EP2935260A1 - Dihydropyridopyrazinones inhibitrices de protéine bet - Google Patents
Dihydropyridopyrazinones inhibitrices de protéine betInfo
- Publication number
- EP2935260A1 EP2935260A1 EP13807998.3A EP13807998A EP2935260A1 EP 2935260 A1 EP2935260 A1 EP 2935260A1 EP 13807998 A EP13807998 A EP 13807998A EP 2935260 A1 EP2935260 A1 EP 2935260A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dimethyl
- amino
- oxo
- pyrazin
- tetrahydropyrido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 230000002401 inhibitory effect Effects 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 308
- 239000000543 intermediate Substances 0.000 claims abstract description 220
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 27
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 11
- 208000036142 Viral infection Diseases 0.000 claims abstract description 8
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 8
- 230000009385 viral infection Effects 0.000 claims abstract description 8
- 230000035558 fertility Effects 0.000 claims abstract description 7
- 230000003143 atherosclerotic effect Effects 0.000 claims abstract description 6
- -1 oxazolin-2-yl Chemical group 0.000 claims description 281
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 255
- 229910052739 hydrogen Inorganic materials 0.000 claims description 133
- 239000001257 hydrogen Substances 0.000 claims description 130
- 125000004043 oxo group Chemical group O=* 0.000 claims description 110
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 104
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 95
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 79
- 238000002360 preparation method Methods 0.000 claims description 78
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 77
- 229910052731 fluorine Inorganic materials 0.000 claims description 69
- 239000011737 fluorine Substances 0.000 claims description 69
- 229910052757 nitrogen Inorganic materials 0.000 claims description 67
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 61
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 57
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 57
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 57
- 150000002431 hydrogen Chemical class 0.000 claims description 45
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical compound OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 43
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 42
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- 125000003386 piperidinyl group Chemical group 0.000 claims description 37
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- 238000002560 therapeutic procedure Methods 0.000 claims description 34
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 28
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 22
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- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 13
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- 208000027866 inflammatory disease Diseases 0.000 claims description 10
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- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- HIGOCZJARKJCGG-UHFFFAOYSA-N 3,4-dihydro-1h-pyrido[2,3-b]pyrazin-2-one Chemical compound C1=CC=C2NC(=O)CNC2=N1 HIGOCZJARKJCGG-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000002393 azetidinyl group Chemical group 0.000 claims description 5
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- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
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- AVYKFAYOZMYSRM-GOSISDBHSA-N (3r)-6-[3-methoxy-4-(4-methylpiperazin-1-yl)sulfonylanilino]-1,3-dimethyl-4-(oxan-4-yl)-3h-pyrido[2,3-b]pyrazin-2-one Chemical compound N1([C@H](C)C(=O)N(C)C2=CC=C(N=C21)NC=1C=C(C(=CC=1)S(=O)(=O)N1CCN(C)CC1)OC)C1CCOCC1 AVYKFAYOZMYSRM-GOSISDBHSA-N 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- QZEAJAZZVVYMOM-UHFFFAOYSA-N ethyl 4-[[4-(2-methoxyethyl)-1,3-dimethyl-2-oxo-3H-pyrido[2,3-b]pyrazin-6-yl]amino]benzoate Chemical compound COCCN1C2=C(N(C(C1C)=O)C)C=CC(=N2)NC2=CC=C(C(=O)OCC)C=C2 QZEAJAZZVVYMOM-UHFFFAOYSA-N 0.000 claims description 2
- XJFMEPWWXNDJMI-QGZVFWFLSA-N n-[2-(dimethylamino)ethyl]-4-[[(3r)-1,3-dimethyl-4-(oxan-4-yl)-2-oxo-3h-pyrido[2,3-b]pyrazin-6-yl]amino]-3-methoxybenzamide Chemical compound COC1=CC(C(=O)NCCN(C)C)=CC=C1NC1=CC=C(N(C)C(=O)[C@@H](C)N2C3CCOCC3)C2=N1 XJFMEPWWXNDJMI-QGZVFWFLSA-N 0.000 claims description 2
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- 229960003895 verteporfin Drugs 0.000 description 1
- 229950005577 vesnarinone Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229960004449 vismodegib Drugs 0.000 description 1
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
Definitions
- the present invention relates to BET protein-inhibitory, in particular B RD4-inhibi toric Dihydropyridopyrazinone, intermediates for the preparation of the compounds of the invention, pharmaceutical compositions containing the compounds of the invention and their
- the human BET family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and HR DT) containing two related bromodomaines and one extra-terminal domain (Wu and Chiang, J. Biol. Chem. , 2007, 282: 13 141-13 145).
- 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 F-KB 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., 201 1, 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, 201 1, 13: 1295-1304).
- BRD4 is essential for transcription elongation and recruits the elongation complex P-TEFb, which consists of CDK9 and cyclin Tl, resulting in the activation of RNA polymerase 11 (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, el 003047). BRD2 and BRD3 bind to transcribed genes in hyperacetylated chromatin regions and promote transcription by RNA polymerase 11 (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 that are activated in the Gl phase, such as cyclin D1 and D2 (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040 -9048).
- BRD2 and BRD4 knockout mice die prematurely during embryogenesis (Gyuris et al., Biochim Biophys Acta, 2009, 1789: 413-421, Houzelstein et al., Mol. Cell Biol., 2002, 22: 3794-3802 ).
- Heterozygous BRD4 mice have various growth defects attributable to reduced cell proliferation (Houzelstein et al., Mol. Cell. Biol., 2002, 22: 3794-3802).
- BET proteins play an important role in various tumor types.
- the fusion between the BET proteins BRD3 or BRD4 and NUT results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet, Cytogenet., 2010, 203: 16 -20).
- the fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 2011, 286: 27663-27675).
- the growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073).
- BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, 478, 524-528). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo. Further experiments with a BRD4 inhibitor show that BRD4 plays a role in various hematological tumors, such as multiple myeloma (Delmore et al., Cell, 2011, 146, 904-917) and Burkitt's lymphoma (Mertz et al., Proc Natl.
- BRD4 also plays an important role in solid tumors, such as lung cancer (Lockwood et al., Proc, Natl. Acad. 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 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 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 novel treatment routes 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 from expression of inflammatory genes, such as I L-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1179-1123).
- 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).
- a BET inhibitor which also inhibits RDT results in a decrease in sperm production and infertility (Matzuk et al., Cell, 2012, 150: 673-684). All these studies show that the BET proteins play an essential role in various pathologies and also in male fertility. It would therefore be desirable to find potent and selective inhibitors that prevent the interaction between the BET proteins and acetylated proteins, particularly acetylated histone H4 peptides. These new inhibitors should also have suitable pharmacokinetic properties that allow in vivo, ie in the patient, to inhibit these interactions.
- 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).
- Other 4-phenyl-6i7-thieno [3,2-j [1,2,4] triazolo [4,3-a] [1, 4] diazepines and related compounds with alternative rings as fusion partners instead of the benzo moiety become generic claimed or explicitly described in WO2012 / 075456 (Constellation Pharmac eutical s).
- This application relates to 6-substituted-4-bis-soxazolo [5.4-d] [2] benzazepines and 4-iso-isoxazolo [3,4-ii] [2] benzazepines, including such compounds at position 6 optionally substituted phenyl and also analogues with alternative heterocyclic fusion partners instead of the benzo moiety, such as thieno or Pyridoazepine.
- Another structural class of BRD4 inhibitors is described as 7-isoxazoloquinolines and related quinolone derivatives (Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967).
- WO2011 / 054845 Gaxo SmithKline
- further benzodiazepines are described as B MM inhibitors.
- the compounds according to the invention are substituted 3,4-dihydropyrido [2,3-b] pyrazine-2 (1H) -one derivatives, which differ structurally in manifold forms from the chemotypes of BRD4 inhibitors discussed above , Due to the significant structural differences, it was not to be assumed that the compounds claimed here are also BRD4-inhibitory. It is therefore surprising that the compounds according to the invention have a good inhibitory effect despite the considerable structural differences.
- 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 2006/005510 (Boehringer Ingelheim) describes 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives as inhibitors of PLK-1 for the treatment of hyperproliferative diseases.
- the position of the pyrido-nitrogen distinguishes the substances disclosed herein from the compounds of the invention.
- WO 2008/117061 (Sterix Ltd) describes a number of bicyclic chemotypes as inhibitors of steroid sulfatase, inter alia, for use in inhibiting the growth of tumors.
- US 2006/0019961 (PE Mahaney et al.) Describes substituted 3,4-dihydroquinoxaline-2 (1H) -one derivatives as modulators of the estrogen receptor for the treatment of various inflammatory, cardiovascular and autoimmune diseases.
- WO 2006/050054, WO 2007/134169 and US 2009/0264384 (Nuada LLC) describe a number of bicyclic chemotypes as inhibitors of tumor necrosis factor alpha (T F- ⁇ ) as well as various isoforms of Pho sphodi esteras e for the treatment, inter alia of inflammatory diseases.
- WO 2012/088314 discloses a series of bicyclic chemotypes as modulators of pyruvate kinase M2.
