WO2017060322A2 - Conjugué anticorps-médicament (adc) inhibiteur de ptefb - Google Patents

Conjugué anticorps-médicament (adc) inhibiteur de ptefb Download PDF

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WO2017060322A2
WO2017060322A2 PCT/EP2016/073825 EP2016073825W WO2017060322A2 WO 2017060322 A2 WO2017060322 A2 WO 2017060322A2 EP 2016073825 W EP2016073825 W EP 2016073825W WO 2017060322 A2 WO2017060322 A2 WO 2017060322A2
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alkyl
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hydrogen atom
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WO2017060322A3 (fr
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Pierre Wasnaire
Nils Griebenow
Niels Böhnke
Ulrich LÜCKING
Hans-Georg Lerchen
Beatrix Stelte-Ludwig
Christoph Mahlert
Ulf Bömer
Simone Greven
Lisa Dietz
Carsten TERJUNG
Kunzeng ZHENG
Gao Ping
Gang Chen
Jiajun XI
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6857—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from lung cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to novel conjugates of a binder or a derivative thereof with one or more molecules of an active component, wherein the active component is a CDK9 kinase inhibitor, which is conjugated to the binder via a linker Z as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-pro liferative disorders.
  • CDK cyclin-dependent kinase
  • the family of cyclin-dependent kinase (CDK) proteins consists of members that are key regulators of the cell division cycle (cell cycle CDK's), that are involved in regulation of gene transcription (transcriptional CDK's), and of members with other functions. CDKs require for activation the association with a regulatory cyclin subunit.
  • the cell cycle CDKs CDKl/cyclin B, CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, and CDK6/cyclinD get activated in a sequential order to drive a cell into and through the cell division cycle.
  • Positive transcription factor b is a heterodimer of CDK9 and one of four cyclin partners, cyclin Tl, cyclin K, cyclin T2a or T2b.
  • CDK9 NCBI GenBank Gene ID 1025
  • CAK CDK-activating kinase
  • RNA polymerase II Transcription of genes by RNA polymerase II is initiated by assembly of the pre- initiation complex at the promoter region and phosphorylation of Ser 5 and Ser 7 of the CTD by CDK7/cyclin H. For a major fraction of genes RNA polymerase II stops mRNA transcription after it moved 20-40 nucleotides along the DNA template. This promoter-proximal pausing of RNA polymerase II is mediated by negative elongation factors and is recognized as a major control mechanism to regulate expression of rapidly induced genes in response to a variety of stimuli (Cho et al., Cell Cycle 9, 1697, 2010).
  • P-TEFb is crucially involved in overcoming promoter-proximal pausing of RNA polymerase II and transition into a productive elongation state by phosphorylation of Ser 2 of the CTD as well as by phosphorylation and inactivation of negative elongation factors.
  • PTEFb activity is regulated by several mechanisms. About half of cellular PTEFb exists in an inactive complex with 7SK small nuclear RNA (7SK snRNA), La-related protein 7 (LARP7/PIP7S) and hexamethylene bis-acetamide inducible proteins 1/2 (HEXIM1/2, He et al., Mol Cell 29, 588, 2008). The remaining half of PTEFb exists in an active complex containing the bromodomain protein Brd4 (Yang et al., Mol Cell 19, 535, 2005). Brd4 recruits PTEFb through interaction with acetylated histones to chromatin areas primed for gene transcription.
  • 7SK snRNA 7SK small nuclear RNA
  • LRP7/PIP7S La-related protein 7
  • HEXIM1/2 hexamethylene bis-acetamide inducible proteins 1/2
  • Brd4 recruits PTEFb through interaction with acetylated histones to chromatin areas primed for gene transcription.
  • PTEFb is maintained in a functional equilibrium: PTEFb bound to the 7SK snRNA complex represents a reservoir from which active PTEFb can be released on demand of cellular transcription and cell proliferation (Zhou & Yik, Microbiol Mol Biol Rev 70, 646, 2006). Furthermore, the activity of PTEFb is regulated by posttranslational modifications including phosphorylation/de- phosphorylation, ubiquitination, and acetylation (reviewed in Cho et al., Cell Cycle 9, 1697, 2010).
  • CDK9 kinase activity of the PTEFb heterodimer is associated with a variety of human pathological settings such as hyper-proliferative diseases (e.g. cancer), virally induced infectious diseases or cardiovascular diseases:
  • Cancer is regarded as a hyper-proliferative disorder mediated by a disbalance of proliferation and cell death (apoptosis).
  • High levels of anti-apoptotic Bcl-2-family proteins are found in various human tumors and account for prolonged survival of tumor cells and therapy resistance.
  • Inhibition of PTEFb kinase activity was shown to reduce transcriptional activity of RNA polymerase II leading to a decline of shortlived anti-apoptotic proteins, especially Mcl-1 and XIAP, reinstalling the ability of tumor cells to undergo apoptosis.
  • a number of other proteins associated with the transformed tumor phenotype are either short-lived proteins or are encoded by short-lived transcripts which are sensitive to reduced RNA polymerase II activity mediated by PTEFb inhibition (reviewed in Wang & Fischer, Trends Pharmacol Sci 29, 302, 2008).
  • RNA polymerase II gets recruited to the promoter region within the viral LTR's.
  • the viral transcription activator (Tat) protein binds to nascent viral transcripts and overcomes promoter-proximal RNA polymerase II pausing by recruitment of PTEFb which in turn promotes transcriptional elongation.
  • the Tat protein increases the fraction of active PTEFb by replacement of the PTEFb inhibitory proteins HEXIM1/2 within the 7SK snRNA complex.
  • Cardiac hypertrophy the heart's adaptive response to mechanical overload and pressure (hemodynamic stress e.g. hypertension, myocardial infarction), can lead, on a long term, to heart failure and death. Cardiac hypertrophy was shown to be associated with increased transcriptional activity and RNA polymerase II CTD phosphorylation in cardiac muscle cells. PTEFb was found to be activated by dissociation from the inactive 7SK snRNA/HEXIMl/2 complex. These findings suggest pharmacological inhibition of PTEFb kinase activity as a therapeutic approach to treat cardiac hypertrophy (reviewed in Dey et al., Cell Cycle 6, 1856, 2007).
  • CDK9 kinase activity of the PTEFb heterodimer
  • CDK9 and one of four cyclin partners, cyclin Tl, cyclin K, cyclin T2a or T2b represents an innovative approach for the treatment of diseases such as cancer, viral diseases, and/or diseases of the heart.
  • CDK9 belongs to a family of at least 13 closely related kinases of which the subgroup of the cell cycle CDK's fulfills multiple roles in regulation of cell proliferation.
  • co- inhibition of cell cycle CDKs e.g.
  • CDKl/cyclin B, CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, CDK6/cyclinD) and of CDK9 is expected to impact normal proliferating tissues such as intestinal mucosa, lymphatic and hematopoietic organs, and reproductive organs.
  • CDK9 kinase inhibitors molecules with high selectivity towards CDK9 are required.
  • CDK inhibitors in general as well as CDK9 inhibitors are described in a number of different publications: WO2008129070 and WO2008129071 both describe 2,4 disubstituted aminopyrimidines as CDK inhibitors in general. It is also asserted that some of these compounds may act as selective CDK9 inhibitors (WO2008129070) and as CDK5 inhibitors (WO2008129071), respectively, but no specific CDK9 ICso (WO2008129070) or CDK5 IC 50 (WO2008129071) data is presented.
  • WO2008129080 discloses 4,6 disubstituted aminopyrimidines and demonstrates that these compounds show an inhibitory effect on the protein kinase activity of various protein kinases, such as CDK1, CDK2, CDK4, CDK5, CDK6 and CDK9, with a preference for CDK9 inhibition (example 80).
  • WO2005026129 discloses 4,6 disubstituted aminopyrimidines and demonstrates that these compounds show an inhibitory effect on the protein kinase activity of various protein kinases, in particular CDK2, CDK4, and CDK9.
  • WO 2009118567 discloses pyrimidine and [l,3,5]triazine derivatives as protein kinase inhibitors, in particular CDK2, CDK7 and CDK9.
  • WO2011116951 discloses substituted triazine derivatives as selective CDK9 inhibitors.
  • WO2012117048 discloses disubstituted triazine derivatives as selective CDK9 inhibitors.
  • WO2012117059 discloses disubstituted pyridine derivatives as selective CDK9 inhibitors.
  • WO2012143399 discloses substituted 4-aryl-N-phenyl-l,3,5-triazin-2-amines as selective CDK9 inhibitors.
  • EP1218360 Bl which corresponds to US2004116388A1, US7074789B2 and WO2001025220A1, describes triazine derivatives as kinase inhibitors, but does not disclose potent or selective CDK9 inhibitors.
  • WO2008079933 discloses aminopyridine and aminopyrimidine derivatives and their use as CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9 inhibitors.
  • WO2011012661 describes aminopyridine derivatives useful as CDK inhibitors.
  • WO2011026917 discloses carboxamides derived from substituted 4-phenylpyridine-2-amines as inhibitors of CDK9.
  • WO2012066065 discloses phenyl-heterorayl amines as inhibitors of CDK9. A selectivity towards CDK9 over other CDK isoforms is preferred, however disclosure of CDK-inhibition data is confined to CDK 9.
  • alkoxy phenyls can be regarded as encompassed, but there is no suggestion for a specific substitution pattern characterised by a fluoro atom attached to C5 of the pyrimidine ring, and an aniline at C2 of the pyrimidine, featuring a substituted sulfonyl-methylene group in meta position.
  • Compounds shown in the examples typically feature a substituted cycloalkyl group as R 1 but no phenyl.
  • WO2012066070 discloses 3-(aminoaryl)-pyridine compounds as inhibitors of CDK9.
  • the biaryl core mandatorily consists of two heteroaromatic rings.
  • WO2012101062 discloses substituted bi-heteroaryl compounds featuring a 2-aminopyridine core as inhibitors of CDK9.
  • the biaryl core mandatorily consists of two heteroaromatic rings.
  • WO2012101063 discloses carboxamides derived from substituted 4-(heteroaryl)-pyridine-2-amines as inhibitors of CDK9.
  • WO 2012101064 discloses N-acyl pyrimidine biaryl compounds as inhibitors of CDK9.
  • WO 2012101065 discloses pyrimidine biaryl compounds as inhibitors of CDK9.
  • the biaryl core mandatorily consists of two heteroaromatic rings.
  • WO 2012101066 discloses pyrimidine biaryl compounds as inhibitors of CDK9.
  • Substitution R 1 of the amino group attached to the heteroaromatic core is confined to non-aromatic groups but does not cover substituted phenyls.
  • the biaryl core mandatorily consists of two heteroaromatic rings.
  • WO 2011077171 discloses 4,6-disubstituted aminopyrimidine derivatives as inhibitors of CDK9.
  • WO 2014031937 discloses 4,6-disubstituted aminopyrimidine derivatives as inhibitors of CDK9.
  • WO 2013037896 discloses disubstituted 5-fluoropyrimidines as selective inhibitors of CDK9.
  • WO 2013037894 discloses disubstituted 5-fluoropyrimidine derivatives containing a sulfoximine group as selective inhibitors of CDK9.
  • WO 2014060376 discloses substituted 4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amine derivatives containing a sulfone group as selective inhibitors of CDK9.
  • WO 2014060375 discloses substituted 5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfone group as selective inhibitors of CDK9.
  • WO 2014060493 discloses substituted N-(pyridin-2-yl)pyrimidin-4-amine derivatives containing a sulfone group as selective inhibitors of CDK9.
  • WO 2014076028 discloses substituted 4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amine derivatives containing a sulfoximine group as selective inhibitors of CDK9.
  • WO 2014076091 discloses substituted 5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfoximine group as selective inhibitors of CDK9.
  • WO 2014076111 discloses substituted N-(pyridin-2-yl)pyrimidin-4-amine derivatives containing a sulfoximine group as selective inhibitors of CDK9.
  • WO 2015001021 discloses 5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfoximine group as selective inhibitors of CDK9.
  • WO 2015136028 discloses 5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfone group as selective inhibitors of CDK9.
  • WO2004009562 discloses substituted triazine kinase inhibitors. For selected compounds CDK1 and CDK4 test data, but no CDK9 data is presented.
  • WO2004072063 describes heteroaryl (pyrimidine, triazine) substituted pyrroles as inhibitors of protein kinases such as ERK2, GSK3, PKA or CDK2.
  • WO2010009155 discloses triazine and pyrimidine derivatives as inhibitors of histone deacetylase and/or cyclin dependent kinases (CDKs). For selected compounds CDK2 test data is described.
  • WO2003037346 (corresponding to US7618968B2, US7291616B2, US2008064700A1, US2003153570A1) relates to aryl triazines and uses thereof, including to inhibit lysophosphatidic acid acyltransferase beta (LPAAT-beta) activity and/or proliferation of cells such as tumor cells.
  • LPAAT-beta lysophosphatidic acid acyltransferase beta
  • WO2005037800 discloses sulfoximine substituted anilino-pyrimidines as inhibitors of VEGFR and CDK kinases, in particular VEGFR2, CDK1 and CDK2, having no aromatic ring directly bonded to the pyrimidine ring and having the sulfoximine group directly bonded to the aniline group. No CDK9 data are disclosed.
  • WO2008025556 describes carbamoyl sulfoximides having a pyrimidine core, which are useful as kinase inhibitors. No CDK9 data is presented. No molecules are exemplified, which possess a fluoropyrimidine core.
  • WO2002066481 describes pyrimidine derivatives as cyclin dependent kinase inhibitors. CDK9 is not mentioned and no CDK9 data is presented.
