 1.42-1.55 (m, 3H); 1.70-1.90 (m, 4H); 2.10-2.20 (m + d, 3H); 3.30 (s, 3H); 3.85-3.05 (m, IH); 4.09 (q, IH); 4.40 (d, IH); 4.49 (d, IH); 6.12 (s, IH); 7.16-7.32 (m, 3H); 7.32-7.41 (m, 4H); 7.74-7.88 (m, 3H); 8.00-8.08 (m, IH); 8.79-8.85 (m, IH). Example 27:

1-Benzyl-2,4-dimethyl-7 - {[3- (2-oxa-6-azaspiro [3.3] hept-6-ylcarbonyl) -phenyl] -amino} -l, 4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one

A solution of 90 mg Intermediate 17, 128 mg 2-oxa-6-azaspiro [3.3] heptane oxalate (2: 1) (CAS 1045709-32-7), 0.13 ml triethylamine and 127 mg HATU in 3.1 ml DMF was used for 16 hours stirred at RT. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μηι 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 60 mg of 1-benzyl-2,4-dimethyl-7- {[3- (2-oxa-6-azaspiro [3.3] hept-6-ylcarbonyl) phenyl] -amino} -1,4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 3H); 3.31 (s, 3H); 4.09 (q, IH); 4.19 (bs, 2H); 4.41 (d, IH); 4.45 (bs, 2H); 4.52 (d, IH); 4.68 (s, 4H); 6.10 (s, IH); 7.01 (d, IH); 7.22 (t, IH); 7.26-7.32 (m, IH); 7.33-7.41 (m, 4H); 7.58 (d, IH); 7.80 (s, IH); 7.96 (t, IH); 8.85 (s, IH).

Example 28:

1-Benzyl-2,4-dimethyl-7 - {[3- (8-oxa-3-azabicyclo [3.2.1] oct-3-ylcarbonyl) -phenyl] -amino} -l, 4-dihydropyrido [3,4- b] pyrazin-3 (2H) -one

A solution of 90 mg Intermediate 17, 67 mg 8-oxa-3-azabicyclo [3.2.1] octane hydrochloride (1: 1) (CAS 54745-74-3), 0.13 ml triethylamine and 127 mg HATU in 3.1 ml DMF was added Stirred for 16 hours at RT. The batch was added to semisaturated saline and washed three times

Extracted ethyl acetate. The combined organic phases were washed with brine, 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). 61 mg of 1-benzyl-2,4-dimethyl-7- {[3- (8-oxa-3-azabicyclo [3.2.1] oct-3-ylcarbonyl) phenyl] -amino} -1,4-dihydropyrido were obtained. 3,4-b] pyrazin-3 (2H) -one.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.18 (d, 3H); 1.60-1.86 (m, 4H); 3.30 (s, 3H); 4.10-4.33 (m + q, 4H); 4.46 (d, 1H); 5.55 (d, 1H); 6.10 (s, 1H); 6.84 (d, 1H); 7.24 (t, 1H); 7.27-7.42 (m, 6H); 7.62 (bs, 1H); 7.73 (s, 1H); 8.97 (bs, 1H).

Example 29:

 3 (1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl) -amino] -N- [2- (dimethylamino) -ethyl] benzamide

A solution of 90 mg of intermediate 17, 39 mg of N, N-dimethylethane-1,2-diamine (CAS 108-00-9), 0.13 ml of triethylamine and 127 mg of HATU in 3.1 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, 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). 24 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] -N- [24] were obtained. 2- (dimethylamino) ethyl] benzamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 3H); 2.23 (s, 6H); 2.46 (t, 2H); 3.30 (s, 3H); 3.35 (q, 2H); 4.09 (q, 1H); 4.41 (d, 1H); 4.50 (d, 1H); 6.12 (s, 1H); 7.20-7.25 (m, 2H); 7.26-7.32 (m, 1H); 7.32-7.40 (m, 4H); 7.72-7.77 (m, 1H); 7.78 (s, 1H); 7.94 (bs, 1H); 8.22 (t, 1H); 8.84 (s, 1H).

Example 30:

 N- (1-acetylpiperidin-4-yl) -3 (1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] benzamide

A solution of 90 mg of intermediate 17, 64 mg of 1- (4-aminopiperidin-1-yl) ethanone (CAS 160357-94-8), 0.13 ml of triethylamine and 127 mg of HATU in 3.1 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, 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). 32 mg of N- (1-acetylpiperidin-4-yl) -3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b]) were obtained. pyrazine-7-y 1) amino] benzamide.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.29 (d, 3H); 1.36 (dq, IH); 1.46 (dq, IH); 1.74-1.89 (m, 2H); 2.01 (s, 3H); 2.67 (dt, IH); 3.13 (dt, IH); 3.30 (s, 3H); 3.82 (bd, IH); 3.96-4.07 (m, IH); 4.29-4.42 (m, 2H); 4.60 (s, 2H); 6.06 (s, IH); 7.25-7.41 (m, 7H); 7.49-7.60 (m + s, 2H); 7.71 (s, IH); 8.25 (d, IH); 9.38 (bs, IH).

Example 31:

 3 (1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) -amino] -N- (cyclopropylmethyl) -benzamide

A solution of 90 mg of intermediate 17, 32 mg of 1-cyclopropylmethanamine (CAS 2516-47-4), 0.13 ml of triethylamine and 127 mg of HATU in 3.1 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried 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). 70 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (cyclopropylmethyl) benzamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 0.19-0.25 (m, 2H); 0.39-0.45 (m, 2H); 0.96-1.07 (m, 1H); 1.25 (d, 3H); 3.13 (t, 2H); 4.25-4.35 (m, 1H); 4.50-4.63 (m, 2H); 6.08 (s, 1H); 7.26-7.50 (m, 8H); 7.64 (s, 1H); 7.78 (s, 1H); 8.47 (t, 1H); 9.22 (bs, 1H).

Example 32:

1-Benzyl-2,4-dimethyl-7 (3 - {[4- (2,2,2-trifluoroethyl) -piperazine] -yl] carbonyl} -phenyl) -amino] -l, 4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one

A solution of 90 mg of intermediate 17, 75 mg of 1- (2,2,2-trifluoroethyl) -piperazine (CAS 13349-90-1), 0.13 ml of triethylamine and 127 mg of HATU in 3.1 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried 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). 69 mg of 1-benzyl-2,4-dimethyl-7 - [(3- {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] carbonyl} phenyl) amino] -1, dihydropyrido [3,4-b] pyrazin-3 (2H) -one.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.17 (d, 3H); 2.55-2.72 (m, 2H); 3.22 (t, 2H); 3.30 (s, 3H); 3.52-3.68 (m, 1H); 4.16 (q, 1H); 4.45 (d, 1H); 4.55 (d, 1H); 6.09 (s, 1H); 6.84 (bd, 1H); 7.24 (t, 1H); 7.27-7.43 (m, 6H); 7.66 (bs, 1H); 7.74 (s, 1H); 8.98 (bs, 1H).

Example 33:

 3 (1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) -amino] -N- [2- (4-methylpiperazine) 1 -yl) ethyl] benzamide

A solution of 90 mg of intermediate 17, 64 mg of 2- (4-methylpiperazin-1-yl) ethanamine (CAS 934-98-5), 0.13 ml of triethylamine and 127 mg of HATU in 3.1 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, 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). 40 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzamide.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 3H); 2.17 (s, 3H); 2.30-2.49 (m, 8H); 3.27- 3.39 (m + s, 7H); 4.09 (q, 1H); 4.40 (d, 1H); 4.49 (d, 1H); 6.11 (s, 1H); 7.18-7.24 (m, 2H); 7.25-7.32 (m, 1H); 7.32-7.42 (m, 4H); 7.70-7.76 (m, 1H); 7.78 (s, 1H); 7.94 (s, 1H); 8.21 (t, 1H); 8.85 (s, 1H).

Example 34:

 3 (1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] -N- (1-methylazetidin-3-yl ) benzamide

A solution of 90 mg of intermediate 17, 71 mg of 3-amino-1-methylazetidine dihydrochloride (CAS 1139634-75-5), 0.13 ml of triethylamine and 127 mg of HATU in 3.1 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by RP-HPLC chromatography (column: X-Bridge C18 5μηι 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 40 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methylazetidin-3-yl) benzamide.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.14 (d, 3H); 2.34 (s, 3H); 3.11-3.18 (m, 2H); 3.30 (s, 3H); 3.67-3.724.10 (q, 1H); 4.32-4.54 (m, 3H); 6.11 (s, 1H); 7.22-7.28 (m, 2H); 7.32-7.42 (m, 4H); 7.75-7.81 (m, 2H); 7.92 (bs, 1H); 8.22 (s, 1H); 8.70 (d, 1H); 8.86 (s, 1H).

Example 35:

 2,4-Dimethyl-7 - ({3 (4-methylpiperazin-1-yl) carbonyl] -phenyl} -amino) -1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4- b] pyrazin-3 (2H) -one

A solution of 350 mg of intermediate 15, 177 mg of N-methylpiperazine (CAS 109-01-3), 0.49 ml of triethylamine and 504 mg of HATU in 12.3 ml of DMF was stirred at RT for 16 hours. The reaction was added to semisaturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over

Dried sodium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol gradient to 1% methanol content). 380 mg of 2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1, 4 were obtained -dihydropyrido [3,4-b] pyrazine-3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.59-1.69 (m, 1H); 1.78 (qd, 1H); 1.84-1.20 (m, 4H); 2.18 (t, 2H); 2.24-2.34 (m, 2H); 2.69 (s, 3H); 3.26 (s, 3H); 3.38-3.51 (m, 2H); 3.71 (tt, 1H); 3.92-4.05 (m, 2H); 4.19 (q, 1H); 6.35 (s, 1H); 6.80 (d, 1H); 7.27 (t, 1H); 7.58 (d, 1H); 7.80 (s, 1H); 7.84 (s, 1H); 8.91 (s, 1H).

Example 36:

 (2 f) -2,4-Dimethyl-7 - ({3 (4-methylpiperazin-1-yl) carbonyl] phenyl} amino) - (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [ 3,4-b] pyrazin-3 (2H) -one

380 mg of 2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [ 3,4-b] pyrazine-3 (2H) -one (Example 35) were converted to the enantiomers by chiral HPLC (Chiralpak IC 5μηι 250x40 mm, ethanol / methanol / diethylamine 50: 50: 0.1 (v / v / v)) separated. 101 mg of (2R) -2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) were obtained. - 1, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one and the (S) -enantiomer, see Example 153.

