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WO2024126617A1 - Composés bifonctionnels pour la dégradation de kinases par l'intermédiaire d'une voie de l'ubiquitine protéosome - Google Patents

Composés bifonctionnels pour la dégradation de kinases par l'intermédiaire d'une voie de l'ubiquitine protéosome Download PDF

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WO2024126617A1
WO2024126617A1 PCT/EP2023/085688 EP2023085688W WO2024126617A1 WO 2024126617 A1 WO2024126617 A1 WO 2024126617A1 EP 2023085688 W EP2023085688 W EP 2023085688W WO 2024126617 A1 WO2024126617 A1 WO 2024126617A1
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tmkb
group
alkyl
formula
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Inventor
Adrianus Petrus Antonius De Man
Rogier Christian Buijsman
Jan Gerard STERRENBURG
Joeri Johannes Petrus DE WIT
Freek VAN CAUTER
Sander Petrus Wilhelmus VAN GEMERT
Martine Berendina Wilhemina PRINSEN
Winfried Robert Mulder
Michelle MULLER
Diep VU-PHAM
Yvonne Gertruda Theodora Hendrika VAN MIL
Rik Casper Petrus August REMMERS
Joost Cornelis Marinus UITDEHAAG
Milan Jurgen HOFFMANN
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Crossfire Oncology Holding BV
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Crossfire Oncology Holding BV
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Priority to EP23824937.9A priority Critical patent/EP4634184A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to bifunctional compounds for degrading kinases via ubiquitin proteosome pathway. More specifically, the invention relates to macrocyclic bifunctional compounds for degrading kinases via ubiquitin proteosome pathway, along with processes to prepare the bifunctional compounds, uses of the bifunctional compounds and methods for treating diseases modulated by specific kinases. Specifically, the invention relates to bifunctional compounds formed by conjugation of reversible macrocyclic kinase inhibitors with E3 ligase binding moieties, which function to recruit targeted protein kinases to E3 ubiquitin ligase for degradation of the targeted protein kinases.
  • kinases are enzymes that transfer a phosphate group from ATP to a protein while phosphatases remove a phosphate group from protein. Together, these two enzymatic processes regulate cellular functions such as cell proliferation, subcellular translocation, apoptosis, inflammation and metabolism (Attwood M.M. et al (2021 ) Nat Rev Drug Discov).
  • the human kinome is composed of over 500 kinases.
  • small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy.
  • inhibitors for EGFR asfatinib, osimertinib
  • BTK ibrutinib, acalabrutinib and zanubrutinib
  • RET cabozantinib, selpercatinib
  • MET capmatinib, tepotinib
  • FLT-3 gilteritinib, midostaurin
  • BTK Bruton's tyrosine kinase
  • BTK small molecule inhibitors
  • small molecule inhibitors such as the FDA approved irreversible BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib
  • CLL Chronic Lymphocytic Leukemia
  • MCL Mantle Cell Lymphoma
  • WM Macroglobulinemia
  • SLL Small Lymphocytic Lymphoma
  • BTK is also expressed and plays also pro-tumorigenic roles in several solid tumors (Xianhui Wang et al. 2021 ).
  • BTK inhibition with ibrutinib or acalabrutinib inhibited cell growth (Kokabee et al 2015).
  • Ibrutinib has also been shown to inhibit in vivo (xenograft) breast cancer cell growth (Wang et al., 2016) and inhibition of BTK with ibrutinib blocked gastric cancer cell growth (Wang et al., 2016).
  • BTK inhibitors have also showed inhibition of cellular proliferation and migration, and induced apoptosis and autophagy in glioblastoma cell lines (Wei et al., 2016; Wang et al., 2017).
  • BTK In addition to its role in BCR signaling, BTK is also involved in many other immunological pathways which provides a rationale for the targeting of BTK in the context of inflammatory and systemic autoimmune disease (Stefan F. H. Neys et al. 2021 ).
  • a drawback of the currently approved irreversible inhibitors is that drug resistance in malignant diseases can develop when BTK variations at the catalytic site and the gatekeeper of the BTK are not able to bind efficiently to irreversible inhibitors in patients treated with currently approved BTK inhibitors. This is a rather common event in patients treated with irreversible inhibitors and who experience relapse.
  • a major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481 ) mutations. These mutations hamper binding of irreversible inhibitors such as ibrutinib and acalabrutinib which form a covalent bond with this amino acid.
  • BTK gatekeeper residue threonine 474 T474 mutations which can reduce BTK inhibitor access to BTK (Rula Zain et al. 2021 , Shenqiu Wang et al. 2019).
  • Second-generation BTK inhibitors include acalabrutinib, zanubrutinib, and tirabrutinib which offer greater BTK selectivity. While these agents may limit off-target toxicity, they do not overcome common mechanisms of resistance to ibrutinib due to mutations.
  • kinase inhibitors are known, e.g. for the kinases LCK (Lymphocyte-Specific Protein Tyrosine Kinase), FGFR1 (Fibroblast Growth Factor Receptor 1 ), FLT3 (FMS-like tyrosine kinase 3), PDGFR-p (Platelet Derived Growth Factor Receptor Beta), FMS (Colony Stimulating Factor 1 Receptor), LYN (LCK/YES Novel Tyrosine Kinase), MEK1 (Mitogen-Activated Protein Kinase Kinase 1 ), AUR-B (Aurora B Kinase), ITK (IL2 inducible T cell kinase), VEGFR (Vascular Endothelial Growth Factor Receptor), EGFR (Epidermal Growth Factor Receptor) and TEC (TEC Protein Tyrosine Kinase).
  • LCK Lymphocyte-Specific Protein Tyrosine Kinase
  • Mutations of one or more of these kinases are reported and are known to alter and /or disturb molecular pathways.
  • the mutations of the particular kinases have been reported to be associated with disorders including cancer types. It has been found that advanced tumors find escape routes to circumvent target inhibition, leading to drug resistance.
  • Drug resistance mechanisms related to mutations have been studied: drug resistance occurs primarily through four main mechanisms. Acquired drug resistance mutations most commonly affect the binding of the drug to its target. Acquired oncogenic amplifications or rearrangements can activate downstream signaling to bypass inhibition of the drug target. Mutations in downstream effectors can activate signaling pathways despite effective inhibition of an upstream kinase target. State transformation can lead to kinase inhibitor insensitivity (Cohen et al. Kinase drug discovery 20 years after imatinib: progress and future directions; Nature Reviews Drug Discovery volume 20, pages 551-569 (2021 )).
  • UPS ubiquitin-proteasome system
  • proteins to be degraded are covalently tagged with ubiquitin (Ub, a 76-amino acid protein), and this tagging process is catalyzed by three enzymes known as Ub- activating enzyme (E1 ), Ub-conjugating enzyme (E2) and Ub-ligase (E3): free Ub is activated by E1 and then attached to the cysteine residue (Cys) of E1 to form a thioester bond via an ATP-dependent reaction; the Ub-tagged E1 transfers its Ub to the Cys of E2 through a trans-thioesterification reaction; E3 recruits Ub-tagged E2 and E3 substrate to label the ubiquitin at the lysine residue (Lys) of the substrate.
  • E1 Ub- activating enzyme
  • E2 Ub-conjugating enzyme
  • E3 Ub-ligase
  • HBC heterobifunctional compounds
  • POI protein of interest
  • HBC consists of three covalently-bonded moieties: a ligand moiety to bind the POI (POI ligand), another ligand moiety to recognize E3 ligase (E3 ligand) and a linker to conjugate the two ligands moieties.
  • E3 ligand E3 ligase
  • HBC simultaneously recruits E3 ligase and POI, forming the “E3-HBC-POI” ternary complex.
  • the HBC technology aims to eliminate whole functions of proteins, rather than merely inhibiting their enzymatic activity. Therefore the resistance to inhibition activity caused by the kinase mutants can be overcome by HBCs.
  • HCSs targeting kinases are described in literature (Cao C. et al. Chemistries of bifunctional PROTAC degraders. Chem. Soc. Rev., (2022) 51 , 7066 and Aublette M.C. et al., Selective WEE1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. Bioorg. Med. Chem. Lett., (2022) 64,128636 and He M. et al., PROTACs great opportunities for academia and industry. Signal Trans. Target.
  • an aim of the present invention is to provide bifunctional compounds providing improved pharmacological activity towards kinases, in particular towards mutant kinases.
  • Another aim of certain embodiments of this invention is to provide cancer treatments.
  • Another aim of certain embodiments of the invention is to provide bifunctional compounds which are effective as degrader towards at least one or more of wt-BTK, and/or BTK mutations C481 S, T474I, C481 S/T474I, V416L and L528W.
  • Another aim of certain embodiments of the invention is to provide bifunctional compounds which are effective as degrader towards other kinases, in particular towards Lymphocyte-Specific Protein Tyrosine Kinase (LCK), and/or "REarranged during Transfection” receptor tyrosine kinase (RET) and/or Epidermal Growth Factor Receptor (EGFR).
  • LCK Lymphocyte-Specific Protein Tyrosine Kinase
  • RET receptor tyrosine kinase
  • EGFR Epidermal Growth Factor Receptor
  • Targeting Ligase Binder is a group that is capable of binding to a E3 ligase
  • Targeting Macrocyclic Kinase Binder is a group that is capable of binding to a target protein kinase
  • the Linker is a group that covalently links the Targeting Macrocyclic Kinase Binder (TMKB) to the Targeting Ligase Binder (TLB), wherein said compound is in embodiments as further described below, provides improved kinase degradation.
  • TMKB Targeting Macrocyclic Kinase Binder
  • the Targeting Ligase Binder is a group that is capable of binding to a E3 ligase
  • the Targeting Macrocyclic Kinase Binder is a group that is capable of binding to a target protein kinase
  • the Linker (DL) is a group that covalently links the Targeting Macrocyclic Kinase Binder (TMKB) to the Targeting Ligase Binder (TLB), wherein the Targeting Macrocyclic Kinase Binder (TMKB) contains: bicyclic scaffold structure A selected from the group consisting of Formula (TMKB l-a) to (TMKB I- f):
  • X being a connecting group of the Targeting Macrocyclic Kinase Binder (TMKB), which covalently connects the Targeting Macrocyclic Kinase Binder to the Linker (DL), wherein X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N); wherein R 1 is wherein :
  • W is a direct bond or an aryl group having 6-10 carbon or a heteroaryl group having 1-9 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, (1-2C)alkyl, (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro;
  • V is selected from the group consisting of: a direct bond, O, -OCH2- , -CH(Ri v )-, -C(O)-, -C(O)-N(R2v)-,
  • Riv is hydrogen or (1 -2C)alkyl
  • R2V is hydrogen or (1-2C)alkyl
  • Rsv is hydrogen or (1-2C)alkyl
  • R4V is hydrogen or (1 -2C)alkyl
  • U is an aryl group having 6-10 carbon, a heteroaryl group having 1-9 carbon or a cycloalkyl group having 3-6 carbon; wherein any of said aryl group, heteroaryl group and cycloalkyl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (6-10C) aryl, (1-5C)heteroaryl, (1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl or (3- 6C)heterocycloalkyl; wherein any of said aryl, heteroaryl, alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; wherein R 2 is selected from the group consisting of Formula (TMKB 11-1 ) to (TMKB 11-13):
  • TMKB 11-11 (TMKB 11-12) (TMKB 11-13) wherein Q is a monocyclic ring selected from a (3-7C)cycloalkyl and a (3-6C)heterocycloalkyl, wherein Xi, X2 and X3 are independently selected from CH2, -CH2CH2-, O, N and a direct bond; wherein any of said cycloalkyl, heterocycloalkyl and alkyl group is optionally and independently substituted with one or more substituents selected from halogen, hydroxy, (1 -3C)alkyl, (1-3C)alkoxy or (3- 4C)cycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; wherein X in Formula (TMKB II-7) to (TMKB 11-13) is the connecting group X shown in Formula I; wherein X in any one of Formula (TMKB 11-8), Formula (TMKB 11-11 ), Formula (TMKB
  • TMKB 111-1) (TMKB HI-2) (TMKB HI-3) (TMKBIII-4) (TMKBHI-5) (TMKBIH-6) (TMKB HI-7)
  • TMKB HI-55 (TMKB HI-56) (TMKB HI-57) (TMKB HI-58) (TMKB HI-59) (TMKB IH-60)
  • I * marks the position of R 3 in any one of Formula (TMKB l-a) to (TMKB l-f); wherein the f” in any one of Formula (TMKB 111-1 ) to Formula (TMKB HI-33) marks the position of R 4 of any one of Formula TMKB II-7 to TMKB 11-13; and wherein the T ⁇ in any one of Formula (TMKB III-34) to Formula (TMKB III-60) marks the position of R 4 of any one of Formula TMKB 11-1 to TMKB II-6; and wherein the denotes the point of attachment to the Linker (DL); wherein any of said macrocycle linkers is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, amino, CDs, (1-4C)alkyl, (1- 5C)
  • a compound according to the invention or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a compound according to the invention or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound according to the invention or a pharmaceutically acceptable salt thereof for use in the treatment of Bruton's Tyrosine Kinase (BTK) mediated disorders.