  • WO2008109943 concerns phenyl aminopyri(mi)dine compounds and their use as kinase inhibitors, in particular as JAK2 kinase inhibitors.
  • the specific examples mainly focus on compounds having a pyrimidine core.
  • WO2009032861 describes substituted pyrimidinyl amines as JNK kinase inhibitors.
  • the specific examples mainly focus on compounds having a pyrimidine core.
  • WO2011046970 concerns amino-pyrimidine compounds as inhibitors of TBK1 and/or IKK epsilon. The specific examples mainly focus on compounds having a pyrimidine core.
  • WO2012142329 concerns amino-pyrimidine compounds as inhibitors of TBK1 and/or IKK epsilon.
  • WO2012139499 discloses urea substituted anilino-pyrimidines as inhibitors of various protein kinases.
  • WO2014106762 discloses 4-pyrimidinylamino-benzenesulfonamide derivatives as inhibitors of polo-like kinase- 1.
  • Macrocyclic compounds have been described as therapeutically useful substances, in particular of various protein kinases including cyclin dependent kinases. However, the documents listed below do not disclose specific compounds as inhibitors of CDK9.
  • WO 2007147574 discloses sulfonamido-macrocycles as inhibitors of Tie2 showing selectivity over CDK2 and Aurora kinase C, inter alia for the treatment of diseases accompanied with dysregulated vascular growth.
  • WO 2007147575 discloses further sulfonamido-macrocycles as inhibitors of Tie2 and KDR showing selectivity over CDK2 and Plkl, inter alia for the treatment of diseases accompanied with dysregulated vascular growth.
  • WO 2006066957 / EP 1674470 discloses further sulfonamido-macrocycles as inhibitors of Tie2 showing low cytotoxicity, inter alia for the treatment of diseases accompanied with dysregulated vascular growth.
  • WO 2006066956 / EP 1674469 discloses further sulfonamido-macrocycles as inhibitors of Tie2 showing low cytotoxicity, inter alia for the treatment of diseases accompanied with dysregulated vascular growth.
  • WO 2004026881 / DE 10239042 discloses macrocyclic pyrimidine derivatives as inhibitors of cyclin dependent kinases, in particular CDKl and CDK2, as well as VEGF-R, inter alia for the treatment of cancer.
  • the compounds of the present invention differ from those disclosed in WO 2004026881 in featuring a mandatory biaromatic portion within the macrocyclic ring system.
  • none of the example compounds disclosed in WO 2004026881 features a group -CFh-A-R 1 , in which A and R 1 are as defined for the compounds of the formula (I) of the present invention, attached to one of the two aromatic portions of the macrocyclic ring system.
  • WO 2007079982 / EP 1803723 discloses macrocyclic benzenacyclononaphanes as inhibtors of multiple protein kinases, e.g. Aurora kinases A and C, CDKl, CDK2 and c-Kit, inter alia for the treatment of cancer.
  • WO 2006106895 / EP 1710246 discloses sulfoximine-macrocycle compounds as inhibitors of Tie2 showing low cytotoxicity, inter alia for the treatment of diseases accompanied with dysregulated vascular growth.
  • WO 2012009309 discloses macrocyclic compounds fused to benzene and pyridine rings for the reduction of beta-amyloid production.
  • WO 2009132202 discloses macrocyclic compounds as inhibitors of JAK 1, 2 and 3, TYK2 and ALK and their use in the treatment of JAK/ALK-associated diseases, including inflammatory and autoimmune disease as well as cancer.
  • ChemMedChem 2007, 2(1), 63-77 describes macrocyclic aminopyrimidines as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activity.
  • the compounds of the present invention differ from those disclosed in said journal publication in featuring a mandatory biaromatic portion within the macrocyclic ring system.
  • none of the compounds disclosed in ChemMedChem 2007, 2(1), 63-77 features a group -CH2-A-R 1 in which A and R 1 are as defined for the compounds of the formula (I) of the present invention, attached to one of the two aromatic portions of the macrocyclic ring system.
  • Cancer diseases are the consequence of uncontrolled cell growth of the most diverse tissues. In many cases, the new cells penetrate into existing tissue (invasive growth), or they metastase into remote organs. Cancer diseases occur in the most diverse organs and often have tissue-specific courses of the disease.
  • the term cancer as a generic term therefore describes a large group of defined diseases of various organs, tissue and cell types.
  • Tumours in early stages can possibly be removed by surgical and radiotherapy measures. Metastased tumours as a rule can only be treated palliatively by chemotherapeutics.
  • the aim here is to achieve the optimum combination of an improvement in the quality of life and prolonging of life.
  • Conjugates of binder proteins with one or more active compound molecules are known, in particular in the form of antibody drug conjugates (ADCs) in which an internalising antibody directed against a tumour-associated antigen is covalently attached via a linker to a cytotoxic agent.
  • ADCs antibody drug conjugates
  • either the cytotoxic agent itself or a cytotoxic metabolite formed therefrom is released within the tumour cell and can unfold its action therein directly and selectively.
  • damage to normal tissue is contained in significantly narrower limits [see, for example,. J. M. Lambert, Curr. Opin. Pharmacol. 5, 543-549 (2005); A. M. Wu and P. D. Senter, Nat.
  • WO2012/171020 describes ADCs in which a plurality of toxophor molecules are attached via a polymeric linker to an antibody.
  • toxophors WO2012/171020 mentions, among others, the substances SB 743921, SB 715992 (Ispinesib), MK-0371, AZD8477, AZ3146 and ARRY- 520.
  • a particular object of the invention is to provide binder drug conjugates of CDK9 kinase inhibitors, which show an improved anti-proliferative activity in tumor cell lines, such as NCI-H292, compared to the compounds known from prior art.
  • the invention provides conjugates of a binder or derivatives thereof with one or more active compound molecules, the active compound molecule being a CDK9 inhibitor attached to the binder via a linker L.
  • the binder is preferably a binder protein or peptide, particularly preferably a human, humanized or chimeric monoclonal antibody or an antigen-binding fragment thereof, in particular an anti-TWEAKR antibody or an antigen-binding fragment thereof or an anti-EGFR antibody or an antigen-binding fragment thereof.
  • an anti-TWEAKR antibody which binds specifically to amino acid D in position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibody TPP-2090, or the anti-EGFR antibodies cetuximab, TPP-4030, TPP-5653, or nimotuzumab.
  • the inventors have found a number of ways to attach the binder to the CDK9 inhibitor in order to achieve the object mentioned above.
  • the CDK9 inhibitor may have the structure (I) below: 1
  • one carbon atom of said C2-C6-alkylene group forms a three- or four-membered ring together with a bivalent group to which it is attached, wherein said bivalent group is selected from -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-;
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 3 , R 4 represent, independently from each other, a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-;
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
  • Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, halo-Ci-C3-alkyl-, C3-C7-cycloalkyl-,
  • said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, wherein one of the substituents R 1 or R 5 is Z-#l,
  • Z stands for the linker and #1 for the bond to the binder
  • the CDK9 inhibitor may be attached to the binder via a linker by substitution of one of the substituents R 1 or R 5 .
  • the CDK9 inhibitor which is attached to the binder is preferably a compound of the formula (la) below:
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • substituents R 1 or R 5 wherein one of the substituents R 1 or R 5 is Z-#l, wherein Z stands for the linker and #1 for the bond to the binder;
  • the conjugates according to the invention can have chemically labile linkers, enzymatically labile linkers or stable linkers. Particular preference is given to stable linkers and linkers which can be cleaved by cathepsin.
  • the invention furthermore provides processes for preparing the conjugates according to the invention, and also precursors and intermediates for the preparation.
  • the preparation of the conjugates according to the invention regularly comprises the following steps:
  • Attachment of the reactive group may also take place after the construction of an optionally protected CDK9 inhibitor/linker precursor conjugate.
  • succinimide- linked ADCs may, after conjugation, be converted according to Scheme A into the open-chain succinamides, which have an advantageous stability profile.
  • conjugation of the linker precursor to a low-molecular weight CDK9 inhibitor may take place by substitution of R 1 or R 5 in formula (I), or R 1 or R 5 in formula (la) with the linker.
  • any functional groups present may also be present in protected form. Prior to the conjugation step, these protective groups are removed by known methods of peptide chemistry. Conjugation can take place chemically by various routes, as shown in an exemplary manner in Schemes 8 to 26 in the examples.
  • it is optionally possible to modify the low-molecular weight CDK9 inhibitor for conjugation to the linker for example by introduction of protective groups or leaving groups to facilitate substitution.
  • the group -Z-#3 is also possible for the group -Z-#3 to be present in the compound, where Z represents the linker and #3 represents the reactive group for binding to the binder or the derivative thereof.
  • Compounds comprising -Z-#3 are reactive compounds which react with the binder or the derivative thereof.
  • #3 is preferably a group which reacts with an amino or thiol group with formation of a covalent bond, preferably with the cysteine residue in a protein.
  • the cysteine residue in a protein may of course be present naturally in the protein, may be introduced by biochemical methods or, preferably, may be generated by prior reduction of disulphides of the binder.
  • the invention furthermore provides CDK9 inhibitor-linker-intermediates which are compounds of general formula ( ⁇ )
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z or a group selected from Ci-C6-alkyl-, C3-C6-alkenyl, C3-C6-alkynyl, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, phenyl-Ci-C3-alkyl- and heteroaryl-Ci-C3-alkyl-,
  • R 3 , R 4 represent, independently from each other, a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, halo-Ci-C3-al
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
  • Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-,
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, halo-Ci-C3-alkyl-, C3-C7-cycloalkyl-,
  • said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, wherein one of the substituents R 1 or R 5 is Z,
  • the invention provides conjugates of a binder or derivative thereof with one or more active compound molecules, the active compound molecule being a CDK9 kinase inhibitor (CDK9 inhibitor) attached to the binder via a linker Z.
  • CDK9 inhibitor CDK9 kinase inhibitor
  • the conjugate according to the invention can be represented by the general formula AEMZ-MC
  • AB represents the binder, preferably an antibody
  • Z represents the linker
  • MC represents the CDK9 inhibitor
  • n represents a number from 1 to 50, preferably from 1.2 to 20 and particularly preferably from 2 to 8.
  • n is a mean of the number of CDK9 inhibitor/linker conjugates per BINDER.
  • CDK9 preferably has the formula (I) shown above.
  • the binder is preferably a binder peptide or protein such as, for example, an antibody.
  • the linker is preferably attached to different amino acids of the binder peptide or protein or derivative thereof. Particular preference is given to binding to different cysteine or lysine residues of the binder, even more preferable is binding to different cysteine residues of the binder.
  • Binders which can be used according to the invention, CDK9 inhibitors which can be used according to the invention and linkers which can be used according to the invention which can be used in combination without any limitation are described below.
  • the binders represented in each case as preferred or particularly preferred can be employed in combination with the CDK9 inhibitors represented in each case as preferred or particularly preferred, optionally in combination with the linkers represented in each case as preferred or particularly preferred.
  • CDK9 kinase inhibitors Despite the fact that various inhibitors of CDKs are known, there remains a need for selective CDK9 inhibitors to be used for the treatment of diseases such as hyper-proliferative diseases, viral diseases, and/or diseases of the heart, which offer one or more advantages over the compounds known from prior art, such as :
  • the CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show an improved anti-proliferative activity in tumor cell lines, such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 or MOLM-13, compared to the compounds known from prior art. Further, the CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show an increased potency to inhibit CDK9 activity (demonstrated by a lower IC50 value for CDK9/Cyclin Tl) compared to the compounds known from prior art.
  • CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show an increased potency to inhibit CDK9 activity at high ATP concentrations compared to the compounds known from prior art.
  • the CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show an increased target residence time compared to the compounds known from prior art. Further, the CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show an improved pharmacokinetic profile, e.g. a higher metabolic stability and/or a longer terminal half- life upon administration in vivo.
  • CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show an improved duration of action, e.g. by improved pharmacokinetics and / or improved target residence time.
  • CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show an improved CaCo-2 permeability and/or an improved CaCo-2 efflux ratio, compared to the compounds known from prior art.
  • the CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show an improved aqueous solubility compared to the compounds known from prior art. Further, the CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show, compared to the compounds known from prior art, an increased selectivity for CDK9/Cyclin Tl as compared to CDK2/Cyclin E.
  • the CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show, compared to the compounds known from prior art, an improved anti-proliferative activity in tumor cell lines, such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 or MOLM-13, and/or which show an increased potency to inhibit CDK9 activity (demonstrated by a lower IC50 value for CDK9/Cyclin Tl), and/or which show an increased potency to inhibit CDK9 activity at high ATP concentrations, and/or which show an improved pharmacokinetic profile, e.g. a higher metabolic stability and/or a longer terminal half-life upon administration in vivo, and/or which show an increased target residence time compared to the compounds known from prior art.
  • tumor cell lines such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780
  • the CDK9 inhibitors used in the binder drug conjugates according to the invention preferably show, compared to the compounds known from prior art, an improved CaCo-2 permeability and/or an improved CaCo-2 efflux ratio, and/or which show an improved aqueous solubility, and/or show an increased selectivity for CDK9/Cyclin Tl as compared to CDK2/Cyclin E.