- WO 2003/020722 and WO 2004/076454 disclose 7,8-dihydropteridine-6 (5H) -ones as inhibitors of specific cell cycle kinases for the treatment of hyperproliferative diseases.
- WO 2006/018182 (Boehringer Ingelheim) describes pharmaceutical preparations of 7,8-dihydropteridine-6 (5H) -ones in combination, inter alia, with various cytostatics for the treatment of tumor diseases.
- WO 2006/018185 (Boehringer Ingelheim) describes the use of 7,8-dihydropteridine-6 (5H) -ones for the therapy of various tumor diseases.
- WO 2011/101369 Boehringer Ingelheim
- WO 2011/113293 Jiangsu Hengrui Medicine
- WO 2009/141575 Choroma Therapeutics
- WO 2009/071480 Neviano Medical Sciences
- WO 2006/021378, WO 2006/021379 and WO 2006 / 021548 disclose further 7,8-dihydropteridine-6 (5H) -one derivatives as inhibitors of PLK-1
- WO 2007/022638 (Methylgene Inc.) generally discloses HDAC inhibitors of several chemotypes, however, the structures of the exemplified compounds disclosed differ significantly from the compounds of the present invention.
- WO 1999/050254 (Pfizer) describes a series of bicyclic chemotypes as inhibitors of
- A is -NH- or -O-
- X is -N-
- n 0 or 1
- oxazolin-2-yl which may optionally be monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl,
- R 2 is hydrogen, halogen, cyano, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Halo-C iC 4 alkyl, GC 4 alkoxy, C i -C 4 alkoxy-C i -C 4 alkyl, halo-C i-
- C 4 alkoxy, C 1 -C 4 -alkylthio, halogeno-C 1 -C 4 -alkylthio, or -NR 10 R " represents halogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy , C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl,
- Aromatics can be linked,
- G-Ce-alkyl may optionally be mono-, di- or trisubstituted by identical or different substituents with fluoro, oxo, cyano, hydroxy, C 1 -C 3 -alkoxy- or -NR'V,
- phenyl radical in each case j is optionally mono-, di-, or may be three times by identical or different substituents selected from halogen, cyano, GC 4 - alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 4 alkoxy, halogen-C iC 4 alkyl or halogen-C 1 -C 4 alkoxy,
- 4- to 8-membered heterocycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, fluoro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylcarbonyl- or C1-C4 alkoxycarbonyl,
- C 1 -C 6 -alkyl which may optionally be monosubstituted, disubstituted or trisubstituted, identically or differently, with hydroxyl, oxo, fluorine, cyano,
- C 3 -Cs -cycloalkyl or for C 3 -Cs -cycloalkyl, C 1 -C 5 -cycloalkenyl, C 5 -C 1 -silycycloalkyl-, it bridges Ce-Cn-cycloalkyl- or Ce-Cn-bicycloalkyi, which may be mono- or di-twice, the same or may be substituted by hydroxy, oxo, cyano, fluorine, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, trifluoromethyl, -NR 10 R ", or 4 to 8-membered heterocycloalkyl,
- 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, are 4- to 8-membered heterocycloalkyl, 4 to 8-membered heterocycloalkenyl, C 5 -C 11-
- R 10 and R "independently of one another represent hydrogen or G 1 -C 6 -alkyl optionally mono-, di- or trisubstituted identically or differently with hydroxyl, oxo or fluorine,
- R 10 and R 11 together with the nitrogen atom to which they are attached, represent 4- to 8-membered heterocycloalkyl, which may optionally be monosubstituted or disubstituted by identical or different substituents, with hydroxyl, oxo, cyano, fluoro, C 1 - C3 alkyl, halogen-Ci-C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-Ci-C 3 alkyl, benzyl or C 1 -C 4 alkoxycarbonyl,
- A stands for -NH-
- X is -N-
- n 0 or 1
- R 2 is hydrogen, fluorine, chlorine, cyano, GC 3 alkyl, fluorine-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 -alkoxy, C 1 -C 3 -alkylthio or fluoro-C 1 -C 3 -alkylthio,
- R 3 is fluorine, chlorine, methoxy, ethoxy or cyano and with each of the still free
- R 4 is methyl or ethyl
- R 5 is C 1 -C 3 -alkyl
- R is C 2 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl or phenyl-C 1 -C 3 -alkyl-,
- C 2 -Ce-alkyl optionally mono-, di- or trisubstituted by identical or different substituents with fluorine, GC 3 -alkoxy- or -NR 10 R U , and wherein the phenyl radical in each case optionally one, two or may be substituted with fluorine, chlorine, bromine, cyano, GC 3 alkyl, C 1 -C 3 -alkoxy- or trifluoromethyl,
- 4- to 8-membered heterocycloalkyl may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, fluoro, G-
- R 8 is G-Ce-alkyl which may optionally be monosubstituted, disubstituted or trisubstituted, identically or differently, by hydroxy, oxo, fluorine, cyano, GG-alkoxy-, fluoro-C 1 -C 3 - Alkoxy, -NR 10 R H , 4- to 8-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl,
- the 4- to 8-membered heterocycloalkyl may optionally be monosubstituted with oxo, G-C4-alkyl or C 1 -G -alkoxycarbonyl-, and wherein phenyl and 5- to 6-membered heteroaryl optionally one or two times, same or may be substituted by fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy, or represents GG-cycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, cyano, fluoro, -NR i0 R n , or 4- to 8-membered heterocycloalkyl,
- R 9 is hydrogen or C 1 -C 3 -alkyl
- R 8 and R 9 together with the nitrogen atom to which they are attached, are 4- to 8-membered heterocycloalkyl, Ce-Cs-heterospirocycloalkyl, bridged Ce-Cio-heterocycloalkyl or Ce-Cio-heterobicycloalkyl, which may be on or may be monosubstituted, identically or differently substituted with oxo, cyano, fluorine, C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, -NR 10 R ", C 1 -C 4 -alkylcarbonyi- or C 1 -C 4 -alkoxycarbonyl- .
- R 10 and R independently of one another represent hydrogen or optionally G-Ct-alkyl optionally mono-, di- or trisubstituted by identical or different hydroxy, oxo or fluoro,
- R 10 and R H together with the nitrogen atom to which they are attached, represent 4- to 7-membered heterocycloalkyl, which may optionally be monosubstituted or disubstituted by identical or different substituents, such as hydroxyl, oxo, cyano, fluoro, C 1 - C 3 alkyl, fluoro-C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 5 -C 6 -cycloalkylmethyl, benzyl or C 1 -C 4 -alkoxycarbonyl-,
- A stands for -NH-
- X is -N-
- n 0 or 1
- R ' is hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or ethoxy
- R 3 is methoxy- and with each of the still free positions of the aromatic
- R 4 is methyl
- R 5 is methyl or ethyl, R 'is hydrogen,
- R is C 2 -C 5 -alkyl, C 3 -C 6 -cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or phenyl-C 1 -C 8 -alkyl-,
- C 2 -C 5 -alkyl may optionally be monosubstituted with C 1 -C 3 -alkoxy
- 5- to 6-membered heterocycloalkyl may optionally be monosubstituted with G-C4-alkoxycarbonyl-,
- R 8 is C 1 -C 4 -alkyl which may optionally be monosubstituted by
- NR 10 R " 4- to 8-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl,
- the 4- to 8-membered heterocycloalkyl may optionally be monosubstituted with oxo, Ci-C4-alkyl or C 1 -C4 -alkoxycarbonyl-, and wherein phenyl and 5- to 6-membered heteroaryl optionally one or two times, the same or may be substituted by fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy, or is C 3 -Cs-cycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, -NR 10 R ", or 5- to 6-membered heterocycloalkyl,
- R 8 and R 9 together with the nitrogen atom to which they are attached, are 5- or 6-membered heterocycloalkyl or Ce-Cs-heterospirocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, fluoro, C 1 -C 3 -alkyl, C 3 -C 5 -cycloalkyl, -NR 10 R H , C 1 -C 4 -alkylcarbonyl- or C 1 -C 4 -alkoxycarbonyl-,
- R 10 and R independently of one another represent hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxycarbonyl,
- R i0 and R ! i together with the nitrogen atom to which they are attached are 5- to 6-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, fluoro, C 1 -C 3 -alkyl, fluoro-ci C3 alkyl, C 3 -Cs-cycloalkyl, Cs-Cs-cycloalkylmethyl or C 1 -C 4 alkoxycarbonyl, and their diastereomers, racemates, he Polymo and physiologically acceptable salts thereof.
- Very particular preference is given to those compounds of the general formula I in which
- A stands for -NH-
- X is -N-
- n 0 or 1
- R 2 is hydrogen, fluorine, methyl, or methoxy
- R 3 is methoxy- and with each of the still free positions of the aromatic
- R 4 is methyl
- R 5 is methyl or ethyl
- R 6 is hydrogen
- R is C 2 -C 4 -alkyl, Cs-Cy-cycloalkyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl,
- C 2 -C 4 -alkyl may optionally be monosubstituted with
- pyrrolidinyl and piperidinyl may optionally be monosubstituted with methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl-,
- R 8 is C 1 -C 2 -alkyl which may optionally be monosubstituted with N, N-
- pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl may optionally be monosubstituted by methyl, ethyl or tert-butoxycarbonyl,
- phenyl and pyridinyl may optionally be monosubstituted with fluorine, chlorine, methyl or methoxy-,
- Cs-Ce-cycloalkyl which may be optionally monosubstituted with hydro xy, oxo, -NR R I0 H, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
- R 9 is hydrogen or methyl
- R 8 and R 9 together with the nitrogen atom to which they are attached, for
- Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1-thia-6-azaspiro [3.3] hept-6 yl or 2-oxa-6-azaspiro [3.3] hept-6-yl are, which may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, fluoro, C 1 -C 3 alkyl, cyclopropyl, piperidine-l -yl or tert.
