WO2015193228A1 - 1,4-dihydropyrido[3,4-b]pyrazinones inhibitrices de protéine bet, à groupe éther ou amino aromatique para-substitué - Google Patents

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

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WO2015193228A1
WO2015193228A1 PCT/EP2015/063299 EP2015063299W WO2015193228A1 WO 2015193228 A1 WO2015193228 A1 WO 2015193228A1 EP 2015063299 W EP2015063299 W EP 2015063299W WO 2015193228 A1 WO2015193228 A1 WO 2015193228A1
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alkyl
unsubstituted
monosubstituted
dimethyl
amino
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Norbert Schmees
Bernard Haendler
Detlef Stoeckigt
Simon Holton
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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
    • 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
    • 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
    • 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

Definitions

  • BET protein inhibitory 1 4-dihydropyrido
  • the present invention relates to BET protein inhibitory, in particular
  • 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-CB 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, which leads to the activation of RNA polymerase 11 (Yang et al., Mol. Cell. 2005, 1: 535-545; Schröder et al., J. Biol.
  • 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 require transcription by RNA polymerase II (LeRoy et al., Mol. Cell. 2008, 30: 51-60).
  • BRD4 b / w. inhibition of interaction with acetylated histones in various cell lines results in an 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 that can be attributed 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 that is normally only expressed in the testes, leads to an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet., Cytogenet, 2010, 203: 16- 20).
  • the fusion protein prevents cell differentiation and requires proliferation (Yan et al., J. Biol. Chem., 2011,
  • 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). The reduction of BRD4 expression leads to a selective arrest of the cell cycle and to apoptosis. Treatment with an Ii RD4 inhibitor prevents the proliferation of an AML xenograft in vivo.
  • 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. Sci. 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 R D2 there is data related to a role in tumors. A transgenic mouse that selectively expresses BRD2 selectively in B-lines 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 to 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 H IV! (Bisgrove et al., Proc Natl Acad., USA, 2007, 104: 13690-13695).
  • Treatment with a BRD4 inhibitor stimulates the quiescent, untreatable reservoir of H IV-1 virus in T cells (Banerjee et al., J. Leukoc Biol., 2012, 92, 1147-1154). This reactivation could allow for new treatment pathways for AIDS treatment (Zinchenko et al., J. Leukoc Biol., 2012, 92, 1127-1129).
  • a critical role of BRD4 in DNA replication of polyomaviruses has also been reported (Wang et al., PLoS Pathog., 2012, 8, doi: 10.1371).
  • BET proteins are also involved in inflammatory processes.
  • BRD2 hypomorphic mice show 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 expression of inflammatory genes, such as IL-! or I L -6 (Nicodeme et al., Nature, 2010, 468: 119191 123).
  • BET proteins are also involved in the regulation of the ApoAl gene (Mirguet et al., Bioorg. Med. Chem. Leti, 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 be potentially useful for the treatment of atherosclerosis (Mirguet 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 of these studies show that 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.
  • BET-protininhibi toric 1, 4-dihydropyrido [3, 4-b] pyrazinone with /? Ara-substituted aromatic amino or ether group have the desired properties, i. show a BET protein, in particular a BRD4 protein inhibitory effect with high selectivity against PLK-1.
  • the compounds according to the invention thus represent valuable active ingredients for prophylactic and therapeutic use in hyperproliferative diseases, in particular in tumor diseases.
  • the compounds according to the invention can be used in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic erotic diseases and in male fertility control come.
  • BRD4 inhibitors were diazepines. So z. B. phenylthieno-triazolo-1,4-diazepines (4-phenyl-6,7-thieno [3,2-j [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-6H-thieno [3,2- /
  • Applicant's application WO 2015/011084 discloses dihydropyridopyazinone derivatives as dual inhibitors of BRD4 and polio-1 kc kinase-1 (PLK-1).
  • the compounds according to the invention are .beta.-protein-inhibiting 1,4-dihydropyrido [3,4-b] pyrazinones with ara-substituted aromatic amino or .alpha
  • Ether group which differ structurally in a variety of forms from the above-discussed chemo types of BRD4 inhibitors. 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 1, 4-dihydropyrido [3, 4-b] pyrazine-3 (2H) -one derivatives disclosed in WO 2006/005510 or US2006 / 0009457 and their activity data, it was furthermore not possible to assume that the substances described here present invention have a high selectivity against PLK-1. It is therefore surprising that the compounds according to the invention have good BRD4-inhibitory activity with high selectivity against PLK-1, despite the considerable structural differences to known B D4 inhibitors.
  • 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, inter alia, from the compounds according to the invention 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 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 disorders.
  • These differ from the compounds of the present invention inter alia by the substitution of the bonded via a heteroatom to C-7 aromatic group.
  • 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 chemo types as inhibitors of steroid sulfatase, including for use in inhibiting the growth of tumors.