  • BTK Bruton's Tyrosine Kinase
  • a compound of according to the invention or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • composition which comprises the compound according to the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • a method for treating of cancer in a subject in need thereof comprising administering to the subject the compound according to the invention or a pharmaceutically acceptable salt thereof in an amount effective to treat cancer.
  • a method for treating a subject suffering with a Bruton’s Tyrosine Kinase (BTK) mediated disorder comprising administering to the subject the compound of the invention in an amount effective to treat the BTK mediated disorder.
  • BTK Tyrosine Kinase
  • RET receptor tyrosine kinase
  • a method for treating a subject suffering with a Epidermal Growth Factor Receptor (EGFR) mediated disorder comprising administering to the subject the compound of the invention in an amount effective to treat the EGFR mediated disorder.
  • EGFR Epidermal Growth Factor Receptor
  • a method for treating a subject suffering with a Lymphocyte-Specific Protein Tyrosine Kinase (LCK) mediated disorder comprising administering to the subject the compound of the invention in an amount effective to treat the LCK mediated disorder.
  • LCK Lymphocyte-Specific Protein Tyrosine Kinase
  • Each of the sub-formulas 1-138 of the compounds of the invention is a preferred embodiment of the present application.
  • composition as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.
  • phrases “pharmaceutically acceptable” as used herein has its conventional meaning and refers to compounds, material, compositions and/or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • the term "effective amount’ as used herein refers to an amount of the compound of the invention, and/or an additional therapeutic agent, or a composition thereof, that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a subject suffering from a kinase-mediated disease or disorder, such as a BTK-mediated disease or disorder.
  • as effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • a “subject” is a human or non-human mammal. In one embodiment, a subject is a human.
  • controlling is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of the diseases and conditions affecting the mammal. However, “controlling” does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.
  • excipient as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid oral dosage formulation.
  • salt as used herein has its conventional meaning and includes the acid addition and base salts of the compound of the invention.
  • solvate as used herein has its conventional meaning.
  • One or more compounds of the invention or the pharmaceutically acceptable salts thereof may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association Involves varying degrees of ionic and covalent bonding. Including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates. Examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H2O and includes any hydrate of the compound or the salt of said compound.
  • treatment has its conventional meaning and refers to curative, palliative and prophylactic treatment.
  • unit dosage form has its conventional meaning and refers to a dosage form which has the capacity of being administered to a subject, preferably a human, to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising the therapeutic agent, i.e. the compound of the invention.
  • BTK Bruton's tyrosine kinase
  • Src-related Tec family of protein kinases which are a large subset of kinases which play a central role in the regulation of a wide variety of cellular signaling processes.
  • BTK plays a key role in the B-cell receptor signaling and a critical role in the regulation of survival, proliferation, activation and differentiation of B-lineage cells.
  • BTK small molecule inhibitors
  • small molecule inhibitors such as the FDA approved irreversible BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib
  • CLL Chronic Lymphocytic Leukemia
  • MCL Mantle Cell Lymphoma
  • WM Macroglobulinemia
  • SLL Small Lymphocytic Lymphoma
  • BTK degrader as used herein has its conventional meaning and refers to a degrader for BTK.
  • a BTK degrader may be a small molecule degrader. Degraders eliminate whole functions of the BTK protein, rather than merely inhibiting its enzymatic activity .
  • mutant-BTK has its conventional meaning and refers to mutations of BTK. Mutations of BTK may be referred to by an altered amino acid target (such as C as single-letter data-base code for cysteine) at a certain position of the BTK structure (such as 481 ). Additionally, the amino acid substitution at the mutation position may be referred to by an additional amino acid singleletter data-base code, such as C481 S for serine substitution and C481T for threonine substitution of cysteine at the 481 position. Additionally, BTK mutations may include single mutations, such as C481 S, T474I, V416L and L528W, and double mutations, such as C481 S/T474I.
  • a drawback of the currently approved irreversible inhibitors is that drug resistance in malignant diseases can develop when BTK variations at the catalytic site and the gatekeeper of the BTK are not able to bind efficiently to irreversible inhibitors in patients treated with currently approved BTK inhibitors. This is a rather common event in patients treated with irreversible inhibitors and who experience relapse.
  • a major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481 ) mutations. These mutations hamper binding of irreversible inhibitors such as ibrutinib and acalabrutinib which form a covalent bond with this amino acid.
  • BTK gatekeeper residue threonine 474 T474 mutations
  • C481 S double mutation C481 S/T474I, V416L, and L528W, which can reduce BTK inhibitor binding to BTK.
  • wt-BTK or “WT-BTK” or “BTK ⁇ ” as used herein has its conventional meaning and refers to wild-type Bruton's Tyrosine Kinase.
  • a wild-type BTK has the regular meaning of a phenotype of the typical form of BTK as it occurs in nature. Originally, the wild-type was conceptualized as a product of the standard “normal” allele at a locus, in contrast to that produced by a non-standard, “mutant” allele.
  • microcycle as used herein has its conventional meaning and refers to a part of a molecule containing a ring consisting of 12 or more ring atoms forming said ring. In an example, a twelve membered ring consist of 12 atoms forming said ring.
  • IC50 as used herein has its conventional meaning and refers to the concentration of a substance that results in a 50% effect on some measure of biochemical function or substance-target binding interaction.
  • DC50 as used herein has its conventional meaning and refers to the half-maximal degradation concentration that resulted in a 50% targeted protein degradation.
  • a bicyclic ringsystem refers to heterocyclic (heterocyclyl) groups, to cyclic groups having carbon groups only, i.e. without hetero atoms, within the cycle, and to combinations of a heterocyclic (heterocyclyl) group and a cyclic group having carbon groups only, i.e. without hetero atoms, within the cycle.
  • a bicyclic ringsystem includes 6-12 (e.g. 8-12, or 9-, 10-, or 11-) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g. two atoms in common).
  • Bicyclic ring systems include bicycloaliphatics (e.g. bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.
  • the rings can be different in size and nature, or identical in size and nature. Examples include spirobutane, spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One of both rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • a (C3-Ci2)spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • spiroheterocycloalkyl or “spiroheterocyclyl” means a spirocycle wherein at least one of the rings is a heterocycle wherein one or more of the carbon atoms can be substituted with a heteroatom (e.g., one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings).
  • One or both of the rings in a spiroheterocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • a monocylic ringsystem refers both to a heterocyclic (heterocyclyl) group, and to a cyclic group having carbon groups only, i.e. without hetero atoms, within the cycle.
  • heterocyclic (heterocyclyl) group refers to both heteroaryl groups and heterocycloalkyl groups.
  • a heterobicyclic group refers to a bicyclic group having one or more heteroatoms, which is saturated, partially unsaturated or unsaturated.
  • aromatic groups include aromatic carbocyclic ring systems (e.g. phenyl) and fused polycyclic aromatic ring systems (e.g. naphthyl and 1 ,2,3,4-tetrahydronaphthyl).
  • heteroaryl refers to an aryl group having one or more heteroatoms.
  • alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms.
  • an alkyl group contains, for example, from 1 to 6 carbon atoms ( 1 -6C)Alkyl or from 1 to 3 carbon atoms (1-3C)Alkyl.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • an alkyl group is linear. In another embodiment, an alkyl group is branched.
  • alkyl includes both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms; for example, “(1-6C)Alkyl” includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • Alkylene refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments; for example, the term “A-C4 alkylene-B” represents, for example, A-CH2-CH2-CH2-CH2-B, A-CH2-CH2-CH(CH 3 )-CH2-B, A-CH2-CH(CH2CH 3 )-B, A-CH2- C(CH 3 )(CH 3 )-B, and the like.
  • alkylcarbonyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond attached to a carbonyl group, wherein the aliphatic hydrocarbon group has the specified number of carbon atoms.
  • an alkyl group or aliphatic hydrocarbon group contains, for example, from 1 to 6 carbon atoms (1 -6C)Alkyl or from 1 to 3 carbon atoms (1-3C)Alkyl.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • an alkyl group is linear. In another embodiment, an alkyl group is branched.
  • Cycloalkyl means a cycloalkyl group having the recited number of carbon atoms, with the same meaning as previously defined, such as cyclopropyl, cyclobutyl, or cyclopentyl. “Cycloalkyl” refers to a cycloalkyl-group represented by an indicated number of carbon atoms; for example “(3-6C)cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Heterocycloalkyl means a cycloalkyl group having the recited number of carbon atoms, and 1- 3 heteroatoms selected from N, O and/or S, with the same meaning as previously defined.
  • Haloalkyl means a branched or unbranched alkyl group having the recited number of carbon atoms, in which one and up to all hydrogen atoms are replaced by a halogen; halogen is as defined herein.
  • branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo and iodo.
  • a halo(1-3C)alkyl means a branched or unbranched alkyl group having 1 ,2, or 3 carbon atoms, in which at least one hydrogen atom is replaced by a halogen.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and perfluoro-n-propyl.
  • Alkoxy means an alkoxy group having the recited number of carbon atoms, the alkyl moiety having the same meaning as previously defined, e.g., “Alkoxy” refers to an alkyl-O-group represented by a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; for example “(1-6C)Alkoxy” includes CH3-O-, CH2CH3-O-, CH(CH3)2-O-, (CH2)sCH3-O-, and the like.
  • Cycloalkoxy means a cycloalkyl group having the recited number of carbon atoms, with the same meaning as previously defined, attached via a ring carbon atom to an exocyclic oxygen atom, such as cyclopropoxyl, cyclobutoxyl.or cyclopentoxyl.
  • Cycloalkoxy refers to a cycloal kyl-O-g roup represented by a cycloalkyl group of indicated number of carbon atoms attached through an oxygen bridge; for example “(3-6C)cycloalkoxy” includes cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, or cyclohexyl-O-.