- Butoxycarbonyl, R 10 and R 11 are independently hydrogen, C 1 -C 3 alkyl or tert. Butoxycarbonyl,
- R i0 and R 11 together with the nitrogen atom to which they are attached, for pyrrolidinyl
- Piperidinyl, piperazinyl or morpholinyl which may optionally be mono- or di-substituted by identical or different substituents with fluorine, 2,2,2-trifluoroethyl, cyclopropyl, Cyclopropylmethyl- or tert. Butoxycarbonyl, and their diastereomers, racemates, polymorphs and physiologically acceptable salts.
- A stands for -NH-
- X is -N-
- n 0 or 1
- R represents hydrogen, fluorine, methyl or methoxy
- R 4 is methyl
- R 5 is methyl
- R ' is hydrogen
- R is wo-propyl, 2-methoxy-ethyl, Cs-C-C-cycloalkyl, T is hydro-pyran-4-yl,
- piperidin-4-yl may optionally be monosubstituted on the nitrogen atom contained therein with tert-butoxycarbonyl-,
- A is -NH- or -O-
- X is -N-
- R 1 is a group selected from
- R 2 is hydrogen, halogen, cyano, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl,
- R 3 is halogen, C 1 -C 3 -alkyl, C 1 -C 5 -alkoxy, trifluoromethyl or cyano and may be linked to any of the aromatic positions which are still free,
- R 4 is methyl or ethyl
- R 5 is hydrogen or C 1 -C 3 -alkyl
- R is hydrogen or C 1 -C 3 -alkyl
- R is G-Ce-alkyl, C 3 -Cs -cycloalkyl, 4- to 8-membered heterocycloalkyl or
- phenyl is optionally mono-, di- or three times, may be the same or different substituents selected from halogen, cyano, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 - alkynyl, Ci-C 4 -alkoxy, halogen-C 1 -C 4 alkyl or halogen-C iC 4 alkoxy, R 8 is C-Ce-alkyl optionally and independently one another once, twice, three times, or may be substituted by hydroxy, oxo, fluorine, cyano, GC 4 -alkoxy, halo-C 1 -C 4 -alkoxy, -NR 10 R n , 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C 5 -C n Heterospirocycloalkyl, bridged Ce-Cn-heterocycloalkyl, Ce-C
- 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-C may contain 11 -Heterospirocycloalkyl, bridged C6 -C 1 2 -Heterocy cl Oalkyl, Ce-Cn heterobicycloalkyl j in each case optionally one or more further heteroatoms and optionally once may be substituted by oxo, and wherein phenyl and 5- to 6-membered heteroaryl may be optionally substituted once or twice by halogen, cyano, trifluoromethyl, Ci-C 3 alkyl or Ci-Cs-alkoxy, or is C3-C6-alkenyl or C3-C6-alkynyl,
- C 3 -C 8 -cycloalkyl or C 4 -C -cycloalkenyl which may optionally be monosubstituted or disubstituted by hydroxyl, oxo, cyano, fluorine, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy-, trifluoromethyl-, -NR 10 R n , or 4- to 8-membered heterocycloalkyl, or 4- to 8-membered heterocycloalkyl, 4- to 8-membered
- 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- or 8-membered heterocycloalkyl, 4- or 8-membered heterocycloalkenyl, C 5 -C 1 1 -heterospirocycloalkyl, bridged Ce-Cn-heterocycloalkyl or ce- Cn- Heterobicycloalkyl, wherein in said radicals in each case optionally one or more further heteroatoms may be contained, and wherein said radicals may optionally be substituted once or twice by
- n 0 or 1
- R 10 and R are independently hydrogen or optionally hydroxy, oxo or
- Heterocycloalkyl which may optionally contain one or more further heteroatoms and may optionally be monosubstituted or disubstituted by identical or different substituents with hydroxyl, oxo, cyano, fluorine, G-Cs-alkyl, C3-C6-
- A stands for -NH-
- X is -N-
- R ' is hydrogen, fluorine, chlorine, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl-, C 1 -C3- alkoxy, fluoro-Ci-C 3 alkoxy, Ci-C3 alkylthio or fluoro-C 1 -C 3 alkylthio,
- R 3 is fluorine, chlorine or cyano and with each of the still free positions of the
- Aromatics can be linked,
- R 4 is methyl or ethyl
- R 5 is C 1 -C 3 -alkyl
- R is C2-C5-alkyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl or
- phenyl radical in which the phenyl radical can optionally be substituted once or twice, identically or differently, by fluorine, chlorine, bromine, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy-, or trifluoromethyl-,
- R 8 is C 1 -C 6 -alkyl which may optionally be substituted once, twice or three times by hydroxyl, oxo, fluorine, cyano, C 1 -C 3 -alkoxy, fluoro-C 1 -C 3 - Alkoxy, -NR 10 R ", 4- to 8-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl,
- 4- to 8-membered heterocycloalkyl may optionally contain one or more further heteroatoms and may optionally be substituted once by oxo,
- R 9 is hydrogen or C 1 -C 3 -alkyl
- R 8 and R 9 together with the nitrogen atom to which they are attached, represent 4- or 8-membered heterocycloalkyl, Ce-Cs-heterospirocycloalkyl, bridged G-Go heterocycloalkyl or Ce-Go heterobicycloalkyl, wherein in said Each optionally one or more further heteroatoms may be contained radicals, and wherein said radicals may optionally be substituted by oxo or Ci-C3-alkyl,
- n 0 or 1
- R 10 and R are independently hydrogen or optionally hydroxy, oxo or
- Heterocycloalkyl which may optionally contain one or more further heteroatoms and optionally once or twice, may be the same or different substituted with hydroxy, cyano, fluoro, Ci-C3-alkyl, cyclopropyl, cyclopropylmethyl, benzyl or Ci-C4-alkoxycarbonyl -
- A stands for -NH-
- X is -N-
- R ! stands for a group selected
- R is hydrogen, fluorine, chlorine, methoxy or ethoxy
- R 4 is methyl
- R 5 is methyl or ethyl
- R is Cs-Cs-alkyl, C3-C6-cycloalkyl, 5- to 6-membered heterocycloalkyl or
- R 8 is C 1 -C 4 -alkyl or C 3 -C 12 -cycloalkyl which may optionally be substituted once by -NR 1 R 11 or 4 to 8-membered heterocycloalkyl, or represents 4 to 8-membered heterocycloalkyl,
- Cs-Ce-cycloalkyl or 4-8-membered heterocycloalkyl may optionally be substituted once by oxo, and wherein the 4-8 membered heterocycloalkyl may optionally contain one or more further heteroatoms,
- R 9 is hydrogen or methyl
- R 8 and R 9 together with the nitrogen atom to which they are bonded, represent 5-membered 6-membered heterocycloalkyl or Ce-Cs-heterospirocycloalkyl, it being possible where appropriate to contain one or more further heteroatoms in the abovementioned radicals, and optionally be substituted once mentioned radicals may be represented by oxo or Ci-C3-alkyl,
- n 0
- R 10 and R are independently of one another hydrogen or Ci-Gt-alkyl
- R 10 and R 11 together with the nitrogen atom to which they are attached, represent 5- to 6-membered heterocycloalkyl, which may optionally contain a further heteroatom, and which may optionally be monosubstituted with C 1 -C 3 -alkyl, Cyclopropyl, cyclopropylmethyl, benzyl or ieri-butoxycarbonyl, and their diastereomers, racemates, polymorphs and physiologically acceptable salts.
