Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61P15/16—Masculine contraceptives
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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

Definitions

• the present invention relates to substituted dihydropyrido [3,4-] pyrazinones as dual
• Inhibitors of BET proteins in particular BRD4 proteins and polo-like kinases, in particular pic-1 proteins, intermediates for the preparation of the compounds according to the invention, pharmaceutical agents containing the compounds according to the invention and theirs
• this invention relates to the use of the dihydropyrido [3,4-py] pyrazinones according to the invention 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 3 or histone 4) 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; Zhang et al., J.
• 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 play a role in chromatin modulation and regulation of
• 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 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, Grayson et al., 2013, doi: 10-1038 / onc.2013.126).
• 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
• 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 be new
• 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).
• Tumor cells are also characterized by an unrestrained cell-cycle process. This is based on the one hand on the loss of control proteins such as RB, p16, p21, p53, etc., and the activation of so-called accelerators of the cell cycle process, the cyclin-dependent kinases (CDKs).
• the CDKs are a pharmaceutically approved anti-tumor target protein.
• Plk-1 A high expression rate of Plk-1 has been found in non-small cell-hung cancer (Wolf et al Oncogene, 14, 543ff, 1997), in melanomas (Strebhardt et al., JAMA, 283, 479ff, 2000). Squamous cell carcinomas' (Knecht et al., Cancer Res, 59, 2794ff, 1999) and in 'esophageal carcinomas' (Tokumitsu et al., Int J Oncol 15, 687ff, 1999).
• Plk-1 in NIH-3T3 cells resulted in malignant transformation (increased proliferation, growth in soft agar, colony formation, and tumor development in nude mice (Smith et al., Biochem Biophys Res Conan, 234, 397ff. , 1997).
• Microinjections of Plk-1 antibodies into HeLa cells resulted in defective mitosis (Lane et al., Journal Cell Biol, 135, 1701ff, 1996).
• a '20 -mer 'antisense oligo inhibited the expression of Plk-1 in A549 cells and stopped their viability. Likewise, a clear anti-tumor effect could be shown in nude mice (Mündt et al., Biochem Biophys Res Conan, 269, 377ff., 2000).
• antisense oligo molecules did not inhibit the growth and viability of primary human mesangial cells (Mündt et al., Biochem Biophys Res Comm, 269, 377ff., 2000).
• sequence identity within the polypic spiking domains is between 40 and 60%, so that in part interactions of inhibitors of one kinase with one or more other kinases of this family occur.
• the compounds according to the invention can be used in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.
• the compounds according to the invention inhibit both the BET proteins and the polo like kinases, as well as their action against, for example, cancer, such as solid tumors and leukemia, autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis,
• Chemotherapeutic-induced alopecia and mucositis cardiovascular diseases such as stenosis, arteriosclerosis and restenosis, infectious diseases such.
• cardiovascular diseases such as stenosis, arteriosclerosis and restenosis
• infectious diseases such.
• unicellular parasites such as Trypanosoma, Toxoplasma or Plasmodium, or caused by fungi, nephrological diseases such.
• Glomerulonephritis chronic neurodegenerative diseases such as Huntington 's disease, amyotropic lateral sclerosis, Parkinson' s disease, AIDS dementia and Alzheimer 's disease, acute neurodegenerative diseases
• Cytomegalovirus infections herpes, hepatitis B and C, and HIV related disorders.
• BRD4 inhibitors were diazepines. So z. B. phenylthienetriazolo- 1, 4-diazepine (4-phenyl-6-thieno [3,2- /] [1,2,4] triazolo [4,3-a] [1, 4] diazepine) in WO2009 / 084693 (Mitsubishi Tanabe Pharma Corporation) and as compound JQ1 in
• Azepines as BRD4 inhibitors are described in WO2012 / 075383 (Constellation Pharmaceuticals). This application relates to 6-substituted-4 / f-isoxazolo [5,4-öf] [2] benzazepines and 4H-isoxazolo [3,4-öf] [2] benzazepines, including those compounds which have optionally substituted phenyl at position 6 and also analogues with alternative heterocyclic
• BRD4 inhibitors are 7-isoxazoloquinolines and related quinolone derivatives (Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967).
• WO2011 / 054845 GaxoSmithKline
• further benzodiazepines are described as BRD4 inhibitors.
• Cell cycle kinases for example, of Plk-1, are described, but partly directed to completely different mechanisms of action and in part to other indications.
• WO 2006/005510 or US 2006/009457 describes 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives as inhibitors of Plk-1 for the treatment of hyperproliferative diseases.
• the claimed substances are characterized by an aniline group attached to C-7 of the dihydropyridopyrazinone skeleton via -NH-, and in turn substituted in the jara position with a carboxamide.
• the compounds of the present invention comprise a substituted aminopyridine at the site of the above-mentioned anilinic group.
• 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 by the position of the nitrogen in the pyridine part of the pyridopyridazine skeleton, as well as by the type and position of the substitution present there.
• WO 2011/031965 (Gilead Sciences) describes 3-deacapteridinone derivatives (corresponding to 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives) as modulators of toll-like receptors for the treatment of various Diseases.
• the substances disclosed there differ from the compounds according to the invention inter alia by the obligate amino substitution at C-5 and by the lack of substitution at N-4.
• WO 2003/020722 and WO 2004/076454 (Boehringer Ingelheim) disclose 7,8-dihydropteridine-6 (5H) -ones as inhibitors of specific cell cycle kinases for the treatment of hyperproliferative
• 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 Japanese 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 for the treatment of hyperproliferative diseases.
• WO 2012/085176 Hoffmann-La Roche AG
• JNK Janus kinases
• WO 2008/117061 (Sterix Ltd) describes a number of bicyclic chemotypes, including 3,4-dihydroquinoxaline-2 (1H) -one derivatives, 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, including 3,4-dihydroquinoxaline-2 (1H) -one derivatives, as inhibitors of tumor necrosis factor alpha ( TNF- ⁇ ) as well as various isoforms of phosphodiesterase for the treatment of, inter alia, inflammatory diseases.