  • Heterocycloalkoxy means a cycloalkyl group having the recited number of carbon atoms, and 1-3 heteroatoms selected from N, O and/or S, with the same meaning as previously defined, attached via a ring carbon atom to an exocyclic oxygen atom.
  • alkyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom. It should be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • compositions comprising components A and B
  • the only enumerated components of the composition are A and B, and further the claim should be interpreted as including equivalents of those components.
  • indefinite article “a” or “an” does not exclude the possibility that more than one of the element or component are present, unless the context clearly requires that there is one and only one of the elements or components.
  • the indefinite article “a” or “an” thus usually means “at least one”.
  • B BTK and phosphorylated-BTK protein levels in wildtype 293 (GripTite 293 MSR) cells compared to (non-IgM treated) RAMOS cells.
  • the invention provides a new class of bifunctional reversible macrocyclic kinase binder with a strong kinase target binding activity and having kinase degrading functionality via ubiquitin proteosome pathway.
  • bifunctional compounds according to the invention provide an improved reversible binding activity towards various kinases, including BTK, LCK, FGFR1 , FLT3, PDGFR-p, FMS, LYN, MEK1 , AUR-B, ITK, VEGFR, EGFR, RET and TEC, including mutants of some of these kinases.
  • the compounds according to the invention have a Targeting Ligase Binder (TLB), which is a group that is capable of binding to a E3 ligase, a Targeting Macrocyclic Kinase Binder (TMKB), which is a group that is capable of binding to a target protein kinase, and a Linker (DL), which is a group that covalently links the Targeting Macrocyclic Kinase Binder (TMKB) to the Targeting Ligase Binder.
  • TLB Targeting Ligase Binder
  • TMKB Targeting Macrocyclic Kinase Binder
  • TMKB contains a macrocyclic moiety, which is able in combination with specific pharmacophores (e.g.
  • bifunctional compounds of the invention provide an enhanced degrading activity towards mutant kinase forms, such as BTK mutant forms.
  • the inventors have demonstrated the enhanced binding and degrading activity towards BTK mutants BTK C481 S, BTK T474I, BTK C481 S/T474I, BTK V416L and BTK L528W.
  • Macrocyclic natural products have advanced to achieve numerous biochemical functions, and their pharmacological properties have led to their development as drugs.
  • Macrocycles have been defined as a ring system consisting of 12 or more atoms (Driggers E.M. (2008) Nat Rev Drug Discov).
  • a macrocycle provides diverse functionalities and stereochemical complexity in a conformationally preorganized ring structure, which can result in superb physicochemical and pharmacological properties.
  • Macrocyclic ligands can be designed to displace ordered water molecules from a binding site, unoccupied by non-macrocyclic inhibitors, into bulk solvent. This is generally assumed to provide a second favorable entropic contribution (classical hydrophobic effect) (Mallinson J.M. and Collins I. (2012) Future Med Chem), leading to enhanced potencies of these inhibitors on their target protein.
  • bifunctional compounds according to the invention wherein the bifunctional compounds comprise a macrocyclic moiety in addition to active binding parts, provide an improved binding activity towards one or more of BTK, LCK, FGFR1 , FLT3, PDGFR-p, FMS, LYN, MEK1 , AUR-B, ITK, VEGFR, EGFR, RET and TEC, including mutants of some of these kinases, as compared to similar compounds, which provide a binding activity, but do not contain a macrocycle.
  • these bifunctional compounds according to the invention, wherein the bifunctional compounds comprise a macrocyclic moiety in addition to active binding parts provide an improved degrading effect on these kinases, including mutants of some of these kinases.
  • the Targeting Ligase Binder is a group that is capable of binding to a E3 ligase
  • the Targeting Macrocyclic Kinase Binder is a group that is capable of binding to a target protein kinase
  • the Linker is a group that covalently links the Targeting Macrocyclic Kinase Binder (TMKB) to the Targeting Ligase Binder, wherein said compound is in embodiments as further described below.
  • the Targeting Ligase Binder is a group that is capable of binding to a E3 ligase
  • the Targeting Macrocyclic Kinase Binder is a group that is capable of binding to a target protein kinase
  • the Linker is a group that covalently links the Targeting Macrocyclic Kinase Binder (TMKB) to the Targeting Ligase Binder, wherein the Targeting Macrocyclic Kinase Binder (TMKB) contains: bicyclic scaffold structure A selected from the group consisting of Formula (TMKB l-a) to (TMKB I- f):
  • TMKB l-d TMKB l-e
  • TMKB l-f X being a connecting group of the Targeting Macrocyclic Kinase Binder (TMKB), which covalently connects the Targeting Macrocyclic Kinase Binder to the Linker (DL), wherein X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N); wherein R 1 is wherein :
  • W is a direct bond or an aryl group having 6-10 carbon or a heteroaryl group having 1-9 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, (1 -2C)alkyl, (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro;
  • V is selected from the group consisting of: a direct bond, O, -OCH2- , -CH(Ri v )-, -C(O)-, -C(O)-N(R2v)-, -N(R2V)-C(O)-,-NH-C(O)-NH-, -NH-C(O)-C(R3V)(R4V)-C(O)-NH-, -NH-SO2-, -NH-C(O)-O-, -CH(Riv)-NH-C(O)-, -CH(Riv)-C(O)-NH-, -CEC-, and -CH2O- ;
  • Riv is hydrogen or (1-2C)alkyl
  • R2V is hydrogen or (1-2C)alkyl
  • Rsv is hydrogen or (1-2C)alkyl
  • R4V is hydrogen or (1 -2C)alkyl
  • U is an aryl group having 6-10 carbon, a heteroaryl group having 1-9 carbon or a cycloalkyl group having 3-6 carbon; wherein any of said aryl group, heteroaryl group and cycloalkyl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (6-10C) aryl, (1-5C)heteroaryl, (1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl or (3- 6C)heterocycloalkyl; wherein any of said aryl, heteroaryl, alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; wherein R 2 is selected from the group consisting of Formula (TMKB 11-1 ) to (TMKB 11-13):
  • Q is a monocyclic ring selected from a (3-7C)cycloalkyl and a (3-6C)heterocycloalkyl, wherein Xi, X2 and X3 are independently selected from CH2, -CH2CH2-, O, N and a direct bond; wherein any of said cycloalkyl, heterocycloalkyl and alkyl group is optionally and independently substituted with one or more substituents selected from halogen, hydroxy, (1 -3C)alkyl, (1-3C)alkoxy or (3- 4C)cycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; wherein X in Formula (TMKB II-7) to (TMKB 11-13) is the connecting group X shown in Formula I; wherein X in any one of Formula (TMKB 11-8), Formula (TMKB 11-11 ), Formula (TMKB 11-12), and Formula (TMKB 11-13) is a tertiary
  • TMKB III-1) (TMKB HI-2) (TMKB HI-3) (TMKBIII-4) (TMKBIII-5) (TMKBIII-6) (TMKB 111-7)
  • TMKB HI-8 (TMKB HI-9) (TMKB 111-10) (TMKB HI-11 ) (TMKB 111-12) (TMKB HI-13) (TMKB 111-14) (TMKB 111-15) (TMKB 111-16) (TMKB 111-17) (TMKB 111-18) (TMKB 111-19) (TMKB HI-20) (TMKB 111-21 )
  • TMKB HI-22 (TMKB HI-23) (TMKB HI-25) (TMKB IH-26) (TMKB III-27) (TMKB HI-28) (TMKB HI-29)
  • ⁇ T ⁇ * marks the position of R 3 in any one of Formula (TMKB l-a) to (TMKB l-f); wherein the " ⁇ 1 in any one of Formula (TMKB 111-1 ) to Formula (TMKB III-33) marks the position of R 4 of any one of Formula (TMKB II-7) to (TMKB 11-13); and wherein the I in any one of Formula (TMKB III-34) to Formula (TMKB III-60) marks the position of R 4 of any one of Formula TMKB 11-1 to TMKB II-6; and wherein the # denotes the point of attachment to the Linker (DL); wherein any of said macrocycle linkers is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, amino, CD3, (1-4C)alkyl, (1- 5C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkoxy or (1-6C)alkylcarbonyl; wherein any of said alkyl and
  • TMKB Macrocyclic Kinase Binder
  • the Targeting Macrocyclic Kinase Binder (TMKB) of the invention have bicyclic scaffold structure A selected from the group consisting of Formula (TMKB-l-a) to (TMKB-l-f):
  • BTK inhibitors which do not contain a macrocycle are generally known from the prior art, wherein said known BTK inhibitors have a bicyclic scaffold structure according to any one of Formula (TMKB l-a) to (TMKB l-f):
  • the present invention concerns novel compounds having a scaffold according to any one Formula (TMKB l-a) to (TMKB l-f), and further having a macrocycle as defined according to the embodiments of the invention.
  • the compound comprises a bicyclic scaffold A selected from:
  • R 5 is hydrogen, NH2 or methyl.
  • the compound comprises a bicyclic scaffold A selected from:
  • R 1 of the compounds of the invention has the formula: wherein :
  • W is a direct bond or an aryl group having 6-10 carbon or a heteroaryl group having 1-9 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, (1-2C)alkyl, (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro;
  • V is selected from the group consisting of: a direct bond, O, -OCH2- , -CH(Ri v )-, -C(O)-, -C(O)-N(R2v)-, -N(R 2 V)-C(O)-,-NH-C(O)-NH-, -NH-C(O)-C(R3V)(R4V)-C(O)-NH-, -NH-SO2-, -NH-C(O)-O-, -CH(Riv)-NH-C(O)-, -CH(Riv)-C(O)-NH-, -CEC-, and -CH2O- ;
  • Riv is hydrogen or (1 -2C)alkyl
  • R2V is hydrogen or (1 -2C)alkyl
  • Rsv is hydrogen or (1 -2C)alkyl
  • R4V is hydrogen or (1-2C)alkyl
  • U is an aryl group having 6-10 carbon, a heteroaryl group having 1-9 carbon or a cycloalkyl group having 3-6 carbon; wherein any of said aryl group, heteroaryl group and cycloalkyl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (6-10C) aryl, (1-5C)heteroaryl, (1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl or (3- 6C)heterocycloalkyl; wherein any of said aryl, heteroaryl, alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen;
  • R 1 is:
  • W is an aryl group having 6-10 carbon or a heteroaryl group having 1-9 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, (1 -2C)alkyl, (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; and
  • V is a direct bond
  • R 1 is: the phenyl group is optionally and independently substituted with one or more substituents selected from halogen, (1 -2C)alkyl , (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; and
  • U is an aryl group having 6-10 carbon or an heteroaryl group having 1-9 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (6-10C) aryl, (1-5C)heteroaryl, (1-6C)alkyl, (1- 6C)alkoxy, (3-6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said aryl, heteroaryl, alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.
  • substituents selected from halogen, cyano, (6-10C) aryl, (1-5C)heteroaryl, (1-6C)alkyl, (1- 6C)alkoxy, (3-6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said aryl, heteroaryl, alkyl and alkoxy group is optionally and
  • V is in this embodiment selected from the group consisting of: a direct bond, O, -OCH2- , -CH(R1v)-, - C(O)-, -C(O)-N(R2v)-, -N(R2v)-C(0)-,-NH-C(0)-NH-, -NH-C(O)-C(R3v)(R4v)-C(O)-NH-, -NH-SO2-, -NH-C(0)-0-, -CH(R1v)-NH-C(0)-, -CH(R1v)-C(0)-NH-, -CEC-, and -CH20- .