  • CDK9 inhibitors are described by the following structure: 1
  • L represents a C2-C6-alkylene group,
  • one carbon atom of said C2-C6-alkylene group forms a three- or four-membered ring together with a bivalent group to which it is attached, wherein said bivalent group is selected from -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-;
  • Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N; represents -Z-#l or a group selected from Ci-C6-alkyl-, C3-C6-alkenyl, C3-C6-alkynyl, C3-C7- cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, phenyl-Ci-C3-alkyl- and heteroaryl-Ci-C3-alkyl-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, Ci-C6-alkyl-, halo-Ci-C3- alkyl-, Ci-C6-alkoxy-, Ci-C3-fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-
  • R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
  • Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, or R 6 and R 7 , together with the nitrogen atom they are attached to, form a cyclic amine;
  • R 8 represents a group selected from Ci-C6-alkyl-, halo-Ci-C3-alkyl-, C3-C7-cycloalkyl-,
  • said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, wherein one of the substituents R 1 or R 5 is Z-# 1 ,
  • CDK9 inhibitors or precursors thereof used for the synthesis of the conjugate according to the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds of the hereinafter recited formula which are encompassed by formula (I) and the salts, solvates and solvates of the salts thereof, and the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments and the salts, solvates and solvates of the salts thereof, where the compounds which are encompassed by formula (I) and are mentioned hereinafter are not already salts, solvates and solvates of the salts.
  • the CDK9 inhibitors or precursors thereofof formula (I) may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates to the enantiomers or diastereomers and respective mixtures thereof.
  • the stereoisomerically pure constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.
  • the present invention encompasses all tautomeric forms.
  • the CDK9 inhibtors or precursors thereof can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any physiologically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention.
  • salts which are not suitable for pharmaceutical applications per se, but which, for example, can be used for the isolation or purification of the compounds according to the invention are also comprised.
  • physiologically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention, for example, see S. M. Berge, et al. "Pharmaceutical Salts,” J. Pharm Sci. 1977, 66, 1-19.
  • Physiologically acceptable salts of the compounds according to the invention encompass acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, hydroiodic, sulfuric acid, bisulfuric acid, phosphoric acid, nitric acid or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3 -hydroxy-2 -naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, ita
  • Physiologically acceptable salts of the compounds according to the invention also comprise salts of conventional bases, such as, by way of example and by preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C atoms, such as, by way of example and by preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N- methylglucamine, dimethylglucamine, ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol, tri
  • the compounds according to the invention may form salts with a quartemary ammonium ion obtainable e.g. by quarternisation of a basic nitrogen containing group with agents such as lower alkylhalides such as methyl-, ethyl-, propyl-, and butylchlorides, -bromides and -iodides ; dialkylsulfates such as dimethyl-, diethyl-, dibutyl- and diamylsulfates, long chain halides such as decyl-, lauryl-, myristyl- and stearylchlorides, -bromides and -iodides, aralkylhalides such as benzyl- and phenethylbromides and others.
  • agents such as lower alkylhalides such as methyl-, ethyl-, propyl-, and butylchlorides, -bromides and -iodides ; dialkyl
  • Suitable quartemary ammonium ions are tetramethylammonium, tetraethylammonium, tetra( «-propyl)ammonium, tetra (n-butyl)ammonium, or N-b enzy 1-N N N-trimethy lammonium.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • Solvates is the term used for the purposes of the invention for those forms of the CDK9 inhibtors or precursors thereof which form a complex with solvent molecules by coordination in the solid or liquid state. Hydrates are a special form of solvates in which the coordination takes place with water. Hydrates are preferred as solvates within the scope of the present invention.
  • the invention also includes all suitable isotopic variations of a CDK9 inhibtor or precursors thereof.
  • An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • Certain isotopic variations of a compound of the invention for example, those in which one or more radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution studies.
  • Tritiated and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • the present invention includes all possible crystalline forms, or polymorphs, of the CDK9 inhibitors or precursors thereof, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio. Accordingly, the present invention includes all possible salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g. : esters) thereof, and diastereoisomeric forms of the the CDK9 inhibtors or precursors thereof as single salt, polymorph, metabolite, hydrate, solvate, prodrug (e.g.
  • esters thereof, or diastereoisomeric form, or as mixture of more than one salt, polymorph, metabolite, hydrate, solvate, prodrug (e.g. : esters) thereof, or diastereoisomeric form in any ratio.
  • the term metabolite is understood as the product of the (e.g., enzymatic or chemical) cleavage of the conjugate of a binder or a derivative thereof according to the present invention. Accordingly, the metabolite will comprise a molecule of an active component, wherein the active component is a CDK9 kinase inhibitor.
  • the conjugate according to the invention comprises a stable linker
  • the metabolite of the CDK9 inhibitor as such comprises an amino acid residue, preferably a cysteine or a lysine residue.
  • the conjugate according to the invention comprises an instable linker
  • the metabolite of the CDK9 inhibitor as such is possibly connected with only part of the linker moiety, i.e. the metabolite of the CDK9 inhibitor as such does not comprise a cysteine and/or a lysine residue which originally belonged to the binder protein or peptide.
  • halogen represents fluorine, chlorine, bromine and iodine, particularly bromine, chlorine or fluorine, preferably chlorine or fluorine, more preferably fluorine.
  • alkyl represents a linear or branched alkyl group having the number of carbon atoms specifically indicated, e.g. Ci-Cio one, two, three, four, five, six, seven, eight, nine or ten carbon atoms, e.g.
  • alkyl represents a linear or branched alkyl group having, as a rule, 1 to 9, particularly 1 to 6, preferably 1 to 4 carbon atoms. Particularly, the alkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms (“Ci-C6-alkyl”), e.g.
  • the alkyl group has 1, 2 or 3 carbon atoms ("Ci-C3-alkyl”), methyl, ethyl, ⁇ -propyl-, isopropyl, n-butyl, teri-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1- methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3- methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2- dimethylbutyl, 1,1 -dimethylbutyl, 2,3-dimethylbutyl, 1,3 -dimethylbutyl, or 1,2- dimethylbutyl.
  • the alkyl group has
  • C2-C6-alkylene is to be understood as preferably meaning a linear, bivalent and saturated hydrocarbon group having 2 to 6, particularly 2, 3 or 4 carbon atoms, as in "C2-C i-alkylene” e.g. ethylene, ⁇ -propylene, n-butylene, n-pentylene, or n-hexylene, preferably ⁇ -propylene or n-butylene.
  • C 2 -C6-alkenyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 2, 3, 4, 5 or 6 carbon atoms (“C2-C6- alkenyl").
  • said alkenyl group is a C2-C3-alkenyl, C3-C6-alkenyl or C3-C i-alkenyl group.
  • Said alkenyl group is, for example, a vinyl, allyl, (£')-2-methylvinyl, (Z)-2-methylvinyl or isopropenyl group.
  • C2-C6-alkynyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms.
  • said alkynyl group is a C2-C3-alkynyl, C3-C6-alkynyl or C3-C i-alkynyl group.
  • Said C2-C3- alkynyl group is, for example, an ethynyl, prop-l-ynyl or prop-2-ynyl group.
  • C3-C7-cycloalkyl is to be understood as preferably meaning a saturated or partially unsaturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms.
  • Said C3-C7-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
  • Said cycloalkyl ring is non-aromatic but can optionally contain one or more double bonds e.g.
  • cycloalkenyl such as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated.
  • said cycloalkyl group is a C i-C6-cycloalkyl, a Cs-Ce-cycloalkyl or a cyclohexyl group.
  • C3-C5-cycloalkyl is to be understood as preferably meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4 or 5 carbon atoms.
  • said C3-Cs-cycloalkyl group is a monocyclic hydrocarbon ring such as a cyclopropyl, cyclobutyl or cyclopentyl group.
  • said "C3-C5-cycloalkyl” group is a cyclopropyl group.
  • C3-C4-cycloalkyl is to be understood as preferably meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3 or 4 carbon atoms.
  • said C3-C4-cycloalkyl group is a monocyclic hydrocarbon ring such as a cyclopropyl or cyclobutyl group.
  • heterocyclyl is to be understood as meaning a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and further containing 1 , 2 or 3 heteroatom-containing groups selected from oxygen, sulfur, nitrogen.
  • heterocyclyl is to be understood as meaning a “4- to 10-membered heterocyclic ring”.
  • a 4- to 10-membered heterocyclic ring is to be understood as meaning a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and further containing 1, 2 or 3 heteroatom-containing groups selected from oxygen, sulfur, nitrogen.
  • a C3-C9-heterocyclyl is to be understood as meaning a heterocyclyl which contains at least 3, 4, 5, 6, 7, 8 or 9 carbon atoms and additionally at least one heteroatom as ring atoms. Accordingly in case of one heteroatom the ring is 4- to 10-membered, in case of two heteroatoms the ring is 5- to 11 -membered and in case of three heteroatoms the ring is 6- to 12-membered.
  • Said heterocyclic ring is for example, a monocyclic heterocyclic ring such as an oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, 1 ,4-dioxanyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, 1,3-dithianyl, thiomorpholinyl, piperazinyl, or chinuclidinyl group.
  • a monocyclic heterocyclic ring such as an oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolidinyl, pyrazolidin
  • said heterocyclic ring can contain one or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-lH-pyrrolyl, 1,3-dioxolyl, 4H-1,3,4- thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothienyl, 2,3-dihydrothienyl, 4,5- dihydrooxazolyl, 4,5-dihydroisoxazolyl, or 4H-l,4-thiazinyl group, or, it may be benzo fused.
  • 4H-pyranyl 2H-pyranyl, 2,5-dihydro-lH-pyrrolyl, 1,3-dioxolyl, 4H-1,3,4- thiadiazinyl
  • 2,5-dihydrofuranyl 2,3-dihydrofuranyl
  • a C3-C7-heterocyclyl is to be understood as meaning a heterocyclyl which contains at least 3, 4, 5, 6, or 7 carbon atoms and additionally at least one heteroatom as ring atoms. Accordingly in case of one heteroatom the ring is 4- to 8-membered, in case of two heteroatoms the ring is 5- to 9-membered and in case of three heteroatoms the ring is 6- to 10-membered.
  • a C3-C6-heterocyclyl is to be understood as meaning a heterocyclyl which contains at least 3, 4, 5 or 6 carbon atoms and additionally at least one heteroatom as ring atoms. Accordingly in case of one heteroatom the ring is 4- to 7-membered, in case of two heteroatoms the ring is 5- to 8-membered and in case of three heteroatoms the ring is 6- to 9-membered.
  • heterocyclyl is to be understood as being a heterocyclic ring which contains 3, 4 or 5 carbon atoms, and 1, 2 or 3 of the above-mentioned heteroatom-containing groups (a "4- to 8- membered heterocyclic ring"), more particularly said ring can contain 4 or 5 carbon atoms, and 1, 2 or 3 of the above-mentioned heteroatom-containing groups (a "5- to 8-membered heterocyclic ring”), more particularly said heterocyclic ring is a "6-membered heterocyclic ring", which is to be understood as containing 4 carbon atoms and 2 of the above-mentioned heteroatom-containing groups or 5 carbon atoms and one of the above-mentioned heteroatom-containing groups, preferably 4 carbon atoms and 2 of the above-mentioned heteroatom-containing groups.
  • Ci-C6-alkoxy- is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, z ' o-propoxy, n-butoxy, z ' o-butoxy, teri-butoxy, eobutoxy, pentyloxy, iso- pentyloxy, n-hexyloxy group, or an isomer thereof.
  • the "Ci-C6-alkoxy-” group is a "C1-C4- alkoxy-", a “Ci-C3-alkoxy-", a methoxy, ethoxy, or propoxy group, preferably a methoxy, ethoxy or propoxy group. Further preferred is a "Ci-C2-alkoxy-” group, particularly a methoxy or ethoxy group.
  • Ci-C3-fluoroalkoxy- group is, for example a 1 , 1 -difluoromethoxy-, a 1,1,1-trifluoromethoxy-, a 2-fluoroethoxy-, a 3-fluoropropoxy-, a 2,2,2-trifluoroethoxy-, a 3,3,3-trifluoropropoxy-, particularly a "Ci-C2-fluoroalkoxy-" group.
  • the term “alkylamino-" is to be understood as preferably meaning an alkylamino group with one linear or branched alkyl group as defined supra.
  • (Ci-C3)-alkylamino- for example means a monoalkylamino group with 1, 2 oder 3 carbon atoms,
  • the term "alkylamino-" comprises for example methylamino-, ethylamino-, n-propylamino-, z o-propylamino-, tert.- butylamino-, n-pentylamino- or n-hexylamino-.
  • the term arrivingdialkylamino- is to be understood as preferably meaning an alkylamino group having two linear or branched alkyl groups as defined supra, which are independent from each other.
  • (Ci-C3)-dialkylamino- for example represents a dialkylamino group with two alkyl groups each of them having 1 to 3 carbon atoms per alkyl group.
  • dialkylamino- comprises for example: N,N-dimethylamino-, N,N-diethylamino-, N-ethyl-N-methylamino-, N-methyl-N-n-propylamino-, N-wo-propyl-N-n-propylamino-, N-tert-butyl-N-methylamino-, N-ethyl-N-n-pentylamino- and N-n-hexyl-N-methylamino-.
  • cyclic amine is to be understood as preferably meaning a cyclic amine group.
  • a cyclic amine means a saturated, monocyclic group with 4 to 10, preferably 4 to 7 ring atoms of which at least one ring atom is a nitrogen atom.
  • Suitable cyclic amines are especially azetidine, pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, thiomorpholine, which could be optionally substituted by one or two methyl groups.
  • halo-Ci-C3-alkyl- or, used synonymously, "Ci-C3-haloalkyl-" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C3-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, identically or differently, i.e. one halogen atom being independent from another.