  • WO 2006/050054, WO 2007/134169 and US 2009/0264384 describe a number of bicyclic chemo ty en as inhibitors of tumor necrosis factor alpha (TNF- ⁇ ) and various isoforms of Pho sphodie steras e for the treatment under other of inflammatory
  • WO 2012/088314 discloses a number of bicyclic chemotypes as modulators of pyruvate kinase M2.
  • 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 number of bicyclic chemotypes as inhibitors of serine proteases for antithrombotic therapy, but these compounds differ clearly by the nature and position of the substituents of the inventive compounds.
  • C-6 having an aromatic amino group the phenyl group of which is in turn substituted by a para-substituted amide group
  • substituted 3,4-dihydroquinoxaline-2 (1H) -one derivatives corresponding to 2-oxo-1,2) 3,4-tetrahydroquinoxaline derivatives
  • Chemical Abstracts as "Chemical Library” substances without literature reference [see 4 - ⁇ [(3R) -4-cyclopentyl-3-ethyl-1-methyl-2-oxo-1] 2, 3,4-tetrahydroquinoxalin-6-yl] amino ⁇ -3-methoxy-N- [2-methyl-1- (pyrrolidin-1-yl) -propan-2-yl] -benzamide, CAS Registry-No.
  • Prophylaxis and therapy of diseases in particular of hyperproliferative diseases, and especially of tumor diseases.
  • A is -NH-, -N (C 1 -C 3 -alkyl) - or -O-,
  • X is -N-, -CH- or -C R -,
  • Y is -N-, -CH- or -CR 2 -,
  • n 0, 1 or 2
  • 5-membered monocyclic heteroaryl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents from halogen, cyano, Ci-C 4 -Alkyi-, C 2 -C 4 alkenyl, C 2 C 4 alkynyl, halo C 1 -C 4 acyl,
  • C 1 -C 4 -alkylthio or halogeno-C 1 -C 4 -alkylthio, and if n is 2, may be identical or different,
  • Ci-Ce-alkyl- which is unsubstituted or monosubstituted with
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, GC 4 alkyl, C 2 -C 4 alkylene, C 2 -C 4 alkynyl, GC 4 alkoxy, halogen-GC 4 -Aikyi- or halogen-GC 4 -Aikoxy-, and wherein CVCVC ' yclralkyl- and 4- to 8-membered heterocycloalkyl- are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with G-Cs-alkyl, or
  • the 4- to 8-membered heterocycloalkyl is in turn unsubstituted or substituted once or twice, identically or differently, by CVCVAlkvl or GC 4 -alkoxycarbonyl-, is C 1 -C 4 -alkyl which is substituted or monosubstituted with cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl, C 3 -C 8 -cycloalkyl or
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, GC 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Ci -Aikoxy- -C 4, halogen-Ci-C 4 -Alkyi- or halogen-Ci-C 4 alkoxy, and
  • C 1 -C 6 -cycloalkyl- or 4- to 8-membered heterocycloalkyl groups which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 4 -alkyl- or C 1 -C 4 -alkoxycarbonyl- , with the proviso that that
  • GG-cycloalkyl- is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with GG-alkyl, Ci-C 3 -Aikoxy- or -NR ! 3 R ! 4 , and
  • GG-cycloalkyl cyclopropylmethyl, C 1 -C 3 alkylcarbonyl or C 1 -C 4 alkoxycarbonyl
  • R 12 is G-Ce-alkyl or phenyl-Ci-C 3 alkyl-
  • R 13 and R 14 independently of one another represent hydrogen or C 1 -C 4 -alkyl
  • A is -NH- or -N (methyl) -
  • Y is -CH -
  • n 0, 1 or 2
  • oxazolyl is oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen,
  • R- represents hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, ethyl, methoxy or
  • R 2 may be the same or different, R 3 is methyl or ethyl,
  • R 4 is hydrogen, methyl or ethyl
  • R 5 is hydrogen, methyl or ethyl
  • R ' is C: -C -alkyl-
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted, is identical or different substituted with fluorine, chlorine, bromine, cyano, C ' i -C.-.- alkyl or CVC -.- alkoxy, and
  • phenylene- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl-,
  • 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by methyl or terf-butoxycarbonyl
  • phenyl in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, CVCVAlkyl- or GC 3 -alkoxy-, and
  • C3-Cs-cycloalkyl- or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C -alkyl- or C 1 -C 4 -alkoxycarbonyl-, with with the proviso that the 4- to 8-membered heterocycloalkyl - is not bonded via a nitrogen atom to the carbonyl or sulfonyl group in R 1 ,
  • C 3 -C 6 -cycloalkyl- in turn is unsubstituted or monosubstituted with G-CValkyl or NR 13 R 14 , and
  • R "and R 14 independently of one another represent hydrogen or C 1 -C 4 -alkyl
  • R 13 and R 14 together with the nitrogen atom to which they are attached, for
  • A stands for - H-
  • Y stands for -CH-
  • n 0 or 1
  • oxazolyl or oxadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with G -C -alkyl,
  • R 2 is hydrogen, fluorine, chlorine, methyl or methoxy
  • R 3 is methyl
  • R 4 is methyl or ethyl
  • R 5 represents hydrogen
