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WO2015193229A1 - 1,4-dihydropyrido[3,4-b]pyrazinones inhibitrices de protéine bet, à groupe éther ou amino aromatique meta-substitué - Google Patents

1,4-dihydropyrido[3,4-b]pyrazinones inhibitrices de protéine bet, à groupe éther ou amino aromatique meta-substitué Download PDF

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Publication number
WO2015193229A1
WO2015193229A1 PCT/EP2015/063305 EP2015063305W WO2015193229A1 WO 2015193229 A1 WO2015193229 A1 WO 2015193229A1 EP 2015063305 W EP2015063305 W EP 2015063305W WO 2015193229 A1 WO2015193229 A1 WO 2015193229A1
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Prior art keywords
amino
dimethyl
oxo
pyrazine
alkyl
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English (en)
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Norbert Schmees
Bernard Haendler
Detlef Stoeckigt
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Bayer Pharma AG
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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 ).
  • bromodomains can recognize additional acetylated proteins.
  • BRD4 binds to RelA, resulting in the stimulation of NF- ⁇ B and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell. Biol., 2009, 29: 1375-1387).
  • 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).
  • 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.
  • 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).
  • BRD4 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 ).
  • 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 results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet, Cytogenet., 2010, 203: 16 -20).
  • the fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 2011, 286: 27663-27675).
  • the growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073).
  • BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, 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.
  • 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).
  • 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).
  • BRD4 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).
  • BRD4 regulates a number of genes involved in inflammation.
  • Macrophages prevent a BRD4 inhibitor from expression of inflammatory genes, such as IL-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1119-1123).
  • 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
  • HDL Higher density lipoprotein
  • 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
  • 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.
  • 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.
  • 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
  • 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-
  • 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).
  • WO2011 / 054845 GaxoSmithKline
  • further benzodiazepines are described as BRD4 inhibitors.
  • Applicant's application WO 2015/011084 discloses dihydropyridopyazinone derivatives as dual inhibitors of BRD4 and polo-like kinase-1 (PLK-1).
  • 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.
  • WO 2006/005510 or US2006 / 0009457 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 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
  • 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.
  • PARP poly-ADP-ribose polymerase
  • 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.
  • WO 2006/050054, WO 2007/134169 and US 2009/0264384 describe a number of bicyclic chemotypes as inhibitors of tumor necrosis factor alpha (TNF- ⁇ ) as well as of various isoforms of phosphodiesterase for the treatment of inter alia inflammatory diseases.
  • TNF- ⁇ tumor necrosis factor alpha
  • WO 2012/088314 discloses a series of bicyclic chemotypes as modulators of pyruvate kinase M2.
  • WO 2003/020722 and WO 2004/076454 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 Choroma Therapeutics
  • WO 2009/071480 Neviano Medical Sciences
  • WO 2006/021378, WO 2006/021379 and WO 2006 / 021548 disclose further 7,8-dihydropteridine-6 (5H) -one derivatives as inhibitors of PLK-1
  • 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 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.
  • 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 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.
  • 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 0, 1 or 2
  • R 2 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,
  • Ci-Cö-alkyl- which is unsubstituted or monosubstituted with Ci-C 3 alkoxy, phenyl, Cs-Cs-cycloalkyl or 4- to 8-membered
  • phenyl 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
  • 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,
  • Ci-C3-alkyl or 4- to 8-membered heterocycloalkyl are Ci-C3-alkyl or 4- to 8-membered heterocycloalkyl
  • 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-,
  • 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-,
  • 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,
  • 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
  • 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 ,
  • 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,
  • 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-,
  • Ci-C 3 alkoxy-substituted Ci-C 3 -alkyl- 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,
  • 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
  • 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
  • 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-,
  • 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 ,
  • R 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,
  • A is -NH- or -N (methyl) -
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0, 1 or 2
  • 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 ,