  • a halo-Ci-C3-alkyl- group is a fluoro-Ci-C3-alkyl- or a fluoro-Ci-C2-alkyl- group, such as for example -CF3, -CHF2, -CH2F, -CF2CF3, or -CH2CF3, more preferably it is -CF3.
  • hydroxy-Ci-C3-alkyl- is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C3-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by hydroxy group, preferably not more than one hydrogen atom per carbon atom being replaced by a hydroxy group.
  • a hydroxy-Ci-C3-alkyl- group is, for example,
  • phenyl-Ci-C3-alkyl- is to be understood as preferably meaning a phenyl group, in which one of the hydrogen atoms is replaced by a Ci-C3-alkyl group, as defined supra, which links the phenyl-Ci-C3- alkyl- group to the rest of the molecule.
  • the "phenyl-Ci-C3-alkyl-” is a phenyl-Ci-C 2 -alkyl-, preferably it is a benzyl- group.
  • heteroaryl is to be understood as preferably meaning a monovalent, aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 (a “5-membered heteroaryl") or 6 (a “6-membered heteroaryl”) or 9 (a"9-membered heteroaryl") or 10 ring atoms (a "10-membered heteroaryl”), and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic, or tricyclic, and in addition in each case can be benzo-condensed.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azo
  • 5-membered heteroaryl is understood as preferably meaning a monovalent, aromatic ring system having 5 ring atoms and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur.
  • “5-membered heteroaryl” is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl.
  • 6-membered heteroaryl is understood as preferably meaning a monovalent, aromatic ring system having 6 ring atoms and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur.
  • heteroatom being such as oxygen, nitrogen or sulfur.
  • 6-membered heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.
  • heteroaryl-Ci-C3-alkyl- is to be understood as preferably meaning a heteroaryl, a 5-membered heteroaryl or a 6-membered heteroaryl group, each as defined supra, in which one of the hydrogen atoms is replaced by a Ci-C3-alkyl group, as defined supra, which links the heteroaryl-Ci-C3- alkyl- group to the rest of the molecule.
  • the "heteroaryl-Ci-C3-alkyl-" is a heteroaryl-Ci-C2- alkyl-, a pyridinyl-Ci-C3-alkyl-, a pyridinylmethyl-, a pyridinylethyl-, a pyridinylpropyl-, a pyrimidinyl- Ci-C3-alkyl-, a pyrimidinylmethyl-, a pyrimidinylethyl-, a pyrimidinylpropyl-, preferably a pyridinylmethyl- or a pyridinylethyl- or a pyrimidinylethyl- or a pyrimidinylpropyl- group.
  • a leaving group refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halo, in particular chloro, bromo or iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo- benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl- benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfony
  • Ci-C3-alkylbenzene refers to a partially aromatic hydrocarbon consisting of a benzene ring which is substituted by one or two Ci-C3-alkyl groups, as defined supra.
  • Ci-C3-alkylbenzene is toluene, ethylbenzene, cumene, n-propylbenzene, ori/zo-xylene, meia-xylene or para-xylene.
  • "Ci-C3-alkylbenzene” is toluene.
  • C r C 2 -alkyl in which G represents -CH2-, -CH2-CH2- or -CH2-CH2-CH2-.
  • “carboxamide based solvent” is N,N-dimethylformamide, NN-dimethylacetamide or N-methylpyrrolidin-2-one.
  • “carboxamide based solvent” is N-methyl-pyrrolidin-2-one.
  • C1-C10 as used throughout this text, e.g. in the context of the definition of "Ci-Cio-alkyl” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 10, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. It is to be understood further that said term “C1-C10” is to be interpreted as any sub-range comprised therein, e.g.
  • Ci-Ce as used throughout this text, e.g. in the context of the definition of "Ci-C6-alkyl", “Ci-C6-alkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “Ci-Ce” is to be interpreted as any sub-range comprised therein, e.g.
  • Ci-Ce Ci-Cs Ci-Cs, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, C5-C6.
  • C1-C4 as used throughout this text, e.g. in the context of the definition of "Ci-C4-alkyl", “Ci-C4-alkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms. It is to be understood further that said term “C1-C4" is to be interpreted as any sub-range comprised therein, e.g. C1-C4, C1-C3, C1-C2, C2-C4, C2-
  • C1-C3 as used throughout this text, e.g. in the context of the definition of "Ci-C3-alkyl", “Ci-C3-alkoxy” or “Ci-C3-fluoroalkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 3, i.e. 1, 2 or 3 carbon atoms. It is to be understood further that said term “C1-C3" is to be interpreted as any sub-range comprised therein, e.g. Ci-
  • C3-C6 as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C3-C5 , C3-C4 , C4-C6 , C4-C5 , C5-C6.
  • C3-C7 as used throughout this text, e.g. in the context of the definition of "C3-C7-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C7” is to be interpreted as any sub-range comprised therein, e.g. C3-
  • a symbol at a bond denotes the linkage site in the molecule.
  • the term "one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention is understood as meaning one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C6-alkylene group
  • one carbon atom of said C2-C6-alkylene group forms a three- or four-membered ring together with a bivalent group to which it is attached, wherein said bivalent group is selected from -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-;
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z-#l, a group selected from Ci-C6-alkyl-, C 3 -C6-alkenyl, C 3 -C6-alkynyl, C 3 -C7- cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, phenyl-Ci-C 3 -alkyl- and heteroaryl-Ci-C 3 -alkyl-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, Ci-C6-alkyl-, halo-Ci-C 3 -alkyl-, Ci-C6-alkoxy-, Ci-C 3 -fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,
  • Ci-Ce-alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, heteroaryl wherein said Ci-C6-alkyl, C3-C7-cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-;
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
  • Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, halo-Ci-C3-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
  • said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, - ⁇ 2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, wherein one of the substituents R 1 or R 5 is Z-#l,
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a group selected from Ci-C6-alkyl-, Cs-Cs-cycloalkyl-, phenyl and phenyl-Ci- C 3 -alkyl-,
  • R 2 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, Ci-C2-alkyl-, Ci-C2-alkoxy-, fluoro-C i-C2-alkyl-, Ci-C2-fluoroalkoxy-;
  • R 3 , R 4 represent, independently from each other, a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano Ci-C2-alkyl-, Ci-C2-alkoxy-, fluoro-C i-C2-alkyl-, C1-C2- fluoroalkoxy-;
  • Ci-C6-alkyl, Cs-Cs-cycloalkyl- or phenyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, fluoro-C i-C2-alkyl-, Ci-C2-fluoroalkoxy-;
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C5-cycloalkyl-, phenyl and benzyl,
  • Ci-C6-alkyl-, C3-C5-cycloalkyl-, phenyl or benzyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, fluoro-C i-C 2 -alkyl-, Ci-C 2 -fluoroalkoxy-, or R 6 and R 7 , together with the nitrogen atom they are attached to, form a cyclic amine;
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, Cs-Cs-cycloalkyl-, phenyl and benzyl,
  • said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, fluoro-Ci-C2-alkyl-, Ci-C2-fluoroalkoxy-, wherein one of the substituents R 1 or R 5 is Z-#l,
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a group selected from Ci-C6-alkyl-, Cs-Cs-cycloalkyl-, phenyl and phenyl-Ci- C 3 -alkyl-,
  • Ci-C6-alkyl, Cs-Cs-cycloalkyl- or phenyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, fluoro-Ci-C2-alkyl-, Ci-C2-fluoroalkoxy-;
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C5-cycloalkyl-, phenyl and benzyl,
  • Ci-C6-alkyl-, Cs-Cs-cycloalkyl-, phenyl or benzyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, fluoro-Ci-C2-alkyl-, Ci-C2-fluoroalkoxy-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, Cs-Cs-cycloalkyl-, phenyl and benzyl,
  • said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, fluoro-Ci-C2-alkyl-, Ci-C2-fluoroalkoxy-, wherein one of the substituents R 1 or R 5 is Z-#l,
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a group selected from Ci-C i-alkyl-, C3-Cs-cycloalkyl- and phenyl,
  • R represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-;
  • R 4 represents a hydrogen atom or a fluoro atom
  • Ci-C i-alkyl- group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines;
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C4-alkyl- and C3-C5-cycloalkyl-,
  • Ci-C4-alkyl- or Cs-Cs-cycloalkyl- group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, Cs-Cs-cycloalkyl- and phenyl, wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2,
  • CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a group selected from Ci-C i-alkyl-, C3-Cs-cycloalkyl- and phenyl,
  • said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, Ci-C 2 -alkyl-, G-C 2 -alkoxy-, -NH 2 ;
  • R 2 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-;
  • R 3 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-;
  • R 4 represents a hydrogen atom or a fluoro atom
  • Ci-C i-alkyl- group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, G-C3-alkoxy-, -NH 2 , alkylamino-, dialkylamino-, cyclic amines;
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, G-C4-alkyl- and C3-C5-cycloalkyl-,
  • G-C4-alkyl- or C3-C5-cycloalkyl- group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, G-C 2 -alkyl-, G-C 2 -alkoxy-, -NH 2 , alkylamino-, dialkylamino-, cyclic amines, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, Cs-Cs-cycloalkyl- and phenyl, wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2,
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a group selected from Ci-C i-alkyl-,
  • R 2 represents a hydrogen atom
  • R 3 represents a group selected from a hydrogen atom, a fluoro atom
  • R 4 represents a hydrogen atom
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C i-alkyl- and C3-C5-cycloalkyl-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, C3-Cs-cycloalkyl- and phenyl, wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2, wherein one of the substituents R 1 or R 5 is Z-#l,
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group;
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a group selected from Ci-C i-alkyl-,
  • R 2 represents a hydrogen atom
  • R 3 represents a group selected from a hydrogen atom, a fluoro atom
  • R 4 represents a hydrogen atom
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C i-alkyl- and C3-C5-cycloalkyl-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, C3-Cs-cycloalkyl- and phenyl, wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, - ⁇ 3 ⁇ 4,
  • CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C3-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a methyl- group
  • R 2 represents a hydrogen atom
  • R 3 represents a group selected from a hydrogen atom, a fluoro atom
  • R 4 represents a hydrogen atom
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C2-alkyl-;
  • R 8 represents a Ci-C2-alkyl- group
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a -CH2CH2CH2- group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 2 represents a hydrogen atom
  • R 3 represents a group selected from a hydrogen atom, a fluoro atom
  • R 4 represents a hydrogen atom
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C i-alkyl- and C3-C5-cycloalkyl-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, C3-Cs-cycloalkyl- and phenyl, wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2,
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a -CH2CH2CH2- group;
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a methyl- group; represents a hydrogen atom;
  • R represents a group selected from a hydrogen atom, a fluoro atom represents a hydrogen atom;
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C2-alkyl-;
  • R 8 represents a Ci-C2-alkyl- group
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a Ci-C i-alkyl- group
  • R 2 represents a hydrogen atom
  • R 3 represents a group selected from a hydrogen atom, a fluoro atom
  • R 4 represents a hydrogen atom
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C i-alkyl- and
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, Cs-Cs-cycloalkyl- and phenyl, wherein said group is optionally substituted with one substituent selected from the group consisting of hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-,
  • one of the substituents R 1 or R 5 is Z-#l, wherein Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a -CH2CH2CH2- group;
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a methyl- group;
  • R 2 represents a hydrogen atom
  • R 3 represents a fluoro atom
  • R 4 represents a hydrogen atom
  • R 6 represents an ethyl- group
  • R 7 represents a hydrogen atom
  • R 8 represents a Ci-C2-alkyl- group
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a Ci-C i-alkyl- group,
  • said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, a fluoro atom, Ci-C2-alkoxy-, -NH 2 ;
  • R 2 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-;
  • R 3 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-;
  • R 4 represents a hydrogen atom or a fluoro atom
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom and Ci-C 4 -alkyl-,
  • Ci-C i-alkyl- group is optionally substituted with one substituent selected from the group consisting of hydroxy, Ci-C2-alkoxy-, -Nth, alkylamino-, dialkylamino-, cyclic amines, wherein one of the substituents R 1 or R 5 is Z-#l,
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C2-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a Ci-C i-alkyl- group
  • R 2 represents a hydrogen atom or a fluoro atom
  • R 3 represents a hydrogen atom or a fluoro atom
  • R 4 represents a hydrogen atom
  • R 6 , R 7 represent, independently from each other, a group selected from a hydrogen atom and
  • Z stands for the linker and #1 for the bond to the binder; or the salts, solvates or salts of solvates thereof.
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C3-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a methyl group
  • R 2 represents a hydrogen atom
  • R 3 represents a fluoro atom
  • R 4 represents a hydrogen atom
  • R 5 represents -Z#l or a hydrogen atom
  • Z stands for the linker and #1 for the bond to the binder
  • the CDK9 inhibitors are compounds of formula (I), wherein
  • L represents a C3-C i-alkylene group
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z#l or a methyl group
  • R 2 represents a hydrogen atom
  • R 3 represents a fluoro atom
  • R 4 represents a hydrogen atom
  • R 5 represents -Z#l or a hydrogen atom
  • Z stands for the linker and #1 for the bond to the binder
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C2-C6-alkylene group,
  • said group is optionally substituted with one substituent selected from hydroxy, C2-C3-alkenyl, C2- C 3 -alkynyl, C 3 -C 4 -cycloalkyl, hydroxy-Ci-C 3 -alkyl, -(CH 2 )NR 6 R 7 ,
  • one carbon atom of said C2-C6-alkylene group forms a three- or four-membered ring together with a bivalent group to which it is attached, wherein said bivalent group is selected from -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-.