  • R 6 is C 3 -C 5 -alkyl-
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,
  • R is C i -O-alkyl-, which is unsubstituted or monosubstituted with cyano,
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • R 10 and R 11 are independently hydrogen or unsubstituted or simply with
  • R 14 are substituted C 1 -O-alkyl- or C 5 -C 6 -cycloalkyl- or 6-membered heterocycloalkyl-,
  • Cs-Ce-cycloalkyl- is in turn unsubstituted or monosubstituted with C iC -.- alkyl- or -NR 13 R 14 , and
  • 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with C 1 -C 4 -alkyl-,
  • X is -C -C -
  • Y stands for -CH-
  • n 0 or I
  • R is hydrogen, methyl or methoxy
  • R 3 is methyl
  • R 5 represents hydrogen
  • R is C 1 -C 3 -alkyl-
  • R 10 and R 11 are independently hydrogen or unsubstituted or simply with
  • R 14 is substituted C 1 -C 4 -alkyl-, or represents cyclohexyl- or piperidinyl-,
  • R 10 and R H together with the nitrogen atom to which they are attached represent piperazinyl or 2-oxa-6-azaspiro [3.3] heptyi, which are unsubstituted or monosubstituted by methyl, isopropyl or 2, 2,2-trifluoroethyl, and
  • R 13 and R 14 are each methyl
  • R 13 and R 14 together with the nitrogen atom to which they are attached, represent piperazinyl which is monosubstituted by methyl or cyclopropylmethyl, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which R) - form predominates, as well as polymorphs and physiologically acceptable salts.
  • piperazinyl which is monosubstituted by methyl or cyclopropylmethyl, and their racemates, diastereomers, (R) -enantiomers and mixtures of isomers, in which R) - form predominates, as well as polymorphs and physiologically acceptable salts.
  • Y stands for -CH-
  • n 0 or 1
  • R is hydrogen or methoxy
  • R 3 is methyl
  • R 4 is methyl
  • R 5 is hydrogen
  • R 6 is isopropyl
  • A stands for -NU-
  • Y stands for -CH-
  • n 0,
  • ⁇ V stands for methyl
  • R 4 is methyl
  • -N (methyl) - stands. Preference is given to compounds of the general formula (I) in which A is -N (methyl) -. Preference is given to compounds of the general formula (I) in which X is -N- or -CH-. Preference is given to compounds of the general formula (I) in which X is -N-.
  • oxazolyl, thia / olyl, oxadiazolyl or thiadiazolyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C; -C; -alkyl, trifluoromethyl, CVC -, - alkoxy, trifluoromethoxy or -NR '° R ".
  • R 1 is oxazolyl, thia / olyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 2 -C 4 -alkyl -, Trifluoromethyl, ( " VC; - alkoxy, trifluoromethoxy or -NR '° R".
  • R 1 is oxazolyl or oxadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents (VC -.- alkyl -.
  • R 1 represents
  • phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, G - VAlkyl- or
  • phenyl or 5- to 6-membered heteroaryl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl,
  • 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with methyl or ieri-butoxycarbonyl.
  • phenyl in which phenyl is in turn unsubstituted or monosubstituted, disubstituted or trisubstituted, identically or differently, by fluorine, chlorine, bromine, cyano, C 1 -C 4 -alkyl or C 1 -C 3-
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, G -C alkyl or
  • 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl, in which the 6-membered heterocycloalkyl is in turn unsubstituted or simply is substituted with methyl or tert-butoxycarbonyl.
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl.
  • Tetrahydropyran-4-yl is.
  • R 7 is C 1 -C 4 -alkyl which is unsubstituted or monosubstituted by cyano, C 1 -C 4 -alkoxy, C 1 -C 3 -alkylamino, phenyl or 4 to 8 heterocycloalkyl,
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano,
  • R ' is C 1 -C 4 -alkyl which is unsubstituted or monosubstituted by cyano, G 1 -alkoxy, C 1 -C 3 -alkylamino, phenyl or 4-hydroxyalkyl. to 8-membered heterocycloalkyl,
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano,
  • R is GG-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with G-G-alkyl- or C 1 -C 4 -alkoxycarbonyl-, with the proviso that the 4- to 8-membered heterocycloalkyl group does not have a nitrogen atom on the carbonyl or sulfonyl group in R ! is bound.
  • R represents G-C-C-alkyl which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,
  • phenyl in which phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or
  • R represents G-C-C-alkyl which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,
  • phenyl in which phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or
  • Trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethylene Particular preference is given to compounds of the general formula (I) in which R is C 1 -C 4 -alkyl.