Chiral HPLC: Rt = 7.83 min

Instrument: Agilent 1200; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: ethanol / methanol / diethylamine 50: 50: 0.1 (v / v / v); Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 2: 1); DAD 996 scan: 280 nm.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.59-1.69 (m, 1H); 1.78 (qd, 1H); 1.84-1.20 (m, 4H); 2.18 (t, 2H); 2.24-2.34 (m, 2H); 2.69 (s, 3H); 3.26 (s, 3H); 3.38-3.51 (m, 2H); 3.71 (tt, 1H); 3.92-4.05 (m, 2H); 4.19 (q, 1H); 6.35 (s, 1H); 6.80 (d, 1H); 7.27 (t, 1H); 7.58 (d, 1H); 7.80 (s, 1H); 7.84 (s, 1H); 8.91 (s, 1H). Table 1:

Analogously to Example 23, the following examples were prepared from the respective intermediates:

The retention time was determined by the following UPLC-MS method:

Instrument: Waters Acquity UPLC-MS SQD; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.1% by volume of formic acid, 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.

Eg Structure Name Intermediate / Analytical

Amine data (M ⁽⁺⁾ + l,

 Retention time)

37 3- {[2,4-dimethyl-3-intermediate 15; (M ⁽⁺⁾ + l = 476, oxo-1 - (tetrahydro-2H-3-amino-1-Rt = 0.65 min pyran-4-yl) -1,2,3,4-methylpyrazole

 tetrahydropyrido [3,4- (CAS 1904-31-b] pyrazine-7-0)

methyl-lH-pyrazol-3- yl)benzamid yl] amino} - / V- (l-

methyl-1H-pyrazol-3-yl) benzamide

38 2,4-dimethyl-7 - [(3-intermediate 15; (M ⁽⁺⁾ + 1 = 562,

 {[4- (1-l- (1-methyl-4-Rt = 0.45 min methylpiperidine-4-piperidinyl) pipe

 yl) piperazine-l-razin (CAS

 yl] carbonyl} phenyl) a 23995-88-2)

 mino] - 1 - (tetrahydro-

2H-pyran-4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

39 / V- (3-cyanophenyl) -3-intermediate 15; (M ⁽⁺⁾ + l = 497,

 {[2,4-dimethyl-3-oxo-3-Rt = 0.78 min 1- (tetrahydro-2H-aminobenzonitr

 pyran-4-yl) -1,3,3,4-il (CAS 2237-tetrahydropyrido [3,4- 30-1]

 b] pyrazine-7-yl] amino}

Bsp Struktur Name Intermediat/ Analytische benzamide

Eg Structure Name Intermediate / Analytical

Amine data (M ⁽⁺⁾ + l,

 Retention time)

140 L-isopropyl-2,4-intermediate 21; (M ⁽⁺⁾ + l = 436, dimethyl-7 - ({3 - [(3-3 Rt = 0.84 min) methylpiperidine-1-methylpiperidine

 yl) carbonyl] phenyl} (CAS 626-56-2)

 H JL amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

Example 141:

3 - {[(2α) -cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (1) methylpiperidin-4-yl) benzenesulfonamide

Eine Mischung aus 150 mg Intermediat 24, 216 mg Intermediat 28, 49 mg

A mixture of 150 mg Intermediate 24, 216 mg Intermediate 28, 49 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 262 mg of cesium carbonate and 31 mg of xanthphos (CAS 161265-03-8) in 5.8 ml of dioxane was stirred for 8 hours under an argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was through

Chromatography on silica gel (dichloromethane / methanol gradient to 10% methanol content). The crude product was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.2% by volume of formic acid) gradient). 40 mg of 3- {[(2R) -l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} were obtained. -N- (1-methylpiperidin-4-yl) benzenesulfonamide. Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.06 (d, 3H); 1.35- 1.53 (m, 2H); 1.53-1.83 (m, (8H); 1.94-2.05 (m, 4H); 2.19 (s, 3H); 2.69-2.81 (m, 2H); 2.02-3.07 (m, 1H); 3.28 (s, 3H) 3.73-3.87 (m, 1H), 4.15 (q, 1H), 6.30 (s, 1H), 7.23 (d, 1H), 7.41 (t, 1H), 7.66 (d, 1H), 7.77-7.85 (m , 2H), 8.21 (s, 1H), 8.25 (bs, lH), 9.16 (s, 1H).

Optical rotation: [a] _D ²⁰ = -55.6 ° +/- 0.16 ° (c = 7.0 mg / ml, methanol).

Example 142:

3 - {[(2S) -Cyclopentyl-2,4-dimethyl-3-oxo, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1-methylpiperidine) 4-yl) benzenesulfonamide

Eine Mischung aus 150 mg Intermediat 46, 216 mg Intermediat 28, 49 mg

A mixture of 150 mg Intermediate 46, 216 mg Intermediate 28, 49 mg

 Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 262 mg of cesium carbonate and 31 mg of xanthphos (CAS 161265-03-8) in 5.8 ml of dioxane was stirred for 8 hours under an argon atmosphere at 120 ° C. The reaction was poured onto water and extracted twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The residue was through

Chromatography on silica gel (dichloromethane / methanol gradient to 10% methanol content). The crude product was purified by RP-HPLC chromatography (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.1% by volume of formic acid) gradient). 40 mg of 3- {[(2, S ^, ) -l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl were obtained ] amino} -N- (1-methylpiperidin-4-yl) benzenesulfonamide.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.06 (d, 3H); 1.35- 1.53 (m, 2H); 1.53-1.83 (m, (8H); 1.94-2.05 (m, 4H); 2.19 (s, 3H); 2.69-2.81 (m, 2H); 2.02-3.07 (m, 1H); 3.28 (s, 3H) 3.73-3.87 (m, 1H), 4.15 (q, 1H), 6.30 (s, 1H), 7.23 (d, 1H), 7.41 (t, 1H), 7.66 (d, 1H), 7.77-7.85 (m , 2H), 8.21 (s, 1H), 8.25 (bs, 1H), 9.16 (s, 1H).

Optical rotation: [a] _D ²⁰ = 58.7 ° +/- 0.13 ° (c = 7.0 mg / ml, methanol). Example 143:

 (2 f) -7 - {[2-Methoxy-5- (morpholin-4-ylsulfonyl) -phenyl] -amino} -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4 -dihydropyrido [3,4-b] pyrazin-3 (2H) -one

A mixture of 150 mg Intermediate 9, 207 mg 2-methoxy-5- (morpholin-4-ylsulfonyl) aniline (CAS 56807-17-1), 248 mg cesium carbonate and 40 mg (2'-aminobiphenyl-2-yl) ( chloro) palladium dicyclohexyl [2 ', 4', 6 ^, -tri (propan-2-yl) biphenyl-2-yl] phosphine (1: 1) (CAS 1310584-14-5, commercially available) in 7.8 ml 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, over

Dried 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 (0.2% by volume ammonia 35%) - gradient). This gave 64 mg of (2R) -7- {[2- methoxy-5- (morpholin-4-ylsulfonyl) phenyl] amino} -2 _^

l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one. H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.07 (d, 3H); 1.62 (bd, 1H); 1.76 (qd, 1H); 1.86-2.00 (m, 2H); 2.83-2.92 (m, 4H); 3.28 (s, 3H); 3.41-3.53 (m, 2H); 3.60-3.67 (m, 4H); 3.72 (tt, 1H); 3.93-4.44 (m, 5H); 4.19 (q, 1H); 6.82 (s, 1H); 7.16-7.23 (m, 2H); 7.80 (s, 1H); 8.21 (s, 1H); 8.97 (d, 1H).

Example 144:

 (2 f) -7 - {[5- (isopropylsulfonyl) -2-methoxyphenyl] amino} -2,4-dimethyl-1- (tetrahydropyran-4-yl) -1,4-dihydropyrido [3,4- b] pyrazin-3 (2H) -one

A mixture of 150 mg Intermediate 9, 174 mg Intermediate 41, 248 mg cesium carbonate and 40 mg (2'-aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl [2 ', 4', 6'-tri (propane-2 -yl) biphenyl-2-yliphosphane (1: 1) (CAS 1310584-14-5, commercially available) in 7.8 ml of dioxane was stirred for 8 hours under an 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 (0.2% by volume ammonia 35%) - gradient). 49 mg of (2R) -7- {[5- (isopropylsulfonyl) -2-methoxyphenyl] amino} -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido were obtained [3,4-b] pyrazin-3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.07 (d, 3H); 1.16 (d, 6H); 1.62 (bd, IH); 1.75 (qd, IH); 1.86-2.00 (m, 2H); 3.20-3.31 (m + s, 4H); 3.42-3.52 (m, 2H); 3.73 (tt, IH); 3.93-4.03 (m + s,

5H); 4.19 (q, IH); 6.82 (s, IH); 7.29 (d, IH); 7.30 (dd, IH); 7.81 (s, IH); 8.18 (s, IH); 9.05 (d, IH).

Example 145:

 (2 f) -7 - {[5- (cyclopropylsulfonyl) -2-methoxyphenyl] amino} -2,4-dimethyl-1- (tetrahydropyran-4-yl) -1,4-dihydropyrido [3,4- b] pyrazin-3 (2H) -one

A mixture of 150 mg Intermediate 9, 173 mg Intermediate 45, 248 mg cesium carbonate and 40 mg (2'-aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl [2 ', 4', 6'-tri (propane-2 -yl) biphenyl-2-yl] phosphine (1: 1) (CAS 1310584-14-5, commercially available) in 7.8 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

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 (0.2% by volume ammonia 35%) - gradient). This gave 84 mg of (2R) -7- {[5- (cyclopropylsulfonyl) -2-methoxyphenyl] amino} -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 0.96-1.12 (m, 7H); 1.62 (bd, 1H); 1.75 (qd, 1H); 1.86-2.00 (m, 2H); 2.65-2.75 (m, 1H); 3.28 (s, 3H); 3.41-3.53 (m, 2H); 3.73 (tt, 1H); 3.92-4.04 (m + s, 5H); 4.20 (q, 1H); 6.82 (s, 1H); 7.18 (d, 1H); 7.33 (dd, 1H); 7.84 (s, 1H); 8.19 (s, 1H); 9.13 (d, 1H).