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C2-C6-alkylene group,
  • one carbon atom of said C2-C6-alkylene group forms a three- or four-membered ring together with a bivalent group to which it is attached, wherein said bivalent group is selected from -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-.
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C2-C i-alkylene group,
  • said group is optionally substituted with one substituent selected from hydroxy, C3-C4-cycloalkyl, hydroxy-Ci-Cs-alkyl, -(CH 2 )NR 6 R 7 ,
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C2-C i-alkylene group,
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C2-C4-alkylene group,
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C2-C4-alkylene group, wherein said group is optionally substituted with
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C2-C i-alkylene group, wherein said group is optionally substituted with one or two methyl groups.
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C2-C i-alkylene group.
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a C3-C i-alkylene group. In another particularly preferred embodiment of the present invention, the CDK9 inhibitors are compounds of formula (I) in which L represents a group -CH2CH2CH2- or -CH2CH2CH2CH2-.
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a group -CH2CH2CH2-.
  • the CDK9 inhibitors are compounds of formula (I) in which L represents a group -CH2CH2CH2CH2-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a group selected from Ci-C6-alkyl-, C3-C6-alkenyl, C3-C6-alkynyl, C3-C7- cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, phenyl-Ci-C3-alkyl- and heteroaryl-Ci-C3-alkyl-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, Ci-C6-alkyl-, halo-Ci-C3-alkyl-, Ci-Ce- alkoxy-, Ci-C3-fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acet
  • R 1 represents -Z#l or a group selected from Ci-C6-alkyl-, C3-Cs-cycloalky
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a group selected from Ci-C i-alkyl-, C3-Cs-cycloalkyl- and phenyl, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a group selected from Ci-C i-alkyl-, Cs-Cs-cycloalkyl- and phenyl,
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a Ci-C i-alkyl- group,
  • said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, a fluoro atom, Ci-C2-alkoxy-, -NH2.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a Ci-C i-alkyl- group,
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a Ci-C i-alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a Ci-C3-alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a Ci-C2-alkyl- group. In another particularly preferred embodiment of the present invention, the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or an ethyl group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a methyl group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l .
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents a methyl group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a Ci-C i-alkyl- group, and R 2 represents a hydrogen atom or a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a Ci-C i-alkyl- group, and R 2 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l, and R 2 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents a Ci-C i-alkyl- group, and R 2 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l or a methyl group, and R 2 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents -Z#l, and R 2 represents a hydrogen atom. In another particularly preferred embodiment of the present invention, the CDK9 inhibitors are compounds of formula (I) in which R 1 represents a methyl group, and R 2 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 2 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 2 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, Ci-C2-alkyl-, Ci-C2-alkoxy-, fluoro-Ci-C2-alkyl-, Ci-C2-fluoroalkoxy-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 2 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 2 represents a hydrogen atom or a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 2 represents a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 2 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 2 represents a hydrogen atom, R 3 represents a fluoro atom, and R 4 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents a methyl group, R 2 represents a hydrogen atom, R 3 represents a fluoro atom, and R 4 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 and R 4 represent, independently from each other, a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, halo-Ci-C3-alkyl-, C1-C3- fluoroalkoxy-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 and R 4 represent, independently from each other, a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano Ci-C2-alkyl-, Ci-C2-alkoxy-, fluoro-Ci-C2-alkyl-, C1-C2- fluoroalkoxy-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 and R 4 represent, independently from each other, a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 and R 4 represent, independently from each other, a hydrogen atom or a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, and in which R 4 represents a hydrogen atom or a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano Ci-C2-alkyl-, Ci-C2-alkoxy-, fluoro-Ci-C2-alkyl-, Ci-C2-fluoroalkoxy-, and in which R 4 represents a hydrogen atom or a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano Ci-C2-alkyl-, Ci-C2-alkoxy-, fluoro-Ci-C2-alkyl-, Ci-C2-fluoroalkoxy-, and in which R 4 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-, and in which R 4 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a hydrogen atom or a fluoro atom, and in which R 4 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a fluoro atom, and in which R 4 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a hydrogen atom or a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 4 represents a group selected from a hydrogen atom, a fluoro atom, a chloro atom, cyano, methyl, methoxy-, trifluoromethyl-, trifluoromethoxy-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 4 represents a hydrogen atom or a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 4 represents a fluoro atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 4 represents a hydrogen atom.
  • Ci-C6-alkyl, C3-C7-cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, -Nth, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-;
  • Ci-C i-alkyl- group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines.
  • Ci-C i-alkyl- group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines.
  • CDK9 inhibitors are compounds of formula (I) in which R 5 represents -Z#l or a group selected from a hydrogen atom, cyano,
  • CDK9 inhibitors are compounds of formula (I) in which R 5 represents
  • CDK9 inhibitors are compounds of formula (I) in which R 5 represents a group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 5 represents a Ci-C i-alkyl- group. In another preferred embodiment of the present invention the CDK9 inhibitors are compounds of formula (I) in which R 5 represents a methyl- group.
  • CDK9 inhibitors are compounds of formula (I) in which R 5 represents a cyano group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 5 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a fluoro atom, R 4 represents a hydrogen atom, and R 5 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 3 represents a fluoro atom, R 4 represents a hydrogen atom, and R 5 represents -Z#l .
  • CDK9 inhibitors are compounds of formula (I) in which R 1 represents a methyl group, R 3 represents a fluoro atom, R 4 represents a hydrogen atom, and R 5 represents -Z#l .
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents a methyl group, R 2 represents a hydrogen atom, R 3 represents a fluoro atom, R 4 represents a hydrogen atom, and R 5 represents -Z#l .
  • the CDK9 inhibitors are compounds of formula (I) in which R 1 represents a methyl group and R 5 represents -Z#l .
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
  • Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C5-cycloalkyl-, phenyl and benzyl,
  • Ci-C6-alkyl-, C3-C5-cycloalkyl-, phenyl or benzyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci- C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, fluoro-Ci-C2-alkyl-, C1-C2- fluoroalkoxy-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a group selected from a hydrogen atom, Ci-C6-alkyl-, C3-C5-cycloalkyl-, phenyl and benzyl, wherein said Ci-C6-alkyl-, C3-C5-cycloalkyl-, phenyl or benzyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci- C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, fluoro-Ci-C2-alkyl-, C1-C2- fluoroalkoxy-, and in which R 7 represents a hydrogen atom or a C1-C3 alkyl- group, or
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a group selected from a hydrogen atom, Ci-C6-alkyl- and phenyl,
  • Ci-Ce-alkyl- or phenyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, C1-C3- alkoxy-, dialkylamino-, and in which R 7 represents a hydrogen atom or a C1-C3 alkyl- group, or R 6 and R 7 , together with the nitrogen atom they are attached to, form a cyclic amine.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a group selected from a hydrogen atom, Ci-C6-alkyl- and phenyl,
  • Ci-Ce-alkyl- or phenyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, C1-C3- alkoxy-, dialkylamino-, and in which R 7 represents a hydrogen atom or a C1-C3 alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 and R 7 , together with the nitrogen atom they are attached to, form a cyclic amine.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci- C i-alkyl- and C3-C5-cycloalkyl-,
  • Ci-C 4 -alkyl- or Cs-Cs-cycloalkyl- group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a group selected from a hydrogen atom, Ci-C 4 -alkyl- and C3-C5- cycloalkyl-,
  • Ci-C 4 -alkyl- or Cs-Cs-cycloalkyl- group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines,
  • R 7 represents a hydrogen atom or a C1-C3 alkyl- group
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a group selected from a hydrogen atom, Ci-C i-alkyl- and C3-C5- cycloalkyl-,
  • Ci-C i-alkyl- or Cs-Cs-cycloalkyl- group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines,
  • R 7 represents a hydrogen atom or a C1-C3 alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom and Ci- C 4 -alkyl-,
  • Ci-C i-alkyl- group is optionally substituted with one substituent selected from the group consisting of hydroxy, Ci-C2-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a group selected from a hydrogen atom and Ci-C i-alkyl-,
  • Ci-C i-alkyl- group is optionally substituted with one substituent selected from the group consisting of hydroxy, Ci-C2-alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines,
  • R 7 represents a hydrogen atom or a C1-C3 alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C i-alkyl- and C3-Cs-cycloalkyl-, or
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom, Ci-C i-alkyl- and C3-Cs-cycloalkyl-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom and Ci-C 2 -alkyl-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a group selected from a hydrogen atom and
  • Ci-C 2 -alkyl- and in which R 7 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a group selected from a hydrogen atom and Ci-C 2 -alkyl-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 7 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a Ci-C 2 -alkyl- group, and in which R 7 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents a Ci-C 2 -alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents an ethyl- group, and in which R 7 represents a hydrogen atom.
  • the CDK9 inhibitors are compounds of formula (I) in which R 6 represents an ethyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a group selected from Ci-C6-alkyl-, halo-Ci-C3-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
  • said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -Nth, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, C1-C3- fluoroalkoxy-.
  • substituents identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -Nth, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, C1-C3- fluoroalkoxy
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, C3-C5-cycloalkyl-, phenyl and benzyl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -Nth, alkylamino-, dialkylamino-, cyclic amines, fluoro-Ci-C2-alkyl-, Ci-C2-fluoroalkoxy-.
  • R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, C3-C5-cycloalkyl-, phenyl and benzyl, wherein said group is optionally substituted with one, two or three
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a group selected from Ci-C6-alkyl-, fluoro-Ci-C3-alkyl-, C3-C5-cycloalkyl- and phenyl, wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, Ci-C2-alkyl-, Ci-C2-alkoxy-, -N3 ⁇ 4.
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a group selected from Ci-C i-alkyl-, fluoro-Ci-C3-alkyl-.
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a Ci-C i-alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a Ci-C 2 -alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a methyl- group. In another preferred embodiment of the present invention, the CDK9 inhibitors are compounds of formula (I) in which R 8 represents an ethyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a fluoro-Ci-C3-alkyl- group.
  • the CDK9 inhibitors are compounds of formula (I) in which R 8 represents a trifluoromethyl- group.
  • the present invention covers compounds of formula (I) which are disclosed in the Example section of this text, infra.
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 5 represents -Z-#l or a group selected from a hydrogen atom, cyano,
  • Ci-C6-alkyl-, C3-C 7 -cycloalkyl-, heterocyclyl-, phenyl, heteroaryl wherein said Ci-Ce- alkyl, C3-C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N- acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-;
  • Z stands for the linker and #1 for the bond to the binder
  • the CDK9 inhibitor is a compound of the formula (la), wherein X represents N and Y represents CH.
  • R 1 represents -Z-#l ;
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • Z stands for the linker and #1 for the bond to the binder
  • R 1 represents a methyl group
  • R 5 represents -Z-#l
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • Z stands for the linker and #1 for the bond to the binder
  • the CDK9 inhibitor which is attached to the binder is a compound of the formula (la), wherein
  • R 1 represents -Z-#l ;
  • X represents N and Y represents CH;
  • Z stands for the linker and #1 for the bond to the binder
  • R 1 represents a methyl group
  • X represents N and Y represents CH;
  • Z stands for the linker and #1 for the bond to the binder
  • the literature discloses various options for covalently coupling (conjugating) organic molecules to binders such as, for example antibodies (see, for example, K. Lang and J. W. Chin. Chem. Rev. 2014, 114, 4764-4806, M. Rashidian et al. Bioconjugate Chem. 2013, 24, 1277-1294).
  • Preference according to the invention is given to conjugation of the CDK9 inhibitors to an antibody via one or more sulphur atoms of cysteine residues of the antibody which are either already present as free thiols or generated by reduction of disulphide bridges, and/or via one or more NH groups of lysine residues of the antibody.
  • linkers can be categorized into the group of the linkers which can be cleaved in vivo and the group of the linkers which are stable in vivo (see L. Ducry and B. Stump, Bioconjugate Chem. 2J_, 5-13 (2010)).
  • the linkers which can be cleaved in vivo have a group which can be cleaved in vivo, where, in turn, a distinction may be made between groups which are chemically cleavable in vivo and groups which are enzymatically cleavable in vivo.
  • “Chemically cleavable in vivo” and “enzymatically cleavable in vivo” means that the linkers or groups are stable in circulation and are cleaved only at or in the target cell by the chemically or enzymatically different environment therein (lower pH; elevated glutathione concentration; presence of lysosomal enzymes such as cathepsin or plasmin, or glyosidases such as, for example, B-glucuronidases), thus releasing the low-molecular weight CDK9 inhibitor or a derivative thereof.
  • Groups which can be cleaved chemically in vivo are in particular disulphide, hydrazone, acetal and aminal; groups which can be cleaved enzymatically in vivo are in particular the 2-8-oligopeptide group, especially a dipeptide group or glycoside.
  • Peptide cleavage sites are disclosed in Bioconjugate Chem. 2002, 13, 855-869, and Bioorganic & Medicinal Chemistry Letters 8 (1998) 3341-3346 and also Bioconjugate Chem. 1998, 9, 618-626. These include, for example, valine- alanine, valine-lysine, valine-citrulline, alanine- lysine and phenylalanine- lysine (optionally with additional amide group).
  • Linkers which are stable in vivo are distinguished by a high stability (less than 5% metabolites after 24 hours in plasma) and do not have the chemically or enzymatically in vivo cleavable groups mentioned above.