• TNF- ⁇ tumor necrosis factor alpha
• the compounds according to the invention are substituted 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives, which are structurally diverse in manifold forms from the chemotypes of BRD4 and Pik 1 discussed above Differentiate inhibitors. Due to the substantial structural differences, but also with regard to the structures themselves, it was not to be expected that the compounds claimed herein would have a dual activity, i. that they are both BRD4-inhibitory, as well as Plk-inhibitory. It is therefore surprising that the compounds according to the invention, despite the considerable
• Structural differences have a dual mode of action and thus a good inhibitory effect.
• oxazolin-2-yl which may optionally be monosubstituted or disubstituted by
• C 1 -C 6 -alkyl- which may optionally be monosubstituted by phenyl, Cs-Cs-cycloalkyl, or 4 to 8-membered heterocycloalkyl, in which phenyl, in turn, optionally mono-, di- or trisubstituted, the same may be or different substituted with: halogen, cyano, Ci-C 4 alkyl, C 2 -C 4 - alkenyl, C 2 -C 4 alkynyl, GC 4 alkoxy, halogen GC 4 alkyl , Halogen GC 4 - alkoxy,
• Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl may in turn optionally be mono- or disubstituted by Ci-C3-alkyl, or
• Heterocycloalkyl 4- to 8-membered heterocycloalkenyl, Cs-Cn-spirocycloalkyl, Cs-Cn-heterospirocycloalkyl, bridged C6-C-cycloalkyl, bridged C6-Ci2-heterocycloalkyl, C0-C-bicycloalkyl, C6 -C12- Heterobicycloalkyl- optionally one or two times, the same or different substituents may be substituted with: hydroxy, fluorine, oxo, cyano, Ci-C 3 alkyl, fluoro-Ci-C 3 alkyl, Cs-Ce-cycloalkyl , Cyclopropylmethyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl or -NR 10 R n ,
• phenyl and 5- to 6-membered heteroaryl may be optionally substituted once or twice, identically or differently, with: halogen, cyano, trifluoromethyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy-,
• Cs-Cs-cycloalkyl-C t -Cs -cycloalkenyl, Cs-Cn-spirocycloalkyl, bridged C6-Ci2-cycloalkyl or C6-Ci2-bicycloalkyl- which optionally substituted once or twice, identically or differently substituted may be: hydroxy, oxo, cyano, fluoro, C 1 -C 8 -alkyl, C 1 -C 3 -alkoxy, trifluoromethyl, -NR 10 R n , or 4- to 8-membered heterocycloalkyl, 4- to 8-membered
• R 9 is hydrogen or optionally once or twice, the same or
• R 8 and R 9 together with the nitrogen atom to which they are attached represent 4- to 8-membered heterocycloalkyl, 4 to 8-membered heterocycloalkenyl, C 5 -C 11 -
• Heterospirocycloalkyl-, bridged C6-Ci 2 -Heterocycloalkyl- or C6-C 12 - Heterobicycloalkyl- are, which may optionally be monosubstituted or disubstituted by identical or different substituents with: hydroxy, fluoro, oxo, cyano, C 1 -C 3 alkyl , Fluoro-G-Cs-alkyl, C 3 -C 6 -cycloalkyl, cyclopropylmethyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl or -NR 10 R n ,
• R 10 and R 11 are independently hydrogen or optionally on or
• Ci-Cs-alkyl or fluoro-Ci-C 3 alkyl
• R 10 and R 11 together with the nitrogen atom to which they are bonded, represent 4- to 8-membered heterocycloalkyl groups, which may optionally be monosubstituted or disubstituted by identical or different substituents, with: hydroxyl, fluorine, oxo, cyano, C1-C3-alkyl, fluoro-Ci-C 3 alkyl, C 3 -C 6 cycloalkyl, cyclopropylmethyl, C 1 -C 3 - alkylcarbonyl or Ci-C4-alkoxycarbonyl,
• R 12 is Ci-Ce-alkyl or phenyl-Ci-C 3 alkyl-
• n 0 or 1
• BET proteins in particular BRD4 and an acetylated histone 4-peptide and the kinase Plk-1 and thus have the properties described above via said dual mechanism and in particular inhibit the growth of cancer cells.
• A stands for -NH-
• methyl or ethyl which may be monosubstituted with phenyl- or 4- to 8-membered heterocycloalkyl-,
• phenyl in which phenyl, in turn, may optionally be monosubstituted or disubstituted by identical or different substituents with: fluorine, chlorine, bromine, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, trifluoromethyl-,
• C 3 -C 6 -cycloalkyl- or 4- to 8-membered heterocycloalkyl- which may optionally be monosubstituted or disubstituted by methyl, C 1 -C 6 -alkyl-, which may be mono-, di-, or trisubstituted by identical or different substituents may be substituted with: hydroxy, oxo, fluorine, cyano, C 1 -C 3 alkoxy, fluoro C 1 -C 3 -alkoxy, -NR 10 R n , 4 to 8-membered heterocycloalkyl, Phenyl or 5- to 6-membered heteroaryl,
• 4- to 8-membered heterocycloalkyl optionally may be monosubstituted with: hydroxy, oxo, Ci-C3-alkyl, fluoro-Ci-C3-alkyl, cyclopropyl,
• phenyl and 5- to 6-membered heteroaryl may optionally be monosubstituted or disubstituted by identical or different substituents with: fluorine, chlorine,
• R 9 is hydrogen or C 1 -C 3 -alkyl-
• R 8 and R 9 together with the nitrogen atom to which they are bonded, represent 4- to 8-membered heterocycloalkyl, C 6 -C 8 -heterospirocycloalkyl, bridged C 6 -C 10 -alkyl,
• R 10 and R 11 are independently hydrogen or optionally simply with
• Ci-C3-alkyl- or trifluoromethyl stand, or
• R 10 and R 11 together with the nitrogen atom to which they are bonded, are 4- to 7-membered heterocycloalkyl groups which may optionally be monosubstituted or disubstituted by identical or different substituents with: hydroxyl, oxo, C 1 -C 3 Alkyl, fluoro-C 1 -C 3 -alkyl, cyclopropyl, cyclopropylmethyl, acetyl or tert-butoxycarbonyl, and