- A stands for -NH-
- X is -N-
- R ! for a group is selected
- R 2 is hydrogen or methoxy
- R 5 is methyl
- R 6 is hydrogen
- R represents where -propyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl or benzyl,
- R 9 is hydrogen or methyl
- n 0,
- A stands for -NH-
- R ! stands for a group selected
- R 2 is hydrogen or methoxy
- R 4 is methyl
- R 5 is methyl
- R ' is hydrogen
- R 7 is where propyl, cyclopentyl, cyclohexyl or tetrahydropyran-4-yl, R 8 is
- R ' is hydrogen or methyl
- A is -NH- or -O-
- X is -N-
- R 1 is a group selected from
- R - is hydrogen, halogen, cyano, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl,
- R 3 is halogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, trifluoromethyl or cyano and may be linked to any of the still free positions of the aromatic,
- R 4 is methyl or ethyl
- R 5 is C 1 -C 3 -alkyl
- R 6 is hydrogen or C 1 -C 3 -alkyl
- R ' is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl or phenyl-C 1 -C 3 -alkyl-,
- phenyl is optionally mono-, di- or three times, may be the same or different substituents selected from halogen, cyano, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 - alkynyl, Ci-C 4 Alkoxy, haloC 1 -C 4 alkyl or haloC 1 -C 4 alkoxy, represents C 1 -C 6 -alkyl which may optionally be substituted once, twice or three times by hydroxy, oxo, fluorine, cyano, C 1 -C 4 -alkoxy, halogeno-C 1 -C 4 -alkoxy , -NR'V, 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, Cs-C 11 heterospirocycloalkyl, bridged Ce-Cn-heterocycloalkyl, Ce-Cn-heterobicycloalky
- 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-C 11 heterospirocycloalkyl, bridged Ce-Cn-heterocycloalkyl, Ce-Cn-heterobicycloalkyl may each optionally contain one or more further heteroatoms and optionally once substituted may be oxo, and wherein phenyl and 5- to 6-membered heteroaryl may be optionally substituted once or twice by halogen, cyano, trifluoromethyl, Ci-C3-alkyl or Ci-C 3 alkoxy, or for Cs Ce-alkenyl or Cs-Cö-alkynyl, or is C3-Cs-cycloalkyl or C4-C8-cycloalkenyl, which may be optionally mono- or disubstituted by hydroxy, oxo, cyano, fluoro, Ci-C3-alkyl, C 1 -C 3
- Heterocycloalkyl which may optionally contain one or more further heteroatoms and may optionally bear one or two substituents which are independently selected from hydroxy, oxo, cyano, fluorine or C 1 -C 5 -alkyl,
- A is -NH- or -O-
- X is -N-
- R ! stands for a group selected
- R 2 is hydrogen, fluorine, chlorine, cyano, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl-, C 1 -C3-
- R 3 is fluorine, chlorine or cyano and with each of the still free positions of the
- Aromatics can be linked,
- R 4 is methyl or ethyl
- R 5 is C 1 -C 3 -alkyl
- R ' is hydrogen
- R ' is C 2 -C 5 -alkyl, C 3 -C 6 -cycloalkyl or phenyl-C 1 -C 3 -alkyl-,
- phenyl radical in which the phenyl radical can optionally be substituted once or twice, identically or differently, by fluorine, chlorine, bromine, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy-, or trifluoromethyl-,
- R 8 is Ci-Cö-alkyl, which optionally and independently of one, two, or
- 4- to 8-membered heterocycloalkyl may optionally contain one or more further heteroatoms and may optionally be substituted once by oxo,
- C 3 -C 6 -cycloalkyl which may optionally be monosubstituted or disubstituted by hydroxy, oxo, cyano, fluorine, or -NR 10 R H , or represents 4- to 8-membered heterocycloalkyl, Ce-Cg-heterospirocycloalkyl, bridged it is Ce-Cio-heterocycloalkyl or Ce-Cio-Heterobicycloalkyl, wherein in each case one or more further heteroatoms may optionally be contained in said radicals, and wherein the optionally be substituted once or twice by hydroxy, oxo, cyano, fluorine, cis
- R 9 is hydrogen or C 1 -C 3 -alkyl
- R 8 and R 9 together with the nitrogen atom to which they are attached represent 4- or 8-membered heterocycloalkyl, Ce-Cs-heterospirocycloalkyl, bridged C 6 -C 10
- n 0 or 1
- R 10 and R are independently hydrogen or optionally hydroxy, oxo or
- Heterocycloalkyl which may optionally contain one or more further heteroatoms and may optionally bear one or two substituents which are independently selected from hydroxy, cyano, fluorine or C 1 -C 3 -alkyl,
- R ' for R 8 represents C 1 -C 4 -alkyl, which may optionally be substituted once by -NR 10 R n or 4- to 8-membered heterocycloalkyl, or represents Cs-Ce-cyeloalkyl, or represents 4- to 8-membered heterocycloalkyl,
- Cs-Ce-cycloalkyl or 4-8-membered heterocycloalkyl may optionally be substituted once by oxo, and wherein the 4-8 membered heterocycloalkyl may optionally contain one or more further heteroatoms,
- R 9 is hydrogen or methyl
- R 8 and R 9 together with the nitrogen atom to which they are attached, are 5- or 6-membered heterocycloalkyl or Ce-Cs-heterospirocycloalkyl, it being possible where appropriate to contain one or more further heteroatoms in the radicals mentioned, and Radicals may optionally be substituted by oxo or C 1 -C 3 -alkyl,
- n 0
- R 10 and R independently of one another represent hydrogen, methyl or ethyl
- A is -NH- or -O-
- X is -N-
- R ! for a group is selected
- R is hydrogen or methoxy
- R 4 is methyl
- ⁇ is methyl
- R 6 is hydrogen
- R is z ' so-propyl, cyclopentyl, cyclohexyl or benzyl,
- R is hydrogen or methyl
- R 8 and R 9 together with the nitrogen atom to which they are attached, for
- n 0,
- A stands for -NH-
- X is -N-
- R 2 is hydrogen or methoxy
- R 4 is methyl
- R 7 is z ' so-propyl, cyclopentyl, cyclohexyl or benzyl, R for
- R 9 is hydrogen or methyl
- n 0,
- A is -O-
- X is -N-
- R 1 is a group selected from
- R 2 is hydrogen or methoxy
- R 4 is methyl
- R 5 is methyl
- R is hydrogen
- R 7 is ⁇ -propyl, cyclopentyl, cyclohexyl or benzyl,
- R 9 is hydrogen or methyl
- R 8 and R 9 together with the nitrogen atom to which they are attached, for
- n 0,
- R is hydrogen, fluorine, chlorine, C 1 -C 3 -alkyl or GC 3 -alkoxy.
- R 2 is hydrogen, fluorine, chlorine, C 1 -C 3 -alkyl or C 1 -C -alkoxy-, and in which n is the number 0.
- R is hydrogen, fluorine, chlorine, methyl or methoxy.
- R "is hydrogen is preferred.
- 5- to 6-membered heterocycloalkyl may optionally be monosubstituted with Ci-C4-alkoxycarbonyl-.
- R is 5- to 6-membered heterocycloalkyl, where 5- to 6-membered heterocycloalkyl may optionally be monosubstituted with G-Cr alkoxycarbonyl-.
- R is C 2 -C 4 -alkyl, C 5 -C 7 -cycloalkyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, phenyl or benzyl,
- C 2 -C 4 -alkyl may optionally be monosubstituted with methoxy-
- pyrrolidinyl and piperidinyl may optionally be monosubstituted with methoxy carbonyl, ethoxycarbonyl or tert. Butoxy carbonyl -.
- R is C 2 -C 4 -alkyl in which C 2 -C 4 -alkyl may optionally be monosubstituted with methoxy-,
- pyrrolidinyl and piperidinyl may optionally be monosubstituted with
- pyrrolidinyl and piperidinyl may optionally be monosubstituted with tert-butoxycarbonyl-.
- R is pyrrolidinyl or piperidinyl
- pyrrolidinyl and piperidinyl may optionally be monosubstituted with
- pyrrolidinyl and piperidinyl may optionally be monosubstituted with tert-butoxycarbonyl-.
- R is piperidin-4-yl
- piperidin-4-yl on the nitrogen atom contained therein may optionally be monosubstituted by methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl-.
- R is piperidin-4-yl
- piperidin-4-yl on the nitrogen atom contained therein may optionally be monosubstituted with tert-butoxycarbonyl-.
- R 8 is C 1 -C 4 -alkyl which may optionally be monosubstituted with -NR 10 R H , 4- to 8-membered heterocycloalkyl, phenyl or 5-6 heteroaryl,
- 4- to 8-membered heterocycloalkyl may optionally be monosubstituted with oxo, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxycarbonyl-,
- 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,
- C3-Cs-cycloalkyl which is optionally mono- or may be disubstituted by identical or different substituents selected from hydroxy, oxo, -NR R I0 ", or 5- to 6-membered heterocycloalkyl, or 4- to 8-membered Heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, Ci-C3-alkyl, -NR I 0 R ", Ci-C 4 -alkylcarbonyl- or Ci-C 4 -alkoxycarbonyl-.
- R 8 is C 1 -C 4 -alkyl which may optionally be monosubstituted with -NR 10 R H , 4- to 8-membered heterocycloalkyl, phenyl or 5-6 -liked heteroaryl,
- 4- to 8-membered heterocycloalkyl may optionally be monosubstituted with oxo, Ci-C 4 alkyl or GC 4 alkoxycarbonyl-,
- 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.
- substituents with fluorine, chlorine, cyano, trifluoromethyl, methyl or methoxy.
- C3-C8-cycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with hydroxy, oxo, -NR 10 R ", or 5- to 6-membered heterocycloalkyl.
- R 8 is 4- to 8-membered heterocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, C 1 -C 3 -alkyl, -NR 10 R Preferred are compounds of the general formula (I) in which R 8 is C 1 -C 4 -alkyl or C 3 -C 6 -cycloalkyl, optionally once may be substituted by -NR 10 R H or 4- to 8-membered heterocycloalkyl,
- Cs-Ce-cycloalkyl or 4-8-membered heterocycloalkyl may optionally be substituted once by oxo, and wherein the 4-8 membered heterocycloalkyl may optionally contain one or more further heteroatoms.