  • the linker -Z- preferably has one of the basic structurs (i) to (iv) below:
  • ⁇ represents the attachment point to the active component
  • ⁇ ⁇ represents the attachment point to the binder
  • m is 0 or 1
  • v is 0, 1 or 2
  • SG is a (chemically or enzymatically) in vivo cleavable group (in particualar disulphide, hydrazone, acetal and aminal; or a 2-8-oligopeptide group which can be cleaved by cathepsin or plasmin)
  • SGI is an oligopeptide group or preferably a dipeptide group
  • LI independently of one another represent in vivo stable organic groups
  • L2 represents a coupling group to the binder or a single bond.
  • coupling is preferably to a cysteine residue or a lysine residue of the binder.
  • coupling can be to a tyrosine residue, glutamine residue or to an unnatural amino acid of the binder.
  • the unnatural amino acids may contain, for example, aldehyde or keto groups (such as, for example, formylglycine) or azide or alkyne groups (see Lan & Chin, Cellular Incorporation of Unnatural Amino Acids and Bioorthogonal Labeling of Proteins, Chem.Rev. 2014, 114, 4764-4806).
  • the basic linker structure (iii) in particular when the binder is an anti-TWEAKR antibody or an anti-EGFR antibody.
  • the administration of a conjugate according to the invention having a basic linker structure (iii) and coupling of the linker to a cysteine or lysine residue of the binder protein or peptide leads to cysteine or lysine derivatives of the formulae below:
  • L2 is preferably derived from a group which reacts with the sulphhydryl group of the cysteine. These include haloacetyls, maleimides, aziridines, acryloyls, arylating compounds, vinylsulphones, pyridyl disulphides, TNB thiols and disulphide-reducing agents. These groups generally react in an electrophilic manner with the sulphhydryl bond, forming a sulphide (e.g. thioether) or disulphide bridge. Preference is given to stable sulphide bridges. L2 is preferably
  • # l denotes the point of attachment to the sulphur atom of the binder
  • # 2 denotes the point of attachment to group LI
  • R 22 represents COOH, COOR, COR, CONHR, CONR 2 (where R in each case represents C1-3- alkyl), CONH2, preferably COOH.
  • Particularly preferred for L2 is:
  • # l denotes the point of attachment to the sulphur atom of the binder
  • # 2 denotes the point of attachment to the active compound
  • x represents 1 or 2
  • the bonds to a cysteine or lysine residue of the binder are present, to an extent of preferably more than 80%, particularly preferably more than 90%> (in each case based on the total number of bonds of the linker to the binder), particularly preferably as one of the two structures of the formula Al or A2.
  • the structures of the formula Al or A2 are generally present together, preferably in a ratio of from 60:40 to 40:60, based on the number of bonds to the binder. The remaining bonds are then present as the structure
  • R 1 is the linker Z
  • v is preferably 2 and m is preferably 0.
  • R 5 is the linker Z
  • v is preferably 0 and m is preferably 0.
  • R 1 is the linker Z
  • v is preferably 2 and m is preferably 0.
  • R 5 is the linker Z
  • v is preferably 0 and m is preferably 1.
  • LI is preferably represented by the formula
  • R represents H, NH 2 or Ci-C,-alkyl
  • Gl represents -NHCO- , -CONH- or / ; (R is preferably not NH2, if Gl represents N N-CO- NHCO or ) ⁇
  • n 0 or 1 ;
  • 0 is 0 or 1 ;
  • G2 represents a straight-chain or branched hydrocarbon chain which has 1 to 100 carbon atoms from arylene groups and/or straight-chain and/or branched and/or cyclic alkylene groups and which may be interrupted once or more than once by one or more of the groups -0-, -S-, -SO-, SO2, -NR y -, -NR y CO-, - C(NH)NR y -, CONR y -, -NR y NR y -, -S0 2 NR y NR y -, -CONR ⁇ R ⁇ (where R y represents H, phenyl, C1-C10- alkyl, C 2 -Cio-alkenyl or C 2 -Cio-alkynyl, each of which may be substituted by NHCONH 2 , -COOH, -OH, - NH 2 , NH-CNNH2, sulphonamide, sulphone, s
  • hydrocarbon chain including any side chains may be substituted by
  • G2 represents a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms from arylene groups and/or straight-chain and/or branched and/or cyclic alkylene groups and which may be interrupted once or more than once by one or more of the groups -0-, -S-, -SO-, SO2, -NH-, -CO-, -NHCO-, -CONH- , -NMe-, -NHNH-, -SO2NHNH-, -CONHNH- and a 5- to 10-membered aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, or -SO- — N N-CO—
  • hydrocarbon chain including the side chains may be substituted by -NHCONH2, -COOH, -OH, -NH 2 , NH-CN H 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid.
  • Rx represents H, Ci-C3-alkyl or phenyl.
  • # l is the bond to the CDK9 inhibitor and # 2 is the bond to the coupling group to the binder (e.g. L2).
  • a straight-chain or branched hydrocarbon chain of arylen groups and/or straight-chain and/or branched and/or cyclic alkylene groups generally comprises a ⁇ , ⁇ - divalent alkyl radical having the respective number of carbon atoms stated.
  • Examples which may be mentioned as being preferred are: methylene, ethane- 1 ,2-diyl (1 ,2-ethylene), propane-l ,3-diyl (1 ,3-propylene), butane- 1 ,4-diyl (1 ,4-butylene), pentane- 1 ,5-diyl (1 ,5-pentylene), hexane-l ,6-diyl (1 ,6-hexylene), heptane- 1 ,7-diyl (1 ,7-hexylene), octane-l ,8-diyl (1,8-octylene), nonane-l,9-diyl (1,9-nonylene), decane-l,10-diyl (1,10-decylene).
  • alkylene groups in the hydrocarbon chain may also be branched, i.e. one or more hydrogen atoms of the straight- chain alkylene groups mentioned above may optionally be substituted by Ci-io-alkyl groups, thus forming side chains.
  • the hydrocarbon chain may furthermore contain cyclic alkylene groups (cycloalkanediyl), for example 1 ,4-cyclohexanediyl or 1,3-cyclopentanediyl. These cyclic groups may be unsaturated.
  • aromatic groups for example phenylene, may be present in the hydrocarbon group.
  • one or more hydrogen atoms may optionally be substituted by Ci-io-alkyl groups.
  • Ci-io-alkyl groups may optionally be substituted by Ci-io-alkyl groups.
  • an optionally branched hydrocarbon chain is formed.
  • This hydrocarbon chain has a total of 0 to 100 carbon atoms, preferably 1 to 50, particularly preferably 2 to 25 carbon atoms.
  • the side chains may be substituted by -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CN H 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid.
  • the hydrocarbon chain may be interrupted once or more than once by one or more of the groups -0-, -S-, -SO-, S0 2 , -NH-, -CO-, -NHCO-, -CONH-, -NMe-, -NHNH-, -SO2NHNH-, -CONHNH- and a 5- to 10- membered aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, -SO- or -SO2- (preferably
  • the linker corresponds to the formula below:
  • v 0, 1 or 2
  • n 0 or 1 ;
  • ⁇ represents the bond to the active compound molecule and ⁇ ⁇ represents the bond to the binder peptide or protein, and
  • LI has the formula -NR U B-, where
  • R 11 represents H
  • B represents -[(CH 2 ) x -(X 4 ) y ]w-(CH 2 ) z -
  • X 4 represents -0-, -CONH- or -NHCO- .
  • #4 represents the bond to the binder peptide or protein
  • R 11 represents H or N3 ⁇ 4
  • B represents -[(CH 2 ) x -(X 4 ) y ]w-(CH2) z - :
  • X 4 represents -0-, -CONH-, -NHCO- or
  • #4 represents the bond to the binder peptide or protein
  • R 11 represents H ⁇ ⁇ 3 ⁇ 4
  • B represents -[(CH 2 ) x -(X 4 ) y ]w-(CH 2 ) z -
  • X 4 represents -0-, -CONH-, -NHCO- or
  • Preferable linker substructures are as follows below, where #1 represents the (generally thioether) linkage to the binder peptide or protein and #2 the point of attachment to the modifiedactive compound molecule:
  • the bonds to a cysteine or lysine residue of the binder are present, to an extent of preferably more than 80%, particularly preferably more than 90%> (in each case based on the total number of bonds of the linker to the binder), particularly preferably as one of the two structures of the formula A3 or A4:
  • # l denotes the point of attachment to the sulphur atom of the binder
  • R 22 represents COOH, COOR, COR, CONHR (where R in each case represents Cl-3-alkyl), CONH 2 , preferably COOH.
  • the structures of the formula A3 or A4 are generally present together, preferably in a ratio of from 60:40 to 40:60, based on the number of bonds to the binder. The remaining bonds are then present as the structure
  • linkers -Z- attached to a cysteine side chain, lysine side chain, cysteine residue, or lysine residue have the formula below:
  • ⁇ represents the bond to the active compound molecule
  • ⁇ ⁇ represents the bond to the binder peptide or protein
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • p is 0 to 20;
  • o 0 or 1 ;
  • G3 represents a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms from arylene groups and/or straight-chain and/or cyclic alkylene groups and which may be interrupted once or more than once by one or more of the groups -0-, -S-, -SO-, S0 2 , -NH-, -CO-, -NHCO-, -CONH-, -NMe-, - NHNH-, -SO2NHNH-, -CONHNH- and a 3- to 10-membered (preferably 5- to 10-membered) aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, -
  • n 0, 1 or 2;
  • n 0;
  • 0 is 0 or 1 ;
  • G 3 represents -(CH 2 CH 2 0)s(CH2)t(CONH) u (CH 2 CH 2 0)v(CH2)w-, where
  • s, t, v and w each independently of one another are from 0 to 20 and u is 0 or 1.
  • Preferred groups LI in the formula ⁇ -(CH2)v-(CO)m-Ll-L2- ⁇ above are those below, where r in each case independently of one another represents a number from 0 to 20, preferably from 0 to 15, particularly preferably from 1 to 20, especially preferably from 2 to 10. It is understood that the groups LI below are read from left to right, meaning that the left-hand symbol in the Table below denotes the linkage site to ⁇ -(CH2)v-(CO)m- and the right-hand symbol in the Table below denotes the linkage site to -L2- ⁇ . 76
  • linker moiety LI examples include a linker moiety LI and A-II below.
  • the table furthermore states the preferred value for m, this is whether there is a carbonyl group in front of LI or not (cf. ⁇ - (CH2)v-(CO)m-Ll-L2- ⁇ ). If the preferred value for m is 1, v (i.e. the number of CFh groups in front of LI not (cf. ⁇ -(CH2)v-(CO)m-Ll-L2- ⁇ )) is preferably 0.
  • linker moiety LI is given in Table A-III.
  • the table furthermore states with which group L2 these examples of LI are preferably combined and also the preferred coupling point (R 1 or R 5 ), and the preferred value for m, this is whether there is a carbonyl group in front of LI or not (cf. ⁇ -(03 ⁇ 4) ⁇ - (CO)m-Ll-L2- ⁇ ).
  • the preferred value for v in these examples is 0, this is whether there is a Cf3 ⁇ 4 group in front of LI or not (cf. ⁇ -(CH 2 )v-(CO)m-Ll-L2- ⁇ ).
  • the first column furthermore states the example numbers for the cetuximab ADCs in which the linkers in question are used, but which likewise apply in each row for ADCs with other antibodies.
  • L2 is a succinimide or derived therefrom, this imide may also be fully or partially in the form of the hydrolysed open-chain succinamide, as described above. Depending on LI, this hydrolysis to open-chain succinamides may be more or less pronounced or not present at all.
  • linker moiety LI is given below, wherein LI represents -(CH2) q -L'-, wherein q is O or 1.
  • Examples of a linker moiety L' are given in Tables A-IV and A-V below.
  • the table furthermore states with which group L2 these examples of LI are preferably combined.
  • the preferred value for v in these examples is 0, this is whether there is a CLh group in front of LI or not (cf. ⁇ -(CH2)v-(CO)m-Ll-L2- ⁇ ), and the preferred value for m is 0, this is whether there is a carbonyl group in front of LI or not (cf. ⁇ - (CH2)v-(CO)m-Ll-L2- ⁇ ).
  • the first column furthermore states the example numbers for the cetuximab ADCs in which the linkers in question are used, but which likewise apply in each row for ADCs with other antibodies.
  • L2 is a succinimide or derived therefrom, this imide may also be fully or partially in the form of the hydrolysed open-chain succinamide, as described above. Depending on LI, this hydrolysis to open-chain succinamides may be more or less pronounced or not present at all.
  • linkers LI given in these rows are attached to a linker L2 selected from:
  • the bonds to a cysteine or lysine residue of the binder are present, to an extent of preferably more than 80%, particularly preferably more than 90% (in each case based on the total number of bonds of the linker to the binder), particularly preferably as one of the two structures of the formula A5 or A6.
  • the structures of the formula A5 or A6 are generally present together, preferably in a ratio of from 60:40 to 40:60, based on the number of bonds to the binder. The remaining bonds are then present as the structure
  • conjugates having corresponding linkers have the following structures, where A, R 1 to R 4 , L, X, Y and LI have the meanings given above, AB represents an antibody attached via a cysteine or a lysine residue and n is a number from 1 to 10.
  • AB is a human, humanized or chimeric monoclonal antibody or an antigen-binding fragment thereof, in particular an anti-TWEAKR antibody or an antigen-binding fragment thereof or an anti-EGFR antibody or an antigen-binding fragment thereof.
  • an anti-TWEAKR antibody which binds specifically to amino acid D in position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibody TPP-2090, or the anti-EGFR antibodies cetuximab, TPP-4030, TPP-5653, or nimotuzumab.