  • V is any one of: -OCH2- , -C(0)-N(R2v)-, -N(R2v)-C(0)-,-NH-C(0)-NH-, -NH- C(O)-C(R 3V )(R4V)-C(O)-NH-,
  • Riv is hydrogen or (1 -2C)alkyl
  • R2V is hydrogen or (1 -2C)alkyl
  • R 3 V is hydrogen or (1 -2C)alkyl
  • R4V is hydrogen or (1-2C)alkyl
  • R 3V and R4V form together with the carbon atom they are attached to a (3-6C)cycloalkyl.
  • R1 is any one of: wherein: the phenyl group is optionally and independently substituted with one or more substituents selected from halogen, (1 -2C)alkyl , (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; and
  • U is an aryl group having 6-10 carbon or an heteroaryl group having 1-9 carbon, wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (6-10C) aryl, (1-5C)heteroaryl, (1-6C)alkyl, (1- 6C)alkoxy, (3-6C)cycloalkyl and (3-6C)heterocycloalkyl; wherein any of said aryl, heteroaryl, alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.
  • R 1 is:
  • R 1w is selected from: hydrogen, halogen, (1 -2C)alkyl, (1-2C)alkoxy), (3-6C)cycloalkyl, (6-10C)aryl, and (1-5C)heteroaryl; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, (1-2C)alkyl, (1- 2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; and
  • V is selected from the group consisting of: a direct bond, -CH(Riv)-, -CH(Riv)-NH-C(O)-, -CH2O- ; Riv is hydrogen or (1 -2C)alkyl.
  • R 1 is:
  • R 1w is selected from hydrogen, halogen, (1 -2C)alkyl, (1-2C)alkoxy, (3-6C)cycloalkyl, (6- 10C)aryl, and (1-5C)heteroaryl; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, (1 -2C)alkyl, (1- 2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; and
  • V is a direct bond
  • R 1 is:
  • W is a direct bond
  • U is hydrogen or an aryl group having 6-10 carbon or an heteroaryl group having 1-9 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (6-10C) aryl, (1-5C)heteroaryl, (1 -6C)alkyl, (1- 6C)alkoxy, (3-6C)cycloalkyl and (3-6C)heterocycloalkyl; wherein any of said aryl, heteroaryl, alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.
  • R 1 is:
  • W is a direct bond
  • U is hydrogen or an aryl group having 6-10 carbon or an heteroaryl group having 1-9 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (6-10C) aryl, (1-5C)heteroaryl, (1 -6C)alkyl, (1- 6C)alkoxy, (3-6C)cycloalkyl and (3-6C)heterocycloalkyl; wherein any of said aryl, heteroaryl, alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.
  • R 1 is selected from the group consisting of:
  • R 1w and R 2w are independently selected from hydrogen, halogen, (1 -2C)alkyl, and (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro;
  • V is any one of O, -C(O)-NH-, -NH-C(O)-, -CH(R 1v )-NH-C(O)-, -CH(R 1v )- ;
  • R 1v is hydrogen or (1 -2C)alkyl
  • U is an aryl group having 6-10 carbon or an heteroaryl group having 1-5 carbon; wherein any of said aryl group and heteroaryl group is optionally and independently substituted with one or more substituents selected from halogen, cyano, (1 -4C)alkyl, (1-5C)alkoxy, (3-6C)cycloalkyl and (3- 6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.
  • R 1 is selected from the group consisting of: wherein:
  • R 1w and R 2w are independently selected from hydrogen, halogen, (1 -2C)alkyl, (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro;
  • V is any one of O, -C(O)-NH-, -NH-C(O)-, -CH(R 1v )-NH-C(O)-, -CH(R 1v )- ;
  • R 1v is hydrogen or (1 -2C)alkyl; wherein R 1u and R 2u are independently selected from hydrogen, halogen, cyano, (1 -4C)alkyl, (1- 5C)alkoxy, (3-6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; and wherein X u is selected from CH and N.
  • V is any one of O, -C(O)-NH-, -CH(R 1v )-NH-C(O)-, and -CH(R 1v )-; wherein R 1v is hydrogen or (1 -2C)alkyl.
  • R 1 is selected from the group consisting of: wherein R 1w and R 2w are independently selected from hydrogen, halogen, (1 -2C)alkyl, (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; wherein R 1u and R 2u are independently selected from hydrogen, halogen, cyano, (1 -4C)alkyl, (1- 5C)alkoxy, (3-6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; and wherein X u is selected from CH and N.
  • R 1 is selected from the group consisting of: wherein R 2w is selected from hydrogen, halogen, (1 -2C)alkyl, (1-2C)alkoxy; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro; and wherein R 3u is selected from hydrogen, halogen, cyano, (1 -4C)alkyl, (1-5C)alkoxy, (3-6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro.
  • R 1 is: wherein R 2w is selected from hydrogen, fluoro, methyl or methoxy; wherein R 3u is selected from hydrogen, halogen, cyano, (1 -4C)alkyl, (1-2C)alkoxy, (3-6C)cycloalkyl or (3-6C)heterocycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three fluoro.
  • R 2 of the compounds is selected from the group consisting of Formula
  • TMKB 11-11 (TMKB 11-12) (TMKB 11-13) wherein Q is a monocyclic ring selected from a (3-7C)cycloalkyl and a (3-6C)heterocycloalkyl, wherein Xi, X2 and X3 are independently selected from CH2, -CH2CH2-, O, N and a direct bond; wherein any of said cycloalkyl, heterocycloalkyl and alkyl group is optionally and independently substituted with one or more substituents selected from halogen, hydroxy, (1 -3C)alkyl, (1-3C)alkoxy or (3- 4C)cycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; wherein X in Formula (TMKB II-7) to (TMKB 11-13) is the connecting group X shown in Formula (I); wherein X in any one of Formula (TMKB 11-8), Formula (TMKB 11-11 ), Formula (TMKB
  • R 2 comprises the connecting group X, which is shown in Formula (I).
  • X in any one of Formula (TMKB 11-8), Formula (TMKB 11-11 ), Formula (TMKB 11-12), and Formula (TMKB 11-13) is a tertiary carbon atom (-CH-).
  • R 2 is selected from the group consisting of:
  • TMKB 11-11 C (TMKB II-12C) wherein Q is a monocyclic ring selected from a (3-7C)cycloalkyl and a (3-6C)heterocycloalkyl, wherein Xi, X2 and X3 are independently selected from CH2, -CH2CH2-, O, N and a direct bond; wherein any of said cycloalkyl, heterocycloalkyl and alkyl group is optionally and independently substituted with one or more substituents selected from halogen, hydroxy, (1 -3C)alkyl, (1-3C)alkoxy or (3- 4C)cycloalkyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; wherein X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N) ; wherein the denotes the point of attachment to the Linker (DL); and wherein the marks the position of
  • R 2 is selected from the group consisting of:
  • TMKB H-9a (TMKB 11-10a) (TMKB II-11C) (TMKB II-12C) wherein any of said cycloalkyl, heterocycloalkyl and alkyl group is optionally and independently substituted with hydroxy, methyl or methoxy; wherein the denotes the point of attachment to the Linker (DL); and wherein the T ⁇ marks the position of R 2 in any one of Formula (TMKB l-a) to (TMKB l-f).
  • Each of the compounds of the invention comprises the macrocycle linker (L) represented by R 3 and R 4 .
  • the macrocycle linker represented by R 3 and R 4 is according to any one of Formula (TMKB 111-1 ) to Formula (TMKB III-60).
  • the macrocycle linker is a part of the whole macrocycle of each of the Targeting Macrocyclic Kinase Binder (TMKB) of the compounds of the invention.
  • the macrocycle linker is directly connected to the bicyclic scaffold A of any one of Formula (TMKB l-a) to (TMKB l-f) at the position of the "TTM * (i.e. the wavy with a star).
  • the macrocycle of the Targeting Macrocyclic Kinase Binder is formed by the connections between the macrocycle linker, R 2 and the bicyclic scaffold A of Formula (TMKB l-a) to (TMKB l-f).
  • R 2 is directly connected to the macrocycle linker at the position of R 4 .
  • the bicyclic scaffold A of Formula (TMKB l-a) to (TMKB l-f) is connected to the macrocycle linker, at another end of the macrocycle linker, at the position of R 3 .
  • the macrocycle linker may comprise at least 12 atoms forming said macrocycle, and may comprise any number of atoms from 12 - 18 forming said macrocycle linker, preferably from 13 - 15 atoms forming said macrocycle linker.
  • the macrocycle linker comprises the connecting group X which covalently connects the Targeting Macrocyclic Kinase Binder (TMKB) to the Linker (DL).
  • the connecting group X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N).
  • X in any one of Formula (TMKB HI-36), Formula (TMKB HI-40), Formula (TMKB H-49) to Formula (TMKB HI-57), Formula (TMKB III-59) and Formula (TMKB HI-60) is a tertiary carbon atom (-CH-).
  • the macrocycle linker represented by R 3 and R 4 is selected from the group consisting of:
  • TMKB HI-9 (TMKB 111-10) (TMKB HI-11 ) (TMKB 111-12) (TMKB 111-13) (TMKB 111-14)
  • TMKB HI-15 (TMKB 111-16) (TMKB HI-17) (TMKB 111-18) (TMKB 111-19) (TMKB HI-20) (TMKB HI-21 )
  • TMKB III-49C (TMKB III-50C) (TMKB 111-51 C) (TMKB III-52C) (TMKB III-53C) (TMKB III-54C)
  • TMKB HI-55C (TMKB HI-56C) (TMKB HI-57C) (TMKB HI-58N) (TMKB HI-59C) (TMKB HI-60C)
  • ⁇ T * marks the position of R 3 in any one of Formula (TMKB l-a) to (TMKB l-f); wherein the T ⁇ in any one of Formula (TMKB 111-1 ) to Formula (TMKB III-33) marks the position of R 4 of any one of Formula TMKB 11-7 to TMKB 11-13; and wherein the T ⁇ in any one of Formula (TMKB III-35) to Formula (TMKB III-60C) marks the position of R 4 of any one of Formula (TMKB 11-1 ) to (TMKB II-6); and
  • any of said macrocycle linkers is optionally and independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, amino, CD3, (1-4C)alkyl, (1- 5C)alkoxy, (3-6C)-cycloalkyl, (3-6C)cycloalkoxy or (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen; wherein X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N).
  • any one of Formula (TMKB 111-35) to Formula (III-36C), Formula (TMKB 111-38) to Formula (TMKB 111-45) and Formula (TMKB III-49C) to Formula (TMKB 60C) marks the position of R 4 of any one of Formula (TMKB 11-1 ) to (TMKB II-6).
  • the macrocycle linker represented by R 3 and R 4 is selected from the group consisting of:
  • TMKB HI-42 (TMKB IH-49C) (TMKB III-50C) (TMKB HI-51 C) (TMKB III-52C) (TMKB III-53C)
  • the in any one of Formula (TMKB 111-1 ) to Formula (TMKB HI-6), Formula (TMKB III-9) to Formula (TMKB 111-13), Formula (TMKB 111-15) to Formula (TMKB HI- 23), Formula (TMKB HI-25) and Formula (TMKB IH-28) to Formula (TMKB-33) marks the position of R 4 of any one of Formula (TMKB 11-7) to (TMKB 11-13).
  • the '"T" in any one of Formula (TMKB III-35) to Formula (TMKB III-36C), Formula (TMKB III-38) to Formula (TMKB IH-42), Formula (TMKB III-49C) to Formula (TMKB III-53C) and Formula (TMKB III-55C) to Formula (TMKB III-60C) marks the position of R 4 of any one of Formula (TMKB 11-1 ) to (TMKB II-6).