  • R 10 and R independently of one another represent hydrogen or unsubstituted or monosubstituted or simply hydroxy, oxo or -NR 13 R 14 -substituted CVC-alkyl, or 6-membered heterocycloalkyl-,
  • CVC is cycloalkyl- in turn unsubstituted or monosubstituted with CC alkyl or NR 13 R 14 , and
  • R 10 and R 11 together with the nitrogen atom to which they are attached, are 4- to 7-membered heterocycloalkyl- or Ce-Cio-heterospirocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxy , Fluoro, oxo, C 1 -C 4 -alkyl, fluoro-C 1 -C 4 -alkyl, cyclopropyl, cyclopropylmethyl, acetyl or tert-butoxycarbonyl-.
  • NR 13 R 14 substituted CVCVAlkyl-, or C 3 -C 6 cycloalkyl, - compounds of the general formula (I) in which R 10 and R "are independently hydrogen or unsubstituted or monosubstituted with hydroxy, oxo or preferably or 5- to 6-membered
  • CVC C ycloalkyl- in turn unsubstituted or monosubstituted with Ci-Cs-alkyl- or NR 13 R 14 , and
  • 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with CVCVAlkyl-.
  • Ce-Cio-Heterospirocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, C i -C -alkyl, fluorine-CVCVAIkvl-, cyclopropyl, cyclopropylmethyl-, Acetyl or terf-butoxycarbonyl.
  • R 10 and R ! 1 is independently of one another hydrogen or unsubstituted or monosubstituted with -NR 13 R 14 substituted C i -C -alkyl, or for Cs-Ce-cycloalkyl or 6-membered Heterocycloalkyl-, wherein Cs-Ce-cycloalkyl itself unsubstituted or monosubstituted with Ci-Cs-alkyl- or -NR 13 R ! 4 , and
  • 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with G-CValkyl
  • R 10 and R together with the nitrogen atom to which they are attached represent 5- to 6-membered heterocycloalkyl- or Ce-Cs-heterospirocycloalkyl- which are unsubstituted or monosubstituted by C i -C -alkyl -, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or iert-butoxycarbonyl -.
  • R 10 and R 1 1 are independently hydrogen or unsubstituted or monosubstituted with -NR 13 R 14 substituted C j -CVAlkyl-, or Cs-cycloalkyl or COE 6-membered Heterocycloalkyl-, wherein Cs-Ce-Cycloalkyi- in turn is unsubstituted or monosubstituted with
  • 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with CVC, alkyl.
  • Heterocycloalkyl- or Ce-Cs-Heterospirocycloalkyl- are unsubstituted or monosubstituted with G-Cs-Aikyi-, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or iert-butoxycarbonyl-.
  • R 10 and R together with the nitrogen atom to which they are attached represent piperazinyl or 2 -Ox a -6-a / as pi ro [3.3] h ep! Y I - which are unsubstituted or monosubstituted With
  • Methyl, isopropyl or 2,2,2-trifluoroethylene isopropyl or 2,2,2-trifluoroethylene.
  • R 10 and R independently of one another represent hydrogen or unsubstituted or -NR 13 R 14 -substituted O-Cs-alkyl-, or cyclohexyl- or piperidinyl- .
  • Methyl isopropyl or 2,2,2-trifluoroethyl.
  • Phenyl-Ci-C 2 alkyl stands. Preference is given to compounds of the general formula (I) in which R 12 is C 1 -C 4 -alkyl.
  • R 13 and R 14 together with the nitrogen atom to which they are attached, represent 4- to 7-membered heterocycloalkyl which is unsubstituted or monosubstituted by C 1 -C 1 -alkyl, cyclopropylmethyl or tert-butoxycarbonyi ,
  • (VG alkyl, or a C 1 -C 6 -alkyl group is meant a linear or branched, saturated, monovalent hydrocarbon radical, such as, for example, a methyl, ethyl, propyl, butyl, pentyl, hexyi, zso-propyl, n-butyl, sec-butyl, ferf-butyl, zso-pentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, weo-pentyl, 1, 1-dimethylpropyl, 4-
  • G-Ce-Aikyl or a GG-alkyl-C is G-alkyl, C 2 -C 4 -alkyl or GG-alkyl, particularly preferably GG-alkyl or a methyl, ethyl, propyl or isopropyl Rest to understand.
  • Ethynyl, propargyi (prop-1-ylinyl), or biun-1-yl-rcst Preferred are ethynyl and propargyl.
  • G - VAIkoxy-, or a (- VAlkoxy-i imup is C-alkoxy, particularly preferably a methoxy or ethoxy radical to understand.
  • G-G-alkylthio or a C>-CJ-A 1 k y 11 h i o -G ru p p c is a linear or branched, saturated Alkylthioetherrest S-alkyl to understand such. a methylthio, ethylthio, n-propylthio, isopropylthio, or tert. Butylthio radical.
  • C i - VAIkvIthio or a C i -G-alkylthio-G nippe C1-C3-alkylthio, particularly preferably a methylthio or ethylthio radical to understand.
  • Ci-C3-Aikylamino group is an amino radical with one or two (independently selected) alkyl substituents having 1 to 3 carbon atoms as defined above to understand.
