Bifunctional compounds for degrading kinases via ubiquitin proteosome pathway

Abstract

The invention relates to bifunctional compounds according to Formula (I) for degrading kinases via ubiquitin proteasome pathway. More specifically, the invention relates to macrocyclic bifunctional compounds according to Formula (I) 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.

Description

[0001] Bifunctional compounds for degrading kinases via ubiquitin proteosome pathway

[0002] Field of the invention

[0003] 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.

[0004] Background of the invention

[0005] 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.

[0006] There is clinical evidence that supports the driver role of kinases in cancer owing to their aberrant activation by either translocations or activating mutations. Chromosomal translocations produce fusion proteins with abnormal localization that can be potentially oncogenic. Identification and characterization of these disease drivers has facilitated the design and approval of molecularly guided cancer therapies, beginning with the pioneering example of imatinib to treat CML driven by the BCR- ABL translocation, which results in a protein with elevated tyrosine kinase activity. Many of smallmolecule kinase inhibitors approved by the FDA that target kinases have oncology indications. Recent developments of kinase inhibitors, including developments of kinase inhibitors for oncology, have been reported, see: Attwood et al. (2021 ) “Trends in kinase drug discovery targets, indications and inhibitor design.” Nat Rev Drug Discov 20, pages 839-861 (2021 ).

[0007] The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Among them are inhibitors for EGFR (afatinib, osimertinib), BTK (ibrutinib, acalabrutinib and zanubrutinib), RET (cabozantinib, selpercatinib), MET (capmatinib, tepotinib) and FLT-3 (gilteritinib, midostaurin). Nevertheless, many factors influence the clinical efficacy of these molecules.

[0008] Bruton's tyrosine kinase (BTK) is a member of the 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. Targeting of BTK with small molecule inhibitors such as the FDA approved irreversible BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib has proven to be efficacious in several B cell malignancies including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Waldenstrom’s Macroglobulinemia (WM) and Small Lymphocytic Lymphoma SLL. Combinations of BTK inhibitors with other novel drugs or regimens results in more profound responses and much higher rates of minimal residual disease negativity.

[0009] BTK is also expressed and plays also pro-tumorigenic roles in several solid tumors (Xianhui Wang et al. 2021 ). In prostate cancer cells 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).

[0010] 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 ).

[0011] A drawback of the currently approved irreversible inhibitors, e.g. ibrutinib, 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. Other mutations that can result in acquired resistance to both irreversible covalent and reversible non-covalent BTK inhibitors are 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).

[0012] 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.

[0013] Other 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). Mutations of one or more of these kinases are reported and are known to alter and / or disturb molecular pathways. In several studies 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 )).

[0014] UPS (ubiquitin-proteasome system) is a highly conserved mechanism for degradation of both normal, mutated and misfolded proteins in eukaryotic cells, thus keeping intracellular protein homeostasis (Bard JA et al. Structure and function of the 26S proteasome. Annu Rev Biochem. (2018) 87, 697-724; Kleiger G et al. Perilous journey: a tour of the ubiquitin-proteasome system. Trends Cell Biol. (2014) 24, 352-359; Hipp MS et al. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol. (2019) 20, 421-435). In UPS, 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. Such repeated ubiquitination processes generate a poly-Ub chain (mainly linked through Lys48 of Ub) on the target protein, which guides the substrate to 26S proteasome for degradation (Komander D et al. The ubiquitin code. Annu Rev Biochem. (2012) 81 , 203-229; Yau R, Rape M. The increasing complexity of the ubiquitin code. Nat Cell Biol. (2016) 18, 579-586). In human proteome, there are two E1s, about forty E2s and more than 600 E3s. Among them, the E3 ligases are responsible for specifically recognizing substrates.

[0015] Inspired by UPS, researchers designed heterobifunctional compounds (HBC) to hijack the UPS and degrade a protein of interest (POI). 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. 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. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev. Drug. Discov. (2017) 16, 101-114). Current HBC developments have mainly been focused on three E3 ligases, i.e. Von-Hippel-Lindau (VHL), inhibitors of apoptosis proteins (lAPs) and cereblon (CRBN).