  • the macrocycle linker represented by R 3 and R 4 is selected from the group consisting of:
  • the "T” in any one of Formula (TMKB 111-1 ) to Formula (TMKB HI-6), Formula (TMKB HI-9) to Formula (TMKB 111-13), Formula (TMKB 111-15) to Formula (TMKB HI- 18) and Formula (TMKB III-28) to Formula (TMKB-33) marks the position of R 4 of any one of Formula (TMKB 11-7) to (TMKB 11-13).
  • the "T” in any one Formula (TMKB III-35) to Formula (TMKB III-36C), Formula (TMKB III-38) to Formula (TMKB HI-42), Formula (TMKB 111-51 C) to Formula (TMKB III-53C) and Formula (TMKB III-55C) to Formula (TMKB III-58N) marks the position of R 4 of any one of Formula (TMKB 11-1 ) to (TMKB II-6).
  • any of said macrocycle linkers is independently substituted with one or more substituents selected from deuterium, halogen, oxo, hydroxy, amino, CD3, (1-4C)alkyl, (1-5C)alkoxy, (3-6C)-cycloalkyl, (3-6C)cycloalkoxy or (1-6C)alkylcarbonyl; wherein any of said alkyl and alkoxy group is optionally and independently substituted with one, two or three halogen.
  • a secondary amine group of the macrocycle linker represented by R 3 and R 4 is substituted by (1-6C)alkylcarbonyl, preferably by methylcarbonyl or ethylcarbonyl.
  • the secondary amine group of any one of Formula (111-19) to (III-33) or (HI-38) may be substituted by (1- 4C)alkylcarbonyl, such as by methylcarbonyl or ethylcarbonyl.
  • a carbon group of the macrocycle linker represented by R 3 and R 4 is substituted by (1 -4)alkyl, preferably by methyl or ethyl, thereby providing a tertiary carbon group.
  • X is a connecting group of the Targeting Macrocyclic Kinase Binder (TMKB), which covalently connects the Targeting Macrocyclic Kinase Binder to the Linker (DL).
  • TMKB Targeting Macrocyclic Kinase Binder
  • X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N).
  • X is a tertiary amine atom (N).
  • the Targeting Macrocyclic Kinase Binder contains one connecting group X which covalently connects the Targeting Macrocyclic Kinase Binder to the Linker (DL).
  • the connecting group may in embodiments be provided in the macrocycle linker represented by represented by R 3 and R 4 , in particular according to any one of Formula (TMKB III-34) to (TMKB HI-60).
  • the connecting group may in embodiments be provided in the R 2 moiety, in particular according to any one of Formula (TMKB II-7) to (TMKB 11-13).
  • the Linker (DL) is a group that covalently links the Targeting Macrocyclic Kinase Binder (TMKB) to the Targeting Ligase Binder (TLB). At one end the Linker (DL) is connected to the connecting group (X) of the Targeting Macrocyclic Kinase Binder (TMKB). At another end the Linker (DL) is covalently connected to the Targeting Ligase Binder.
  • the Linker (DL) is -L1-L2-L3-L4-L5- , wherein Li is connected to the Targeting Ligase Binder (TLB) and the Ls is connected to the Targeting Macrocyclic Kinase Binder (TMKB), wherein:
  • L 2 is independently selected from the group consisting of: a direct bond, -N(R L2 )-, -O-, (1 -4C)alkyl, - CH 2 -CH 2 -N(R L2 )-, -(CH 2 -CH 2 -O) m -, -(CH 2 -CH 2 -CH 2 -O)m-, -(O-CH 2 -CH 2 ) m -, (6-10C)aryl, (3- 12C)cycloalkyl, (3-12C)heterocycloalkyl, 7-12 membered spiro bicyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spiro bicyclic cycloalkyl and 7-12 membered fused bicyclic cycloalkyl; wherein any of said alkyl, cycloalkyl or heterocycloalkyl group is optionally and independently substituted with one, two
  • L 3 is independently selected from the group consisting of: a direct bond, (1 -8C)alkyl, -CHC-, -N(R L3 )-, -O-, -N(R L3 )-C(O)-, -C(O)-N(R L3 )-, -C(O)-, -(O-CH 2 -CH 2 ) n -, -(CH 2 -CH 2 -O) n - and (3- 12C)heterocycloalkyl; wherein any of said heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1 -3C)alkyl or (1-3C)alkoxy; each R L3 is independently -H or (1-4C)alkyl;
  • L 4 is independently selected from the group consisting of: a direct bond, (1 -4C)alkyl , -N(R L4 ), -C(O)-, -(O-CH 2 -CH 2 ) P -, -(CH 2 -CH 2 -O) P -, (3-12C)cycloalkyl, (3-12C)heterocycloalkyl, 7-12 membered spiro bicyclic heterocycloalkyl and 7-12 membered fused bicyclic heterocycloalkyl; wherein any of said alkyl, cycloalkyl or heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1 -3C)alkyl or (1-3C)alkoxy; each R L4 is independently -H or (1- 4C)alkyl;
  • L 5 is independently selected from the group consisting of: a direct bond, -N(R L5 )-, -N(R L5 )-C(O)-, - C(O)-, (1 -4C)alkyl, -(O-CH 2 -CH 2 ) q - and -(O-CH 2 -CH 2 -CH 2 ) q -; each R L5 is independently -H or (1- 4C)alkyl; each m, n, p and q is independently an integer from 1 to 3.
  • linker (DL) is connected to the Targeting Ligase Binder (TLB) at Li and is connected to the Targeting Macrocyclic Kinase Binder (TMKB) at Ls.
  • Li is selected from the group consisting of: a direct bond, -N(R L1 )-, -O-, - C(O)-N(R L1 )-, -N(R L1 )-C(O)-, -C(O)-, -CHC-; each R L1 is independently -H or methyl.
  • L 2 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -CH 2 - CH 2 -N(R L2 )-, -(CH 2 -CH 2 -O)m-, -(CH 2 -CH 2 -CH 2 -O) m -, (6-10C)aryl, (3-12C)cycloalkyl, (3- 12C)heterocycloalkyl, 7-12 membered spiro bicyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spiro bicyclic cycloalkyl and 7-12 membered fused bicyclic cycloalkyl; wherein any of said alkyl, cycloalkyl or heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1-3C)alkyl or (1- 3C)alkoxy;
  • L3 is selected from the group consisting of: a direct bond, (1 -8C)alkyl, - N(R L3 )-, -O-, -N(R L3 )-C(O)-, -C(O)-N(R L3 )-, -C(O)-, -(O-CH 2 -CH 2 ) n -, -(CH 2 -CH 2 -O) n - and (3- 12C)heterocycloalkyl; wherein any of said or heterocyclo-alkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1-3C)alkyl or (1- 3C)alkoxy; each R L3 is independently -H or methyl; n is an integer from 1 to 2.
  • l_4 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -(O- CH2-CHz)p-, -(CH2-CH2-O) P -, (3-12C)cycloalkyl and (3-12C)heterocycloalkyl; wherein any of said alkyl, cycloalkyl or heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1-3C)alkyl or (1-3C)alkoxy; p is an integer from 1 to 2.
  • Ls is selected from the group consisting of: a direct bond, -N(R L5 )-, -N(R L5 )- C(O)-, -C(O)-, ( 1 -4C)alkyl, -(O-CH2-CH 2 ) q and -(O-CH2-CH2-CH2) q ; each R L5 is independently -H or methyl; q is independently an integer from 1 to 2.
  • Li is selected from the group consisting of: a direct bond, -NH-, -0-, - C(O)-NH-, -NH-C(O)-, -C(0)-, -CEC-.
  • L2 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -CH2-CH2-NH-, -(CH2-CH2-O)m-, wherein any of said alkyl, cycloalkyl or heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1 -3C)alkyl or (1-3C)alkoxy; m is an integer from 1 to 2.
  • L3 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -N(R L3 )-, -O-, -N(R L3 )-C(O)-, -C(O)-N(R L3 )-, -C(O)-, -(O-CH 2 -CH 2 ) n -, -(CH 2 -CH 2 -O) n - and (3- 12C)heterocycloalkyl; wherein any of said alkyl or heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1-3C)alkyl or (1- 3C)alkoxy; each R L3 is independently -H or methyl; n is an integer from 1 to 2.
  • l_4 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -N(R L4 ), -C(O)-, -(O-CH 2 -CH 2 ) P -, -(CH 2 -CH 2 -O) P -,
  • any of said alkyl, cycloalkyl or heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1 -3C)alkyl or (1-3C)alkoxy; each R L4 is independently hydrogen or methyl; p is an integer from 1 to 2.
  • Ls is selected from the group consisting of: a direct bond, -N(R L5 )-, - N(R L5 )-C(O)-, -C(O)- and (1 -4C)alkyl; each R L5 is independently hydrogen or methyl.
  • the Linker (DL) is -L-i-DLX-, wherein Li is selected from the group consisting of: a direct bond, -NH-, -O-, -C(O)-NH-, -NH-C(O)-, -C(O)-, -CHC-, -OCH2C(O)-, (1 -4C)alkyl; wherein Li is connected to the Targeting Ligase Binder (TLB) and DLX is connected to the Targeting Macrocyclic Kinase Binder (TMKB), and wherein DLX is selected from the group consisting of: wherein the marks the point of attachment to Li or marks the point of attachment to the
  • TLB Targeting Ligase Binder in case Li is a direct bond; and wherein the marks the point of attachment to the connecting group X; and wherein each R L is hydrogen or methyl; and wherein s is an integer from 0 to 5; and wherein t is an integer from 0 to 6.
  • Li is a direct bond, and the marks the point of attachment to the
  • TLB Targeting Ligase Binder
  • Linker (DL) is selected from the group consisting of:
  • TLB Targeting Ligase Binder
  • TLB Targeting Ligase Binder
  • TLB Targeting Ligase Binder
  • HBC heterobifunctional compounds
  • POI protein of interest
  • HBC consists of three covalently-bonded moieties: a ligand to bind POI (POI ligand), another ligand to recognize E3 ligase (E3 ligand) and a linker to conjugate the two ligands.
  • E3 ligand another ligand to recognize E3 ligase
  • HBC simultaneously recruits E3 ligase and POI, forming the “E3-HBC-POI” ternary complex. This complex potentiates the substrate recognition by E3 ligase and promotes the transfer of Ub to POI, accelerating the poly-ubiquitination and subsequent proteasome-mediated degradation of POI (Lai AC and Crews CM.
  • VHL Von-Hippel-Lindau
  • lAPs inhibitors of apoptosis proteins
  • CRBN Cereblon
  • TLB Targeting Ligase Binder
  • each R TLB1 is independently halo, cyano or (1 -4C)alkyl, wherein any of said alkyl group is optionally and independently substituted with one, two or three halogen, cyano, -COOH, COONH2, -NH2 or CF 3 ;
  • t is the number of R(TLB1 ) substituents and is independently an integer from 0 to 2;
  • each R TLB4 is independently hydrogen, (1 -4C)alkyl or (1-3C)alkoxy;
  • each R TLB5 is independently hydrogen, halo, cyano or (1 -3C)alkyl;
  • Z is -C(R TLB6 ) 2 or -C(O)-; each R TLB6 is independently hydrogen or (1 -4C)alkyl;
  • Z’ is a bond, -C(O)- or -CH 2 C(O)-;
  • Z is -CH2- or -NH-
  • HAr is a (1-9C)heteroaryl optionally substituted with fluoro, methyl or methoxy; and heterocyclic ring D is selected from:
  • R(TLB1 ) and R TLB1 refer to the same substituents.