- R 8 is a C 1 -C 4 -alkyl group which may optionally be substituted once by -NR 10 R H or a 4-8-membered heterocycloalkyl group which may be an or may contain more heteroatoms and optionally may be substituted once by oxo.
- R 8 is a C 3 -C 6 -cycloalkyl group which may optionally be substituted once by -NR 1 R 11 or oxo.
- R 8 is a C 3 -C 6 -cycloalkyl group which may optionally be substituted once by - R 10 R n .
- R 8 is a C 3 -C 6 -cycloalkyl group which may optionally be substituted once by oxo.
- R 8 is a C 3 -C 6 -cycloalkyl group.
- R 8 is a 4- to 8-membered heterocycloalkyl group which optionally contains one or more further heteroatoms can and optionally be substituted once by oxo.
- R 8 is a 4- to 7-membered heterocycloalkyl group which may optionally contain one or more further heteroatoms and may optionally be substituted once by oxo.
- R 8 is a 5- to 6-membered heterocycloalkyl group which may optionally contain one or more further heteroatoms and may optionally be substituted once by oxo.
- R 8 is a C 12 -C 20 heterospirocycloalkyl group which may optionally contain one or more further heteroatoms and may optionally be substituted once by oxo.
- R 8 is a C ⁇ -CIO-
- Heterobicycloalkyl group which may optionally contain one or more further heteroatoms and may optionally be substituted once by oxo.
- R 8 is a bridged Ce-Cio-heterocycloalkyl group which may optionally contain one or more further heteroatoms and may optionally be substituted once by oxo.
- R 8 is C 1 -C 2 -alkyl which may optionally be monosubstituted with N, N-dimethylamino-, N-ethyl-N-methylamino-, N, N -diethylamino- , Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl or pyridinyl, in which pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl may optionally be monosubstituted with methyl, ethyl or ieri.-butoxycarbonyl-,
- phenyl and pyridinyl may optionally be monosubstituted with fluorine, chlorine, methyl or methoxy-,
- Cs-Ce-cycloalkyl which may optionally be monosubstituted with hydroxy, oxo, -NR 10 R n , pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
- R 8 is C 1 -C 2 -alkyl, which may optionally be substituted once with N, N-dimethylamino, N-ethyl-N-methylamino, N, A r diethylamino -, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl or pyridinyl, wherein pyrrolidinyl, piperidinyl, piperazinyl and Mo may be monoline optionally monosubstituted with methyl, ethyl or ieri.-butoxycarbonyl,
- phenyl and pyridinyl may optionally be monosubstituted with fluoro, chloro, methyl or methoxy.
- R 8 is C 1 -C 2 -alkyl which may optionally be monosubstituted with N, N-dimethylamino, piperazinyl, morpholinyl, phenyl or pyridinyl,
- piperazinyl and morpholinyl may optionally be monosubstituted with methyl or ferric. butoxycarbonyl.
- C5-C6-cycloalkyl which may optionally be monosubstituted with hydroxy, oxo, - NR 10 R ", pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.
- R 8 is oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl or piperidinyl, which may optionally be monosubstituted by methyl, ethyl or acetyl.
- R 8 and R 9 are Ce-Cs-heterospirocycloalkyl which may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, fluorine, C 1 -C 8 -alkyl, C 3 -C 5 -cycloalkyl, -NR 10 R H , GC 4 -alkylcarbonyl or GC 4 -alkoxycarbonyl-.
- R 8 and R together with the nitrogen atom to which they are bonded, represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1-thia-6-azaspiro [3.3] hept-6 yl or 2-oxa-6-azaspiro [3.3] hept-6-yl are, which may optionally be monosubstituted or disubstituted by identical or different substituents with oxo, fluoro, G-C3-alkyl, cyclopropyl, piperidine-l -yl or teri-butoxycarbonyl-.
- R 8 and R 9 are 4- to 7-membered heterocycloalkyl which may optionally contain one or more further heteroatoms and optionally may be substituted once by oxo or G-C3-alkyl.
- R i0 and R "independently of one another are hydrogen or C 1 -C 4 -alkyl optionally substituted by hydroxyl or fluorine.
- R 10 and R 11 independently of one another, are hydrogen or C 1 -C 8 -alkyl optionally substituted by hydroxyl or fluorine.
- R 10 and R 11 independently of one another are hydrogen or C 1 -C -cycloalkyl which is optionally monosubstituted, disubstituted or trisubstituted identically or differently with hydroxyl, oxo or fluorine,
- R 10 and R 11 independently of one another are hydrogen or C 1 -C 4 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl.
- R 10 is hydrogen or C 1 -C 4 -alkyl.
- R H is hydrogen or C 1 -C 4 -alkyl.
- R 10 is hydrogen, methyl or ethyl.
- R 1 1 is hydrogen, methyl or ethyl.
- R 10 is C 1 -C 4 -alkoxycarbonyl - and R ! 'stands for hydrogen.
- R 10 and R 11 independently of one another are hydrogen, G-C 3 -alkyl or tert-butoxycarbonyl.
- R 10 is G-Gralkyl and R 11 is hydrogen.
- R 10 is G-C 3 -alkyl and R "is C 1 -C 3 -alkyl
- Particularly preferred are compounds of the general formula (I) in which R 10 is C 1 C 2 alkyl and R H is Ci-C 2 alkyl.
- R 10 and R i! together with the nitrogen atom to which they are attached represent 4- to 7-membered heterocycloalkyl, which may optionally be monosubstituted or disubstituted by identical or different substituents, with hydroxyl, oxo, cyano, fluoro, C 1 -C 3 -alkyl, Fluorine-GC 3 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl, benzyl or C 1 -C 4 -alkoxycarbonyl-.
- R i0 and R "together with the nitrogen atom to which they are attached represent 4- to 7-membered heterocycloalkyl, which may optionally contain one or more further heteroatoms and optionally one - or two, the same or different, may be substituted with hydroxy, cyano, fluorine, GC 3 alkyl, cyclopropyl, cyclopropylmethyl, benzyl or G-C4-alkoxycarbonyl-.
- R 10 and R 11 together with the nitrogen atom to which they are bonded, are 4- to 7-membered heterocycloalkyl which may optionally contain one or more further heteroatoms and optionally one or two substituents independently selected from hydroxy, oxo, cyano, fluoro or G-Cs-alkyl.
- Compounds of general formula (I) are those in which R 10 and R 11 together with the nitrogen atom to which they are bonded, represent 5- to 6-membered heterocycloalkyl, which is optionally mono- or disubstituted by identical or different substituents can with oxo, fluorine, O-C 3 -alkyl, fluoro-Ci-Cs-alkyl, C 3 -C 5 -Cycloaikyl, Cs-Cs-cycloalkylmethyl or GC 4 - alkoxycarbonyl.
- Heterocycloalkyl which may be simply substituted with Ci-C 3 alkyl, cyclopropyl, cyclopropylmethyl, benzyl or feri-butoxycarbonyi-.
- R 10 and R "together with the nitrogen atom to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, which may be monosubstituted or disubstituted by identical or different substituents may be fluorine, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or ferric. butoxycarbonyl.
- Ci-Ce-alkyl, or a G-Ce-Aikyl group is a linear or branched, saturated, monovalent hydrocarbon radical to understand, such as a methyl, ethyl, propyl, butyl, pentyl, hexyl iso-propyl, zso-butyl, sec-butyl, tert-butyl, z ' is pentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, eo -Pentyl, 1, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 2,3-dimethylbutyl, 1, 3-dimethylbutyl or
- Ci-Cö-alkyl or a G-Ce-alkyl group Ci-C4-alkyl, C2-C4-alkyl or C 2 -Cs-alkyl, particularly preferably Ci-C3-alkyl or a methyl, ethyl , Propyl or isopropyl radical to understand.
- C2-Cs-alkylene or a C2-C5-alkylene group
- a linear or branched, saturated, divalent hydrocarbon radical such as, for example, an ethylene, propylene, butylene, pentylene, zso-propylene, z ' is-butylene, sec-butylene, teri-butylene, z, so-pentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropyl ene, 1,2-dimethylpropylene, eo-pentyl ene or 1,1-dimethylpropylene radical.
- C2-C6-alkenyl or a C2-C6-alkenyl group is meant a linear or branched, monovalent hydrocarbon radical having one or two C double bonds, such as an ethenyl, (is) -prop-2 -enyl, (Z) -prop-2-enyl, allyl (prop-1-enyl), allenyl-buten-1-yl, or buta-1, 3-dienyl.
- C3-Ce-Aikenyl or C 2 -C4-alkenyl is preferred, ethenyl and allyl are particularly preferred.
- C 2 -C 6 -alkynyl or a C 2 -C 6 -alkynyl group
- G-C4-alkoxy or a Ci-C4-alkoxy group is meant a linear or branched, saturated alkyl ether radical -O-alkyl, such as. a methoxy, ethoxy, n-propoxy, isopropoxy or ieri.-butoxy radical.
- Ci -Ct-alkoxy or a Ci-C4-alkoxy group Ci-C3-alkoxy, especially 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, for example a methylthio, ethylthio, n-propylthio, isopropylthio, or tert. Butylthio radical.