[0016] Unlike traditional inhibitors, 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.

[0017] The principle of induced degradation of protein targets as a potential therapeutic approach has been described by Crews, J. Med. Med. 61 (2): 403-404 (2018) and references cited therein.

[0018] It has been clear that induced protein degradation offers several potential advantages over traditional target inhibition. First, only sub-stoichiometric drug concentrations are needed given the repeating turnover nature of many degrader molecules. Furthermore, greater target selectivity can be achieved, even when starting with promiscuous binding ligands (Bondeson D. et al. Lessons in PROTAC design from selective degradation with promiscuous warheads. Cell. Chem. Biol. (2018) 25, 78-87). Also the ability to overcome target upregulating feedback loops and the ability to address scaffolding functions of target proteins that are not addressable with inhibitor molecules (Samaransinghe K.T.G. and Crews C.M. Targeted protein degradation: a promise for undruggable targets. Cell Chem Biol (2021 ) 28, 934-951 ).

[0019] 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. Ther., (2022) 7, 181 ) and are disclosed in WO2018 / 071606, WO2020 / 264499, W02021 / 011871 , WO2021 / 194878, WO2021 / 226262, WO2022 / 068849 and WO2022 / 093742.

[0020] There is a need for more effective protein (mutant) kinase modulators including for specific mutations of protein kinases and the present application addresses the generation of bifunctional degrader molecules that are directed to a variety of protein (mutant) kinase targets for in-vivo target validation and as therapeutics.

[0021] Therefore, an aim of the present invention is to provide bifunctional compounds providing improved pharmacological activity towards kinases, in particular towards mutant kinases.

[0022] Another aim of certain embodiments of this invention is to provide cancer treatments. In particular, it is an aim of certain embodiments of this invention to provide bifunctional compounds which have comparable activity to existing cancer treatments but are also effective against kinase mutations.

[0023] 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.

[0024] 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).

[0025] Summary of the invention

[0026] The inventors have found that a bifunctional compound of Formula (I):

[0027] Targeting Macrocyclic Kinase Binder

[0028] Formula (I), 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 Macrocyclic Kinase Binder (TMKB) 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 said compound is in embodiments as further described below, provides improved kinase degradation.

[0029] The inventors have found that these bifunctional compounds of the invention, wherein the Targeting Macrocyclic Kinase Binder (TMKB) comprises a macrocyclic moiety, provides improved kinase degradation.

[0030] Aspects of the invention

[0031] In a first aspect of the invention is provided a bifunctional compound of of Formula (I):

[0032] Targeting Macrocyclic Kinase Binder

[0033] Formula (I), or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, wherein: the Targeting Ligase Binder (TLB) is a group that is capable of binding to a E3 ligase; the Targeting Macrocyclic Kinase Binder (TMKB) 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):

[0034] (TMKB l-d) (TMKB l-e) (TMKB l-f)

[0035] 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 R1is wherein :

[0036] 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;

[0037] V is selected from the group consisting of: a direct bond, O, -OCH2- , -CH(Riv)-, -C(O)-, -C(O)-N(R2v)-,

[0038] Riv is hydrogen or (1 -2C)alkyl;

[0039] R2V is hydrogen or (1-2C)alkyl;

[0040] Rsv is hydrogen or (1-2C)alkyl;

[0041] R4V is hydrogen or (1 -2C)alkyl; or

[0042] Rsv and R4V form together with the carbon atom they are attached to a (3-6C)cycloalkyl;

[0043] 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 R2is selected from the group consisting of Formula (TMKB 11-1 ) to (TMKB 11-13):

[0044] (TMKB 11-1) (TMKB II-2) (TMKB II-3)

[0045] (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 11-12), and Formula (TMKB 11-13) is a tertiary carbon atom (-CH-); wherein the denotes the point of attachment to the Linker (DL); wherein the marks the position of R2in any one of Formula (TMKB l-a) to (TMKB l-f); wherein R3and R4together represent a macrocycle linker having Formula (TMKB 111-1 to TMKB III-60) selected from the group consisting of:

[0046] (TMKB 111-1) (TMKB HI-2) (TMKB HI-3) (TMKBIII-4) (TMKBHI-5) (TMKBIH-6) (TMKB HI-7)

[0047] (TMKB HI-55) (TMKB HI-56) (TMKB HI-57) (TMKB HI-58) (TMKB HI-59) (TMKB IH-60) wherein the I * marks the position of R3in 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 R4of 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 R4of 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)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 in Formula (TMKB III-34) to (TMKB IH-60) is the connecting group X shown in Formula I; and wherein R5is hydrogen, NH2 or methyl.

[0048] In a second aspect of the invention is provided a compound according to the invention or a pharmaceutically acceptable salt thereof, for use as a medicament. In another aspect of the invention is provided a compound according to the invention or a pharmaceutically acceptable salt thereof, for use in therapy.

[0049] In another aspect of the invention is provided 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.

[0050] In another aspect of the invention is provided a compound of according to the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0051] In another aspect of the invention is provided a use of the compound according to the invention or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.

[0052] In another aspect of the invention is provided a pharmaceutical composition which comprises the compound according to the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0053] In another aspect of the invention is provided 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.

[0054] In another aspect of the invention is provided 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.

[0055] In another aspect of the invention is provided a method for treating a subject suffering with a "REarranged during Transfection" receptor tyrosine kinase (RET) mediated disorder comprising administering to the subject the compound of the invention in an amount effective to treat the RET mediated disorder.

[0056] In another aspect of the invention is provided 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.

[0057] In another aspect of the invention is provided 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.

[0058] Each of the sub-formulas 1-138 of the compounds of the invention is a preferred embodiment of the present application.

[0059] The present invention will be illustrated further by means of the following non-limiting examples.

[0060] Definitions

[0061] The term “pharmaceutical composition” as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.

[0062] The term “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. In the combination therapies of the present invention, 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.

[0063] A "subject" is a human or non-human mammal. In one embodiment, a subject is a human.

[0064] The term “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.

[0065] The term “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.

[0066] The term “salt” as used herein has its conventional meaning and includes the acid addition and base salts of the compound of the invention.

[0067] The term “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.

[0068] The term ’’treatment” as used herein has its conventional meaning and refers to curative, palliative and prophylactic treatment.

[0069] The term “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.

[0070] The term “BTK” as used herein has its conventional meaning and refers to Bruton’s Tyrosine Kinase. Bruton's tyrosine kinase (BTK) is a member of the 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. Targeting of BTK with small molecule inhibitors such as the FDA approved irreversible BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib has proven to be efficacious in several B cell malignancies including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Waldenstrom’s Macroglobulinemia (WM) and Small Lymphocytic Lymphoma SLL. Combinations of BTK inhibitors with other novel drugs or regimens results in more profound responses and much higher rates of minimal residual disease negativity.

[0071] The term ”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 .

[0072] The term “mutant-BTK” as used herein 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.

[0073] 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. Other mutations that can result in acquired resistance to both irreversible covalent and reversible non-covalent BTK inhibitors are BTK gatekeeper residue threonine 474 (T474) mutations, or other mutations such as C481 S, double mutation C481 S / T474I, V416L, and L528W, which can reduce BTK inhibitor binding to BTK.

[0074] The term “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.

[0075] The term “macrocycle” 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.

[0076] The term “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.

[0077] The term “DC50" as used herein has its conventional meaning and refers to the half-maximal degradation concentration that resulted in a 50% targeted protein degradation.

[0078] A bicyclic ringsystem, as used herein, 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.

[0079] As used herein, “spirocycloalkyl” or spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. 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. For example, a (C3-Ci2)spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.

[0080] As used herein, “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.

[0081] A monocylic ringsystem, as used herein, refers both to a heterocyclic (heterocyclyl) group, and to a cyclic group having carbon groups only, i.e. without hetero atoms, within the cycle.