• n 0 or 1
• A stands for -NH-
• oxazolin-2-yl- which may optionally be monosubstituted or disubstituted by Ci-C3-alkyl,
• R 2 is hydrogen, methyl, ethyl or methoxy
• R 4 is methyl
• R 5 is methyl or ethyl, stands for hydrogen
• phenyl in which phenyl, in turn, optionally monosubstituted or disubstituted by identical or different substituents with: fluorine, chlorine, cyano, methyl, methoxy, and
• Ci-C t-alkyl- which may optionally be mono- or di-substituted by hydroxy, Ci-C3-alkoxy, -NR 10 R n , 4- to 8-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl,
• 4- to 8-membered heterocycloalkyl may optionally be monosubstituted with: oxo, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, cyclopropyl or cyclopropylmethyl-,
• phenyl and 5- to 6-membered heteroaryl may be optionally substituted once or twice, identically or differently, with: fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy-,
• n 0,
• A stands for -NH-
• oxazolin-2-yl- which may optionally be monosubstituted or disubstituted by Ci-C3-alkyl,
• R 2 represents methyl, ethyl or methoxy
• R 4 is methyl
• R 5 is methyl or ethyl
• R 6 represents hydrogen
• R 7 is C 3 -C 5 -alkyl-
• R 8 is C 1 -C 3 -alkyl, which may optionally be monosubstituted with
• phenyl or 5- to 6-membered heteroaryl- in which phenyl- and 5- to 6-membered heteroaryl may optionally be monosubstituted or disubstituted by identical or different substituents with: fluorine, chlorine , Methyl or methoxy,
• R 9 is hydrogen
• n 0,
• A stands for -NH-
• oxazolin-2-yl- which may optionally be monosubstituted or disubstituted by methyl
• O-C t -alkyl which may optionally be monosubstituted by hydroxy, methoxy or pyridinyl,
• A stands for -NH-
• R 2 is methyl, ethyl or methoxy
• R 4 is methyl
• R 5 is methyl or ethyl
• R 6 is hydrogen
• R 7 is cyclopentyl-
• R 8 is OC t-alkyl, which may optionally be monosubstituted by
• R 9 is hydrogen
• n 0,
• R 1 is oxazolin-2-yl- which may optionally be monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl-,
• R 1 may be substituted with 5-membered monocyclic heteroaryl, which may optionally be mono-, di- or trisubstituted identically or differently
• R 1 is oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which may optionally be monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 Alkyl, trifluoromethyl, C 1 -C 3 alkoxy, trifluoromethoxy or -NR 10 R n .
• R 2 is hydrogen, fluorine, chlorine, cyano, methyl, ethyl, methoxy or ethoxy.
• R 2 represents methyl, ethyl or methoxy.
• phenyl in which phenyl, in turn, optionally monosubstituted or disubstituted by identical or different substituents with: fluorine, chlorine, cyano, methyl, methoxy,
• phenyl in which phenyl, in turn, optionally monosubstituted or disubstituted by identical or different substituents with: fluorine, chlorine, cyano, methyl, methoxy.
• R 8 is C 1 -C 4 -alkyl, which may optionally be monosubstituted by hydroxy, C 1 -C 3 -alkoxy, -NR 10 R n , 4 to 8 - heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl-linked
• 4- to 8-membered heterocycloalkyl may optionally be monosubstituted with: oxo, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, cyclopropyl or cyclopropylmethyl-,
• phenyl and 5- to 6-membered heteroaryl may be optionally substituted once or twice, identically or differently, with: fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy-,
• C 3 -C 6 -cycloalkyl- which may optionally be monosubstituted with hydroxy, fluorine or -NR 10 R n , or for 4- to 8-membered heterocycloalkyl, which may optionally be monosubstituted or disubstituted by identical or different substituents with: oxo, Ci-C3-alkyl, fluoro-Ci-C3-alkyl, cyclopropyl or Cyclopropylmethyl-.
• R 8 is C 1 -C 4 -alkyl, which may optionally be monosubstituted by hydroxy, C 1 -C 3 -alkoxy, -NR 10 R n , 4 to 8 - heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl-linked
• 4- to 8-membered heterocycloalkyl may optionally be monosubstituted with: oxo, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, cyclopropyl or cyclopropylmethyl-,
• phenyl and 5- to 6-membered heteroaryl may optionally be monosubstituted or disubstituted by identical or different substituents with: fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy.
• R 8 is C 3 -C 6 -cycloalkyl-, which may optionally be monosubstituted by hydroxy, fluorine or -NR 10 R n .
• R 8 is a 4- to 8-membered heterocycloalkyl radical which may optionally be monosubstituted or disubstituted by identical or different substituents with: oxo, C 1 -C 3 -alkyl, fluoroalkyl C 1 -C 3 -alkyl, cyclopropyl or cyclopropylmethyl-.
• R 8 is C 1 -C 3 -alkyl, which may optionally be monosubstituted with -NR 10 R n , hydroxy, C 1 -C 3 -alkoxy, phenyl or 5- to 6-membered heteroaryl,
• phenyl and 5- to 6-membered heteroaryl may be optionally substituted once or twice, identically or differently, with: fluorine, chlorine, methyl or methoxy-,
• R 8 is C 1 -C 3 -alkyl, which may optionally be monosubstituted with -NR 10 R n , hydroxy, C 1 -C 3 -alkoxy, phenyl or 5- to 6-membered heteroaryl,
• phenyl and 5- to 6-membered heteroaryl may optionally be monosubstituted or disubstituted by identical or different substituents with: fluorine, chlorine, methyl or methoxy.
• R 8 represents fluorine-Ci-C 3 - Alkyl stands.
• R 8 is 4- to 6-membered heterocycloalkyl, which may optionally be monosubstituted with: oxo or C 1 -C 3 -alkyl-.