- C 1 -C 4 -alkylthio or a C 1 -C 4 -alkylthio group is understood as meaning C 1 -C 3 -alkylthio, particularly preferably a methylthio or ethylthio radical.
- the NHNH of the abovementioned sulfoximine may optionally be substituted by C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl-.
- 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 / ara position.
- a halo-C 1 -C 4 alkylR est a Ci-C 4 alkyl, with at least one
- Halogen substituents preferably having at least one fluorine substituent to understand.
- fluorine-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 8 -alkyl group and which is bonded via the C 1 -C 3 -alkyl radical. Grappe is bound to the rest of the molecule. Benzyl is preferred.
- C3-C6-cycloalkyl-Ci-C3-alkyl or a C3-C6-cycloalkyl-C 1 -C3 -alkyl group is meant a group which is composed of Cs-Ce-cycloalkyl as defined below and a C 1 -C3 alkyl group, and which is bonded via the G -C3 alkyl group to the rest of the molecule. Preference is given to C3-C6-cycloalkylmethyl, particularly preferably cyclopropylmethyl.
- a halogeno-C 1 -C 4 -alkoxy radical is a C 1 -C 4 -alkoxy radical having at least one
- Halogen substituents preferably having at least one fluorine substituent to understand.
- fluoro-C 1 -C 3 -alkoxy radicals for example difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy radicals.
- a halogeno-C 1 -C 4 -alkylthio radical is to be understood as meaning a C 1 -C 4 -alkylthio radical having at least one halogen substituent, preferably having at least one fluorine substituent.
- fluorine-C 1 -C 3 -alkylthio radicals in particular trifluoromethylthio.
- methoxycarbonyl ethoxycarbonyl, or tert. -Butoxycarbonyl-.
- Ci-C 4 alkoxy-GC 4 alkyl is to be understood 4 alkyl radical substituted with a Ci-C G-GrAlkoxy such.
- 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. These ring systems may have 5, 6 or 7 ring atoms or, in the case of condensed or benzo-fused ring systems, also combinations of 5- and 6-membered ring systems, 5- and 5-membered ring systems or also 6- and 6-membered ring systems , Examples include ring systems such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, Oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, be
- Cs-Ce-cycloalkyl, C3-Cs-cycloalkyl or Cs-Cs-cycloalkyl is a monocyclic saturated ring system composed exclusively of carbon atoms with 3 to 6, 3 to 8
- Atoms or 5 to 8 atoms to understand. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
- C 1 -C 6 -cycloalkenyl, C 1 -C 5 -cycloalkenyl or C 5 -C 8 -cycloalkenyl is a monocyclic, mono- or polyunsaturated, non-aromatic ring system having 4 to 6, 4 to 8 atoms or 5, which is composed exclusively of carbon atoms to understand 8 atoms.
- Examples are cyclobuten-1-yl, cyclopenten-1-yl, cyclohexen-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, particularly preferred are 5- to 6-membered heterocycloalkyl groups.
- Heterocycloalkenyl is a 4- to 8-membered monocyclic, mono- or polyunsaturated, non-aromatic ring system which has 1 to 3 heteroatoms as defined above, in any desired combination. Preference is given to 4- to 7-membered heterocycloalkyl groups, particularly preferred are 5- to 6-membered heterocycloalkyl groups.
- Examples which may be mentioned are 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, [1,3] dioxolyl, 4H- [1,3,4] thiadiazinyl, 2,5-dihydrofuranyl, 2,3- Dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H- [1,4] thiazinyl. Under C5-O 1 -spirocycloalkyl or Cs-Cn-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 jhexyl, 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 heteroatom-modified variants such as azabicyclo [3.3.0] octyl, azabicyclo [4.3.0-nonyl, diazabicyclo [4.3.0] nonyl, oxazabicyclo [4.3. 0] nonyl, thiazabicyclo [4.3.0 ionoyl or azabicyclo [4.4.0] decyl and the other possible combinations as defined.
- Preferred is Ce-Oo-Heterobicycloalkyl.
- a bridged Ce-Cn-bridged ring system such as Ce-Cn cycloalkyl or 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.
- both a bridged carbocycle arise as well as a bridged heterocycle (bridged heterocycloalkyl) with a replacement of 1-4 carbon atoms by heteroatoms as defined above in any combination.
- Examples are bicyclo [2.2.1] heptyl, azabicyclo [2.2.1] heptyl, oxazabicyclo [2.2.1] heptyl, thiazabicyclo [2.2.1] heptyl,
- 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 used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to the invention.
- Physiologically acceptable salts of the compounds of this 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,
- 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. Depending on their structure, the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational 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 dural carbon atom.
- the present invention therefore also encompasses diastereomers and their respective mixtures. From such mixtures, the pure stereoisomers can be isolated in a known manner; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on chiral or achiral phase.
- the enantiomers according to the invention inhibit the different degrees of inhibition
- Another object of the present invention are enantiomeric mixtures of the (3i?) - Configured inventive compounds with their (35) enantiomers, in particular the corresponding racemates and enantiomeric mixtures in which outweighs the (3A) form.
- 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
- 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), ! 3 C, 14 C, 15 N, 7 0, ls O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, S2 Br, 123 1, 124 1, 129 I and 13 T.
- Certain isotopic variants of a compound of the invention such as in particular those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or the
- isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
- isotopic variants of the compounds according to the invention can be prepared by the methods known to the person skilled in the art, for example by the methods described below and the instructions reproduced in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
- the compounds according to the invention can act systemically and / or locally.
- they can be administered in a suitable manner, for example orally, parenterally, pulmonary, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunetivally, 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), in dragees, in granules, in pellets, in powders, in emulsions, in suspensions, in aerosols or in solutions.
- the parenteral administration can be done bypassing a ⁇ ⁇
- 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.
- Injections and Infusions Preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- inhalation medicaments i.a.
- 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 include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitanoleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin). .
- excipients e.g., microcrystalline cellulose, lactose, mannitol
- solvents e.g., liquid polyethylene glycols
- emulsifiers and dispersing or wetting agents e.g., sodium dodecyl sulfate, polyoxysorbitanoleate
- binders e.g., polyvinylpyrrolidone
- synthetic and natural polymers e.g., albumin
- Stabilizers for example, antioxidants such as ascorbic acid
- dyes for example, inorganic pigments such as iron oxides
- flavor and / or odoriferous for example, antioxidants such as ascorbic acid
- Stabilizers for example, antioxidants such as ascorbic acid
- dyes for example, 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 per se to the person skilled in the art by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
- auxiliaries customary in galenicals.
- excipients for example, vehicles, fillers, disintegrants,
- Binders humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts to change the osmotic pressure or buffers are used.
- Remington's Pharmaceutical Science 15th ed. Mack Publishing Company, East Pennsylvania (1980).
- the pharmaceutical formulations may be in solid form, for example as tablets, dragees, pills, suppositories, capsules, transdermal systems or in semi-solid form, for example as ointments, creams, gels, suppositories, emulsions or in liquid form, for example as solutions, Tinctures, suspensions or emulsions are present.
- 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.
- excipients may be of natural origin or may be obtained synthetically or partially synthetically.
- oral or oral administration in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question.
- the compounds according to the invention are suitable for the prophylaxis and / or therapy of hyperproliferative diseases such as, for example, psoriasis, keloids and other skin-related hyperplasias, and for the prophylaxis and / or therapy of benign prostate hyperplasia (BPH), solid tumors and hematological tumors.
- hyperproliferative diseases such as, for example, psoriasis, keloids and other skin-related hyperplasias
- BPH benign prostate hyperplasia
- tumors for example, tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the
- Urogenital tract eye, liver, skin, head and neck, thyroid gland, parathyroid gland, bone, connective tissue and metastases of these tumors.
- breast tumors for example, are treatable breast cancers with positive breast cancers
- tumors of the respiratory tract are non-cell monocellular
- tumors of the brain are treatable gliomas, glioblastomas, astrocytomas, meningiomas, and metullobl astomes.
- 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
- Vulvar carcinomas For example, treatable tumors of the gastrointestinal tract are colorectal carcinomas, anal carcinomas, gastric carcinomas, pancreatic carcinomas, esophageal carcinomas.
- Gallbladder carcinomas small bowel carcinomas, salivary gland carcinomas, neuroendocrine tumors and gastrointestinal stromal tumors.
- tumors of the urogenital tract can be treated 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 tumors of the skin are malignant melanomas, basaliomas,
- tumors of the head and neck are treatable with laryngeal carcinomas and carcinomas of the pharynx and 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 acute myeloid leukemias, chronic myeloid leukemias, acute lymphatic 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 carcinomas especially androgen receptor-positive prostate carcinomas
- 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 cancers, in particular androgen receptor-positive prostate carcinomas, Breast cancer, in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
- leukemias in particular acute myeloid leukemias
- prostate cancers 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 diseases of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatoses, especially Boeck's disease.
- Rheumatic diseases / autoimmune diseases / joint diseases 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
- Insect bites Insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis,
- Vasculitides Panarteritis nodosa, temporal arteritis, erythema nodosum,
- atopic dermatitis Psoriasis; Pityriasis rubra pilaris; erytliematous diseases caused by different noxious agents, eg radiation, 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 is more likely to be genesis, for example, 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; Gastro enteritides 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.