  • (C 1 -C 3) -Alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per
  • Examples include:
  • the heteroatom -NH- may be optionally substituted with Cj-C-C alkyl,
  • the NHNH of the abovementioned sulfoximine may optionally be substituted by C 1 -C 3 -alkyl,
  • 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 may be in the ortho, meta or para position. Preference is given to fluorine or chlorine.
  • the preferred position is the meta or para position.
  • a halogeno-C i -Ct-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-O-C-C-alkyl radicals for example, difluoromethyl, trifluoromethyl,
  • perfluorinated alkyl radicals such as trifluoromethyl or pentafluoroethyl.
  • Phcnvi-C -CV AI kyl - is to be understood a group which is composed of an optionally substituted phenyl radical and a Ci-Cs-alkyl group, and on the Ci-Cs-Alkyi- (i nippe to the rest of the Benzyl is preferred.
  • a halogeno-C i -Ci-Alkoxyrcst is a C i -Ci-alkoxy group 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 a C 1 -C -alkylthio radical having at least one
  • Halogen substituents preferably having at least one fluorine substituent to understand.
  • fluorine-C 1 -C 3 -alkylthio radicals in particular trifluoromethylthio.
  • C 1 -C 3 alkylcarbonyl radical is a to understand. Preference is given to acetyl or propanoyi.
  • methoxycarbonyl Ethoxycai'bonyl-, or tert. -Butoxycarbonyl-.
  • alkyl est is a Cj -CVAlkoxy-substituted Ci-C 4 -Alkyirest to understand, such as.
  • aryl is an unsaturated fully conjugated from carbon atoms
  • Heteroaryl is to be understood as meaning ring systems which have an aromatic-conjugated ring system and contain at least one and up to five heteroatoms as defined above. These ring systems may have 5, 6 or 7 ring atoms or, in the case of condensed or benzo-fused ring systems, also combinations of 5- and 6-membered ring systems, 5- and 5-membered ring systems or also 6- and 6-membered ring systems , Examples include ring systems such as pyrrolyl, pyra / olvl.
  • Imidazolyl triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzofuryl,
  • 5-membered monocyclic heteroaryl for example pyrrolyl, pyra / olyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl,
  • Cs-Ce-cycloalkyl, Cs-Cs-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, cycloburyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • C4-C6-cycloalkenyl, C4-Cs-cycloalkenyl, or Cs-Cs-Cycloalkenyi is a monocyclic, mono- or polyunsaturated, non-aromatic ring system made up exclusively of carbon atoms having 4 to 6, 4 to 8 atoms, or 5 to understand 8 atoms.
  • Examples are cyclobutene-1-yl, cyclopenten-1-yl, cyclohexene-2-yl, cyclohexene-1-yl or cycloocta-2,5-dienyl.
  • 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.
  • pyrrolidinyl piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, azepanyl, morpholinyl,
  • 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 Heterocycloalkyi 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- Dihydrofuranyi, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H- [1,4] thiazinyl. Under C5-C11 spirocycloalkyl or C5-C1i heterospirocycloalkyl with a replacement of 1-4
  • Carbon atoms through heteroatoms as defined above in any combination is understood to mean 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,
  • 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 [6.3.0] undecyl and bicyclo [5.4.0] undecyl including variants modified by heteroatoms, e.g. Azabi cyclo [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.
  • bridged Ce-Cn ring system such as bridged C6-Cn-cycloalkyl or bridged C6-Ci2-heterocycloalkyl is meant a fusion of at least two saturated rings which share two atoms that are not directly adjacent to each other.
  • bridged carbocycle bridged cycloalkyl
  • bridged heterocycle bridged heterocycloalkyl
  • Examples are bicyclo [2.2.1] heptyl, Azabicyclo [2.2.1 jheptyl, oxazabicyclo [2.2.1] jheptyl, thiazabicyclo [2.2.1 jheptyl,
  • Salts 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 acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs either as single polymorphs or as a mixture of several polymorphs can be present in all concentration ranges.
  • the present invention also relates to pharmaceutical compositions containing the inventive
  • 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 configuration isomers or optionally also as conformation isomers.
  • the compounds of the invention can am
  • Asymmetric center 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, chromatographic methods are used for this, in particular HPLC chromatography on chiral or achiral phase. As a rule, the enantiomers according to the invention inhibit the different degrees of inhibition
  • Another object of the present invention are enantiomeric engemische the (2i?) - Configured compounds of the invention with their (25) enantiomers, in particular the corresponding racemates and mixtures of enantiomers, in which outweighs the (2i?) - form.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the invention. proper connections.
  • 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.
  • isotopes that 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), ⁇ (tritium), "C , 13 C, 14 C, 15 N, 17 O, ls O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 i, 124 1, 129 I and 13 ° C.
  • isotopic variants of a compound according to the invention in particular those in which one or more radioactive isotopes are incorporated, may be of use, for example for the investigation of the mechanism of action or the distribution of active ingredient in the body; and detectability for this purpose are in particular H - or 14 C-isotope labeled compounds suitable
  • isotopes such as deuterium, which at certain therapeutic benefits as a result of greater metabolic stability.