  • R 2 is hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, ethyl, methoxy or
  • R 2 may be the same or different, or
  • 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
  • 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
  • phenyl or 5- to 6-membered heteroaryl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,
  • 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
  • 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-,
  • 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,
  • 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
  • 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,
  • 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,
  • C 1 -C 3 -alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents with fluoro, cyano, oxo, hydroxy, methoxy or -NR 12 R 13 ,
  • 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
  • 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
  • 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
  • Ci-C3-alkyl Hydroxy or oxo substituted Ci-C3-alkyl or 5- to 6-membered
  • 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.
  • Y stands for -CH-
  • n 0 or 1
  • R 2 is hydrogen, fluorine, chlorine, methyl or methoxy
  • R 3 is methyl, represents methyl or ethyl
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, and
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,
  • 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,
  • 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
  • phenyl is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, or
  • 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 is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • A stands for -NH-
  • Y stands for -CH-
  • n 0 or 1
  • R 2 is hydrogen, methyl or methoxy
  • R 3 is methyl
  • R 4 is methyl
  • R 5 represents hydrogen
  • R 6 is isopropyl
  • 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,
  • cyclohexyl is unsubstituted or monosubstituted with
  • 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,
  • A stands for -NH-
  • Y stands for -CH-
  • n 0 or 1
  • R 2 is hydrogen or methoxy
  • R 3 is methyl
  • R 4 is methyl
  • R 5 represents hydrogen
  • R 6 is isopropyl
  • R is hydrogen or methyl
  • R 7 and R 8 together with the nitrogen atom to which they are attached, for
  • R 9 is methyl, isopropyl or cyclopropyl
  • R 16 is methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl,
  • the present invention further relates to compounds of the general formulas (I) and (Ia)
  • 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 0,1 or 2
  • R 2 may be identical or different,
  • 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
  • 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-,
  • 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-
  • 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-,
  • 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,
  • Cs-Cs-cycloalkyl 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
  • 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-,
  • Ci-C 3 alkoxy-substituted Ci-C 3 -alkyl- 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,
  • 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,
  • 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
  • OR 14 represents C 1 -C 6 -alkyl or C 3 -C 8 -cycloalkyl-,
  • Ci-Cs-alkyl fluoro-Ci-C 3 alkyl, Cs-Ce-cycloalkyl, cyclopropylmethyl, C1-C3
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0,1 or 2
  • 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 ,
  • R 2 is hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, methoxy, ethyl or
  • R 2 may be the same or different, or
  • 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
  • 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
  • phenyl or 5- to 6-membered heteroaryl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,
  • 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
  • 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
  • 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,
  • 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
  • C 1 -C 3 -alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by identical or different substituents with fluoro, cyano, oxo, hydroxy, methoxy or -NR 12 R 13 ,
  • Ci-Cö-alkyl- which is unsubstituted or monosubstituted with cyano, Ci-C3-alkoxy, Ci-C3-alkylamino, phenyl or 4- to 8-membered
  • 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
  • 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 ,
  • 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.
  • A stands for -NH-
  • Y stands for -CH-
  • n 0 or 1
  • R 2 is hydrogen, fluorine, chlorine, methyl or methoxy
  • R 3 is methyl
  • R 4 is methyl or ethyl
  • R 5 represents hydrogen
  • R 6 is C 3 -C 5 -alkyl-, or
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, and
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,
  • 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,
  • 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
  • phenyl is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, or
  • C3-C6-cycloalkyl- which may optionally be monosubstituted or disubstituted by identical or different substituents with: hydroxy, oxo, -NR 12 R 13 ,
  • 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,
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • 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
  • A stands for -NH-
  • Y stands for -CH-
  • n 0 or 1
  • 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
  • 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,
  • cyclohexyl is unsubstituted or monosubstituted with hydroxy or -NR 12 R 13 ,
  • R 8 is hydrogen or methyl
  • R 7 and R 8 together with the nitrogen atom to which they are attached, for