- Neurological diseases associated with inflammatory, allergic and / or proliferative processes brain edema, especially tumor-related brain edema; multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, such as BNS cramps.
- Blood disorders associated with inflammatory, allergic and / or proliferative processes acquired hemolytic anemia; idiopathic thrombocytopenia.
- Tumor diseases associated with inflammatory, allergic and / or proliferative processes acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in mammary, bronchial and prostate cancers.
- Endocrine disorders associated with inflammatory, allergic and / or proliferative processes endocrine orbitopathy; thyrotoxic crisis; Thyreoditis de Quervain; Hashimoto's thyroiditis; Graves' disease.
- Organ and tissue transplants Organ and tissue transplants, graft-versus-host disease.
- Severe states of shock such as anaphylactic shock, systemic shock
- SIRS inflammatory response syndrome
- hypopituitarism acquired secondary adrenal insufficiency, for example postinfectious, tumors, etc. - emesis associated with inflammatory, allergic and / or proliferative processes, for example in combination with a 5-HT3 antagonist in cytostatic vomiting.
- Pain of inflammatory genesis e.g. Lumbago.
- the compounds according to the invention are also suitable for the treatment of viral
- Diseases such as infections caused by papilloma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.
- the compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, peripheral vascular disorders, cardiovascular disorders, angina, pectoris, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.
- the compounds according to the invention are also suitable for the treatment of
- neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease.
- 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
- Estrogen receptor-alpha negative breast carcinoma melanoma or multiple myeloma.
- Another object of the invention is the use of the compounds of the invention for the manufacture of a medicament.
- Another object of the present invention relates to the use of
- Another object of the present application 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,
- Another object of the present invention relates to the use of
- Compounds according to the invention for the manufacture of a medicament for the prophylaxis and / or therapy of leukemias in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, breast cancers, in particular Estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
- Another object of the present invention relates to 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 carcinomas especially androgen receptor-positive prostate carcinomas
- Hormone receptor-positive or BRCA-associated breast carcinomas pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-K unicellular bronchial carcinomas, endometrial carcinomas 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 carcinomas especially androgen receptor-positive prostate carcinomas
- Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
- Another object of the invention relates to the use of the compounds of the invention for the treatment of diseases associated with proliferative processes. 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 according to the invention can 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.
- Abiraterone acetate Abraxane, Acolbifen, Actimmun, Actinomycin D (Dactinomycin), Afatinib, Affini tak, Afinitor, Aldesleukin, Alendronic acid, Alfaferone, Alitretinoin, Allopurinol, Aloprim,
- Etopophos etoposide, everolimus, exatecan, exemestane, fadrozole, farston, fenretinide, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, folotin, formestan , Fosteabin, Fotemustin, Fulvestrant, Gammagard, gefitinib, gemcitabine, gemtuzumab, Gleevec, gliadel, goserelin, gossypol, granisetron hydrochloride, hexamethylmelamine, histamine dihydrochloride, histrelin, holmium-166-DOTPM, hycamtine, hydrocorton, erythro-hydroxynonyladenine, hydroxyurea , Hydroxyprogesterone caproate, ibandr
- Intron A Iressa, irinotecan, ixabepilone, keyhole limpet, hemocyanin, cytril, lanreotide, lapatinib, lasofoxifene, lenalidomide, lentinan sulfate, lestaurtinib, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolic acid calcium salt, levothroid, levoxyl, libra , Liposomal MTP-PE, Lomustine, Lonafarnib, Lonidamm, Marinol, Mechlorethamine, Mecobalamin, Medroxyprogesterone Acetate, Megestrol Acetate, Melphalan, Menest, 6-Mercaptopurine, Mesna, Methotrexate, Metvix, Miltefosine, Minocycline, Minodronate, Miproxifen, Mitomycin C , Mit
- Pazopanib pediapred, pegaspargase, pegasys, pemetrexed, pentostatin, N-phosphonoacetyl-L-aspartate, picibanil, pilocarpine hydrochloride, pirarubicin, plerixafor, plicamycin, PN-401, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, Procarbitol, Procrit, QS-21, Quazepam, R-1589, Raloxifene, Raltitrexed, Ranpirnas, RDEA119, Rebif, Regorafenib, 13-cis Retinoic Acid, Rhenium 186 Etidronate, Rituximab, Roferon A, Romidepsin, Romurtide, Ruxolitinib, Salagen, Salinomycin, Sandostatin, Sargramostim, Satraplatin, Semaxatinib, Se
- Tiludronic acid tipifarnib, tirapazamine, TLK-286, toceranib, topotecan, toremifene,
- the compounds of the invention with antibodies such as
- Aflibercept alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab,
- 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 inhibitors of P-TEFb and / or CDK9 are also particularly suitable because of the possible synergistic effects.
- the combination of the compounds of the invention with other cytostatic or cytotoxic agents can achieve the following objectives: improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to treatment with a single active substance;
- 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:
- NMR signals are given with their respective recognizable Multipiiztician or their combinations.
- s singlet
- d doublet
- t triplet
- q quartet
- qi quintet
- sp septet
- m multiplet
- b broad signal.
- LiHMDS lithium bis (trimethylsilyl) amide
- 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).
- Enantiomerengemische for example racemates, or occur as pure enantiomers.
- the enantiomer mixtures mentioned can be prepared by those familiar to the person skilled in the art
- Scheme 2 illustrates the construction of amides of formula (V) from simple pyridine derivatives such as 3-amino-2,6-dichloropyridine ((II), CAS # 62476-56-6).
- simple pyridine derivatives such as 3-amino-2,6-dichloropyridine ((II), CAS # 62476-56-6).
- the coupling reagents known to the person skilled in the art, such as TBTU, HATU or IX C.
- an inorganic acid chloride such as
- the reaction with trialkyl or triaryl phosphines according to Staudinger can be carried out (Tetrahedron (2012), 68. p697ff, Laschat et al.). Suitable is, for example Trimethylpho sphin.
- 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.
- Scheme 3 Alternative Synthesis Access to Compounds of Formula (IV).
- the secondary amines of formula (V) can be cyclized to give dihydropyridopyrazinones of formula (VI).
- a suitable base for example a trialkylamine such as triethylamine or NN-diisopropylethylamine, at elevated temperature implement (see also
- the further reaction of the resulting compounds of the formula (VII) to the ester derivatives (VIII) can be carried out by reaction with compounds of the formula (VIIa) in which A, R 2 , R 3 and n are defined as in the general formula I, and in which R 1 is Ci-Cö-alkyl, in a palladium-catalyzed coupling reaction according to Buchwald and Hartwig (see, for example, J. Organomet Chem (1999), 576, pl25ff).
- Suitable palladium sources here are, for example, palladium (II) acetate or palladium (dba) complexes, such as, for example, Pd 2 (dba) 3 (CAS No. 51364-51-3 or 52409-22-0).
- the conversion depends strongly on the ligands used.
- the examples listed in the Experimental Part could thus be obtained, for example, by the use of (+) - BINAP or Xanthphos (cf also US2006 / 009457 Al).
- carboxamides of the general formula (Ia) can be carried out according to Scheme 5 by hydrolysis of the respective esters of the formula (VIII) to give the corresponding carboxylic acids of the formula (IX) according to methods known to the person skilled in the art.
- These implementations can be preferably using alkali hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide in aqueous alcoholic solutions, optionally with the addition of a cyclic ether such as T etrahydro furan perform.
- reaction routes allow the use of an enantiomerically pure azido carboxylic acid of the formula (IIa) or an enantiomerically pure, nitrogen-protected amino acid of the formula (IIb) at the beginning of the sequence epimerization or racemization of the stereogenic center on the carbon atom, which at R 5 and R "is bound, can be suppressed as much as possible.
- the compounds of the formula (Ib) according to the invention having a sulfonamide group at the site of R 1 can be prepared according to Scheme 6.
- compounds of the formula (VII) can be reacted in an analogous manner as in Scheme 4 for the reaction of (VII) (VIII), with compounds of the formula (X) in which A, R ⁇ R 3 , R 8 , R 9 and n are defined as in the general formula (I), in a palladium-catalyzed coupling reaction according to Buchwald and Hartwig are reacted directly to the compounds of formula (Ib) according to the invention.
- This reaction can be carried out by reaction in various solvents such as toluene or acetonitrile and with the addition of a base such as potassium carbonate, di-o-propylethylamine or triethylamine at elevated temperature (Org. Lett. (2008), 10, p 2905 et seq, SP Marsden et al.).
- a base such as potassium carbonate, di-o-propylethylamine or triethylamine at elevated temperature
- Dihydropyridopyrazinones of the formula (Via) in which R 7, as defined by the general formula (I), represents optionally substituted phenyl are obtained by cyclization of the compounds of the formula (XIII) in the presence of a suitable base, for example triethylamine, diiso Propyl ethylamine or potassium carbonate under elevated temperature in solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or also
- R and n have the meanings given in the general formula (I) and R E is C 1 -C 6 -alkyl, which can preferably be used to prepare the compounds of the general formula (I) according to the invention.