• Heterospirocycloalkyl bridged Cö-Cio-Heterocycloalkyl- or Cö-Cio-Heterobicycloalkyl-,
• R 8 and R 9 together with the nitrogen atom to which they are attached represent 4-to 8-membered heterocycloalkyl, which is optionally mono- or disubstituted by identical or different may be substituted with: hydroxy, oxo, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, cyclopropyl, cyclopropylmethyl, acetyl or tert-butoxy carbonyl 1-.
• Heterocycloalkyl- which may optionally be monosubstituted or disubstituted by identical or different substituents with: oxo, Ci-C3-alkyl, fluoro-Ci-C3-alkyl, cyclopropyl or
• R 10 and R 11 independently of one another, are hydrogen or optionally C 1 -C 3 -alkyl- or trifluoromethyl- which is optionally monosubstituted by hydroxyl or oxo.
• R 10 and R 11 independently of one another, are hydrogen or C 1 -C 3 -alkyl-.
• n is the number 1.
• 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, ieri-butyl, where-pentyl, 2-methylbutyl, 1- Methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, weo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl , 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-d
• C 1 -C 6 -alkyl or a C 1 -C 6 -alkyl group is preferably C 1 -C -alkyl- or C 2 -C -alkyl-, more preferably C 1 -C 3 -alkyl- or a methyl-, To understand ethyl, propyl or isopropyl radical.
• C2-C4 alkenyl or a C2-C4 alkenyl group is meant a linear or branched, monovalent hydrocarbon radical having one or two C double bonds, such. an ethenyl, (£) prop-2-enyl, (Z) -prop-2-enyl, allyl (prop-1-enyl), allenyl-buten-1-yl, or buta-1 , 3-dienyl radical. Preferred are ethenyl and allyl.
• 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.
• Ci-C4-alkoxy or a Ci-C4-alkoxy group Ci-C3-alkoxy, particularly preferably a methoxy or ethoxy radical to understand.
• a C 1 -C 4 -alkylthio or a C 1 -C 4 -alkylthio group is to be understood as meaning a linear or branched, saturated alkylthioether radical -S-alkyl, as described, for example, in US Pat. a methylthio, ethylthio, n-propylthio, isopropylthio or tert-butylthio radical.
• C 1 -C 4 -alkylthio or C 1 -C 4 -alkylthio group is to be understood as meaning C 1 -C 3 -alkylthio, particularly preferably a methylthio or ethylthio radical.
• Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to sulfur.
• the bond to carbon to form a carbonyl group - (C 0) -.
• halogen is meant fluorine, chlorine, bromine or iodine.
• a halogeno-C 1 -C 4 -alkyl radical or halo-C 1 -C 4 -alkyl radical is to be understood as meaning a C 1 -C 4 -alkyl radical substituted by at least one halogen substituent, preferably by at least one fluorine substituent.
• 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.
• a halogeno-C 1 -C 4 -alkoxy radical or halogen-C 1 -C 4 -alkoxy radical is to be understood as meaning a C 1 -C 4 -alkoxy radical substituted by at least one halogen substituent, preferably by at least one fluorine substituent.
• fluoro-C 1 -C 3 -alkoxy radicals for example difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy.
• a halogeno-C 1 -C 4 -alkylthio radical or halo-C 1 -C 4 -alkylthio is to be understood as meaning a C 1 -C 4 -alkylthio radical substituted with at least one halogen substituent, preferably with at least one fluorine substituent.
• fluorine-C 1 -C 3 -alkylthio radicals in particular trifluoromethylthio radicals.
• a C 1 -C 4 -alkoxycarbonyl radical is to be understood as meaning a C 1 -C 4 -alkoxy-C (0O) group. Preference is given to methoxycarbonyl, ethoxycarbonyl or heptabutoxycarbonyl-.
• 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 an unsaturated fully conjugated system made up of carbon atoms which has 3, 5 or 7 conjugated double bonds, e.g. Phenyl, naphthyl or phenanthryl. Preference is given to phenyl.
• Heteroaryl is to be understood as meaning ring systems which have an aromatic-conjugated ring system and contain at least one and up to five heteroatoms as defined above, contain. These ring systems may have 5, 6 or 7 ring atoms or, in the case of condensed or benzo-fused ring systems, also combinations of 5- and 6-membered ring systems, 5- and 5-membered ring systems or also 6- and 6-membered ring systems , Examples include ring systems such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, thiazolyl,
• 5- to 6-membered monocyclic heteroaryl for example pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, Pyridinyl, pyrimidinyl, pyrazinyl, triazinyl.
• C3-C6-Cycloalkyl, Cs-Cs-cycloalkyl or Cs-Cs-cycloalkyl is understood to mean 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,
• C t -C 6 -cycloalkenyl, C t -C s -cycloalkenyl, or Cs-Cs-cycloalkenyl is a monocyclic, mono- or polyunsaturated, non-aromatic ring system of 3 to 6, 3 to 8 atoms or exclusively composed of carbon atoms To understand 5 to 8 atoms. Examples are cyclobuten-1-yl, cyclopenten-1-yl, cyclohexene-2-yl, cyclohexene-1-yl or cycloocta-2,5-dienyl.
• Heterocycloalkyl- is to be understood as meaning a 4- to 8-membered monocyclic, saturated ring system which has 1 to 3 heteroatoms as defined above, in any desired combination. Preference is given to 4- to 7-membered heterocycloalkyl groups, particularly preferred are 5- to 6-membered heterocycloalkyl groups. Examples which may be mentioned are pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, azepanyl, morpholinyl, thiomorpholinyl or piperazinyl.
• Heterocycloalkenyl is understood as meaning a 4- to 8-membered monocyclic mono- or polyunsaturated, nonaromatic ring system which has 1 to 3 heteroatoms as defined above, in any desired combination. Preference is given to 4- to 7-membered heterocycloalkenyl groups, with particular preference being given to 5- to 6-membered heterocycloalkenyl groups.
• C5-C11 -spirocycloalkyl or Cs-Cn-heterospirocycloalkyl with a replacement of 1 to 4 carbon atoms by heteroatoms as defined above in any combination is meant a fusion of two saturated ring systems sharing a common atom.