Example 146:

 ieri-butyl-4- [7 - {[2-methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-3-oxo-3,4-dihydropyrido [3,4-b] pyrazine-1 (2H) -yl] piperidine-l-carboxylate

A mixture of 300 mg Intermediate 50, 218 mg 2-methoxy-5- (methylsulfonyl) aniline (CAS 20945-70-4), 97 mg sodium ieri-butoxide and 28 mg (2'-aminobiphenyl-2-yl) ( chloro) palladium-dicyclohexyl [2 ', 4 ^, 6'-tri (propan-2-yl) biphenyl-2-yl] -phosphine (1: 1) (CAS 1310584-14-5) in 15 ml of dioxane for 3 hours under an argon atmosphere at 100 ° C stirred. 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 (dichloromethane / methanol gradient to 3% methanol content). This gave 180 mg of tert-butyl 4- [7- {[2-methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-3-oxo-3,4-dihydropyrido [3,4-b ] pyrazine-1 (2H) -yl] piperidine-1-carboxylate.

H-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.06 (d, 3H); 1.42 (s, 9H); 1.51-1.70 (m, 2H); 1.76 (qd, 1H); 1.99 (bd, 1H); 2.78-2.95 (m, 2H); 3.11 (s, 3H); 3.28 (s, 3H); 3.61-3.71 (m, 1H); 3.99 (s, 3H); 4.02-4.21 (m + q, 3H); 6.78 (s, 1H); 7.19 (d, 1H); 7.39 (dd, 1H); 7.85 (s, 1H); 8.13 (s, 1H); 9.11 (d, 1H).

Example 147:

 7 - {[2-Methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-1- (piperidine-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

A solution of 170 mg of Example 146 in 10 ml of dichloromethane and 0.3 ml of trifluoroacetic acid was stirred at RT for 16 hours. With addition of toluene, the solvent was removed in vacuo and the residue was purified by RP-HPLC (column: X-Bridge C18 5μιη 100x30mm, mobile phase: acetonitrile / water (0.2% by volume ammonia 35%) - gradient). There were obtained 30 mg of 7- {[2-methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-1- (piperidin-4-yl) -1,4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one.

Ή-NMR (400 MHz, DMSO-d6): δ = 1.08 (d, 3H); 1.50-1.61 (m, 2H); 1.72 (qd, 1H); 1.94 (bd, 1H); 2.54-2.65 (m, 2H); 2.99-3.13 (m + s, 5H); 3.28 (s, 3H); 3.56 (tt, 1H); 3.99 (s, 3H); 4.15 (q, 1H); 6.78 (s, 1H); 7.18 (d, 1H); 7.38 (dd, 1H); 7.83 (s, 1H); 8.19 (s, 1H); 9.11 (d, 1H).

Example 148:

(2A) -l-Benzyl-7 - {[2-methoxy-5- (methylsulfonyl) -phenyl] -amino} -2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one

Eine Mischung aus von 150 mg Intermediat 13, 142 mg 2-Methoxy-5-(methylsulfonyl)anilin (CAS 20945-70-4), 8.7 mg Tris(dibenzylidenaceton)dipalladium(0) (CAS 51364-51-3), 231 mg Caesiumcarbonat und 11 mg Xanthphos (CAS 161265-03-8) in 4 ml Dioxan wurde 19 Stunden unter einer Argonatmosphäre bei 120°C gerührt. Der Ansatz wurde auf Wasser gegeben und zweimal mit Ethylacetat extrahiert. Die organische Phase wurde mit gesättigter

A mixture of 150 mg Intermediate 13, 142 mg 2-methoxy-5- (methylsulfonyl) aniline (CAS 20945-70-4), 8.7 mg tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 231 mg of cesium carbonate and 11 mg of xanthphos (CAS 161265-03-8) in 4 ml of dioxane was stirred for 19 hours under argon atmosphere at 120 ° C. The batch was added to water and extracted twice with ethyl acetate. The organic phase became more saturated

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). There were obtained 34 mg of (2R) -l-benzyl-7- {[2-methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.12 (d, 3H); 3.10 (s, 3H); 3.94 (s, 3H); 4.00 (q, 1H); 4.35 (d, 1H); 4.57 (d, 1H); 6.67 (s, 1H); 7.16 (d, 1H); 7.26-7.34 (m, 1H); 7.34-7.40 (m, 5H); 7.84 (s, 1H); 8.13 (s, 1H); 9.06 (d, 1H).

Example 149:

 3 - {[(2S) -sopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (1-methylpiperidine) 4-yl) benzenesulfonamide

A mixture of 150 mg Intermediate 51, 239 mg Intermediate 28, 54 mg

Tris (dibenzylideneacetone) dipalladium (0) (CAS 51364-51-3), 289 mg of cesium carbonate and 34 mg of xanthphos (CAS 161265-03-8) in 6.4 ml of dioxane was stirred for 9 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 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 (0.2 vol% ammonia) gradient). 75 mg of 3- {[(2, S ^, ) -l-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl were obtained ] amino} - / V- (1-methylpiperidin-4-yl) benzenesulfonamide. ^X H NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.09 (d, 3H); 1.26-1.32 (m, 6H); 1.32-1.46 (m, 2H); 1.50-1.62 (m, 2H); 1.74-1.88 (m, 2H); 2.07 (s, 3H); 2.55-2.66 (m, 2H); 2.84-2.99 (m, 1H); 3.27 (s, 3H); 3.88 (sept, 1H); 4.21 (q, 1H); 6.31 (s, 1H); 7.21 (bd, 1H); 7.39 (t, 1H); 7.60 (d, 1H); 7.76-7.84 (m, 2H); 8.24 (t, 1H); 9.13 (s, 1H).

Optical rotation: [a] _D ²⁰ = 121.2 ° +/- 0.16 ° (c = 9.0 mg / ml, methanol).

Example 150:

 (2S) -Benzyl-2,4-dimethyl-7 - ({3 (4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one

100 mg of 1-benzyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (Example 7) were separated by chiral HPLC (Chiralpak IA 5μιη 250x30 mm, ethanol / methanol / diethylamine 50: 50: 0.1 (v / v)) into the enantiomers. 32 mg (2 _{l of} S) -l-benzyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) -sulfonyl] -phenyl} -amino) -l, 4-dihydropyrido [3 , 4-b] pyrazine-3 (2H) -one and the (R) -enantiomer, see Example 8.

Chiral HPLC: Rt = 7.63 min

Instrument: Waters Alliance 2695; Column: Chiralpak IA 3μιη 100x4.6 mm; Eluent A: ethanol / methanol / 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 151:

 3 - {[(2S) -Benzyl-2,4-dimethyl-3-oxo], 2,3,4-etrahydropyrido [3,4-b] pyrazin-7-yl] amino} -N- (1-methylpiperidine) 4-yl) benzenesulfonamide

110 mg of 3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1 -methylpiperidin-4-yl) benzenesulfonamide (Example 10) were separated by chiral HPLC (Chiralpak ID 5μιη 250x20 mm, acetonitrile / diethylamine 100: 0.1 (v / v)) into the enantiomers. This gave 50 mg of 3- {[(2 _l S) -1-benzyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl ] amino} - / V- (1-methylpiperidin-4-yl) benzenesulfonamide and the (R) -enantiomer, see Example 11.

Chiral HPLC: Rt = 3.05 min

 Instrument: Waters Alliance 2695; Column: Chiralpak ID 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 152:

(2S) -1-cyclopentyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one

130 mg l-Cyclopentyl-2,4-dimethyl-7-({3-[(4-methylpiperazin-l-yl)carbonyl]phenyl }amino)- l,4- dihydropyrido[3,4-b]pyrazin-3(2H)-on (Beispiel 21) wurden durch chirale HPLC (Chiralpak IC 5μηι 250x30 mm, Ethanol/ Methanol / Diethylamin 50:50:0.1 (v/v)) in die Enantiomere getrennt. Man erhielt 46 mg (2_lS)-l-Cyclopentyl-2,4-dimethyl-7-({ 3-[(4-methylpiperazin-l- yl)carbonyl]phenyl}amino)-l,4-dihydropyrido[3,4-b]pyrazin-3(2H)-on sowie das (R)-Enantiomer, siehe dazu auch Beispiel 22..

130 mg of 1-cyclopentyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) - 1, 4 dihydropyrido [3,4-b] pyrazine-3 (2H) -one (Example 21) were converted to the enantiomers by chiral HPLC (Chiralpak IC 5μηι 250x30 mm, ethanol / methanol / diethylamine 50: 50: 0.1 (v / v)) separated. 46 mg (2 _{l of} S) -1-cyclopentyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] -phenyl} -amino) -l, 4-dihydropyrido [3 , 4-b] pyrazine-3 (2H) -one and the (R) -enantiomer, see also Example 22 ..

Chiral HPLC: Rt = 6.37 min

 Instrument: Waters Alliance 2695; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: ethanol / methanol / 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.

Optical rotation: [a] _D ²⁰ = 39.0 ° +/- 0.16 ° (c = 8.0 mg / ml, methanol).

^X H NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.05 (d, 3H); 1.53-1.80 (m, 6H); 1.97-2.09 (m, 2H); 2.20 (s, 3H); 2.24-2.41 (m, 4H); 3.26 (s, 3H); 3.31-3.47 (m, 2H); 3.47-3.69 (m, 2H); 3.79 (qi, 1H); 4.14 (q, 1H); 6.28 (s, 1H); 6.79 (d, 1H); 7.27 (t, 1H); 7.59 (dd, 1H); 7.80 (t, 1H); 8.91 (s, 1H).