  • R 12 and R 13 independently of one another represent hydrogen or methyl
  • R 12 and R 13 together with the nitrogen atom to which they are attached, for pyrrolidinyl
  • 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.
  • A stands for -NH-
  • Y stands for -CH-
  • n 0,
  • R 3 is methyl
  • R 4 is methyl or ethyl
  • R 5 represents hydrogen
  • R 6 is isopropyl
  • R is methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl,
  • 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.
  • 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-.
  • R 2 is hydrogen, fluorine, chlorine, methyl or methoxy.
  • R 2 is hydrogen, fluorine, chlorine, methyl or methoxy
  • R 2 is hydrogen, methyl or methoxy.
  • R 2 is hydrogen, methyl or methoxy.
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, and
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl.
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, and
  • Tetrahydropyran-4-yl is. Particular preference is given to compounds of the general formula (Ia) in which R 7 is hydrogen,
  • 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,
  • 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
  • phenyl is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy, or
  • 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,
  • 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
  • phenyl is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy,
  • Cs-Cö-cycloalkyl- which may optionally be monosubstituted or disubstituted by identical or different substituents with: hydroxy, oxo, -NR 12 R 13 ,
  • 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,
  • 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
  • phenyl is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or methoxy.
  • 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 .
  • R 7 represents
  • 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,
  • cyclohexyl is unsubstituted or monosubstituted with -NR 12 R 13 , or
  • 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,
  • cyclohexyl is unsubstituted or monosubstituted with hydroxy or -NR 12 R 13 ,
  • 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.
  • 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,
  • cyclohexyl is unsubstituted or monosubstituted with -NR 12 R 13 .
  • cyclohexyl is unsubstituted or monosubstituted with hydroxy or
  • R 7 is piperidinyl or azetidinyl, which is unsubstituted or monosubstituted by oxo, methyl, acetyl or ieri-butoxycarbonyl.
  • R 7 is piperidinyl or azetidinyl, which is unsubstituted or monosubstituted by oxo, methyl or acetyl.
  • R 7 is piperidinyl or azetidinyl, which is unsubstituted or monosubstituted by oxo, methyl or ieri-butoxycarbonyl.
  • R 8 is hydrogen or C 1 -C 3 -alkyl.
  • 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.
  • 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,
  • cyclohexyl is unsubstituted or monosubstituted with -NR 12 R 13 , or
  • R 8 is hydrogen or methyl
  • 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.
  • 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,
  • cyclohexyl is unsubstituted or monosubstituted with hydroxy or -NR 12 R 13 ,
  • R 8 is hydrogen or methyl
  • 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.
  • R 16 is methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl,
  • R 8 is hydrogen or methyl
  • R 7 and R 8 together with the nitrogen atom to which they are attached, for
  • R 16 is methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl
  • R 8 is hydrogen or methyl
  • R 16 is methyl, ethyl, 2,2,2-trifluoroethyl, acetyl, methoxycarbonyl, methylsulfonyl,
  • R 9 is C 1 -C 4 -alkyl- which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • R 9 is C 1 -C 4 -alkyl- which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • 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.
  • R 12 and R 13 independently of one another, are hydrogen or C 1 -C 3 -alkyl
  • 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.
  • R 12 and R 13 independently of one another are hydrogen or C 1 -C 3 -alkyl.
  • 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.
  • 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.
  • 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;
  • 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;
  • 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, 1,3
  • 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.
  • 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-p
  • C 2 -C 6 -alkenyl or a C 2 -C 6 -alkenyl group
  • 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.
  • 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
  • Examples include:
  • 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.
  • Ci-C / t-alkylthio or a Ci-C4-alkylthio group Ci-C 3 -alkylthio, particularly preferably a methylthio or ethylthio radical to understand.
  • Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to sulfur.
  • the bond to carbon is to form a carbonyl group.
  • 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.
  • fluoro-C 1 -C 3 -alkyl radicals for example difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl.
  • perfluorinated alkyl radicals such as trifluoromethyl or pentafluoroethyl.
  • 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.
  • 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.
  • 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.
  • 2,3-dihydro-indenyl is meant a bicyclic ring system according to the structures shown below,
  • 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, benzo
  • 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.
  • 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.