• Examples are spiro [2.2] pentyl, spiro [2.3] hexyl, azaspiro [2.3] hexyl, spiro [3.3] heptyl, azaspiro [3.3] heptyl, oxaazaspiro [3.3] heptyl, thiaazaspiro [3.3] heptyl- , Oxaspiro [3.3] heptyl, oxazaspiro [5.3] nonyl, oxazaspiro [4.3] octyl, oxazaspiro [5.5] undecyl, diazaspiro [3.3] heptyl, thiazaspiro [3.3] heptyl, thiazaspiro [4.3] octyl, Azaspiro [5.5] decyl-, as well as the other homologous spiro [3.4] -, spiro [4.4] -, spiro
• 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,
• Cö-Cio-Heterobicycloalkyl is preferred.
• bridged ring system such as C6-Ci2 cycloalkyl or bridged C-Coe bridged C6-Ci2 heterocycloalkyl is understood to mean a fusion of at least two saturated rings which share two atoms which are not directly adjacent to each other.
• bridged carbocycle bridged cycloalkyl
• bridged heterocycle bridged heterocycloalkyl
• Compounds of the invention are the compounds of the general formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas below and their salts, solvates and solvates of the salts of the general formula (I) and of the general formula (I) included, hereinafter referred to as exemplary embodiments
• Salts which are preferred in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
• Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of
• Hydrochloric hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
• Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs can be present either as a single polymorph or as a mixture of several polymorphs in all concentration ranges.
• the present invention also relates to pharmaceutical compositions containing the inventive
• Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
• the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers.
• the compounds of the invention can am
• the present invention therefore also encompasses diastereomers and their respective mixtures. From such mixtures, the pure stereoisomers can be isolated in a known manner; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on chiral or achiral phase. As a rule, the enantiomers according to the invention inhibit the target proteins differently and have different activity in the cancer cell lines investigated.
• the more active enantiomer is preferred, which is often that at which the center of asymmetry represented by the carbon atom attached to R 5 and R 6 is (R) -configured. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
• the present invention also includes all suitable isotopic variants of the compounds of the invention.
• An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the
• Compound according to the invention is exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass usually or predominantly occurring in nature.
• isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), n C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 1, 124 1, 129 I and 131 I.
• isotopic variants of a compound according to the invention in particular those in which one or more radioactive isotopes may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
• isotopes such as deuterium, may confer certain therapeutic benefits as a result of greater metabolic stability
• the present invention also includes prodrugs of the compounds of the invention.
• prodrugs includes compounds which may themselves be biologically active or inactive but which are converted during their residence time in the body into compounds according to the invention (for example metabolically or hydrolytically.)
• the compounds according to the invention can act systemically and / or locally
• Purpose it can be applied in a suitable manner, such. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
• the compounds of the invention can be used in suitable forms.
• Administration forms are administered.
• parenteral administration can be done bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarally) or with the involvement of resorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
• a resorption step eg intravenously, intraarterially, intracardially, intraspinally or intralumbarally
• the involvement of resorption eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
• parenteral administration are suitable as application forms, inter alia, injection and
• Infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhalation medicines i.a.
• 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 conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• adjuvants include, among others.
• Carriers e.g., microcrystalline cellulose, lactose, mannitol
• solvents e.g., liquid polyethylene glycols
• emulsifiers e.g., emulsifiers and dispersing or wetting agents
• binders e.g., polyvinylpyrrolidone
• synthetic and natural polymers e.g., albumin
• stabilizers e.g.
• Antioxidants such as ascorbic acid
• dyes e.g., inorganic pigments such as iron oxides
• flavor and / or odoriferous agents e.g., ascorbic acid
• dyes e.g., inorganic pigments such as iron oxides
• flavor and / or odoriferous agents e.g., ascorbic acid
• dyes e.g., inorganic pigments such as iron oxides
• compositions containing the compounds of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
• the formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
• excipients for example, vehicles, fillers, disintegrants,
• Binders humectants, lubricants, ab- and adsorbents, 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 of the invention are useful in the prophylaxis and / or treatment of hyperproliferative disorders such as psoriasis, keloids and other skin-related hyperplasia, benign prostatic hyperplasia (BPH), solid tumors and hematological tumors.
• hyperproliferative disorders such as psoriasis, keloids and other skin-related hyperplasia, benign prostatic hyperplasia (BPH), solid tumors and hematological tumors.
• 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.
• hematological tumors for example, multiple myelomas, lymphomas or leukemias are treatable.
• Breast tumors are treatable breast cancers with positive breast cancers
• non-small cell cancers are treatable as tumors of the respiratory tract
• tumors of the brain are treatable gliomas, glioblastomas, astrocytomas, Meningiomas and medulloblastomas.
• tumors of the male reproductive organs are treatable.
• Prostate cancers 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 as tumors of the gastrointestinal tract are colorectal carcinomas, anal carcinomas, gastric carcinomas, pancreatic carcinomas, esophageal carcinomas.
• Gallbladder carcinomas small intestinal carcinomas, salivary gland carcinomas, 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.
• hepatocellular carcinomas can be treated as tumors of the liver
• Treatable as tumors of the skin for example, malignant melanomas, basaliomas,
• tumors of the head and neck are treatable with laryngeal carcinomas and carcinomas of the pharynx and the oral cavity.
• soft-tissue sarcomas and osteosarcomas 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.