  • Lead such as an extension of the half-life in the body or a
  • the compounds according to the invention can act systemically and / or locally.
  • 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.
  • the compounds according to the invention can be administered in suitable administration forms.
  • Suitable for oral administration are all application forms known per se to the person skilled in the art, which can rapidly deliver the compounds according to the invention.
  • the compounds according to the invention may in this case be present in crystalline, amorphous or dissolved form, for example in tablets (non-coated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), in the oral cavity rapidly disintegrating tablets , in films / wafers, in films / lyophilisates, in capsules (for example Hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • the parenteral administration can be done bypassing a resorption step
  • intravenously, intraarterially, intracardially, intraspinal or intralumbar or with the involvement of a resorption (for example, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • parenteral administration are suitable as application forms u.a.
  • Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalation 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.
  • 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, dyes
  • inorganic pigments such as iron oxides
  • flavor and / or odoriferous are examples of inorganic pigments such as iron oxides.
  • Another object of the present invention are pharmaceutical compositions containing the compounds of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients and their use for the purposes mentioned above.
  • the formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known to the person skilled in the art by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
  • auxiliaries customary in galenicals.
  • excipients for example, vehicles, fillers, disintegrants,
  • Binders fillers, lubricants, release and adsorptive agents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents,
  • the pharmaceutical formulations may be in solid form, for example as tablets, dragees, pills, suppositories, capsules, transdermal systems or in semi-solid form, for example as ointments, creams, gels, suppositories, emulsions or in liquid form, for example as solutions, Tinctures, suspensions or emulsions are present.
  • auxiliaries 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.
  • 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.
  • hyperproliferative diseases such as, for example, psoriasis, keloids and other skin-related hyperplasias
  • BPH benign prostate hyperplasia
  • 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.
  • multiple myelomas, lymphomas or leukemias are treatable.
  • breast tumors for example, are treatable breast cancers with positive
  • non-small-cell bronchial carcinomas and small-cell bronchial carcinomas are treatable as tumors of the respiratory tract.
  • tumors of the brain are treatable by gliomas, glioblastomas, astrocytomas, meningiomas, and mediastioblastomas.
  • tumors of the male reproductive organs are treatable.
  • Prostate carcinomas malignant epididymal tumors, malignant testicular tumors and penile carcinomas.
  • tumors of the female reproductive organs are treatable.
  • Endometrial carcinoma cervical carcinoma, ovarian carcinoma, vaginal carcinoma and
  • treatable tumors of the gastrointestinal tract are colorectal carcinomas, anal carcinomas, gastric carcinomas, pancreatic carcinomas, esophageal carcinomas.
  • Gallbladder carcinomas small bowel carcinomas, chondric encephalic tumors, neuroendocrine tumors, and gastrointestinal stromal tumors.
  • tumors of the urogenital tract are treatable by bladder carcinomas, renal cell carcinomas, and carcinomas of the renal pelvis and the urinary tract.
  • retinoblastomas and intraocular melanomas are treatable as tumors of the eye.
  • Treatable hepatocellular carcinomas and cholangiocellular carcinomas are tumors of the liver.
  • Treatable as tumors of the skin are, for example, treatable malignant melanomas, basaliomas, spinaiiomas, Kaposi's sarcomas and Merkel cell carcinomas.
  • tumors of the head and neck are treatable by laryngeal carcinomas and
  • Carcinomas of the pharynx and oral cavity are treatable as sarcomas.
  • non-Hodgkin's lymphomas For example, non-Hodgkin's lymphomas, Hodgkin's lymphomas, cutaneous lymphomas, central nervous system lymphomas, and AIDS-associated lymphomas are treatable as lymphomas.
  • leukemias are treatable acute myeloid leukemias, chronic myeloid leukemias, acute lymphoblastic leukemias, chronic lymphocytic leukemias, and hair cell leukemias.
  • 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
  • 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.
  • the compounds according to the invention can be used particularly advantageously for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as, for example, endometriosis, leiomyoma and benign prostatic hyperplasia.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of inflammatory or autoimmune diseases such as, for example:
  • Pulmonary diseases with inflammatory, allergic and / or proliferative disorders Pulmonary diseases with inflammatory, allergic and / or proliferative disorders
  • Associated processes chronic obstructive pulmonary disease of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatoses, especially Boeck's disease,
  • Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms in degenerative joint disease (Arthroses); traumatic arthritis; Collagenosis of any genesis, such as systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren's syndrome, Still's syndrome, Felty's syndrome,
  • Vasculitides Panarteritis nodosa, temporal arteritis, erythema nodosum,
  • atopic dermatitis Psoriasis; Pityriasis rubra pilaris; erythematous diseases induced by different noxae, e.g. Blasting, chemicals, burns etc .; bullous dermatoses; Diseases of the lichenoid type; pruritus; seborrheic eczema; rosacea; Pemphigus vulgaris; Erythema exudative multiforme; balanitis; vulvitis; Hair loss such as alopecia areata; cutaneous T-cell lymphoma,
  • Kidney diseases associated with inflammatory, allergic and / or proliferative processes nephrotic syndrome; all nephritis,
  • Liver diseases associated with inflammatory, allergic and / or proliferative processes acute liver cell decay; acute hepatitis of various causes, such as viral, toxic, drug-induced; chronic aggressive and / or chronic intermittent hepatitis,
  • Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, for example, gluten-sensitive enteropathy (native sprue),
  • Proctological diseases associated with inflammatory, allergic and / or proliferative processes analgesic; fissures; Hemorrhoids; idiopathic proctitis,
  • Eye diseases associated with inflammatory, allergic and / or proliferative processes allergic keratitis, uveitis, ulceris; 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,
  • Blocings 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,
  • Severe states of shock such as anaphylactic shock, systemic shock
  • Emesis associated with inflammatory, allergic and / or proliferative processes for example in combination with a 5-HT3 antagonist in cytostatic vomiting,
  • Pain of inflammatory genesis e.g. Lumbago.