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Abstract

L'invention concerne des 1,4-dihydropyrido[3,4-b]pyrazinones inhibitrices de protéine BET, à groupe éther ou amino aromatique meta-substitué, ayant les formules générales (I) et (Ia) dans lesquelles A, X, Y, R1, R2, R3, R4, R5, R6 et n ont les significations figurant dans la description, des agents pharmaceutiques contenant les composés selon l'invention, et leur utilisation prophylactique et thérapeutique dans le cadre de maladies hyper-prolifératives, notamment de maladies tumorales. L'invention concerne également l'utilisation d'inhibiteurs de protéine BET dans le cadre d'infections virales, de maladies neurodégénératives, de maladies inflammatoires, de troubles athérosclérotiques et pour le contrôle de la fertilité masculine.
PCT/EP2015/063305 2014-06-19 2015-06-15 1,4-dihydropyrido[3,4-b]pyrazinones inhibitrices de protéine bet, à groupe éther ou amino aromatique meta-substitué Ceased WO2015193229A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2019209757A1 (fr) * 2018-04-24 2019-10-31 Vertex Pharmaceuticals Incorporated Composés de ptéridinone et leurs utilisations

Citations (3)

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WO2003020722A1 (fr) * 2001-09-04 2003-03-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles dihydropteridinones, procedes pour les produire et leur utilisation en tant que medicaments
WO2006005510A1 (fr) * 2004-07-09 2006-01-19 Boehringer Ingelheim International Gmbh Nouveaux pyridodihydropyrazinones, procede de production et utilisation de ces derniers comme medicaments
WO2013071217A1 (fr) * 2011-11-10 2013-05-16 OSI Pharmaceuticals, LLC Dihydroptéridinones

Patent Citations (3)

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WO2003020722A1 (fr) * 2001-09-04 2003-03-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles dihydropteridinones, procedes pour les produire et leur utilisation en tant que medicaments
WO2006005510A1 (fr) * 2004-07-09 2006-01-19 Boehringer Ingelheim International Gmbh Nouveaux pyridodihydropyrazinones, procede de production et utilisation de ces derniers comme medicaments
WO2013071217A1 (fr) * 2011-11-10 2013-05-16 OSI Pharmaceuticals, LLC Dihydroptéridinones

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Title
PIETRO CICERI ET AL: "Dual kinase-bromodomain inhibitors for rationally designed polypharmacology", NATURE CHEMICAL BIOLOGY, vol. 10, no. 4, 2 March 2014 (2014-03-02), pages 305 - 312, XP055171497, ISSN: 1552-4450, DOI: 10.1038/nchembio.1471 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019209757A1 (fr) * 2018-04-24 2019-10-31 Vertex Pharmaceuticals Incorporated Composés de ptéridinone et leurs utilisations
CN112218865A (zh) * 2018-04-24 2021-01-12 沃泰克斯药物股份有限公司 喋啶酮化合物及其用途
US11059826B2 (en) 2018-04-24 2021-07-13 Vertex Pharmaceuticals Incorporated Pteridinone compounds and uses thereof
JP2021522237A (ja) * 2018-04-24 2021-08-30 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ プテリジノン化合物およびその使用
US11572364B2 (en) 2018-04-24 2023-02-07 Vertex Pharmaceuticals Incorporated Pteridinone compounds and uses thereof
IL278122B1 (en) * 2018-04-24 2023-09-01 Vertex Pharma Pteridinone compounds and uses thereof
IL278122B2 (en) * 2018-04-24 2024-01-01 Vertex Pharma Pteridinone compounds and uses thereof
CN112218865B (zh) * 2018-04-24 2024-03-12 沃泰克斯药物股份有限公司 喋啶酮化合物及其用途
JP7479293B2 (ja) 2018-04-24 2024-05-08 バーテックス ファーマシューティカルズ インコーポレイテッド プテリジノン化合物およびその使用
US12384790B2 (en) 2018-04-24 2025-08-12 Vertex Pharmaceuticals Incorporated Pteridinone compounds and uses thereof

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