• Treatable as leukemias are, for example, 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 myeolemic leukemias,
• Prostate cancer especially androgen receptor-positive prostate cancer, Cervical carcinoma, breast cancer, especially of hormone receptor negative,
• Hormone receptor-positive or BRCA-associated breast carcinomas pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal
• 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
• 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 of degenerative joint disease (arthrosis); traumatic
• Vasculitis Panarteritis nodosa, temporal arteritis, erythema nodosum
• Dermatological disorders associated with inflammatory, allergic and / or proliferative processes atopic dermatitis; Psoriasis; Pityriasis rubra pilaris; erythematous diseases induced by different noxae, e.g. Blasting, chemicals, burns etc .; bullous dermatoses; Diseases of the lichenoid type; pruritus; Seborrheic dermatitis; rosacea; Pemphigus vulgaris; Erythema exudative multiforme;
• balanitis vulvitis
• Hair loss such as alopecia areata
• Liver diseases associated with inflammatory, allergic and / or proliferative processes acute liver cell decay; acute hepatitis of different causes, e.g. viral, toxic, drug-induced; Chronic aggressive and / or chronic intermittent hepatitis - Gastrointestinal diseases with inflammatory, allergic and / or proliferative
• 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
• 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, e.g. BNS-seizures
• Blood disorders associated with inflammatory, allergic and / or proliferative processes acquired hemolytic anemia; idiopathic thrombocytopenia Tumor diseases associated with inflammatory, allergic and / or proliferative processes: acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen;
• lymphosarcoma extensive metastases, especially in mammary, bronchial and
• Pro-cancer - Endocrine disorders associated with inflammatory, allergic and / or proliferative disorders associated with inflammatory, allergic and / or proliferative disorders
• Severe states of shock e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
• SIRS systemic inflammatory response syndrome
• Adrenal insufficiency e.g. congenital hypopituitarism
• Adrenal insufficiency e.g. postinfectious, tumors, etc
• Emesis associated with inflammatory, allergic and / or proliferative processes e.g. in combination with a 5-HT3 antagonist in cytostatic vomiting
• Pain of inflammatory genesis e.g. Lumbago.
• the compounds according to the invention are also suitable for the treatment of viral
• Diseases such as infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.
• the compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, periferous vascular diseases, cardiovascular diseases, angina, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.
• the compounds according to the invention are also suitable for the treatment of
• neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. These diseases are well characterized in humans but also exist in others Mammals.
• Another object of the present application are the compounds of the invention for use as medicaments, in particular for the prophylaxis and / or therapy of
• the present invention further relates to the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
• Hormone receptor-positive or BRCA-associated breast cancers pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung cancers, endometrial carcinomas and colorectal
• a further subject of the present application are the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
• Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
• Another object of the invention is the use of the compounds of the invention for the manufacture of a medicament.
• Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases.
• Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of
• Leukemias in particular acute myeolemic leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas .
• Endometrial carcinomas and colorectal carcinomas are endometrial carcinomas and colorectal carcinomas.
• Another object of the present application is the use of the invention Compounds for the manufacture of a medicament for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, breast cancers, in particular
• Estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma Another object of the present application is the use of the compounds of the invention for the prophylaxis and / or therapy of tumor diseases.
• the present application further relates to the use of the compounds according to the invention for the prophylaxis and / or treatment of leukemias, in particular acute myeolemic leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular hormone receptor negatives, hormone receptor-positive or BRCA-associated breast carcinomas .
• leukemias in particular acute myeolemic leukemias
• prostate cancers in particular androgen receptor-positive prostate carcinomas, cervical carcinomas
• breast cancers in particular hormone receptor negatives, hormone receptor-positive or BRCA-associated breast carcinomas .
• a further subject of the present application is the use of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, breast cancers, in particular estrogen receptor-alpha negative breast carcinomas, melanomas or multiple myelomas.
• a further subject of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic 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
• a further subject of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias,
• Prostate cancer especially androgen receptor-positive prostate cancer
• breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
• Another object of the invention is the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.
• Another object of the invention is the use of the compounds of the invention for the treatment of benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurodegenerative conditions
• 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.
• Eflornithine Eligard, Elitek, Ellence, Emend, Enzalutamide, Epirubicin, Epoetin-alfa, Epogen, Epothilone and its Derivatives, Eptaplatin, Ergamisol, Erlotinib, Erythro-Hydroxynonyladenine, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinylestradiol, Ethyol, Etidronic Acid,
• Etopophos etoposide, everolimus, exatecan, exemestane, fadrozole, farston, fenretinide, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), flu-ioxy-imesterone, flutamide , Folotin, Formestan, Fosteabin, Fotemustin, Fulvestrant, Gammagard, Gefitinib, Gemcitabine, Gemtuzumab, Gleevec, Gliadel, Goserelin, Gossypol, Granisetron hydrochloride, Hexamethylmelamine, Histamine dihydrochloride, Histrelin, Holmium-166-DOTPM, Hycamtin, Hydrocorton, erythro Hydroxynonyladenine, hydroxyurea, hydroxyprogesterone caproate, ibandr
• 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, ipilimumab, ofatumumab, panitumumab, pertuzumab, rituximab, tositumumab or trastuzumab and combine with 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 or thalidomide are used.
• angiogenesis-directed therapies such as e.g. Bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib, lenalidomide 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 radiotherapy and / or surgical intervention. Preparation of the compounds according to the invention: In the present description:
• NMR 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.
• T3P 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
• (+) - BINAP R) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (racemic) (benzotriazol-1-ylxy) bis-dimethylaminomethylium fluoroborate dicyclohexylcarbodiimide
• Scheme 1 Compounds of general formula (I) and their subgroups (Ia), (Ib) and (Ic).
• Scheme 2 illustrates the construction of amides of formula (V) from simple pyridine derivatives such as 5-amino-2,4-dichloropyridine ((II), CAS No. 7321-93-9).
• (III) a multiplicity of methods for the preparation of amides starting from the azido-carboxylic acids of the formula (IIa), in which R 5 and R 6 are defined as for the general formula (I), be used.
• coupling reagents known to the person skilled in the art, such as TB TU, HATU or
• DCC are used.
• an inorganic acid chloride such as thionyl chloride, phosphorus oxychloride or oxalyl chloride and subsequent addition of the pyridine amine.
• the preparation of the required azido-carboxylic acids has been described in the literature (Chem Eur J (2010), 16, p7572 et seq, D. Tietze et al., J Org Chem (2010), 75, p6532ff, Katritzky et al.).
• the handling of the carboxylic acid azides should be carried out with the utmost care, since they can decompose explosively.
• storage of the reagents required for the introduction of azide should be avoided.
• the reaction with trialkyl or triarylphosphines according to Staudinger can be carried out (Tetrahedron (2012), 68, p697ff, Laschat et al.).