- a further subject of the present invention are also the intermediates of the compounds of general formula (IX),
- R ⁇ R 3 , R 4 , R ⁇ R ', R and n have the meanings given in the general formula (I), which can likewise preferably be used for the preparation of the compounds of the general formula (I) according to the invention.
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Abstract
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EP13807998.3A EP2935260A1 (fr) | 2012-12-20 | 2013-12-17 | Dihydropyridopyrazinones inhibitrices de protéine bet |
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PCT/EP2013/076784 WO2014095774A1 (fr) | 2012-12-20 | 2013-12-17 | Dihydropyridopyrazinones inhibitrices de protéine bet |
EP13807998.3A EP2935260A1 (fr) | 2012-12-20 | 2013-12-17 | Dihydropyridopyrazinones inhibitrices de protéine bet |
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EP (1) | EP2935260A1 (fr) |
JP (1) | JP2016504990A (fr) |
CN (1) | CN105229002A (fr) |
AR (1) | AR094148A1 (fr) |
CA (1) | CA2895404A1 (fr) |
HK (1) | HK1213899A1 (fr) |
TW (1) | TW201427981A (fr) |
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---|---|---|---|---|
US20160193206A1 (en) * | 2012-12-20 | 2016-07-07 | Bayer Pharma Aktiengesellschaft | Bet-protein-inhibiting dihydropyridopyrazinones |
US9227985B2 (en) | 2013-03-15 | 2016-01-05 | Incyte Corporation | Tricyclic heterocycles as bet protein inhibitors |
US9290514B2 (en) | 2013-07-08 | 2016-03-22 | Incyte Holdings Corporation | Tricyclic heterocycles as BET protein inhibitors |
CA2917562A1 (fr) * | 2013-07-09 | 2015-01-15 | Bayer Pharma Aktiengesellschaft | Dihydroquinoxalinones et dihydropyridopyrazinones inhibitrices de proteine bet modifiees |
WO2015013635A2 (fr) | 2013-07-25 | 2015-01-29 | Dana-Farber Cancer Institute, Inc. | Inhibiteurs des facteurs de transcription et leurs utilisations |
WO2015081203A1 (fr) | 2013-11-26 | 2015-06-04 | Incyte Corporation | Hétérocycles bicycliques servant d'inhibiteurs des protéines bet |
US9315501B2 (en) | 2013-11-26 | 2016-04-19 | Incyte Corporation | Bicyclic heterocycles as BET protein inhibitors |
WO2015095492A1 (fr) | 2013-12-19 | 2015-06-25 | Incyte Corporation | Hétérocycles tricycliques en tant qu'inhibiteurs des protéines bet |
EP3099171A4 (fr) * | 2014-01-31 | 2017-08-09 | Dana-Farber Cancer Institute, Inc. | Dérivés de dihydroptéridinone et leurs utilisations |
RU2016134947A (ru) | 2014-01-31 | 2018-03-01 | Дана-Фарбер Кансер Институт, Инк. | Производные диаминопиримидин бензолсульфона и их применение |
JP2017504651A (ja) | 2014-01-31 | 2017-02-09 | ダナ−ファーバー キャンサー インスティテュート, インコーポレイテッド | ジアゼパン誘導体の使用 |
HUE061770T2 (hu) | 2014-04-23 | 2023-08-28 | Incyte Holdings Corp | 1H-pirrolo[2,3-C]piridin-7(6H)-onok és pirazolo[3,4-C]piridin-7(6H)-onok mint BET fehérjék gátlószerei |
CN106573931A (zh) * | 2014-06-18 | 2017-04-19 | 拜耳医药股份有限公司 | 抑制BET蛋白的具有间位取代的芳族氨基或醚基的3,4‑二氢吡啶并[2,3‑b]吡嗪酮 |
WO2015193217A1 (fr) * | 2014-06-18 | 2015-12-23 | Bayer Pharma Aktiengesellschaft | Dérivés de dihydropyrido[2,3-b]pyrazinone inhibant la protéine bet, à groupe éther ou amino aromatique para-substitué |
KR102633122B1 (ko) | 2014-08-01 | 2024-02-05 | 누에볼루션 에이/에스 | 브로모도메인에 대하여 활성을 갖는 화합물 |
JP2017525759A (ja) * | 2014-08-08 | 2017-09-07 | ダナ−ファーバー キャンサー インスティテュート, インコーポレイテッド | ジヒドロプテリジノン誘導体およびその使用 |
RU2017104897A (ru) | 2014-08-08 | 2018-09-10 | Дана-Фарбер Кэнсер Инститьют, Инк. | Производные диазепана и их применения |
US9527864B2 (en) | 2014-09-15 | 2016-12-27 | Incyte Corporation | Tricyclic heterocycles as BET protein inhibitors |
JP6930913B2 (ja) | 2014-10-14 | 2021-09-01 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニアThe Regents Of The University Of California | 炎症を阻害するためのcdk9及びbrd4阻害剤の使用法 |
GB201504694D0 (en) | 2015-03-19 | 2015-05-06 | Glaxosmithkline Ip Dev Ltd | Covalent conjugates |
AU2016276963C1 (en) | 2015-06-12 | 2021-08-05 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
US10501438B2 (en) | 2015-08-11 | 2019-12-10 | Neomed Institute | Aryl-substituted dihydroquinolinones, their preparation and their use as pharmaceuticals |
WO2017024406A1 (fr) * | 2015-08-11 | 2017-02-16 | Neomed Institute | Lactames bicycliques n-substitués, leur préparation et leur utilisation en tant qu'agents pharmaceutiques |
EP3334719B1 (fr) | 2015-08-12 | 2021-09-15 | Neomed Institute | Benzimidazoles substitués, préparation et utilisation de ceux-ci en tant qu'agents pharmaceutiques |
US11306105B2 (en) | 2015-09-11 | 2022-04-19 | Dana-Farber Cancer Institute, Inc. | Cyano thienotriazolodiazepines and uses thereof |
SG10202007099TA (en) | 2015-09-11 | 2020-08-28 | Dana Farber Cancer Inst Inc | Acetamide thienotriazoldiazepines and uses thereof |
WO2017066876A1 (fr) | 2015-10-21 | 2017-04-27 | Neomed Institute | Imidazopyridines substituées, leur préparation et leur utilisation comme médicaments |
AR106520A1 (es) | 2015-10-29 | 2018-01-24 | Incyte Corp | Forma sólida amorfa de un inhibidor de proteína bet |
CN114957291A (zh) | 2015-11-25 | 2022-08-30 | 达纳-法伯癌症研究所股份有限公司 | 二价溴结构域抑制剂及其用途 |
US10519151B2 (en) | 2016-01-28 | 2019-12-31 | Neomed Institute | Substituted [1,2,4]triazolo[4,3-A]pyridines, their preparation and their use as pharmaceuticals |
DE102017005091A1 (de) | 2016-05-30 | 2017-11-30 | Bayer Pharma Aktiengesellschaft | Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one |
EP3472157B1 (fr) | 2016-06-20 | 2023-04-12 | Incyte Corporation | Formes cristallines solides d'un inhibiteur bet |
CN109350616B (zh) * | 2018-12-18 | 2020-04-21 | 南华大学 | I-brd9或其衍生物在制备抗癫痫药物中的应用 |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
CN113717080A (zh) * | 2021-10-09 | 2021-11-30 | 西安瑞联新材料股份有限公司 | 一种4-氯-2-氰基苯磺酰氯的合成方法 |
WO2023205251A1 (fr) | 2022-04-19 | 2023-10-26 | Nuevolution A/S | Composés actifs vis-à-vis de bromodomaines |
Family Cites Families (6)
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US7351709B2 (en) * | 2004-06-09 | 2008-04-01 | Wyeth | Estrogen receptor ligands |
EP2078016B1 (fr) * | 2006-10-19 | 2012-02-01 | Signal Pharmaceuticals LLC | Composés hétéroaryle, compositions de ceux-ci et procédés de traitement avec ceux-ci |
JP2012197231A (ja) * | 2009-08-06 | 2012-10-18 | Oncotherapy Science Ltd | Ttk阻害作用を有するピリジンおよびピリミジン誘導体 |
CA2799373A1 (fr) * | 2010-05-14 | 2011-11-17 | Dana-Farber Cancer Institute, Inc. | Compositions et procedes permettant de moduler un metabolisme |
US20160193206A1 (en) * | 2012-12-20 | 2016-07-07 | Bayer Pharma Aktiengesellschaft | Bet-protein-inhibiting dihydropyridopyrazinones |
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- 2013-12-17 EP EP13807998.3A patent/EP2935260A1/fr not_active Withdrawn
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- 2013-12-17 WO PCT/EP2013/076784 patent/WO2014095774A1/fr active Application Filing
- 2013-12-19 AR ARP130104872A patent/AR094148A1/es unknown
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US20160193206A1 (en) | 2016-07-07 |
WO2014095774A1 (fr) | 2014-06-26 |
TW201427981A (zh) | 2014-07-16 |
AR094148A1 (es) | 2015-07-15 |
HK1213899A1 (zh) | 2016-07-15 |
JP2016504990A (ja) | 2016-02-18 |
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CA2895404A1 (fr) | 2014-06-26 |
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