  • R(TLB4) and R TLB4 refer to the same substituents.
  • R(TLB5) and R TLB5 refer to the same substituents.
  • TLB Targeting Ligase Binder
  • each R TLB5 is independently hydrogen, fluoro or cyano
  • HAr is a (1-9C)heteroaryl optionally substituted with fluoro, methyl or methoxy.
  • R(TLB5) and R TLB5 refer to the same substituents.
  • TLB Targeting Ligase Binder
  • T ⁇ marks the position of Linker (DL) or L 1 of the Linker (DL).
  • the Targeting Ligase Binder is selected from the group consisting of: wherein the marks the position of Linker (DL) or L 1 of the Linker (DL).
  • Specific Targeting Macrocyclic Kinase Binder TMKB
  • Targeting Macrocyclic Kinase Binder is selected from the group consisting of:
  • X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N).
  • TMKB Targeting Macrocyclic Kinase Binder
  • Novel degraders containing novel Targeting Ligase Binder which is a group that is capable of binding to a E3 ligase
  • TLB-A Formula (TLB-A), or a pharmaceutically acceptable salt, hydrate, solvate thereof, wherein: the Targeting Ligase Binder (TLB) is a group that is capable of binding to a E3 ligase; the Targeting Protein Binder (TPB) is a group that is capable of binding to a target protein; the Linker (DL) is a group that covalently links the Targeting Protein Binder (TPB) to the Targeting Ligase Binder (TLB); wherein the Targeting Ligase Binder (TLB) is selected from the group consisting of: wherein the marks the position of Linker (DL); wherein D is:
  • TLB-A Targeting Ligase Binder
  • L 2 is independently selected from the group consisting of: a direct bond, -N(R L2 )-, -O-, (1 -4C)alkyl, - CH 2 -CH 2 -N(R L2 )-, -(CH 2 -CH 2 -O) m -, -(CH 2 -CH 2 -CH 2 -O)m-, -(O-CH 2 -CH 2 ) m -, (6-10C)aryl, (3- 12C)cycloalkyl, (3-12C)heterocycloalkyl, 7-12 membered spiro bicyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spiro bicyclic cycloalkyl and 7-12 membered fused bicyclic cycloalkyl; wherein any of said alkyl, cycloalkyl or heterocycloalkyl group is optionally and independently substituted with one, two
  • L 4 is independently selected from the group consisting of: a direct bond, (1 -4C)alkyl , -N(R L4 ), -C(O)-, -(O-CH2-CH2)p-, -(CH2-CH2-O) P -, (3-12C)cycloalkyl, (3-12C)heterocycloalkyl, 7-12 membered spiro bicyclic heterocycloalkyl and 7-12 membered fused bicyclic heterocycloalkyl; wherein any of said alkyl, cycloalkyl or heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1-3C)alkyl or (1-3C)alkoxy; each R L4 is independently -H or (1-4C)alkyl;
  • L 5 is independently selected from the group consisting of: a direct bond, -N(R L5 )-, -N(R L5 )-C(O)-, - C(O)-, (1 -4C)alkyl, -(O-CH2-CH2) q - and -(O-CH2-CH2-CH2) q -; each R L5 is independently -H or (1- 4C)alkyl; each m, n, p and q is independently an integer from 1 to 3.
  • TLB-A Targeting Protein Binder
  • TLB-A Targeting Protein Binder
  • TMKB Targeting Macrocyclic Kinase Binder
  • a pharmaceutical composition which comprises the compound according to Formula (TLB- A) or any of the clauses 1 - 5 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • TMKB Targeting Macrocyclic Kinase Binder
  • the bifunctional compound has a sub-formula (1 - 138) selected from the group consisting of:
  • said bifunctional compound has a sub-formula selected from the group consisting of: 18, 20, 22, 23, 44, 48, 60, 66, 68, 69, 87, 89, 90, 93, 94, 95 and 105.
  • Said compounds are in particular suitable for degrading Bruton’s Tyrosine Kinase (BTK).
  • said bifunctional compound has a sub-formula selected from the group consisting of: 18, 20, 22, 44, 66, 68, 69, 87, 93, 94 and 95.
  • Said compounds are in particular suitable for degrading Bruton’s Tyrosine Kinase C481S mutant (BTK C481S).
  • said bifunctional compound has a sub-formula selected from the group consisting of: 18, 20, 22, 44, 48, 66, 68, 69, 87, 89, 93, 94 and 95.
  • Said compounds are in particular suitable for degrading Bruton’s Tyrosine Kinase C481 S/T474I mutant (BTK C481S/T474I).
  • said bifunctional compound has a sub-formula selected from the group consisting of: 18, 20, 22, 34, 44, 45, 48, 66, 67, 68, 87, 89, 93, 94 and 95.
  • Said compounds are in particular suitable for degrading Bruton’s Tyrosine Kinase T474I mutant (BTK T474I).
  • said bifunctional compound has a sub-formula selected from the group consisting of: 2, 4, 20, 22, 45, 66, 89, 93, 94 and 95. Said compounds are in particular suitable for degrading Bruton's Tyrosine Kinase V416L mutant (BTK V416L). In preferred embodiments, said bifunctional compound has a sub-formula selected from the group consisting of: 2, 4, 20, 22, 45, 66, 89, 93 and 95. Said compound is in particular suitable for degrading Bruton's Tyrosine Kinase L528W mutant (BTK L528W).
  • said bifunctional compound has a sub-formula selected from the group consisting of: 4.
  • Said compound is in particular suitable for degrading Lymphocyte-Specific Protein Tyrosine Kinase (LCK).
  • said bifunctional compound has a sub-formula selected from the group consisting of: 111, 112, 115, 117, 118, 120, 123, 124 and 127 - 135.
  • Said compound is in particular suitable for degrading "REarranged during Transfection" receptor tyrosine kinase (RET).
  • said bifunctional compound has a sub-formula selected from the group consisting of: 137 and 138.
  • Said compound is in particular suitable for degrading Epidermal Growth Factor Receptor (EGFR).
  • compositions in accordance with the present invention comprise, as the active ingredient (‘API’), bifunctional compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • a pharmaceutically acceptable salt includes any salt that retains the activity of the active agent(s) and is acceptable for pharmaceutical use.
  • a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
  • the pharmaceutically acceptable salt is the HCI-salt of the compound of the invention.
  • the pharmaceutically acceptable salt of the disclosed compounds may be prepared by methods of pharmacy well known to those skilled in the art.
  • compositions can comprise compounds according to the invention in the form of a solvate, comprising a pharmaceutically acceptable solvent, such as water (‘hydrate’), ethanol, and the like.
  • a pharmaceutically acceptable solvent such as water (‘hydrate’), ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • composition refers to a composition comprising a compound according to the invention or a salt or solvate thereof and, as the case may be, one or more additional, non-toxic ingredients, which composition is in a form suitable for administration to a (human) subject, through any route of administration, and which composition is physiologically tolerated upon such administration.
  • compositions of the invention may thus comprise one or more additional ingredients.
  • the composition comprises one or more carriers and/or excipients.
  • the appropriate choice of excipients is dependent on multiple factors, including the physicochemical properties of the API, the preferred pharmaceutical form, the preferred route of administration, the desired rate of release, etc.
  • the compositions of the invention can be formulated for a variety of routes of administration, oral administration being particularly preferred.
  • the composition is preferably provided in a unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unitary dosage for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with any suitable pharmaceutical carrier(s) and/or excipient(s).
  • Exemplary, non-limiting unit dosage forms include a tablet (e.g., a chewable tablet), caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, gelcap as well as any metered volume of a solution, suspension, syrup or elixir or the like, which may be contained, for instance in a vial, syringe, applicator device, sachet, spray, micropump etc.
  • the unit dosage form is a unit dosage form that is suitable for oral administration. Most preferably, it is a solid unit dosage form, such as a tablet.
  • Pharmaceutically acceptable salts of compounds of the invention include the acid addition and base salts thereof, such as preferably the calcium, potassium or sodium salts.
  • suitable salts reference is made “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • salts of compounds according to the invention may be readily prepared by mixing together solutions of compounds according to the invention and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • the compounds and the pharmaceutical compositions of the present invention are useful as degraders of kinases, in particular tyrosine kinases.
  • compounds of this invention are useful as degraders of tyrosine kinases that are important in hyper-proliferative diseases, especially in cancer and in the process of angiogenesis.
  • the compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Ewing’s sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukaemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
  • cancer related indications such as solid tumors, sarcomas (especially Ewing’s sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukaemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
  • the compounds according to the invention having Formula (I) and pharmaceutical compositions thereof can be used to treat or prevent a variety of conditions, diseases or disorders mediated by any one of the kinases and mutants of these kinases: BTK, LCK, FGFR1 , FLT3, PDGFR-p, FMS, LYN, MEK1 , AUR-B, ITK, VEGFR, EGFR, TEC, ABL, AXL, c-MET, FGFR3, IGFR1 , RET, SRC and YES.
  • Such conditions, diseases or disorders include: (1 ) arthritis, including rheumatoid arthritis, juvenile arthritis, psoriatic arthritis and osteoarthritis; (2) asthma and other obstructive airways diseases, including chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, adult respiratory distress syndrome, recurrent airway obstruction, and chronic obstruction pulmonary disease including emphysema; (3) autoimmune diseases or disorders, including those designated as single organ or single cell-type autoimmune disorders, for example Hashimoto’s thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia including idiopathic thrombopenic purpura, sympathetic ophthalmia, myasthenia gravis.
  • Graves’ disease primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosis, immune thrombocytopenic purpura, rheumatoid arthritis, Sjogren’s syndrome, Reiter’s syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, and additional autoimmune diseases, which can be B-cell (humoral) based or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener’s granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis;
  • systemic autoimmune disorder for example systemic lupus erythematosis, immune thrombocytopenic purpura,
  • cancers or tumors including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma and leukemia (including but not limited to acute myelogenous leukemia, chronic myelogenous leukemia, mantle cell lymphoma, NHL B cell lymphomas (e.g.
  • B-ALL marginal zone B cell lymphoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, mediastinal large B-cell lymphoma), Hodgkin lymphoma, NK and T cell lymphomas; TEL-Syk and ITK-Syk fusion driven tumors, myelomas including multiple myeloma, myeloproliferative disorders kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi’s sarcoma, proliferative diabetic retinopathy, and angiogenic-associated disorders including solid tumors, and pancreatic cancer.
  • diabetes including Type I diabetes and complications from diabetes
  • eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet’s disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren’s ulcer, scleritis, Grave’s ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization; (7) intestinal inflammations, allergies or conditions including Crohn
  • a compound of the invention may be combined with one or more of an anticancer agents.
  • an anticancer agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Heilman (editors), 6 th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • BTK degradation is a novel approach for treating many different human diseases associated with the inappropriate activation of B-cells, including B-cell proliferative disorders, B-cell malignancies, immunological disease for example autoimmune and inflammatory disorders.
  • condition treatable by degradation of BTK may be selected from: cancer, lymphoma, leukemia, autoimmune diseases, inflammatory disorders, heteroimmune conditions, or fibrosis.