  • the compounds according to the invention are also suitable for the treatment of viral
  • viruses such as infections caused by papilloma viruses.
  • herpes Viruses Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.
  • the compounds according to the invention are also suitable for the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, peripheral vascular diseases, cardiovascular diseases.
  • 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.
  • Another object of the present invention relates to the use of
  • Another object of the present invention relates to the use of
  • 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 are endometrial carcinomas and colorectal carcinomas.
  • Another object of the present invention relates to the use of
  • E estrogen re / eptor-alpha negative breast carcinoma, melanoma or multiple myeloma E estrogen re / eptor-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
  • 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
  • Estrogen receptor-alpha negative breast carcinoma melanoma or multiple myeloma.
  • Another object of the present invention relates to the use of
  • Another object of the present invention relates to the use of
  • 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 are endometrial carcinoma and colorectal carcinoma.
  • Another object of the present invention relates to the use of
  • Estrogen receptor-alpha negative breast carcinoma melanoma or multiple myeloma.
  • a further subject of the present invention relates to pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias,
  • Prostate cancer especially androgen receptor-positive prostate cancer
  • 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
  • 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
  • Another object of the invention relates to the use of the invention
  • 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.
  • 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.
  • suitable combination of active ingredients may be mentioned by way of example without this list being exhaustive: Abiraterone acetate, Abraxane, Acolbifen, Actimmun, Actinomycin D (Dactinomycin), Afatinib, Affinitak, Afinitor, Aldesleukin, Alendronic acid, Alfaferon, Alitretinoin, Allopurinol, Aloprim, Aloxi, alpharadin. Altretamine, Aminoglutethimide, Aminopterin, Amifostine, Amrubicin, Amsacrine, Anastrozole, Anzmet, Apatinib, Aranesp, Arglabin.
  • Doxorubicin (adriamycin), dronabinol, dSLIM, dutasteride, DW-166HC, edotecarin, eflornithine, eligard, elitek, ellence, emend, enzalutamide, epirubicin, epoetin-alfa, epogen, epothilone and its derivatives, eptaplatin, ergamisole, erlotinib, erythrocytes Hydroxynonyladenine, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinylestradiol, Ethyol, Etidronic Acid, Etopophos, Etoposide, Everolimus, Exatecan, Exemestane, Fadrozole, Farston, Fenretinide, Filgrastim, Finasteride, Fligrastim, Floxuridine, Fluconazole, Fludarabine
  • Hydroxyprogesterone caproate ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, iniparib.
  • Ondansetron hydrochloride Onko-TCS, Orapred, Osidem, Oxaliplatin.
  • Paclitaxy pamidronate dinatrium, Pa / opanib.
  • Pediapred Pegaspargase, Pegasys, pemetrexed, pentostatin, N-phosphonoacetyl-L-aspartate, picibanil, pilocarpine hydrochloride, pirarubicin, plerixafor, plicamycin, PN-401,
  • Tiludronic acid tipifarnib, tirapazamine, TLK-286, toceranib, topotecan, toremifene,
  • the compounds of the invention can be reacted with antibodies such as e.g.
  • Aflibercept alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab,
  • Denosumab Edrecolomab, Gemtuzumab, Ibritumomab, Ipilim mab. Ofatumumab, panitumumab, pertuzumab, rituximab, tositumumab or trastuzumab, as well as recombinant proteins.
  • 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.
  • 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.
  • the following objectives can be pursued with the combination of the compounds according to the invention with other cytostatic or cytotoxic agents:
  • the compounds of the invention may also be used in conjunction with a
  • Radiotherapy and / or a surgical intervention are used.
  • M R signals are given with their respective recognizable multiplicity or their combinations.
  • s singlet
  • d doublet
  • t triplet
  • q quartet
  • qi quintet
  • sp septet
  • m multiplet
  • b broad signal.
  • the chemical shifts of the signals ( ⁇ ) are given in ppm (parts per miiiion).
  • T3P 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
  • Scheme 1 Compounds of general formula (I) and their subgroups (Ia) and (Ib).