  • Preferred examples of conjugates having corresponding linkers have the following structures, where R 1 to R 4 , L, X, Y and LI has the meanings given above, AB represents an antibody attached via a cysteine residue or a lysine residue and n is a number from 1 to 10.
  • AB is a human, humanized or chimeric monoclonal antibody or an antigen-binding fragment thereof, in particular an anti- TWEAKR antibody or an antigen-binding fragment thereof or an anti-EGFR antibody or an antigen- binding fragment thereof.
  • an anti-TWEAKR antibody which binds specifically to amino acid D in position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti- TWEAKR antibody TPP-2090, or the anti-EGFR antibodies cetuximab, TPP-4030, TPP-5653, or nimotuzumab.
  • HN X O More preferred examples of conjugates having corresponding linkers have the following structures, where X, Y and LI has the meanings given above, AB represents an antibody attached via a cysteine residue or a lysine residue and n is a number from 1 to 10.
  • AB is a human, humanized or chimeric monoclonal antibody or an antigen-binding fragment thereof, in particular an anti-TWEAKR antibody or an antigen-binding fragment thereof or an anti-EGFR antibody or an antigen-binding fragment thereof.
  • an anti-TWEAKR antibody which binds specifically to amino acid D in position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR cetuximab, TPP-4030, TPP-5653, or nimotuzumab.
  • Preference according to the invention is furthermore given to the basic structure (i), where SGI represents a group which can be cleaved by cathepsin and LI and L2 have the meanings given above. Particular preference is given to the following groups if R 1 is a linker Z:
  • R 1 is the linker Z in basic structure (i)
  • v is preferably 2
  • m is preferably 0, and SGI is particularly preferably
  • X represents H or a Ci-io-alkyl group which may optionally be substituted by -NHCONH2, -COOH, -OH, NH 2 , -NH-CN H2 or sulphonic acid.
  • R 5 is the linker Z in basic structure (i)
  • v is preferably 0, m is preferably 0 and SG is particularly preferably
  • X represents H or a Ci-io-alkyl group which may optionally be substituted by -NHCONH2, -COOH, -OH, NH 2 , -NH-CN H2 or sulphonic acid.
  • Preference according to the invention is furthermore given to the basic structure (ii) or (iv), where SG represents a group which can be cleaved by cathepsin and LI and L2 have the meanings given above. Particular preference is given to the following groups:
  • X represents H or a Ci-io-alkyl group which may optionally be substituted by -NHCONH2, -COOH, -OH, NH 2 , -NH-CN H2 or sulphonic acid.
  • Table B below gives examples of a linker moiety -SGI -LI- or -L1-SG-L1-, where SGI and SG are groups which can be cleaved by cathepsin.
  • Table B furthermore states with which group L2 these examples of -SGI -LI- and -L1-SG-L1- are preferably combined, and also the preferred coupling point (R 1 or R 5 ) and the preferred value for m, thus whether there is a carbonyl group in front of LI or not (cf. ⁇ -(CH2)v-(CO)m-Ll-L2- ⁇ ).
  • These linkers are preferably coupled to a cysteine residue.
  • the first column furthermore states the example numbers, given in an exemplary manner for cetuximab ADCs, in which corresponding linkers are used. They apply in the same manner to the corresponding ADCs with other antibodies.
  • the LI group is highlighted in a box. However, these groups LI can be replaced by one of the groups LI given for formula ⁇ -(CH2)v-(CO)m-Ll-L2- ⁇ above. If L2 is a succinamide or derived therefrom, this amide may also be fully or partially in the form of the hydrolysed open-chain succinamide, as described above. Table B
  • conjugates having basic stracture have the following stracture, where Rl, R2, R3, R4, X, Y, SGI and LI have the meanings given above, AB represents an antibody attached via a cysteine residue or a lysine residue and n is a number from 1 to 10.
  • AB is an anti-TWEAKR antibody, in particular an anti-TWEAKR antibody which binds specifically to amino acid D in position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibody TPP-2090, or an anti-EGFR antibodies, in particular cetuximab, TPP-4030, TPP-5653 or nimotuzumab.
  • conjugates having basic structure (i) have the following structure, where Rl, R2, R3, R4, L, X, Y, SGI and LI have the meanings given above, AB represents an antibody attached via a cysteine residue or a lysine residue and n is a number from 1 to 10.
  • AB is an anti- TWEAKR antibody, in particular an anti-TWEAKR antibody which binds specifically to amino acid D in position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibody TPP-2090, or an anti-EGFR antibodies, in particular cetuximab, TPP-4030, TPP-5653 or nimotuzumab.
  • CDK9 inhibitor - linker-intermediates preparation of the conjugates
  • the conjugates according to the invention are prepared by initially providing the low-molecular weight CDK9 inhibitor with a linker.
  • the intermediate obtained in this manner is then reacted with the binder (preferably antibody).
  • the CDK9 inhibitor-linker-intermediates are compounds of general formula ( ⁇ )
  • X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
  • R 1 represents -Z or a group selected from Ci-C6-alkyl-, C3-C6-alkenyl, C3-C6-alkynyl, C3-C 7 -cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, phenyl-Ci-C3-alkyl- and heteroaryl-Ci-C3-alkyl-,
  • R 3 , R 4 represent, independently from each other, a group selected from a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, Ci-C3-alkyl-, Ci-C3-alkoxy-, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-;
  • Ci-C6-alkyl-, C3-C7-cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -Nth, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, or
  • R 6 and R 7 together with the nitrogen atom they are attached to, form a cyclic amine; represents a group selected from Ci-C6-alkyl-, halo-Ci-C3-alkyl-, C3-C7-cycloalkyl-,
  • said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, Ci-C3-alkyl-, Ci-C3-alkoxy-, -Nth, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-Ci-C3-alkyl-, Ci-C3-fluoroalkoxy-, wherein one of the substituents R 1 or R 5 is Z,
  • linker -Z- represents one of the following general structures (v) to (viii):
  • v 0, 1 or 2
  • n 0 or 1
  • ⁇ represents the attachment point to the active component
  • SG and SGI represent the same in vivo cleavable group as described above, LI represent independently of each other in vivo non-cleavable organic groups as described above, and L3 preferably represents wherein
  • # l represents the attachment site to the group LI .
  • Preferred embodiments for the compounds of formula ( ⁇ ) correspond to the preferred binder conjugates described above with the exception that the binding moiety -L2- ⁇ is replaced with -L3.
  • cysteine residue for coupling to a cysteine residue, one of the compounds below is reacted with the cysteine- containing binder such as an antibody, which is optionally partially reduced for this purpose:
  • cysteine residue for coupling to a cysteine residue, one of the compounds below is reacted with the cysteine-containing binder such as an antibody, which is optionally partially reduced for this purpose:
  • the compound may be employed, for example, in the form of its trifluoroacetic acid salt.
  • the compound is preferably used in a 2- to 12-fold molar excess with respect to the binder.
  • succinimide-linked ADCs may, after conjugation, be converted into the open- chain succinamides, which have an advantageous stability profile.
  • This reaction can be carried out at pH 7.5 to 9, preferably at pH 8, at a temperature of from 25°C to 37°C, for example by stirring.
  • the preferred stirring time is 8 to 30 hours.
  • AB is an antibody coupled via a cysteine residue or a lysine residue.
  • AB and AB2 are anti-TWEAKR antibodies, in particular antibodies which bind specifically to amino acid D in position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibody TPP-2090. Binders
  • binder is understood to mean a molecule which binds to a target molecule present at a certain target cell population to be addressed by the binder/active compound conjugate.
  • binder is to be understood in its broadest meaning and also comprises, for example, lectins, proteins capable of binding to certain sugar chains, and phospholipid-binding proteins.
  • binders include, for example, high-molecular weight proteins (binding proteins), polypeptides or peptides (binding peptides), non-peptidic (e.g. aptamers (US5,270,163) review by Keefe AD., et al., Nat. Rev. Drug Discov.
  • Binding proteins are, for example, antibodies and antibody fragments or antibody mimetics such as, for example, affibodies, adnectins, anticalins, DARPins, avimers, nanobodies (review by Gebauer M. et al., Curr. Opinion in Chem. Biol. 2009; 13:245-255; Nuttall S.D. et al., Curr. Opinion in Pharmacology 2008; 8:608-617).
  • Binding peptides are, for example, ligands of a ligand/receptor pair such as, for example, VEGF of the ligand/receptor pair VEGF/KDR, such as transferrin of the ligand/receptor pair transferrin/transferrin receptor or cytokine/cytokine receptor, such as TNFalpha of the ligand/receptor pair TNFalpha/TNF alpha receptor.
  • ligands of a ligand/receptor pair such as, for example, VEGF of the ligand/receptor pair VEGF/KDR, such as transferrin of the ligand/receptor pair transferrin/transferrin receptor or cytokine/cytokine receptor, such as TNFalpha of the ligand/receptor pair TNFalpha/TNF alpha receptor.
  • the literature also discloses various options of covalent coupling (conjugation) of organic molecules to antibodies. Preference according to the invention is given to the conjugation of the toxophores to the antibody via one or more sulphur atoms of cysteine residues of the antibody and/or via one or more NH groups of lysine residues of the antibody. However, it is also possible to bind the toxophore to the antibody via free carboxyl groups or via sugar residues of the antibody.
  • a "target molecule” in the broadest sense is understood to mean a molecule which is present in the target cell population and which may be a protein (for example a receptor of a growth factor) or a non-peptidic molecule (for example a sugar or phospholipid). It is preferably a receptor or an antigen.
  • extracellular target molecule describes a target molecule, attached to the cell, which is located at the outside of a cell, or the part of a target molecule which is located at the outside of a cell, i.e. a binder may bind on an intact cell to its extracellular target molecule.
  • An extracellular target molecule may be anchored in the cell membrane or be a component of the cell membrane.
  • the person skilled in the art is aware of methods for identifying extracellular target molecules. For proteins, this may be by determining the transmembrane domain(s) and the orientation of the protein in the membrane. These data are usually deposited in protein databases (e.g. SwissProt).
  • cancer target molecule describes a target molecule which is more abundantly present on one or more cancer cell species than on non-cancer cells of the same tissue type.
  • the cancer target molecule is selectively present on one or more cancer cell species compared with non-cancer cells of the same tissue type, where selectively describes an at least two-fold enrichment on cancer cells compared to non-cancer cells of the same tissue type (a "selective cancer target molecule”).
  • selective cancer target molecule allows the selective therapy of cancer cells using the conjugates according to the invention.
  • the binder can be attached to the linker via a bond. Attachment of the binder can be via a heteroatom of the binder. Heteroatoms according to the invention of the binder which can be used for attachment are sulphur (in one embodiment via a sulphhydryl group of the binder), oxygen (according to the invention by means of a carboxyl or hydroxyl group of the binder) and nitrogen (in one embodiment via a primary or secondary amine group or amide group of the binder). These heteroatoms may be present in the natural binder or are introduced by chemical methods or methods of molecular biology. According to the invention, the attachment of the binder to the toxophore has only a minor effect on the binding activity of the binder with respect to the target molecule. In a preferred embodiment, the attachment has no effect on the binding activity of the binder with respect to the target molecule.
  • an immunoglobulin molecule preferably comprises a molecule having four polypeptide chains, two heavy chains (H chains) and two light chains (L chains) which are typically linked by disulphide bridges.
  • Each heavy chain comprises a variable domain of the heavy chain (abbreviated VH) and a constant domain of the heavy chain.
  • the constant domain of the heavy chain may, for example, comprise three domains CHI, CH2 and CH3.
  • Each light chain comprises a variable domain (abbreviated VL) and a constant domain.
  • the constant domain of the light chain comprises a domain (abbreviated CL).
  • CL constant domain
  • the VH and VL domains may be subdivided further into regions having hypervariability, also referred to as complementarity determining regions (abbreviated CDR) and regions having low sequence variability (framework region, abbreviated FR).
  • CDR complementarity determining regions
  • FR frame region
  • each VH and VL region is composed of three CDRs and up to four FRs.
  • FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 For example from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • An antibody may be obtained from any suitable species, e.g. rabbit, llama, camel, mouse or rat. In one embodiment, the antibody is of human or murine origin.
  • An antibody may, for example, be human, humanized or chimeric.
  • monoclonal antibody refers to antibodies obtained from a population of substantially homogeneous antibodies, i.e. individual antibodies of the population are identical except for naturally occurring mutations, of which there may be a small number. Monoclonal antibodies recognize a single antigenic binding site with high specificity. The term monocvlonal antibody does not refer to a particular preparation process.
  • the term "intact” antibody refers to antibodies comprising both an antigen-binding domain and the constant domain of the light and heavy chain.
  • the constant domain may be a naturally occurring domain or a variant thereof having a number of modified amino acid positions.
  • modified intact antibody refers to intact antibodies fused via their amino terminus or carboxy terminus by means of a covalent bond (e.g. a peptide bond) with a further polypeptide or protein not originating from an antibody.
  • antibodies may be modified such that, at defined positions, reactive cysteines are introduced to facilitate coupling to a toxophore (see Junutula et al. Nat Biotechnol. 2008 Aug;26(8):925-32).
  • human antibody refers to antibodies which can be obtained from a human or which are synthetic human antibodies.
  • a "synthetic” human antibody is an antibody which is partially or entirely obtainable in silico from synthetic sequences based on the analysis of human antibody sequences.
  • a human antibody can be encoded, for example, by a nucleic acid isolated from a library of antibody sequences of human origin. An example of such an antibody can be found in Soderlind et al., Nature Biotech. 2000, 18:853-856.