Example 153:

(2S) -2,4-dimethyl-7 - ({3 (4-methylpiperazin-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one

380 mg 2,4-Dimethyl-7-({ 3-[(4-methylpiperazin-l-yl)carbonyl]phenyl }amino)-l-(tetrahydro-2H- pyran-4-yl)- l,4-dihydropyrido[3,4-b]pyrazin-3(2H)-on (Beispiel 35) wurden durch chirale HPLC (Chiralpak IC 5μιη 250x40 mm, Ethanol / Methanol / Diethylamin 50:50:0.1 (v/v/v)) in die Enantiomere getrennt. Man erhielt 1 10 mg (2_lS)-2,4-Dimethyl-7-({ 3-[(4-methylpiperazin-l- yl)carbonyl]phenyl } amino)- 1 -(tetrahydro-2H-pyran-4-yl)- 1 ,4-dihydropyrido [3,4-b]pyrazin-3(2H)- on soiwe das (R) -Enantiomere, siehe Beispiel 36. Chirale HPLC: Rt = 9.20 min

380 mg of 2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one (Example 35) were prepared by chiral HPLC (Chiralpak IC 5μιη 250x40 mm, ethanol / methanol / diethylamine 50: 50: 0.1 (v / v / v)) in the Enantiomers separated. This gave 1 10 mg (2 _{l of} S) -2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4 -yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one, the (R) -enantiomer, see Example 36. Chiral HPLC: Rt = 9.20 min

 Instrument: Agilent 1200; Column: Chiralpak IC 3μιη 100x4.6 mm; Eluent: ethanol / methanol / diethylamine 50: 50: 0.1 (v / v / v); Flow 1 ml / min; Temperature: 25 ° C; Injection: 5 μΐ (1 mg / ml ethanol / methanol, 2: 1); DAD 996 scan: 280 nm.

Ή-NMR: (400 MHz, 25 ° C, DMSO-d6): δ = 1.08 (d, 3H); 1.59-1.69 (m, 1H); 1.78 (qd, 1H); 1.84-1.20 (m, 4H); 2.18 (t, 2H); 2.24-2.34 (m, 2H); 2.69 (s, 3H); 3.26 (s, 3H); 3.38-3.51 (m, 2H); 3.71 (tt, 1H); 3.92-4.05 (m, 2H); 4.19 (q, 1H); 6.35 (s, 1H); 6.80 (d, 1H); 7.27 (t, 1H); 7.58 (d, 1H); 7.80 (s, 1H); 7.84 (s, 1H); 8.91 (s, 1H).

Optical rotation: [a] _D ²⁰ = 92.0 ° +/- 0.21 ° (c = 8.0 mg / ml, methanol).

Biological activity of the compounds according to the invention

The following examples describe the biological activity of the compounds according to the invention.

Protein-Protein Interaction Assay: Binding Assay BRD4 / Acetylated Peptide H4 1. Assay Description BRD4 Bromodomain 1 [BRD4 (1)]

To assess the BRD4 (1) binding potency of the substances described in this application, their ability to dose-dependently inhibit the interaction between BRD4 (1) and acetylated histone H4 was quantified. For this purpose, a time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used, demonstrating the binding between N-terminal His6-tagged BRD4 (1) (amino acids 67-152) and a synthetic acetylated histone H4 (acylated histone H4). H4) peptide with sequence

GRGK (Ac) GGK (Ac) GLGK (Ac) GGAK (Ac) RHGSGSK-biotin. 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 / IC50) 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 can be purchased from eg 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 (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 IC50 value was determined by regression analysis based on a 4-parameter equation (minimum, maximum, IC50, Hill, Y = Max + (Min-Max) 1 (1 +

(X / IC50) Hill)). 3. PLK-1 enzyme assay

For the kinase assay, recombinant fusion protein expressed from insect cells (Hi5), purified by glutafion-sepharose affinity chromatography and subsequent gel filtration (Superdex 75), consisting of GST and PLK-1 (kinase domain 33-345, MW 36 kDa, conc 0, 8 μg / μl). Aliquots of this are frozen away in liquid nitrogen and stored at -80 ° C and used only once after thawing.

The assay used was an indirect HTRF assay using the following materials and procedures.

 As a substrate for the kinase reaction, the biotinylated peptide Btn-Ahx-KKLNRTLSFAEPG-amide x TFA, from Biosyntan, sample number: 6178.1 (C-terminus in amide form) is used. This is an artificial sequence that was not derived from any known protein.50 nl of test compounds dissolved in 100% dimethylsulfoxide (DMSO)

(Final concentrations: 0 μΜ and concentrations in the range of 0.001 - 20 μΜ) are mixed with 2 μΐ PLK-1 enzyme working solution in working buffer [25 mM MgC12; ImM DTT; 50 mM Hepes pH 7.0; 0.01% NP40; lx Complete; 0.05% BSA] preincubated for 30 min. The kinase reaction is then started by addition of 3 .mu.ΐ substrate solution [adenosine triphosphates (ATP) and 1.4 .mu.Μ substrate peptide (Biotin-Ttds- KKLNRTLSFAEPG -NH2)] in working buffer, and after 30 min by adding a stop-solution (100 mM EDTA, 100 mM Hepes pH 7.5, 800 mM potassium fluoride, 0.12% BSA, 0.4 μM SA-XLent (0.05 μΜ, from CIS bio international, Marcoule, France), Eu3 + Cryptate-conjugated Rabbit anti Mouse IgG (1.5 nM, a europium cryptate-labeled anti-mouse IgG antibody from CIS bio international, Marcoule, France), 1 nM anti-phospho-serine kinase (a phospho-specific antibody from Upstate Biotechnology, Dundee, Scotland), and incubated at 4 ° C overnight.

 For the experiment with low ATP concentration, a 1.25 ng / μΐ PLK-1 working solution and 16.7 μΜ ATP are used, for the experiment with high ATP concentration, a 0.039 ng / μΐ PLK-1 working solution and 16.7 mM ATP used. Thereafter, the amount of the phosphorylated substrate peptide by measuring the

 Resonance energy transfer from europium-labeled antibody complex to streptavidine-XLent determined. For this purpose, the fluorescence emission at 620 nm and 665 nm after excitation at 350 nm in an HTRF meter, z. Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emissions at 665 nm and at 620 nm is used as a measure of the amount of phosphorylated substrate peptide. The data are normalized (enzyme reaction without inhibitor = 0% inhibition, all others

Assay components, but no enzyme = 100% inhibition), and IC50 values are compared with a 4 Calculated parameter equation (minimum, maximum, IC50, Hill; Y = Max + (Min - Max) 1 (1 + (X / IC50) Hill)).

The compounds according to the invention are distinctly less active, in contrast to very similar compounds of the prior art. References are, for example, 4 - [(1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] -N-cyclopropyl 3-methoxybenzamide (Reference 1: Example 48, US2006 / 0009457) and 4 - [(1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) amino] -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (Reference 2: Example 52, US2006 / 0009457).

4. 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 OVCAR5 cells (ATCC, CRL-9446) were seeded to a concentration of 2000 cells / well in ΙΟΟμΙ growth medium (RPMI with glutamine, 10% FCS) on 96 well microtiter plates. The A2780 cells (ATCC, CRL-9446) were seeded to a concentration of 1000 cells of AVELL in ΙΟΟμΙ growth medium (RPMI 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, OVCAR5, A2780 cells) or 120 (MOLP-8 cells) for hours at 37 ° C. Subsequently, the Fluorescence values 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 IC50 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 2, which exemplify the indicated indications.

Table 2:

 Cell line source indication

 MOLM-13 DSMZ Acute myeloid leukemia

 MOLP-8 DSMZ Multiple Myeloma

 B16F10 ATCC melanoma (BRAF wild type)

 OVCAR5 ATCC ovarian carcinoma

A2780 ECACC ovarian carcinoma

4. Results: 4.1 Binding Assay Table 3 shows the results from the BRD4 (1) binding assay. Table 3:

Example ICso [BRD4 (1)] (nmol / 1)

 1 59

 2 38

 3 291

 4 168

 5 251

 6 72

 7 135

 8 172

 9 633

 10 35

 11 42

 12 47

 13 135

 14 120

 15 173

 16 146

 17 59

 18 22

 19 34

 20 47

 21 106

 22 53

 23 272

24,349 Example ICso [BRD4 (1)] (nmol / 1)

25,367

 26 161

 27,265

 28 108

 29 272

 30 442

 31 484

 32 285

 33 186

 34 216

 35 457

 36,222

 37,540

 38,344

 39,929

 40 568

 41 695

 42 1390

 43 664

 44,295

 45 1200

 46 727

 47 563

 48,801

 49 438

 50 881

 51 532

 52 165

 53,376

 54 1410

 55 682

56 629 Example ICso [BRD4 (1)] (nmol / 1)

57,797

 58 758

 59 347

 60 381

 61 914

 62,350

 63 557

 64 647

 65 690

 66 225

 67 564

 68 1040

 69 160

 70 1550

 71 224

 72 815

 73 299

 74 251

 75 64

 76 230

 77 9060

 78 1020

 79 421

 80,337

 81 391

 82 272

 83 572

 84 265

 85,654

 86 458

 87 136

88 215 Example ICso [BRD4 (1)] (nmol / 1)

89 132

 90 1080

 91 239

 92 349

 93 315

 94 938

 95 233

 96 387

 97 90

 98 476

 99 81

 100 369

 101 329

 102 55

 103 259

 104 667

 105 268

 106 298

 107 77

 108 165

 109,316

 110 531

 111 161

 112 227

 113 313

 114 253

 115,537

 116,300

 117,144

 118 436

 119 990

120 620 Example ICso [BRD4 (1)] (nmol / 1)

121 3000

 122 797

 123 327

 124 272

 125,337

 126 1430

 127 312

 128,584

 129,350

 130 696

 131 1750

 132 438

 133 314

 134 465

 135 187

 136 460

 137 615

 138 130

 139 190

 140 411

 16

 142 2210

 143 223

 144 158

 145 186

 146 346

 147 879

 148 159

 149 4330

 150 3080

 151 262

152 1010 Example ICso [BRD4 (1)] (nmol / 1)

 153 4270

Table 4 shows the results from the BRD4 (2) binding assay. Table 4:

Example ICso [BRD4 (2)] (nmol / 1)

 1 109

 2 115

 3 959

 4,331

 5 61

 6,478

 7 49

 8 52

 9 134

 10 136

 11 47

 12 83

 13 27

 14 140

 15 207

 16 307

 17 74

 18 40

 19 27

 20 89

 21 238

 22 105

 23 46

24 81 Example ICso [BRD4 (2)] (nmol / 1)

25 100

 26 68

 27 54

 28 56

 29 55

 30 80

 31 117

 32 115

 33 62

 34 54

 35 1120

 36 628

 138,336

 141 57

 142 7030

 143 332

 144 208

 145 246

 146 992

 147 2790

 148 47

 149 9670

 150 1260

 151 417

 152 1700

153 14300 Kinase activity assay

Table 5 shows the results of the PLK-1 assay at 10 μΜ ATP for the reference compounds and for selected examples.