• trimethylphosphine is suitable.
• the isolation of the amines (IV) can be carried out as free base or, advantageously, in salt form, for example as hydrochloride.
• the crude amine of the formula (IV) is dissolved in a nonpolar solvent, for example diethyl ether, and precipitated as a salt by adding an acid, for example hydrochloric acid.
• the secondary amines of formula (V) can be cyclized to give dihydropyridopyrazinones of formula (VI) (for further additions to intermediates of formula (VI) see also US 2006/009457).
• a suitable base under elevated temperature (see also WO2010 / 96426 A2, Example 16).
• the subsequent alkylation to compounds (VII) can be carried out by reaction with R '-I .G, wherein R 4 is defined as in the general formula (I) and LG is a leaving group, preferably iodide, in the presence of a suitable base such as Sodium hydride, according to known in the art conditions.
• the further reaction of the resulting compounds of the formula (VII) to the ester derivatives (VIII) can be carried out by reaction with aminopyridines of the formula (VIIa) in which A, K, R 3 and n are defined as in the general formula I, and in where R e is C-Coe-alkyl, (in a palladium-catalyzed coupling reaction by Buchwald and Hartwig see for example, J. Organomet. Chem.
• palladium As a source of palladium, suitable here are e.g. Palladium acetate or palladium
• (dba) complexes such as Pd 2 (dba) 3 (CAS Nos. 51364-51-3 and 52409-22-0, respectively).
• the conversion depends strongly on the ligands used.
• the examples given in the experimental part could thus be obtained, for example, by using (+) - BINAP (cf.
• aminopyridines of the formula (VIIa) are partly commercially available or can be prepared using methods known to those skilled in the art.
• the carboxylic acids thus obtained (IX) can be prepared in the invention carboxamides of the general formula (Ia) converted by reaction with the commercially available, as a rule, for example, to those specified in the examples, amines of the formula R 8 R 9 NH, where R 8 and R 9 are as defined for general formula (I), with additional activation by a method well known to those skilled in the art. Possible methods mentioned here are the use of HATU, HBTU, PyBOB or T3P with addition of a suitable base. Conversion of the carboxylic acids to their amides is generally described in reference books such as "Compendium of Organic Synthetic Methods," Volume I-VI (Wiley Interscience) or "The Practice of Peptide Synthesis,” Bodansky (Springer Verlag).
• this method can also be used as an alternative method for the preparation of carboxamides of the general formula (Ia) by replacing the sulfonamide intermediates (X) by the analogous carboxamides (XI) wherein A, R ⁇ R 3 , R 8 , R 9 and n are defined as in the general formula (I).
• heteroaromatic boronic acid or a corresponding boronic acid ester wherein HetAr is 5-membered monocyclic heteroaryl- as defined for R 1 in formula (I), and R is hydrogen or (VC -alkyl- or -B (OR) - for a Pmacolvlboronklaer, to the compounds of the formula (Ic) according to the invention (see also DG Hall, Boronic Acids, 2 ⁇ 5 WILEY VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8, and literature cited therein).
• Scheme 8 Alternative preparation of the compounds of the formula (Ic) according to the invention from compounds of the formulas (XIII) Furthermore, the compounds of the formula (Ic) according to the invention can also be synthesized from the ester intermediates of the formula (VIII) shown in scheme 4 and also carboxylic acids of the formula (IX) in a manner known to the person skilled in the art.
• the reaction pathways described allow the use of an enantiomerically pure azido-carboxylic acid of formula (IIa) at the beginning of the sequence, an epimerization or
• Racemisiemng the stereogenic center at the carbon atom, which is bound to R 5 and R, can be largely suppressed.
• R E is C 1 -C 6 -alkyl, which are preferred for the preparation of Compounds of the general formula (I) according to the invention can be used.
• Another object of the present invention are the intermediates of the general formula
• IUPAC names were created using the nomenclature software ACD Name batch, version 12.01, from Advanced Chemical Development, Inc., and adapted as needed, for example, to the German-language nomenclature.
• a compound is listed in the form of a salt of the corresponding base or acid, the exact stoichiometric composition of such a salt, as obtained by the respective preparation and / or purification process, is generally not known. Unless specified, therefore, name and structural formula additions such as
• Embodiments or salts thereof were obtained according to the described preparation and / or purification processes in the form of solvates, such as hydrates, whose stoichiometric composition (if defined type) is not known.
• intermediate 4.1 was prepared from 5.17 g Intermediate 2.5 and 6.41 g Intermediate 1.4.
• 3.2 g of 6 - [[(2R) -l-cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] were obtained. amino] -5-methoxypyridine-3-carboxylic acid methyl ester.
• Intermediate 5.2 was prepared from 700 mg Intermediate 2.5 and 791 mg Intermediate 5.1. 395 mg of 6 - [[(2R) -l-cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] were obtained. amino] -5-methylpyridine-3-carboxylic acid methyl ester.