  • Specific conditions treatable by the degradation of BTK may be selected from: B-cell malignancy, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocyte leukemia, nonHodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, follicular lymphoma, chronic lymphocytic lymphoma, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphom
  • hepatic or liver fibrosis includes, but is not limited to, hepatic fibrosis associated with alcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B or D), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, pharmaceutical drugs and environmental toxins), renal fibrosis (e.g., chronic kidney fibrosis), nephropathies associated with injury/fibrosis (e.g., chronic nephropathies associated with diabetes (e.g., diabetic nephropathy)), lupus, scleroderma of the kidney, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosis associated with human chronic kidney disease (CKD), chronic progressive nephropathy (CPN), tubulointer
  • condition treatable by the degradation of BTK may be selected from: cancer, lymphoma, leukemia, autoimmune diseases and inflammatory disorders.
  • Specific conditions treatable by the degradation of BTK may be selected from: B-cell malignancy, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, Richter transformation, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn’s disease, lupus and Sjogren's syndrome.
  • B-cell malignancy B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, Richter transformation, multiple myeloma, bone cancer, bone metastasis, chronic lymphocytic lymphomas, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, and lymphomatoid
  • B-cell malignancy B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, Richter transformation, multiple myeloma, bone cancer and bone metastasis are examples of cancer, lymphoma and leukemia treatable BTK degradation.
  • Graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis are examples of heteroimmune condition treatable by BTK degradation.
  • Pulmonary fibrosis idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, biliary duct injury, biliary fibrosis, cholestatis or cholangiopathies.
  • steatosis e.g., nonalcoholic steatohepatitis (NASH)
  • cholestatic liver disease e.g., primary biliary cirrhosis (PBC)
  • PBC primary biliary cirrhosis
  • hepatic or liver fibrosis includes, but is not limited to, hepatic fibrosis associated with alcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B or D), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, pharmaceutical drugs and environmental toxins), renal fibrosis (e.g., chronic kidney fibrosis), nephropathies associated with injury/fibrosis (e.g., chronic nephropathies associated with diabetes (e.g., diabetic nephropathy)), lupus, scleroderma of the kidney, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosis associated with human chronic kidney disease (CKD), chronic progressive nephropathy (CPN), tubulointer
  • Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn’s disease and lupus are examples of immunological diseases treatable by BTK degradation.
  • Arthritis is an examples of an inflammatory disorder treatable by BTK degradation.
  • Lupus and Sjogren's syndrome are examples of autoimmune diseases treatable by BTK degradation.
  • Any of the conditions disclosed above as being treatable by BTK degradation may be treated by a compound of the invention, or may be treated in a method comprising administering a compound of the invention, or may be treated by a medication manufactured through the use of a compound of the present invention.
  • LCK Lymphocyte-Specific Protein Tyrosine Kinase
  • the compounds of the invention or a pharmaceutically acceptable salt thereof are used for treating Lymphocyte-Specific Protein Tyrosine Kinase (LCK) mediated disorders, in particular for use in the treatment of:
  • LCK Lymphocyte-Specific Protein Tyrosine Kinase
  • a disease or disorder mediated by immune cells selected from T lymphocytes, NK cells, B lymphocytes, e.g. acute or chronic rejection of organ or tissue allo- or xenografts, atheriosclerosis, vascular occlusion due to vascular injury such as angioplasty, restenosis, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS disease such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, cholangiocarcinoma, cytokine release syndrome, lymphodepletion in combination with immunotherapy, such as immunotherapy using NK cells, infectious disease such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock;
  • a chronic T cell disorder like multiple sclerosis and rheumatoid arthritis, or an acute inflammatory disorder in which T cells play a prominent role including transplant rejection, atopic dermatitis and delayed type hypersensitivity.
  • EGFR Epidermal Growth Factor Receptor
  • the compounds of the invention or a pharmaceutically acceptable salt thereof are used for treating Epidermal Growth Factor Receptor (EGFR) mediated disorders, in particular for use in the treatment of cancer, wherein preferably the cancer is selected from a lung cancer, non-small cell lung cancer, a pancreatic cancer, a colon cancer, a breast cancer, colorectal cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a kidney carcinoma, pancreatic cancer, ovarian cancer, gastric cancer, glioma or prostate cancer, or a cancer that is characterized by an oncogenic mutation in the EGFR gene, an amplification, gene fusion or translocation of the EGFR gene, overexpression of EGFR mRNA or protein, overexpression of ligands of EGFR, or enhanced activity of EGFR signaling.
  • the compounds may be used to treat inflammatory diseases caused or aggravated on a molecular level by activity of EGFR or its ligand
  • RET receptor tyrosine kinase
  • the compounds of the invention or a pharmaceutically acceptable salt thereof are used for treating "REarranged during Transfection" receptor tyrosine kinase (RET) mediated disorders, in particular for use in the treatment of cancer, wherein preferably the cancer is selected from thyroid carcinomas and lung cancers, or characterized by oncogenic mutations in the RET gene, a gene fusion or translocation of the RET gene, or otherwise enhanced RET signaling.
  • the compounds, or a pharmaceutically acceptable salt thereof are used to prevent cancer in familial RET-mediated disorders, such as multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma.
  • Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of the present invention can be prepared by methods well known in the art of organic chemistry. See, for example, J. March, ‘Advanced Organic Chemistry 1 4 th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P.G.M. Wutts Protective Groups in Organic Synthesis’ 3 rd Edition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.
  • the products of the reactions are optionally isolated and purified, if desired, using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials are optionally characterized using conventional means, including physical constants and spectral data.
  • Compound IV can, subsequently, be prepared from compound III and benzyl (1R,5R)-5-hydroxycyclohex-3-ene-1- carboxylate using Mitsunobu conditions, for example DIAD/triphenylphosphine in THF at 0 °C.
  • Compound VI can be prepared from compound IV using an appropriate boronic acid or pinacolester (V), in the presence of a suitable palladium catalyst system, for example bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex or fefrak/s(triphenylphosphine)palladium(0) in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • a suitable palladium catalyst system for example bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex or fefrak/s(triphenylphosphine)palladium(0) in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • Reduction of the double bond and deprotection of the benzylester can be accomplished by catalytic hydrogenation in the presence of a suitable catalyst system and solvent, for example palladium on charcoal in ethyl acetate and methanol to provide compounds of Formula VII.
  • a suitable catalyst system and solvent for example palladium on charcoal in ethyl acetate and methanol to provide compounds of Formula VII.
  • Compounds of Formula X can be prepared from compound IX using an appropriate boronic acid or pinacolester, in the presence of a suitable palladium catalyst system, for example CataCXium® A Pd G3 or bis(diphenylphos-phine)palladium(0) palladium(ll)chloride complex in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • a suitable palladium catalyst system for example CataCXium® A Pd G3 or bis(diphenylphos-phine)palladium(0) palladium(ll)chloride complex
  • an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • Derivatives of Formula XI can be prepared from derivatives of Formula X after deprotection of the amino function with TBAF or a strong acid like TFA and subsequent carb
  • Macrocyclization towards compounds of Formula XII can be accomplished with an appropriate couplings reagent such as HATU of EDCLHCI in a suitable solvent like DMF at appropriate temperature.
  • deprotection of compounds of Formula XII can be accomplished using strong acids like HCI or TFA for in the presence of water and a suitable cation scavenger like triisopropylsilane (TIS) at appropriate temperature.
  • TIS triisopropylsilane
  • Subsequent coupling of compounds of Formula XII to obtain compounds with Formula TMKB l-a can be accomplished by amide-coupling, alkylation or reductive amination using appropriate reagents such as HATU, EDCLHCI, NaBH(OAc)a or NaBH(t-BuO) 3 .
  • Scheme III shows a general synthetic route in relation to an exemplary compound of Formula TMKB l-a.
  • Halogenation of compounds of Formula VII can be performed using N-bromosuccinimide or N- iodosuccinimide in a suitable solvent like DCM or DMF at appropriate temperature to obtain compounds of Formula XIII.
  • Compounds of Formula XIV can be prepared from compound XIII using an appropriate boronic acid or pinacolester, in the presence of a suitable palladium catalyst system, for example CataCXium® A Pd G3 or bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • a suitable palladium catalyst system for example CataCXium® A Pd G3 or bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in
  • Derivatives of Formula XV can be prepared from derivatives of Formula XIV after carboxyl acid deprotection using a suitable inorganic base like lithium hydroxide or sodium hydroxide. Macrocyclization towards compounds of Formula XV can be accomplished with an appropriate couplings reagent such as HATU of EDCI.HCI in a suitable solvent like DMF at appropriate temperature. Finally deprotection of compounds of Formula XV can be accomplished using strong acids like HCI or TFA for in the presence of water and a suitable cation scavenger like triisopropylsilane (TIS) at appropriate temperature.
  • a suitable inorganic base like lithium hydroxide or sodium hydroxide.
  • Macrocyclization towards compounds of Formula XV can be accomplished with an appropriate couplings reagent such as HATU of EDCI.HCI in a suitable solvent like DMF at appropriate temperature.
  • deprotection of compounds of Formula XV can be accomplished using strong acids like HCI or TFA for in the presence of
  • TLB-Linker to compounds of Formula XV to obtain compounds with Formula TMKB l-a can be accomplished by amide-coupling, alkylation or reductive amination using appropriate reagents such as HATU, EDCI.HCI, NaBH(OAc) 3 or NaBH(t-BuO) 3 .
  • Compounds of Formula XVII can be prepared from compound III and amino-protected (chiral) aminoalcohols (XVI) using Mitsunobu conditions, for example DIAD/triphenylphosphine in THF at 0 °C.
  • compounds of Formula XVII can be obtained after activation of the alcohol with for example tosylchloride or mesylchloride to perform a substitution reaction in appropriate solvents such as DMF in the presence of an inorganic base like cesium carbonate or potassium carbonate.
  • Compounds of Formula XVIII can be prepared from compound XVII using an appropriate boronic acid or pinacolester (V), in the presence of a suitable palladium catalyst system, for example bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex or tetrafc/s(triphenylphos- phine)palladium(O) in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • a suitable palladium catalyst system for example bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex or tetrafc/s(triphenylphos- phine)palladium(O) in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • halogenation of compounds of Formula XVIII can be performed using N-bromosuccinimide or N- iodosuccinimide in a suitable solvent like DCM or DMF at appropriate temperature to obtain compounds of Formula XIX.
  • Compounds of Formula XX can be prepared from compound XIX using an appropriate boronic acid or pinacolester, in the presence of a suitable palladium catalyst system, for example CataCXium® A Pd G3 or bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex in the presence of a inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • a suitable palladium catalyst system for example CataCXium® A Pd G3 or bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex in the presence of a inorganic base like potassium carbonate, cesium carbon
  • Derivatives of Formula XII can be prepared from derivatives of Formula XX after amine deprotection using and appropriate acid like TFA and subsequent carboxyl acid deprotection using a suitable inorganic base like lithium hydroxide or sodium hydroxide, subsequent macrocyclization towards compounds of Formula XII can be accomplished with an appropriate couplings reagent such as HATU of EDCI.HCI in a suitable solvent like DMF at appropriate temperature. Finally deprotection of compounds of Formula XII can be accomplished using strong acids like HCI or TFA for in the presence of water and a suitable cation scavenger like triisopropylsilane (TIS) at appropriate temperature.
  • TFS triisopropylsilane
  • TLB-Linker to compounds of Formula XV to obtain compounds with Formula TMKB l-a can be accomplished by amide-coupling, alkylation or reductive amination using appropriate reagents such as HATU, EDCI.HCI, NaBH(OAc) 3 or NaBH(t-BuO) 3 .