Table 5:

IC ₅₀ [PLK-1]

 Example (nmol / Ι, ΙΟ μΜ

 ATP)

 Reference 1 29

 Reference 2 25

 4 9180

 20 963

 22 2110

 23 1490

 24,1300

 25 1380

 26 1880

 27 2890

 28 8300

 29 2850

 30 1900

 31 1120

 32 18600

 33 2300

34 3290 4.2 Cell proliferation assay

Table 6 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.

Example IC50 IC50 IC50 IC50 IC50 IC50

 (MOLM-13) (MOLM-13) (MOLP-8) (B16F10) (OVCAR-5) (A2780) (nmol / l) (nmol / l) (nmol / l) (nmol / l) (nmol / l ) (nmol / 1) Method 1 Method 2

 1 1720

 2 594 893 6190

 3 2330

 4 1670

 5 2610

 6 2130

 8 382

 9 1690

 11 101 73 642

 12 421

 13 458

 14 1160

 15 1090

 16 1210

 17 261 230 1130

 18 163 149 817

 19 497

 20 536 122 1770 419

21 1590

22 892 372> 10000 Example IC50 IC50 IC50 IC50 IC50 IC50

(MOLM-13) (MOLM-13) (MOLP-8) (B16F10) (OVCAR-5) (A2780) (nmol / l) (nmol / l) (nmol / l) (nmol / l) (nmol / l ) (nmol / 1) Method 1 Method 2

 23,838

 24,750

 25 1970

 26 515

 27 1540

 28 641

 29 1020

 30 1080

 31 945

 32 1440

 33,756

 34 1160

 35 6520

 36 1660

 37 7010

 38 8130

 > 10000

 39 4820

 40> 10000

 41 7510

 42 4560

 43 3200

 44> 10000

 45> 10000

 46> 10000

 47 6650

 48 3930

 49 6910

50 7920 Example IC50 IC50 IC50 IC50 IC50 IC50

(MOLM-13) (MOLM-13) (MOLP-8) (B16F10) (OVCAR-5) (A2780) (nmol / l) (nmol / l) (nmol / l) (nmol / l) (nmol / l ) (nmol / 1) Method 1 Method 2

 51 4240

 52 1510

 53 4690

 54> 10000

 55 7160

 56 7250

 57 5860

 58 6460

 59> 10000

 60> 10000

 61 7650

 62> 10000

 63 1120

 64 6040

 65> 10000

 66> 10000

 67> 10000

 68> 10000

 69 1540

 70 3300

 71,741

 72 2030

 73 1030

 74,774

 75 277

 76 2610

 78 1330

 79 4870

80 2420 Example IC50 IC50 IC50 IC50 IC50 IC50

(MOLM-13) (MOLM-13) (MOLP-8) (B16F10) (OVCAR-5) (A2780) (nmol / l) (nmol / l) (nmol / l) (nmol / l) (nmol / l ) (nmol / 1) Method 1 Method 2

 81 1740

 82 3960

 83 2820

 84 1270

 85 6890

 86 3080

 87> 10000

 88 2590

 89 1850

 90 547

 91 1180

 92 1220

 93 1750

 94 2070

 95 126

 96 3670

 97 1610

 98 3320

 99 932

 100 1270

 101 1310

 102 1500

 103 4010

 104 2920

 105 1060

 106 1230

 107 2640

 108 3050

109 3530 Example IC50 IC50 IC50 IC50 IC50 IC50

(MOLM-13) (MOLM-13) (MOLP-8) (B16F10) (OVCAR-5) (A2780) (nmol / l) (nmol / l) (nmol / l) (nmol / l) (nmol / l ) (nmol / 1) Method 1 Method 2

 110 3730

 111 2230

 112 3090

 113 3250

 114 1110

 115 2100

 116 2640

 117 1070

 118 2040

 119 4120

 120 5720

 121> 10000

 122 3240

 123 1550

 124 919

 125 2820

 126 2810

 127 2940

 128 2650

 129 2220

 130 1030

 131 3390

 132 3010

 133 2850

 134 2850

 135 2480

 136,656

 137 3120

138 918 Example IC50 IC50 IC50 IC50 IC50 IC50

(MOLM-13) (MOLM-13) (MOLP-8) (B16F10) (OVCAR-5) (A2780) (nmol / l) (nmol / l) (nmol / l) (nmol / l) (nmol / l ) (nmol / 1) Method 1 Method 2

 139 1410

 140 1910

 143 1360 701

 144 956 488

 145 1050

 146 996

 147 4880

 148 649

 151 1120

Claims

claims 1. Compounds of the general formulas (I) and (Ia)