• Example 1 6- ⁇ [1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino ⁇ -N-cyclopropyl 5-methoxypyridin-3-carboxamide
• Example 2 6- ⁇ [(2R) -1-Cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] amino ⁇ - N-cyclopropyl-5-methoxypyridin-3-carboxamide
• Example 3 6- ⁇ [(2R) -1-Cyclopentyl-2-ethyl-4-methyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino ⁇ -N-cyclopropyl-5-ethyl pyridine-3-carboxamide
• Example 5 6 - [[(2R) -1-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl) -amino ] -N-cyclopropyl-5-methoxy-3-pyridine carboxamide
• Example 7 6 - [[(2R) -1-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] -amino ] -5-methoxy-A r - (2,2,2-trifluoroethyl) -3-pyridinecarboxamide
• Example 8 6 - [[(2R) -1-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] -amino ] -5-methoxy-A r - (2-methoxyethyl) -3-pyridinecarboxamide
• Example 9 6- ⁇ [(2R) -1-Cyclopentyl-2-ethyl-4-methyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino ⁇ -5-ethyl-A r - [(3R) -2-tetrahydronaphthalen-3-yl] pyridine-3-carboxamide
• Example 10 6 - [[(2R) -1-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] -amino ] -5-methoxy-A r - (tetrahydro-2H-pyran-4-yl) -3-pyridinecarboxamide
• Example 11 6 - [[(2R) -1-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] -amino ] -A r - (2-hydroxy-1, 1-dimethylethyl) -5-methoxy-3-pyridine carboxamide
• Example 12 6 - [[(2R) -l-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-blpyrazine-T-yl-amino-S-methoxy -A' pyridinylmethy-iS ⁇ -S-pyridine
• Example 13 6- ⁇ [(2R) -1-Cyclopentyl-2-ethyl-4-methyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino ⁇ -A r cyclopropyl-5-methylpyridine-3-carboxamide
• Example 14 6 - [[(2R) -1-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] -amino ] -5-methoxy-A r - (l-methyl-4-piperidinyl) -3-pyridinecarboxamide
• Example 15 6- ⁇ [(2R) -1-Cyclopentyl-2-ethyl-4-methyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino ⁇ -5-methylpyridine-3-carboxamide
• Example 16 6 - [[(2R) -1-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] -amino ] -A r - [(3R) -hexahydro-2-oxo-lH-azepin-3-yl -5-methoxy-3-pyridine carboxamide]
• Example 17 6- ⁇ [(2R) -1-Cyclopentyl-2-ethyl-4-methyl-3-oxo-1,2,3,4-tetrahydropyrido [3,4-b] pyrazine-7-yl] -amino ⁇ -5-methyl- Ar - (tetrahydro-2H-pyran-4-yl) pyridine-3-carboxamide
• Example 18 6 - [[(2R) -1-Cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7-yl] -amino ] -5-methyl- Ar - (1-methyl-4-piperidinyl) pyridine-3-carboxamide
• Example 19 lA r cyclopentyl-7 - [[5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -3-methoxy-2-pyridinyl] amino] - (2R) -ethyl-4A r -methyl-l, 4-dihydro-pyrido [3,4-b] pyrazine-3 (2H) -one
• Example 11 A solution of 45 mg of Example 11 in 4.1 ml of THF was dissolved at 0 ° C with 65 mg Burgess Reagent and 4.1 ml DMF added. After 30 minutes, 66.4 mg of sodium dihydrogen phosphate were added and stirred at room temperature for 14 hours. It was stirred for a further 2 hours at 40 ° C and another 18 hours at room temperature. The approach was saturated
• Example 20 iV-Cyclohexyl-6 - [[(2R) -l-cyclopentyl-2-ethyl-1,2,3,4-tetrahydro-4-methyl-3-oxopyrido [3,4-b] pyrazine-7 -yl] amino] -5-methoxy-pyridine-3-carboxamide
• TR-FRET time-resolved fluorescence resonance energy transfer
• the Ac-H4 peptide may be derived from e.g. Biosyntan (Berlin, Germany).
• Biosyntan typically 11 different concentrations of each substance (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 ⁇ , 0.51 ⁇ , 1.7 ⁇ , 5.9 ⁇ and 20 ⁇ ) were measured as duplicates on the same microtiter plate.
• 100-fold concentrated solutions in DMSO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany).
• Assay buffer [50 mM HEPES pH 7.5, 50 mM sodium chloride (NaCl), 0.25 mM CHAPS and 0.05% serum albumin (BSA)] to the substances in the assay plate. This was followed by a 10 minute incubation step at 22 ° C for the pre-equilibration of putative complexes
• BRD4 (1) / Ac-H4 complexes was determined by measuring the resonance energy transfer from the streptavidin-Eu cryptate to the anti-6His-XL665 antibody that is in the reaction.
• the fluorescence emission at 620 nm and 665 nm after excitation at 330-350 nm were measured in a TR-FRET instrument, eg a Rubystar or Pherastar (both from BMG Lab Technologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer) ,
• the ratio of emission at 665 nm and at 622 nm (ratio) was taken as an indicator of the amount of BRD4 (1) / Ac-H4 complexes formed.
• the data obtained (ratio) were normalized with 0% inhibition equal to the mean of the measurements of a set of controls (typically 32 data points) containing all reagents. Instead of test substances, 50 ⁇ l of DMSO (100%) were used. 100% inhibition was the mean of the measurements from a set of controls (typically 32 data points) containing all reagents except BRD4 (1).
• recombinant fusion protein expressed by insect cells His5
• purified by glutathione-Sepharose affinity chromatography and subsequent gel filtration Superdex 75
• GST and Pik kinase domain 33-345, MW 36 kDa, conc 0.8 ⁇ g / ⁇ l
• the assay used was an indirect HTRF assay using the following materials and procedures.
• the biotinylated peptide Btn-Ahx-KKLNRTLSFAEPG-amide x TFA is used as a substrate for the kinase reaction.
• This is an artificial sequence that was not derived from any known protein.50 nl of the test compounds dissolved in 100% dimethylsulfoxide (DMSO) (final concentrations: 0 ⁇ and concentrations in the range of 0.001-20 ⁇ ) are labeled with 2 ⁇ plugs.
• DMSO dimethylsulfoxide
• Resonance energy transfer from europium-labeled antibody complex to streptavidine-XLent determined.
• the ratio of emissions at 665 nm and at 620 nm is used as a measure of the amount of phosphorylated substrate peptide.
• the ability of the substances to inhibit the proliferation of the MOLM-13 cell line was determined.
• Cell viability was determined using the alamarBlue® reagent (Invitrogen) in a Victor X3 Multilabel Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelength was 590 nM.
• the MOLM-13 cells were seeded in a density of 4000 cells / well in ⁇ growth medium on 96 well microtiter plates. After an overnight incubation at 37 ° C., the fluorescence values were determined (CI values). Then the plates were with different
• Table 1 shows the results from the BRD4 (1) binding assay.
• Table 2 shows the results of the Plk-1 assay at 10 ⁇ ATP.
• Table 3 shows the results of the Plk-1 assay at 10 mM ATP.
• Table 4 shows the results from the MOLM-13 cell proliferation assay.

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