  • 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-Brompropionylbromid (CAS 563-76-8).
  • a suitable solvent such as dichloromethane, THF or methyl-teri-butyl ether and with the addition of a base such as triethylamine, N, N-diisopropylethylamine or pyridine reacted.
  • the base can also be used as a solvent.
  • compounds of the formula (IV) are obtained.
  • Diisopropylethylamine or triethylamine at elevated temperature (Org. Lett. (2008), 10, p 2905 ff, P. P. 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, N, N-diisopropylethylamine or potassium carbonate at elevated temperature in solvents such as N, N-dimethylformamide, N, N-dimethylacetamide , N-methylpyrrolidone or dimethyl sulfoxide (see also
  • Scheme 2a illustrates the alternative construction of intermediates of formula (V) in which the stereochemistry of the stereocenter formed when R 4 and R 5 are different from each other may be defined from R 4 and R 5 and the carbon atom attached to them.
  • PG is a protective group such as Boc, Cbz or Fmoc
  • suitable aminopyridine derivatives For example, 3-amino-4,6-di-chloropyridine ((II), CAS No. 7321-93-9).
  • Coupling reagents such as T3P, TBTU, HATU or IX C used.
  • T3P Transfer reagent
  • TBTU TBTU
  • HATU HATU
  • IX C IX C
  • Carboxylic acids in their amides are generally described in reference books such as Compendium of Organ ic 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).
  • a variety of methods are known, which can be read in standard works (see, for example, TW Greene and PGM Wuts in: Protective Croup in Organ ic Synthesis, 3rd edition, Wiley 1999).
  • Reductant such as sodium triacetoxyborohydride to the secondary amine of formula (X) transformed.
  • the secondary amines of the formula (X) can be converted by cyclization to Dihydropyridopyrazmonen the formula (Via).
  • a suitable base for example a trialkylamine, such as triethylamine or N, N-diisopropyl ethylamine, at elevated temperature (cf.
  • the optionally stereoisomerically pure dihydropyridopyrazinones of the formula (VIa) can be further reacted in the same manner as the analogous, optionally racemic compounds of the formula (VI) in the sense of Schemes 3 and 4 to the compounds of the formulas (Ia) and (Ib) according to the invention.
  • the described reaction routes make it possible that, when an enantiomerically pure protected amino acid of the formula (VII) is used, epimerization or re-emission of the stereogenic center on the carbon atom which is bonded to R 4 and R 5 can be suppressed as far as possible at the beginning of the sequence.
  • Scheme 3 illustrates the reaction of the intermediates of formula (Via), as shown in Scheme 2a, in which R 4 , R 5 and R 'are defined as in general formula (I) to give compounds of formula (Ia) according to the invention Sulfonamides are not present at the site of R 1 .
  • the alkylation of compounds of formula (V) to compounds of formula (XI) can be carried out by reaction with R-L (I. wherein R 3 is defined as in the general formula ( ⁇ ) and LG for a leaving group, preferably iodide, is, in the presence of a suitable base such as sodium hydride, according to known in the art conditions.
  • Suitable here are e.g. Paliadium acetate or palladium (dba) complexes such as Pd2 (dba) s (CAS Nos. 51364-51 -3 and 52409-22-0, respectively). The conversion depends strongly on the ligands used.
  • the examples given in the experimental section could be described e.g.
  • Heteroraryl, as defined in formula (I) for R 1 is inventive compounds of the formula
  • N- [2- (4-methylpiperazin-1-yl) ethyl] -4-nitrobenzenesulfonamide was prepared starting from 3.5 g of 4-nitrobenzenesulfonyl chloride and 2.36 g of 2- (4- Methylpiperazin-1-yl) ethanamine (CAS 934-98-5) with 8.4 ml of triethylamine in 87.5 ml
  • Example 1 illustrate the preparation of the compounds of the invention.
  • 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 aqueous sodium chloride solution, over
  • 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 at 120 ° C for 8 hours under an argon atmosphere.
  • 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 5% methanol content).
  • Tris (dibenzylideneacetone) dipalladium (0) (CAS 5 1364-5 1 -3). 235 mg of cesium carbonate and 1 1 mg of xanthphos (CAS 161265-03-8) in 10 ml of dioxane was stirred for 7 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
  • 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 aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo.

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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 para-substitué, ayant la formule générale (I) dans laquelle 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/EP2015/063299 2014-06-19 2015-06-15 1,4-dihydropyrido[3,4-b]pyrazinones inhibitrices de protéine bet, à groupe éther ou amino aromatique para-substitué Ceased WO2015193228A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
KR101796779B1 (ko) 2015-12-22 2017-11-10 한국화학연구원 다이하이드로프테리딘-온 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 pi3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one

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WO2001019825A1 (fr) * 1999-09-15 2001-03-22 Warner-Lambert Company Pteridinones utilisees comme inhibiteurs de kinases
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
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101796779B1 (ko) 2015-12-22 2017-11-10 한국화학연구원 다이하이드로프테리딘-온 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 pi3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one

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