 and is -NH-, -N (C ₁ -C ₃ -alkyl) - or -O-, represents -N-, -CH- or -CR ² -, represents -N-, -CH- or -CR ² -,  stands for 0, 1 or 2,  for halogen or cyano,  or -C (= 0) NR ⁷ R ^8, -S (= 0) ₂ NR ⁷ R ^8, -S (= 0) ₂ R ^9, -S (= O) (= NR ¹⁰⁾ R ^u, -C (= O) R ⁹ or -NR ¹² R ¹³ ,  or represents phenyl- or 5- to 6-membered monocyclic heteroaryl- which are unsubstituted or monosubstituted, disubstituted 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, halogen-C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, Halo-Ci-C ₄ alkoxy, Ci-C ₄ alkylthio, halo-Ci-C ₄ -Alkylfhio-, -NR ¹² R ^13, -C (= 0) OR ^14, -C (= 0) NR ¹² R ¹³ , -C (= O) R ¹⁴ , -S (= O) ₂ R ¹⁴ or -S (= O) ₂ NR ¹² R ¹³ ,  or  is oxazolin-2-yl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl-, for hydrogen, hydroxyl, halogen, cyano, C ₁ -C 3 -alkyl, C ₂ -C 4 -alkenyl, C ₂ -C ₄ alkynyl, _{halo-Ci-C4-alkyl,} Ci-C ₄ alkoxy, Halo-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 together for a group * -S (= 0) 2-CH 2 -CH 2 - **, * -S (= 0) ₂ -CH ₂ -CH ₂ -CH ₂ - **, * -C (= 0) -CH ₂ -CH ₂ - **, * -C (= O) -CH ₂ -CH ₂ -CH ₂ - **, * -S (= O) ₂ -N (R ¹⁴ ) -CH ₂ - **, * -S (= O) ₂ -N (R ¹⁴ ) -CH ₂ -CH ₂ - **, * -C (= O) -N (R ¹⁴ ) -CH ₂ - ** or * -C (= O) -N (R ¹⁴ ) -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 in which "**" denotes a carbon atom of this ring adjacent to this point of attachment, 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, C 1 -C 3 -alkyl- or 4- to 8-membered heterocycloalkyl-, wherein the 4- turn is unsubstituted to 8-membered heterocycloalkyl or mono- or disubstituted by identical or different substituted with Ci-C3-alkyl or _{Ci-C4-alkoxycarbonyl,} is hydrogen, or represents C 1 -C 6 -alkyl- which is unsubstituted or mono-, di- or tri-aryl, the same or different substituted with hydroxy, oxo, fluoro, cyano, Ci-C ₄ alkoxy, halo-Ci-C ₄ alkoxy, -NR ¹² R ^13, C ₃ -C ₈ cycloalkyl, C4-C8 Cycloalkenyl, 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, Cs-Cn-Spirocycloalkyl-, Cs-CII Heterospirocycloalkyl-, bridged C6-Ci ₂ cycloalkyl, bridged _C6-Ci2 heterocycloalkyl, _C6-Ci2 bicycloalkyl, C6-Ci ₂ -Heterobicycloalkyl-, phenyl or 5- to 6-membered heteroaryl, wherein Cs-Cs-cycloalkyl, C4-C8-cycloalkenyl, 4- to 8-membered heterocycloalkyl, 4- to 8-membered Heterocycloalkenyl, Cs-Cn-spirocycloalkyl, Cs-Cn-heterospirocycloalkyl, bridged C6-Ci ₂ -cycloalkyl, bridged C6-Ci ₂ -heterocycloalkyl-, C6-Ci2-Bicycloalkyl-, C6-Ci2-Heterobicycloalkyl- in turn are unsubstituted or mono- or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, cyano, Ci-C ₃ alkyl, fluoro-Ci-C ₃ Alkyl, C ₃ -C 6 -cycloalkyl, cyclopropylmethyl, C ₁ -C ₃ -alkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl or -NR ¹² R ¹³ , and in which phenyl and 5- to 6-membered heteroaryl unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, trifluoromethyl, Ci-C ₃ alkyl or Ci-C ₃ alkoxy, or is C ₃ -C 6 alkenyl or C ₃ -C 6 alkynyl, or is C ₃ -C ₈ -cycloalkyl, C 4 -C ₈ -cycloalkenyl, Cs-Cn-spirocycloalkyl, bridged C ₆ -C 12 -cycloalkyl or C ₆ -C 12 -cycicycloalkyl- which are unsubstituted or mono- or di-aryl, are substituted identically or differently with: hydroxyl, oxo, cyano, fluorine, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl or -NR ¹² R ¹³ , or for 4- to 8-membered heterocycloalkyl, 4- to 8-membered Heterocycloalkenyl, Cs-Cn-Heterospirocycloalkyl-, bridged Cö-Cn-Heterocycloalkyl- or C0-Cn-Heterobicycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, fluoro, oxo, cyano, Ci C ₃ alkyl, fluoro C ₁ -C ₃ alkyl, C ₃ -C 6 cycloalkyl, cyclopropylmethyl, G-Cs-alkylcarbonyl, Ci-C ₄ -alkoxycarbonyl or -NR ¹² R ¹³ , or is phenyl or 5- to 6-membered heteroaryl which is unsubstituted are mono- or disubstituted 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 , C 1 -C ₄ -alkoxy, halogen-C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkylthio, halogen-C 1 -C ₄ -alkylthio, -NR ¹² R ¹³ , -N (R ¹⁴ ) - S (= 0) ₂ -R ¹⁵ , -N (R ¹⁴ ) -C (= O) -R ¹⁵ 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, or by 2,3-dihydroindenyl, unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, oxo, C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy- or trifluoromethyl-, represents hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxy, oxo or Ci-C ₃ alkoxy-substituted Ci-C ₃ -alkyl-, or fluoro-C ₁ -C ₃ -alkyl- stands, or together with the nitrogen atom to which they are attached, for 4- to 8-membered heterocycloalkyl, 4- to 8-membered Heterocycloalkenyl, Cs-Cn heterospirocycloalkyl, bridged _C6-Ci2 heterocycloalkyl or C6-Ci ₂ are -Heterobicycloalkyl- which are unsubstituted or mono- or Ci-C are disubstituted by identical or different substituents selected from hydroxy, fluoro, oxo, cyano, ₃ alkyl, Fluoro-C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, cyclopropylmethyl-, C ₁ -C ₃ -acylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, -S (= O) ₂ R ¹⁵ , -NR ¹² R ¹³ or unsubstituted or monosubstituted with C ₁ -C ₃ -alkyl  5- to 6-membered heterocycloalkyl, in which C ₁ -C ₃ -alkyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, cyano, oxo, hydroxy, C ₁ -C ₃ -alkoxy- or -NR ¹² R ¹³ , 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 heterocycloalkyl, in which phenyl is in turn unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by halogen, cyano, C ₁ -C -alkyl-, C ₂ -C -alkenyl-, C ₂ -C -alkynyl-, C ₁ -C 4 -alkyl, C is 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 once or twice, the same or are variously substituted by Ci-C3-alkyl,  or  represents halogeno-C 1 -C 4 -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 or sulfonyl group in R ¹ , is cyano, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl or -C (= O) OR ¹⁴ , represents C ₁ -C ₆ -alkyl or C ₃ -C ₈ -cycloalkyl-,  independently of one another for hydrogen or for unsubstituted or mono- or disubstituted, identical or different with hydroxy, oxo or  Ci-C3-alkoxy-substituted Ci-C3-alkyl, or fluoro-C-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  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, fluoro-C ₁ -C ₃ -alkyl, C ₃ -C 6 -cycloalkyl-, Cyclopropylmethyl, C 1 -C 3 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl, represents hydrogen, C 1 -C 6 -alkyl- or phenyl-C 1 -C 3 -alkyl-, and represents C 1 -C 6 -alkyl-, C ₃ - C ₈ -cycloalkyl- or phenyl-C ₁ -C ₃ -alkyl-, and their racemates, diastereomers, (R) -enantiomers and isomeric mixtures in which outweighs the (R) -form, and their polymorphs and physiologically acceptable salts. 2. Compounds of the general formulas (I) and (Ia), 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} -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ , -S (= O) ₂ R ⁹ , -C (= O) R ⁹ or -NR ¹² R ¹³ stands,  or is phenyl or 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 ¹² R ¹³ , or  is oxazolin-2-yl- which is unsubstituted or monosubstituted or disubstituted by methyl, R ^{2 is} hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, ethyl, methoxy or ethoxy, and if n is 2, R ² may be the same or different,  or R ¹ and R ² together represent a group * -S (= O) ₂ -CH ₂ -CH ₂ - **, * -S (= 0) ₂ -CH ₂ -CH ₂ -CH ₂ - **, * -S (= 0) ₂ -N (H) -CH ₂ - **, * -S (= 0) ₂ - N (H) -CH ₂ -CH ₂ - **, * -C (= O) -N (H) -CH ₂ - ** or * -C (= O) -N (H) -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 "**" is adjacent to this point of attachment Carbon atom of this ring means 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  or  is methyl or ethyl which are monosubstituted with C ₁ -C ₃ -alkoxy, phenyl or 4 to 8-membered heterocycloalkyl-,  in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, Bromine, cyano, C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy-, and wherein the 4- to 8-membered heterocycloalkyl in turn is unsubstituted or monosubstituted 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 or methyl, stands for hydrogen, or is Ci-Cö-alkyl- which is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents with hydroxy, oxo, fluoro, cyano, C ₁ -C ₃ -alkoxy, fluoro-Ci-C ₃ Alkoxy, -NR ¹² R ¹³ , C ₃ -C ₈ cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl-, wherein Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently with hydroxy, oxo, cyano, Ci-C3-alkyl, fluoro-Ci-C ₃ Alkyl, cyclopropyl, cyclopropylmethyl, acetyl or ieri-butoxycarbonyl, and  wherein phenyl and 5- to 6-membered heteroaryl are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy, or stands for Cs-Coe-cycloalkyl, which is unsubstituted or mono- or disubstituted by