  • Compounds of Formula XXIII can be prepared from compound III and amino-protected (chiral) aminoalcohols (XXII) using Mitsunobu conditions, for example DIAD/triphenylphosphine in THF at 0 °C.
  • compounds of Formula XXIII can be obtained after activation of the alcohol with for example tosylchloride or mesylchloride to perform a substitution reaction in appropriate solvents such as DMF in the presence of an inorganic base like cesium carbonate or potassium carbonate.
  • Compounds of Formula XXIV can be prepared from compound XXIII using an appropriate boronic acid or pinacolester (V), in the presence of a suitable palladium catalyst system, for example bls(diphenylphosphine)palladium(0) palladium(ll)chloride complex or tefrak/s(triphenylphosphine)paliadium(0) in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • a suitable palladium catalyst system for example bls(diphenylphosphine)palladium(0) palladium(ll)chloride complex or tefrak/s(triphenylphosphine)paliadium(0)
  • an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • halogenation of compounds of Formula XXIV can be performed using N- bromosuccinimide or N-iodosuccinimide in a suitable solvent like DCM or DMF at appropriate temperature to obtain compounds of Formula XXV.
  • Compounds of Formula XXVI can be prepared from compound XXV using an appropriate boronic acid or pinacolester, in the presence of a suitable palladium catalyst system, for example CataCXium® A Pd G3 or bis(diphenyiphosphine)palladium(0) palladium(ll)chloride complex in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • a suitable palladium catalyst system for example CataCXium® A Pd G3 or bis(diphenyiphosphine)palladium(0) palladium(ll)chloride complex in the presence of an inorganic base like potassium carbonate, cesium carbonate or
  • Derivatives of Formula XXVII can be prepared from derivatives of Formula XXVI after deprotection of the amine group with TBAF or a strong acid like TFA and subsequent carboxyl acid deprotection using a suitable inorganic base like lithium hydroxide or sodium hydroxide, following macrocyclization towards compounds of Formula XXVII can be accomplished with an appropriate coupling-reagent such as HATU of EDCI.HCI in a suitable solvent like DMF at appropriate temperature. Finally deprotection of compounds of Formula XII can be accomplished using strong acids like HCI or TFA for in the presence of water and a suitable cation scavenger like triisopropylsilane (TIS) at appropriate temperature.
  • TIS triisopropylsilane
  • TLB-Linker to compounds of Formula XXVII to provide compounds with Formula TMKB l-a can be accomplished by amide-coupling, alkylation or reductive amination using appropriate reagents such as HATU, EDCI.HCI, NaBH(OAc)3 or NaBH(t-BuO)a.
  • Scheme VI shows a general synthetic route in relation to an exemplary compound of Formula TMKB l-b.
  • Reduction of derivative XXX can be accomplished by hydrogenation under elevated pressure in the presence of a suitable catalyst system and solvent, for example Raney-Nickel to provide (6-bromo-3-chloro-pyrazin-2-yl)methanamine (XXXI).
  • a suitable catalyst system and solvent for example Raney-Nickel to provide (6-bromo-3-chloro-pyrazin-2-yl)methanamine (XXXI).
  • XXXII (6-bromo-3-chloro-pyrazin-2-yl)methanamine
  • a solvent such as DMF, THF or DCM
  • a base such as DIPEA, N-methylmorpholine, 4-DMAP or triethylamine
  • a coupling reagent such as PyBOP, TBTU, EDCI or HATU
  • Compounds of Formula XXXIV can be prepared from compound XXXIII using an appropriate boronic acid or pinacolester, in the presence of a suitable palladium catalyst system, for example CataCXium® A Pd G3 or bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water.
  • Cyclisation chloropyrazine of Formula XXXIV can be performed using condensation reagents like phosphorus oxychloride under heating conditions to provide compounds of Formula XXXV.
  • XXXVII 8-Aminoimidazo[1 ,5-a]pyrazine derivatives XXXVII can be prepared from compounds of Formula XXXVI using dimethoxybenzylamine in n-butanol at elevated temperature in a pressure vessel or microwave (> 4 atm.)
  • Compounds of Formula XXXVIII can be prepared from compound XXXVII using an appropriate boronic acid or pinacolester (V), in the presence of a suitable palladium catalyst system, for example bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex or tefrak/s(triphenylphos-phine)palladium(0) in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dio
  • a suitable palladium catalyst system for example bis(diphenylphosphine)palladium(0) palladium(ll)chloride complex or
  • Derivatives of Formula XXXIX can be prepared from derivatives of Formula XXXVIII after deprotection of the amine group with TBAF or a strong acid like TFA and subsequent carboxyl acid deprotection using a suitable inorganic base like lithium hydroxide or sodium hydroxide, following macrocyclization towards compounds of Formula XXXIX can be accomplished with an appropriate coupling-reagent such as HATU of EDCI.HCI in a suitable solvent like DMF at appropriate temperature. Finally deprotection of compounds of Formula XXXIX can be accomplished using strong acids like HCI or TFA for in the presence of water and a suitable cation scavenger like triisopropylsilane (TIS) at appropriate temperature.
  • TIS triisopropylsilane
  • TLB-Linker to compounds of Formula XXXIX to provide compounds with Formula TMKB l-b can be accomplished by amide- coupling, alkylation or reductive amination using appropriate reagents such as HATU, EDCI.HCI, NaBH(OAc) 3 or NaBH(t-BuO) 3 .
  • the eluents used for this system are A (95/5 v/v% Milli-Q water/acetonitrile + 0.1 % formic acid) and B (acetonitrile + 0.1 % formic acid).
  • the eluents used for this system are A (95/5 v/v% Milli-Q water/acetonitrile + 0.1 % formic acid) and B (acetonitrile + 0.1 % formic acid).
  • the eluents used for this system are A (95/5 v/v% Milli-Q water/acetonitrile + 0.1 % formic acid) and B (acetonitrile + 0.1 % formic acid).
  • the benzylester was reduced completely but -31 % of a double-bond containing product remained.
  • the palladium-catalyst was filtered and the filtrate was recharged with 10% Pd/C (1.8 g) and catalytic hydrogenation was continued for 24 h.
  • the palladium-catalyst was filtered and the filtrate was concentrated in vacuo to give 14.74 g of the title compound (Yield: 85.0%).
  • Tri-n-butyltin hydride (84 g, 288.7 mmol) was added to a stirred solution of 1 ,2-trans-2,3-trans- 2-bromo-3-A/-phtalimidocyclohexanol (78 g, 240.6 mmol) and AIBN (0.2M in toluene, 60 mL, 12 mmol) in toluene (700 mL) and methanol (70 mL) and the mixture was stirred at reflux o/n. Additonal AIBN (2x5 mL) and tri-n-butyltin hydride (2x10 mL) were added and the reaction mixture was stirred at reflux o/n.
  • Second batch To a solution of (1 S,3R)-3-aminocyclohexanol (13.74 g, 34.0 mmol) in dioxane (200 mL) was added di-tert-butyl dicarbonate (7.8 g) and the reaction mixture was stirred at room temperature o/w. Dioxane was partly evaporated and ethyl acetate (500 mL) was added to the suspension. The suspension was washed with NaOH-solution (4 g in 200 mL), water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7.54 g of the title compound.
  • Methyl (1 R,3R)-3-aminocyclohexanecarboxylate hydrochloride (1.06 g, 5.47 mmol) was suspended in 10 mL water.
  • Sodium bicarbonate (1.38 g, 16.4 mmol) in 10 mL water was added followed by a drop-wise addition of a solution A/-(benzyloxycarbonyloxy)succinimide (1.50 g, 6.01 mmol) in dioxane (30 mL).
  • the reaction mixture was stirred at room temperature o/n.
  • the mixture was diluted with ethyl acetate (50 mL) and water (50 mL) and the bi-phasic system was stirred 30 minutes at room temperature.
  • Triethylamine (10.4 mL, 74.62 mmol), 4-dimethylaminopyridine (605 mg, 4.95 mmol) and di- tert-butyl dicarbonate (13.5 g, 61.86 mmol) were added sequentially to a solution of 4-nitrobenzene sulfonamide (10 g, 49.46 mmol) in dichloromethane (100 mL).
  • the reaction mixture was stirred for 30 minutes at room temperature.
  • hydrochloric acid (1 N aqueous solution) until it becomes acidic.
  • the organic layer was separated and washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure.
  • Methylmagnesium bromide (3 M in EtzO, 32.3 mL, 96.8 mmol) was added dropwise to a solution of tert-butyl A/-[(1R)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate (10.84 g, 44 mmol) in THF (132 mL) at -15 °C under nitrogen. After stirring at this temperature for 15 min, the mixture was allowed to come to room temperature and stirring was continued for 1 h. The mixture was cooled to 0 °C and sat. aq. NFUCI-solution (40 mL) was added carefully.
  • This compound was prepared in an analogous manner as described in Intermediate BP1 , starting from 2-amino-4-methoxypyridine and 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid, to afford the title compound (900 mg, 51 %).
  • Methyl (6S)-6-hydroxy-8-trimethylsilyl-oct-7-ynoate (4.27 g, 17.6 mmol) was dissolved in DMF (40 mL) and treated with a solution of potassium fluoride (2.05 g, 35.2 mmol) in water (5 mL) at room temperature. After 30 min, 1 M hydrochloric acid (50 mL) was added and the product was extracted with diethyl ether (3x50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo.
  • Triphenylphosphine (563 mg, 2.15 mmol) was dissolved in dichloromethane (8 mL) and cooled to -78 °C.
  • A/-Bromosuccinimide (382 mg, 2.15 mmol) was added in one portion to the mixture and stirring was continued for 30 minutes at -78 °C.
  • 6,6-dideuterio-6-hydroxy-hexanoic acid 230 mg, 1.72 mmol
  • dichloromethane 8 mL
  • the mixture was diluted with water and thoroughly stirred, 15 minutes at rt.
  • 3-Amino-4-methoxybenzoic acid (5 g, 29.9 mmol) was suspended in acrylic acid (8.05 mL, 117 mmol). The resulting suspension was stirred at 100 °C. After 10 min, a thick slurry/solid appeared, which was heated at 100 °C for another 3 h. After cooling, acetic acid (33 mL) was added and the suspension was heated to 100 °C and stirred for 10 min. Then, urea (11 g, 183 mmol) was added and the resulting mixture was stirred at 120 °C o/n. The resulting brown solution was then quenched into a ice-cold solution of water (150 mL) and H Cleone (10 mL).

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Abstract

L'invention concerne des composés bifonctionnels de formule (I) pour dégrader des kinases par l'intermédiaire d'une voie de l'ubiquitine protéasome. Plus particulièrement, l'invention concerne des composés bifonctionnels macrocycliques de formule (I) pour dégrader des kinases par l'intermédiaire de la voie de l'ubiquitine protéosome, ainsi que des procédés pour préparer les composés bifonctionnels, des utilisations des composés bifonctionnels et des méthodes pour traiter des maladies modulées par des kinases spécifiques. En particulier, l'invention concerne des composés bifonctionnels formés par conjugaison d'inhibiteurs de kinase macrocycliques réversibles avec des fractions de liaison à la ligase E3, qui fonctionnent pour recruter des protéines kinases ciblées à l'ubiquitine ligase E3 pour la dégradation des protéines kinases ciblées.
PCT/EP2023/085688 2022-12-14 2023-12-13 Composés bifonctionnels pour la dégradation de kinases par l'intermédiaire d'une voie de l'ubiquitine protéosome Ceased WO2024126617A1 (fr)

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