  • humanized or “chimeric” antibody describes antibodies consisting of a non-human and a human portion of the sequence. In these antibodies, part of the sequences of the human immunoglobulin (recipient) are replaced by sequence portions of a non-human immunoglobulin (donor). In many cases, the donor is a murine immunoglobulin. In the case of humanized antibodies, amino acids of the CDR of the recipient are replaced by amino acids of the donor. Sometimes, amino acids of the framework, too, are replaced by corresponding amino acids of the donor. In some cases the humanized antibody contains amino acids present neither in the recepient nor in the donor, which were introduced during the optimization of the antibody. In the case of chimeric antibodies, the variable domains of the donor immunoglobulin are fused with the constant regions of a human antibody.
  • complementarity determining region refers to those amino acids of a variable antibody domain which are required for binding to the antigen.
  • each variable region has three CDR regions referred to as CDR1, CDR2 and CDR3.
  • Each CDR region may embrace amino acids according to the definition of Kabat and/or amino acids of a hypervariable loop defined according to Chotia.
  • the definition according to Kabat comprises, for example, the region from about amino acid position 24 - 34 (CDR1), 50 - 56 (CDR2) and 89 - 97 (CDR3) of the variable light chain and 31 - 35 (CDR1), 50 - 65 (CDR2) and 95 - 102 (CDR3) of the variable heavy chain (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)).
  • the definition according to Chotia comprises, for example, the region from about amino acid position 26 - 32 (CDR1), 50 - 52 (CDR2) and 91 -96 (CDR3) of the variable light chain and 26 - 32 (CDR1), 53 - 55 (CDR2) and 96 - 101 (CDR3) of the variable heavy chain (Chothia and Lesk; J Mol Biol 196: 901-917 (1987)).
  • a CDR may comprise amino acids from a CDR region defined according to Kabat and Chotia.
  • antibodies may be categorized into different classes. There are five main classes of intact antibodies: IgA, IgD, IgE, IgG and IgM, and several of these can be divided into further subclasses. (Isotypes), e.g. IgGl , IgG2, IgG3, IgG4, IgAl and IgA2.
  • the constant domains of the heavy chain which correspond to the different classes, are referred to as [alpha/a], [delta/ ⁇ ], [epsilon/ ⁇ ], [gamma/ ⁇ ] and [my/ ⁇ ]. Both the three-dimensional structure and the subunit structure of antibodies are known.
  • the term "functional fragment” or "antigen-binding antibody fragment” of an antibody/immunoglobulin is defined as a fragment of an antibody/immunoglobulin (e.g. the variable domains of an IgG) which still comprise the antigen binding domains of the antibody/immunoglobulin.
  • the "antigen binding domain” of an antibody typically comprises one or more hypervariable regions of an antibody, for example the CDR, CDR2 and/or CDR3 region.
  • the "framework" or “skeleton” region of an antibody may also play a role during binding of the antibody to the antigen.
  • the framework region forms the skeleton of the CDRs.
  • the antigen binding domain comprises at least amino acids 4 to 103 of the variable light chain and amino acids 5 to 109 of the variable heavy chain, more preferably amino acids 3 to 107 of the variable light chain and 4 to 111 of the variable heavy chain, particularly preferably the complete variable light and heavy chains, i.e. amino acids 1 - 109 of the VL and 1 to 113 of the VH (numbering according to WO97/08320).
  • “Functional fragments” or “antigen-binding antibody fragments” of the invention encompass, non- conclusively, Fab, Fab', F(ab')2 and Fv fragments, diabodies, Single Domain Antibodies (DAbs), linear antibodies, individual chains of antibodies (single-chain Fv, abbreviated to scFv); and multispecific antibodies, such as bi and tri-specific antibodies, for example, formed from antibody fragments C.
  • Multispecific antibodies are those having identical binding sites. Multispecific antibodies may be specific for different epitopes of an antigen or may be specific for epitopes of more than one antigen (see, for example WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., 1991, J. Immunol. 147:60 69; U. S. Pat. Nos. 4,474,893; 4,714,681 ; 4,925,648; 5,573,920; 5,601,819; or Kostelny et al., 1992, J. Immunol. 148: 1547 1553).
  • An F(ab')2 or Fab molecule may be constructed such that the number of intermolecular disulphide interactions occurring between the Chi and the CL domains can be reduced or else completely prevented.
  • Epitopic determinants refer to protein determinants capable of binding specifically to an immunoglobulin or T cell receptors. Epitopic determinants usually consist of chemically active surface groups of molecules such as amino acids or sugar side chains or combinations thereof, and usually have specific 3-dimensional structural properties and also specific charge properties.
  • “Functional fragments” or “antigen-binding antibody fragments” may be fused with another polypeptide or protein, not originating from an antibody, via the amino terminus or carboxyl terminus thereof, by means of a covalent bond (e.g. a peptide linkage). Furthermore, antibodies and antigen-binding fragments may be modified by introducing reactive cysteines at defined locations, in order to facilitate coupling to a toxophore (see Junutula et al. Nat Biotechnol. 2008 Aug; 26(8):925-32).
  • Polyclonal antibodies can be prepared by methods known to a person of ordinary skill in the art.
  • Monoclonal antibodies may be prepared by methods known to a person of ordinary skill in the art (Kohler and Milstein, Nature, 256, 495-497, 1975).
  • Human and humanized monoclonal antibodies may be prepared by methods known to a person of ordinary skill in the art (Olsson et al., Meth Enzymol. 92, 3-16 or Cabilly et al. US 4,816,567 or Boss et al. US 4,816,397).
  • Antibodies of the invention may be obtained from recombinant antibody libraries consisting for example of the amino acid sequences of a multiplicity of antibodies compiled from a large number of healthy volunteers. Antibodies may also be produced by means of known recombinant DNA technologies. The nucleic acid sequence of an antibody can be obtained by routine sequencing or is available from publically accessible databases.
  • An "isolated” antibody or binder has been purified to remove other constituents of the cell. Contaminating constituents of a cell which may interfere with a diagnostic or therapeutic use are, for example, enzymes, hormones, or other peptidic or non-peptidic constituents of a cell.
  • a preferred antibody or binder is one which has been purified to an extent of more than 95% by weight, relative to the antibody or binder (determined for example by Lowry method, UV-Vis spectroscopy or by SDS capillary gel electrophoresis).
  • an antibody is normally prepared by one or more purification steps.
  • specific binding refers to an antibody or binder which binds to a predetermined antigen/target molecule.
  • Specific binding of an antibody or binder typically describes an antibody or binder having an affinity of at least 10 ⁇ 7 M (as Kd value; i.e. preferably those with smaller Kd values than 10 7 M), with the antibody or binder having an at least two times higher affinity for the predetermined antigen/target molecule than for a non-specific antigen/target molecule (e.g. bovine serum albumin, or casein) which is not the predetermined antigen/target molecule or a closely related antigen/target molecule.
  • Kd value i.e. preferably those with smaller Kd values than 10 7 M
  • the antibodies preferably have an affinity of at least 10 "7 M (as Kd value; in other words preferably those with smaller Kd values than 10 "7 M), preferably of at least 10 "8 M, more preferably in the range from 10" M to 10 u M.
  • Kd values may be determined, for example, by means of surface plasmon resonance spectroscopy.
  • the antibody-drug conjugates of the invention likewise exhibit affinities in these ranges.
  • the affinity is preferably not substantially affected by the conjugation of the drugs (in general, the affinity is reduced by less than one order of magnitude, in other words, for example, at most from 10 "8 M to 10 "7 M).
  • the antibodies used in accordance with the invention are also notable preferably for a high selectivity.
  • a high selectivity exists when the antibody of the invention exhibits an affinity for the target protein which is better by a factor of at least 2, preferably by a factor of 5 or more preferably by a factor of 10, than for an independent other antigen, e.g. human serum albumin (the affinity may be determined, for example, by means of surface plasmon resonance spectroscopy).
  • the antibodies of the invention that are used are preferably cross-reactive.
  • the antibody used in accordance with the invention in order to be able to facilitate and better interpret preclinical studies, for example toxicological or activity studies (e.g. in xenograft mice), it is advantageous if the antibody used in accordance with the invention not only binds the human target protein but also binds the species target protein in the species used for the studies.
  • the antibody used in accordance with the invention in addition to the human target protein, is cross-reactive to the target protein of at least one further species.
  • species of the families of rodents, dogs and non-human primates Preferred rodent species are mouse and rat.
  • Preferred non-human primates are rhesus monkeys, chimpanzees and long- tailed macaques.
  • the antibody used in accordance with the invention in addition to the human target protein, is cross-reactive to the target protein of at least one further species selected from the group of species consisting of mouse, rat and long-tailed macaque (Macaca fascicularis).
  • antibodies used in accordance with the invention which in addition to the human target protein are at least cross-reactive to the mouse target protein. Preference is given to cross-reactive antibodies whose affinity for the target protein of the further non-human species differs by a factor of not more than 50, more particularly by a factor of not more than ten, from the affinity for the human target protein.
  • the target molecule towards which the binder, for example an antibody or an antigen-binding fragment thereof, is directed is preferably a cancer target molecule.
  • the term "cancer target molecule” describes a target molecule which is more abundantly present on one or more cancer cell species than on non-cancer cells of the same tissue type.
  • the cancer target molecule is selectively present on one or more cancer cell species compared with non-cancer cells of the same tissue type, where selectively describes an at least two-fold enrichment on cancer cells compared to non-cancer cells of the same tissue type (a "selective cancer target molecule").
  • selective cancer target molecule allows the selective therapy of cancer cells using the conjugates according to the invention.
  • Antibodies which are specific against an antigen can be prepared by a person of ordinary skill in the art by means of methods with which he or she is familiar (such as recombinant expression, for example) or may be acquired commercially (as for example from Merck KGaA, Germany).
  • Examples of known commercially available antibodies in cancer therapy are Erbitux® (cetuximab, Merck KGaA), Avastin® (bevacizumab, Roche) and Herceptin® (trastuzumab, Genentech).
  • the antibody is produced recombinantly in CHO cells.
  • the target molecule is a selective cancer target molecule.
  • the target molecule is a protein.
  • the target molecule is an extracellular target molecule.
  • the extracellular target molecule is a protein.
  • Cancer target molecules are known to those skilled in the art. Examples of these are listed below.
  • cancer target molecules are:
  • EGF receptor NCBI reference sequence NP 005219.2
  • SEQ ID NO: 213 (1210 amino acids): >gi
  • mesothelin is encoded by amino acids 296-598.
  • Amino acids 37-286 are coding for the megakaryocyte-potentiating factor.
  • Mesothelin is anchored in the cell membrane via a GPI anchor and is localized extracellularly.
  • the extracellular domain is marked by underlining.
  • the mature extracellular domain is marked by underlining.
  • CD52 NCBI reference sequence NP 001794.2
  • SEQ ID NO: 217 >gi
  • Her2 (NCBI reference sequence NP 004439.2), SEQ ID NO: 218 >gi
  • CD20 NCBI reference sequence NP 068769.2
  • SEQ ID NO: 219 >gi
  • lymphocyte activation antigen CD30 (SwissProt ID P28908), SEQ ID NO: 220 >gi
  • transmembrane glycoprotein NMB (SwissProt ID Q14956), SEQ ID NO: 223 >gi

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Abstract

L'invention concerne de nouveaux conjugués d'un liant ou d'un dérivé de celui-ci avec une ou plusieurs molécules d'un composant actif, le composant actif étant un inhibiteur de la kinase CDK9, qui est conjugué au liant par l'intermédiaire d'un lieur Z tel que décrit et défini dans la description. L'invention concerne également des procédés pour leur préparation, leur utilisation pour le traitement et/ou la prophylaxie de troubles, en particulier de troubles d'hyperprolifération.<i />
PCT/EP2016/073825 2015-10-10 2016-10-06 Conjugué anticorps-médicament (adc) inhibiteur de ptefb Ceased WO2017060322A2 (fr)

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US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
CN113603708A (zh) * 2021-07-27 2021-11-05 中国药科大学 一种具有大环骨架结构的新型cdk9抑制剂的制备及其应用
EP3919911A1 (fr) * 2020-06-04 2021-12-08 Urteste S.A. Nouveau marqueur de diagnostic du cancer de la prostate
US11242356B2 (en) 2017-03-28 2022-02-08 Bayer Aktiengesellschaft PTEFb inhibiting macrocyclic compounds
US11254690B2 (en) 2017-03-28 2022-02-22 Bayer Pharma Aktiengesellschaft PTEFb inhibiting macrocyclic compounds
WO2022175595A1 (fr) * 2021-02-16 2022-08-25 Glykos Finland Oy Charges utiles de lieurs et leurs conjugués
WO2023057812A1 (fr) 2021-10-04 2023-04-13 Vincerx Pharma Gmbh Composés, compositions pharmaceutiques et méthodes pour le traitement, la prévention ou la gestion d'un trouble hyperprolifératif
WO2023061405A1 (fr) * 2021-10-12 2023-04-20 成都科岭源医药技术有限公司 Conjugué lieur-médicament ciblé hautement stable
WO2024094171A1 (fr) * 2022-11-04 2024-05-10 江苏恒瑞医药股份有限公司 Composé aminopyrimidine substitué, son procédé de préparation et son utilisation médicale
WO2024153127A1 (fr) 2023-01-18 2024-07-25 泰励生物科技（上海）有限公司 Conjugué anticorps-médicament et son utilisation
WO2025202647A1 (fr) * 2024-03-28 2025-10-02 King's College London Inhibiteurs de cdk conjugués à des fractions de ciblage egfr

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