identical or different substituted with hydroxy, oxo, cyano, fluoro, -NR ¹² R ^13, or ₂ heterocycloalkyl or C6-Ci ₂ is -Heterobicycloalkyl- for 4- to 8-membered heterocycloalkyl, Cs-Cn-Heterospirocycloalkyl-, bridged C6-C, which are unsusbstituiert or mono- or disubstituted by identical or different substituents Hydroxy, oxo, C ₁ -C ₃ -alkyl, Fluoro-C 1 -C 3 -alkyl, cyclopropyl, cyclopropylmethyl, acetyl or ieri-butoxycarbonyl, or is phenyl or 5- to 6-membered heteroaryl which is unsubstituted are monosubstituted or disubstituted by identical or different substituents Halogen, cyano, C ₁ -C ₃ -alkyl, fluorine-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-, Fluoro-Ci-Cs-alkoxy, Ci-Cs-alkylfhio, fluoro-Ci-C ₃ -alkylthio, -NR ¹² R ¹³ , -N (H) -S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ , or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, Oxo, methyl, methoxy or trifluoromethyl, is hydrogen or C 1 -C 3 -alkyl-, or together with the nitrogen atom to which they are attached, for 4- to 8-membered heterocycloalkyl, Cs-Cn-heterospirocycloalkyl, bridged C6-Ci2-heterocycloalkyl or C6-Ci2-Heterobicycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, fluorine , Oxo, Cyano, Ci-C ₃ alkyl, fluoro-Ci-C ₃ alkyl, C ₃ -C ₆ cycloalkyl, cyclopropylmethyl, _{Ci-C3-alkylcarbonyl, Ci-C4-alkoxycarbonyl,} -S (= 0) ₂ R ¹⁵ , -NR ¹² R ¹³ or unsubstituted or monosubstituted with Ci-C ₃ alkyl  5- to 6-membered heterocycloalkyl, wherein C ₁ -C ₃ -alkyl, in turn, is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents with fluoro, cyano, oxo, hydroxy, methoxy or -NR ¹² R ¹³ , 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 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 C ₃ -C 8 -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-, with the proviso that the 4- to 8-membered heterocycloalkyl does not have a Nitrogen atom is bonded to the carbonyl or sulfonyl group in R ¹ , R ¹² and R ^{13 are} independently of each other 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 R ¹² and R ¹³ 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, Ci-C ₃ alkyl, fluoro-Ci-C ₃ alkyl, cyclopropyl -  Cyclopropylmethyl, acetyl or ieri-butoxycarbonyl, and R ^{15 is} C 1 -C ₄ -alkyl-, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which outweighs the (R) -form, and their polymorphs and physiologically acceptable salts. 3. Compounds of general formulas (I) and (Ia), according to claims 1 and 2, in which  A stands for -NH-,  X stands for -CH-,  Y stands for -CH-,  n is 0 or 1, R ^{1 is} -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ or -S (= O) ₂ R ⁹ ,  or  is phenyl- or oxazolyl- or oxadiazolyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with d-Cs-alkyl-, R ^{2 is} hydrogen, fluorine, chlorine, methyl or methoxy,  or R ¹ and R ² together represent a group * -S (= O) 2-N (H) -CH 2 - ** or * -C (= O) -N (H) -CH 2 - ** wherein "*" represents the point of attachment of R ¹ to the phenyl ring to which R ^{1 is} attached, and wherein "**" is a means adjacent to this point of attachment carbon atom of this ring, stands for methyl, represents methyl or ethyl, stands for hydrogen, represents 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 mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, and  wherein the 4- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by methyl, or is C3-C8-cycloalkyl or 4- to 6-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 which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl, stands for hydrogen, or is C 1 -C 6 -alkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, C 1 -C 3 -alkoxy-, -NR ¹² R ¹³ , Cs-C 6 -cycloalkyl-, to 6-membered heterocycloalkyl or phenyl,  in which C 3 -C 6 -cycloalkyl and 4- to 6-membered heterocycloalkyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, C 1 -C 3 -alkyl, trifluoromethyl, acetyl or trimeric Butoxycarbonyl, and  wherein phenyl is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, or is Cs-Cö-cycloalkyl-, which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, -NR ¹² R ¹³ , or is 4- to 6-membered heterocycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, Ci-C3-alkyl, trifluoromethyl, acetyl or ieri-butoxycarbonyl-, or represents phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, C 1 -C 3 -alkyl-, trifluoromethyl-, C 1 -C 3 -alkoxy , Trifluoromethoxy, -NR ¹² R ¹³ , -N (H) -S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ , or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted by fluorine, chlorine, oxo or methyl, is hydrogen or C 1 -C 3 -alkyl-, or together with the nitrogen atom to which they are attached, for 4- to 8-membered heterocycloalkyl, Cö-Cio-Heterospirocycloalkyl- or bridged Cö-Cio-Heterocycloalkyl- stand, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with oxo, G-Cs-alkyl, fluoro -Ci-C ₃ alkyl, cyclopropyl, Ci-C ₃ alkylcarbonyl, Ci-C t-alkoxycarbonyl, -S (= 0) 2R ¹⁵ , -NR ¹² R ¹³ or unsubstituted or simply with Ci-C3 Alkyl substituted piperidinyl,  wherein Ci-C3-alkyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with oxo or -NR ¹² R ¹³ , 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 Ci-C3-alkyl, or is trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl, or represents Cs-C6-cycloalkyl-, independently of one another are hydrogen or C 1 -C 3 -alkyl-, or together with the nitrogen atom to which they are attached, for 5- to 6-membered heterocycloalkyl- which is unsubstituted or or doubly, identically or differently substituted with oxo, C ₁ -C ₃ -alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or ieri-butoxycarbonyl, and R ^{15 is} C ₁ -C ₃ -alkyl-, and their racemates , Diastereomers, (R) -enantiomers and mixtures of isomers in which the (R) -form predominates, as well as their polymorphs and physiologically acceptable salts. 4. Compounds of general formulas (I) and (Ia), according to claims 1 to 3, in which  A stands for -NH-,  X stands for -CH-,  Y stands for -CH-,  n is 0 or 1, R ^{1 represents} -C (= O) NR ⁷ R ⁸ , -S (= O) ₂ NR ⁷ R ⁸ or represents -S (= O) ₂ R ⁹ , R ^{2 is} hydrogen, methyl or methoxy, R ^{3 is} methyl, R ^{4 is} methyl, R ⁵ represents hydrogen, R ^{6 is} isopropyl,  or  stands for benzyl,  or  represents cyclopentyl,  or  represents tetrahydropyranyl,  or is piperidinyl which is unsubstituted or monosubstituted with ieri-butoxycarbonyl-, R ^{7 is} C ₁ -C ₃ -alkyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, methoxy, -NR ¹² R ¹³ , cyclopropyl or phenyl,  wherein phenyl is unsubstituted or monosubstituted by identical or different substituents with methyl,  or is cyclopropyl or cyclohexyl, wherein cyclohexyl is unsubstituted or monosubstituted with -NR ¹² R ¹³ ,  or  are piperidinyl or Azetidinyl- which are unsubstituted or monosubstituted with oxo, methyl, acetyl or ieri-butoxycarbonyl, or is phenyl, pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, pyridinyl or pyridazinyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with cyano, methyl, methoxy, -N (H -S-S (= O) ₂ -R ¹⁵ or -N (H) -C (= O) -R ¹⁵ ,  or for 2,3-dihydroindenyl which is unsubstituted or monosubstituted with oxo, R ^{8 is} hydrogen or methyl,  or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, for Pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, 2-oxa-6-azaspiro [3.3] heptyl or 3-oxa-8-azabicyclo [3.2.1] octyl; are unsubstituted or monosubstituted with methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl, -NR ¹² R ¹³ , N-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-1-yl) ethyl, R ^{9 is} Ci-Cs-alkyl-,  or  represents cyclopropyl, R ¹² and R ¹³ independently of one another represent hydrogen or methyl,  or R ¹² and R ¹³ together with the nitrogen atom to which they are attached, for  Pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl or piperazinyl, which are unsubstituted or monosubstituted by oxo, methyl or cyclopropylmethyl, R ^{15 is} methyl, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which outweighs the (R) -form, and their polymorphs and physiologically acceptable salts. Lenten of the general formulas (I) and (Ia), according to claims 1 to 4, in stands for -NH-,  X stands for -CH-, Y stands for -CH-, n is 0 or 1, R ^{1 represents} -C (= O) NR ⁷ R ⁸ , -S (= O): NR ⁷ R ⁸ or represents -S (= O) ₂ R ⁹ , R ^{2 is} hydrogen or methoxy, R ^{3 is} methyl, R ^{4 is} methyl, R ⁵ represents hydrogen, R ^{6 is} isopropyl,  or  stands for benzyl,  or  represents cyclopentyl,  or  represents tetrahydropyran-4-yl-,  or  represents piperidin-4-yl-,  or for

 stands, where "*" is the point of attachment to the rest of the molecule, R ⁷ for

5

where "*" is the point of attachment to the rest of the molecule, is hydrogen or methyl,  or  together with the nitrogen atom to which they are attached, for

where "*" represents the point of attachment to the rest of the molecule, R ^{9 is} methyl, isopropyl or cyclopropyl, and R ^{16 is} methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl,  Methylsulf onyl- / V-methylpiperidin-4-yl or 2-oxo-2- (pyrrolidin-l-yl) ethyl-, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers in which the (R ) Form predominates, as well as their polymorphs and physiologically acceptable salts. 6. Compounds of the general formulas (I) and (Ia), according to claim 1: 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1-methylpiperidin-4-yl) benzenesulfonamide; 3- {[(2R) -2,4-Dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine 7-yl] amino} -N- (1-methylpiperidin-4-yl) benzenesulfonamide; 2,4-Dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one; 2,4-Dimethyl-1- (tetrahydro-2H-pyran-4-yl) -7- [(3- {[4- (2,2,2-trifluoroethyl) -piperazin-1-yl] -sulfonyl} -phenyl) -amino ] -l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one; A ⁱ - [2- (dimethylamino) ethyl] -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [ 3,4-b] pyrazine-7-yl] amino} benzenesulfonamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide; 1-Benzyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) -sulfonyl] -phenyl} -amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; (2R) -1-Benzyl-2,4-dimethyl-7- ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one; 1-benzyl-2,4-dimethyl-7- [(3- {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] sulfonyl} phenyl) amino] -l, 4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methylpiperidine benzenesulfonamide -4-yl); 3- {[(2R) -1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- ( 1-methylpiperidin-4-yl) benzenesulfonamide; 4- {[2,4-Dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] - / V- [2- (2- dimethylamino) ethyl] benzenesulfonamide; / V- [2- (dimethylamino) ethyl] -3- {[2,4-dimethyl-3-oxo-1- (propan-2-yl) -l, 2,3,4-tetrahydropyrido [3,4- b] pyrazine-7-yl] amino} benzenesulfonamide; 2,4-dimethyl-1 - (propan-2-yl) -7- [(3- {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] sulfonyl} phenyl) amino] - 1, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one; 2,4-Dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1- (propan-2-yl) -1: 4 dihydropyrido [3,4-b] pyrazin-3 (2H) -one; 3- {[2,4-dimethyl-3-oxo-1- (propan-2-yl) -1,3,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N - (1-methylpiperidin-4-yl) benzenesulfonamide; 3- {[(2R) -2,4-Dimethyl-3-oxo-1- (propan-2-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1-methylpiperidin-4-yl) benzenesulfonamide; 3- {[2,4-dimethyl-3-oxo-1- (propan-2-yl) -1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [2- (4-methylpiperazin-1-yl) ethyl] benzenesulfonamide; (2R) -1-cyclopentyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine 3 (2H) -one; 1-cyclopentyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; (2R) -1-cyclopentyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino ^' l, 4-dihydropyrido [3,4-b] pyrazine 3 (2H) -one; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V -cyclopropylbenzamide; 1-Benzyl-2,4-dimethyl-7- ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methylpiperidine benzamide -4-yl); 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] - / V- {cis-4 - [4- (cyclopropylmethyl) piperazine-1-yl] cyclohexylbenzamide; 1-Benzyl-2,4-dimethyl-7- {[3- (2-oxa-6-azaspiro [3.3] hept-6-ylcarbonyl) -phenyl] -amino} -l, 4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one; 1-Benzyl-2,4-dimethyl-7- {[3- (8-oxa-3-azabicyclo [3.2.1] oct-3-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b ] pyrazin-3 (2H) -one; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-l, 23,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- [2- (dimethylamino) ethyl] benzamide; / V- (1-acetylpiperidin-4-yl) -3 - [(1-benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7 -yl) amino] benzamide; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (cyclopropylmethyl) benzamide ; 1-Benzyl-2,4-dimethyl-7- [(3- {[4- (2,2,2-trifluoroethyl) piperazin-1-yl] carbonyl} phenyl) -amino] -l, 4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl) -amino] - / V- [2- (2- 4-methylpiperazin-1-yl) ethyl] benzamide; 3 - [(1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methylazetidine -3-yl) benzamide; 2,4-Dimethyl-7- ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one; (2R) -2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1, 4 -dihydropyrido [3,4-b] pyrazin-3 (2H) -one; 3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (l-methyl-lH-pyrazol-3-yl) benzamide; 2,4-Dimethyl-7- [(3- {[4- (1-methylpiperidin-4-yl) piperazine-1-yl] carbonyl] -phenyl) -amino] -1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one; N- (3-cyanophenyl) -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4- b] pyrazine-7-yl] amino} benzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (2-hydroxyethyl) -N-methylbenzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V-ethylbenzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (3-methoxyphenyl) benzamide; 2,4-Dimethyl-7 - ({3 - [(3-methylpiperidin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one; 2,4-Dimethyl-7- [(3- {[4- (methylsulfonyl) piperazine-1-yl] carbonyl] -phenyl) -amino] -1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one; N- [3- (dimethylamino) propyl] -3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3 , 4-b] pyrazin-7-yl] amino} benzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] benzamide / V- (lH-pyrazol-3-yl) - amino}; 7 - ({3 - [(4-acetylpiperazin-1-yl) carbonyl] phenyl} amino) -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one; 3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (4-methoxyphenyl) benzamide; A ^r - [2- (dimethylamino) -2-oxoethyl] -3- {[2,4-dimethyl-3-oxo-l- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4- tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} - / V-methylbenzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (pyridazin-4-yl) benzamide; 3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V-methyl- / V- (3-methylbenzyl) -benzamide; Methyl 4- (3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydropyrido [3,4-b] pyrazine -7-yl] amino} benzoyl) piperazine-l-carboxylate; N- [3- (dimethylamino) propyl] -3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl) - l, 2,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V-methylbenzamide; N- [2- (dimethylamino) ethyl] -3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3 , 4-b] pyrazine-7-yl] aminobenzamide; 2,4-dimethyl-7 - ({3 - [(4-methyl-1,4-diazepan-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -l , 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; 3- {[2,4-Dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl ] amino} -N- (pyridin-4-yl) benzamide; 7- ({3- [(4-Ethylpiperazin-1-yl) carbonyl] phenyl} amino) -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3 , 4-b] pyrazin-3 (2H) -one; 3- {[2,4-Dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl ] amino} -N- (3-methoxypropyl) benzamide; 3- {[2,4-Dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl ] amino} -N- (1,3-oxazol-2-yl) -benzamide; 2,4-dimethyl-7- {[3- ({4- [2-oxo-2- (pyrrolidin-1-yl) -ethyl] -piperazin-1-yl} -carbonyl) -phenyl] -amino} -1- (tetrahydrofuran) 2H-pyran-4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; 3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [3- (pyrrolidin-l-yl) propyl] benzamide; 3- {[2,4-Dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl ] amino} - N - {3 - [(methylsulfonyl) amino] phenyl} benzamide; 3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (l-oxo-2,3-dihydro-lH-inden-5-yl) benzamide; / V- (4-acetamidophenyl) -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydropyrido [3, 4 -b] pyrazine-7-yl] amino-jbenzamide; 3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4- b] pyrazine-7-yl] amino} -N- (1-methyl-1H-pyrazol-5-yl) -benzamide; 3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (l, 2-oxazol-3-yl) benzamide; 3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [2- (2-oxoimidazolidin-l-yl) ethyl] benzamide; 3- {[2,4-dimethyl-3-oxo-1 - (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] benzamide / V- (lH-imidazol-2-yl) - amino}; 1-cyclopentyl-2,4-dimethyl-7- {[3- (morpholin-4-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; / V- (3-cyanophenyl) -3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzamid; 7 - ({3 - [(4-Acetylpiperazin-1-yl) carbonyl] phenyl} amino) -1-cyclopentyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (3-methoxyphenyl ) benzamide; 3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1-methyl- 1H-pyrazol-5-yl) benzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (3-methoxypropyl ) benzamide; Methyl 4- (3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} benzoyl) piperazine - 1-carboxylate; 1-Isopropyl-2,4-dimethyl-7- {[3- (morpholin-4-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; A ^r - (4-cyanophenyl) -3- {[1-isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzamid; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} - / V- (4-methoxyphenyl ) benzamide; N- (cyclopropylmethyl) -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] aminobenzamide; 1-Isopropyl-2,4-dimethyl-7- ({3- [(4-methyl-1,4-diazepan-1-yl) carbonyl] -phenyl} -amino) -l, 4-dihydropyrido [3,4-b ] pyrazin-3 (2H) -one; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} - / V- (3-methoxypropyl ) benzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [2- (2 oxoimidazolidin-1-yl) ethyl] benzamide; 3 - [(1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V-methyl- / V - (3-methylbenzyl) benzamide; 3 - [(1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl) amino] - / V- (1-methyl -lH-pyrazol-3-yl) benzamide; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} -N- (1H-pyrazole 3-yl) benzamide; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - N- [3- (pyrrolidine - 1 -yl) propyl] benzamide; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} - - [2- (2- oxoimidazolidin-1-yl) ethyl] benzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [2- (dimethylamino ) ethyl] - / V-methylbenzamide; 3- {[1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] py] yl] amino} - / V- (2-methoxyethyl) benzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (4-methoxyphenyl ) benzamide; 1-cyclopentyl-2,4-dimethyl-7- ({3- [(3-methylpiperidino-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; 7- ({3- [(4-acetylpiperazine-1-yl) carbonyl] phenyl} amino) -1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; / V- (4-acetamidophenyl) -3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzamid; N- [2- (dimethylamino) ethyl] -3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl ] amino Jbenzamide; Methyl 4- (3- {[l-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} benzoyl) -piperazine - 1-carboxylate; 3- {[1-isopropyl-2,4-dimethyl-3-oxo-1, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-7-yl] amino} - A ^r - (l, 3 -oxazol-2-yl) benzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (2-hydroxyethyl ) - / V-methylbenzamide; 3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1H-pyrazole) 3-yl) benzamide; 1-cyclopentyl-2,4-dimethyl-7- {[3- ({4- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -piperazin-1-yl} carbonyl) -phenyl] -amino} -1 , 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [3- ( dimethylamino) propyl] benzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [3- ( pyrrolidin-l-yl) propyl] benzamide; 1-cyclopentyl-2,4-dimethyl-7- [(3- {[4- (methylsulfonyl) -piperazin-1-yl] carbonyl] -phenyl) amino] - 1, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; 1-isopropyl-2,4-dimethyl-7- {[3- ({4- [2-oxo-2- (pyrrolidin-1-yl) -ethyl] -piperazin-1-yl} -carbonyl) -phenyl] -amino} -l , 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one; 1-isopropyl-2,4-dimethyl-7- [(3- {[4- (1-methylpiperidin-4-yl) piperazin-1-yl] carbonyl} phenyl) amino] -l, 4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one; 3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - ethylbenzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [3- (dimethylamino ) propyl] - methylbenzamide; 1-cyclopentyl-2,4-dimethyl-7- {[3- (pyrrolidin-1-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; 3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- (1, 3) oxazol-2-yl) benzamide; / V- (2-Hydroxyethyl) -3- {[1-isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] -amino } - / V-methylbenzamide; A ^r - [3- (dimethylamino) propyl] -3- {[l-isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7 yl] amino jbenzamide; A ^r - [3- (dimethylamino) propyl] -3- {[l-isopropyl-2,4-dimethyl-3-oxo-l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine-7 yl] amino J -methylbenzamide; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazino-7-yl] amino} A ^r - (pyridazine-4-) yl) benzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (cyclopropylmethyl) -benzamide ; / V- (4-acetamidophenyl) -3- {[1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzamid; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [2- (dimethylamino ) ethyl] benzamide; 1-Cyclopentyl-7- ({3 - [(4-ethylpiperazin-1-yl) carbonyl] phenyl} amino) -2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- [2- (dimethylamino ) -2-oxoethyl] - / V-methylbenzamide; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (1-methyl benzamide -lH-pyrazol-5-yl); 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- {3- [ (methylsulfonyl) amino] phenyl} benzamide; 2,4-Dimethyl-7- {[3- (morpholin-4-ylcarbonyl) phenyl] amino} -1- (tetrahydro-2H-pyran-4-yl) -1,4-dihydropyrido [3,4-b] pyrazin-3 (2H) -one; / V- (4-cyanophenyl) -3- {[2,4-dimethyl-3-oxo-1- (tetrahydro-2H-pyran-4-yl) -l, 2,3,4-tetrahydropyrido [3, 4 -b] pyrazine-7-yl] amino-jbenzamide; 3- {[l-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- {3- [( methylsulfonyl) amino] phenyl Jbenzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (pyridazine-4 -yl) benzamide; 1-cyclopentyl-2,4-dimethyl-7- [(3- {[4- (1-methylpiperidin-4-yl) piperazin-1-yl] carbonyl} phenyl) amino] -l, 4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one; 1-Isopropyl-2,4-dimethyl-7- ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino} - / V- (3-methoxyphenyl) benzamide; 1-isopropyl-2,4-dimethyl-7- {[3- (pyrrolidin-1-ylcarbonyl) -phenyl] -amino} -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (1-methyl -lH-pyrazol-3-yl) benzamide; 1-Isopropyl-2,4-dimethyl-7 - [(3- {[4- (methylsulfonyl) piperazin-1-yl] carbonyl} phenyl) amino] -1,4-dihydropyrido [3,4-b] pyrazine 3 (2H) -one; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (1-oxo benzamide -2,3-dihydro-lH-inden-5-yl); A ^r - (3-Cyanophenyl) -3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino Jbenzamid; / V-ethyl-3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino-jbenzamide; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- (pyridine-4 -yl) benzamide; 7- ({3- [(4-Ethylpiperazin-1-yl) carbonyl] phenyl} amino) -1-isopropyl-2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; / V- [2- (dimethylamino) -2-oxoethyl] -3- {[1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine -7-yl] amino} - / V-methylbenzamide; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazin-7-yl] amino} - N- (1-oxo) 2, 3-dihydro-1H-inden-5-yl) benzamide; 3- {[1-Isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V-methyl- / V - (3-methylbenzyl) -benzamide; 3- {[l-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} - / V- [3- ( morpholin-4-yl) propyl] benzamide; 1-cyclopentyl-2,4-dimethyl-7- ({3- [(4-methyl-1,4-diazepan-1-yl) carbonyl] phenyl} amino) - l, 4-dihydro-pyrido [3,4-b] pyrazin-3 (2H) -one; 1-Isopropyl-2,4-dimethyl-7- ({3 - [(3-methylpiperidin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine-3 (2H ) -one; 3- {[(2R) -1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- ( 1-methylpiperidin-4-yl) benzenesulfonamide; 3- {[(2 _L S) -1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N - (1-methylpiperidin-4-yl) benzenesulfonamide; (2R) -7- {[2-methoxy-5- (morpholin-4-ylsulfonyl) phenyl] amino} -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4- dihydropyrido [3,4-b] pyrazin-3 (2H) -one; (2R) -7- {[5- (isopropylsulfonyl) -2-methoxyphenyl] amino} -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3, 4-b] pyrazin-3 (2H) -one; (2R) -7- {[5- (Cyclopropylsulfonyl) -2-methoxyphenyl] amino} -2,4-dimethyl-1- (tetrahydro-2H-pyran-4-yl) -l, 4-dihydropyrido [3,4 -b] pyrazin-3 (2H) -one; ieri-butyl-4- [7- {[2-methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-3-oxo-3,4-dihydropyrido [3,4-b] pyrazine-1 (2H) -yl] piperidine-1-carboxylate; 7- {[2-Methoxy-5- (methylsulfonyl) phenyl] amino} -2,4-dimethyl-1- (piperidin-4-yl) -1,4-dihydropyrido [3,4-b] pyrazine-3 ( 2H) -one; (2R) -1-Benzyl-7- {[2-methoxy-5 - (methylsulfonyl) phenyl] amino} -2,4-dimethyl-1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one; 3- {[(2 _L S) -1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N - (1-methylpiperidin-4-yl) benzenesulfonamide; (2 _{l of} S) -l-benzyl-2,4-dimethyl-7 - ({3 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b ] pyrazin-3 (2H) -one; 3- {[(2S) -1-Benzyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino} -N- ( 1-methylpiperidin-4-yl) benzenesulfonamide; (25) - 1-Cyclopentyl-2,4-dimethyl-7 - ({3- [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1,4-dihydropyrido [3,4-b] pyrazine -3 (2H) -one and (25) -2,4-Dimethyl-7- ({3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} amino) -1- (tetrahydro-2H-pyran-4-yl) -l, 4 -dihydropyrido [3,4-b] pyrazine-3 (2H) -one, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which outweighs the (R) -form, and their polymorphs and physiologically acceptable salts. 7. Use of the compounds according to claims 1 to 6 as a medicament. 8. 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. Compounds according to claims 1 to 6 in combination with one or more further pharmacologically active substances. Compounds in combination according to Claim 14, for the prophylaxis and / or therapy of hyperproliferative disorders. 16. Compounds in combination according to claim 14, for the prophylaxis and / or therapy of tumor diseases. 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.