[0082] A heterocyclic (heterocyclyl) group, as used herein, refers to both heteroaryl groups and heterocycloalkyl groups.

[0083] A heterobicyclic group, as used herein, refers to a bicyclic group having one or more heteroatoms, which is saturated, partially unsaturated or unsaturated.

[0084] As used herein, aromatic groups (or aryl groups) include aromatic carbocyclic ring systems (e.g. phenyl) and fused polycyclic aromatic ring systems (e.g. naphthyl and 1 ,2,3,4-tetrahydronaphthyl).

[0085] The term “heteroaryl”, as used herein, refers to an aryl group having one or more heteroatoms.

[0086] The term “alkyl,” as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms. In different embodiments, 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. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

[0087] Unless specified otherwise, “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(CH3)-CH2-B, A-CH2-CH(CH2CH3)-B, A-CH2- C(CH3)(CH3)-B, and the like. The term "alkylcarbonyl," as used herein, 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. In different embodiments, 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. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

[0088] 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.

[0089] 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.

[0090] 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. Examples of such 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.

[0091] For example, 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. Examples of “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.

[0092] 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.

[0093] 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-.

[0094] 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.

[0095] Unless otherwise specifically noted as only “unsubstituted” or only “substituted”, 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.

[0096] The terms first, second, third and the like in the description and in the claims, are used for distinguishing between for example similar elements, compositions, constituents in a composition, or separate method steps, and not necessarily for describing a sequential or chronological order. The terms are interchangeable under appropriate circumstances and the embodiments of the invention can operate in other sequences than described or illustrated herein, unless specified otherwise.

[0097] Furthermore, the various embodiments, although referred to as “preferred” or “e.g.” or “for example” or “in particular” and the like are to be construed as exemplary manners in which the invention may be implemented rather than as limiting the scope of the invention.

[0098] The term “comprising”, used in the claims, should not be interpreted as being restricted to for example the elements or the method steps or the constituents of a compositions listed thereafter; it does not exclude other elements or method steps or constituents in a certain composition. It needs to be interpreted as specifying the presence of the stated features, integers, (method) steps or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps or components, or groups thereof. Thus, the scope of the expression “a method comprising steps A and B” should not be limited to a method consisting only of steps A and B, rather with respect to the present invention, the only enumerated steps of the method are A and B, and further the claim should be interpreted as including equivalents of those method steps. Thus, the scope of the expression “a composition comprising components A and B” should not be limited to a composition consisting only of components A and B, rather with respect to the present invention, the only enumerated components of the composition are A and B, and further the claim should be interpreted as including equivalents of those components.

[0099] In addition, reference to an element or a component by the 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”.

[0100] Legend to the figures

[0101] Figure 1 :

[0102] (A) Stability of (mutant) BTK and phosphorylated-(Tyr223)BTK protein expression in wild-type BTK or in mutant BTK (BTK C481 S; BTK T474I; BTK C481 S / T474I) transfected GripTite 293 MSR cells cultured in DMEM / F-12, GlutaMAX™ supplemented with 1 % Penicillin / Streptomycin, 10% fetal bovine serum, 1x MEM Non-Essential Amino Acids, 50 pg / ml Geneticin and Blasticidin.

[0103] (B) BTK and phosphorylated-BTK protein levels in wildtype 293 (GripTite 293 MSR) cells compared to (non-IgM treated) RAMOS cells.

[0104] (C) Western blot detection of the expression of BTK and HiBiT tag after single cell cloning of transfected GripTite 293 MSR cells. All samples were analyzed on the same blot, thin vertical lines indicate digital removal of redundant samples. Numbers 1A2, 1 F5, 1 D10 indicate individual clones. Figure 2:

[0105] Western blot protein expression results of wt-BTK, BTK C481 S, BTK T474I BTK C481 S / T474I and BTK L528W expressing GripTite 293 MSR cells incubated with 0 to 31600 nM of Example 2;

[0106] Figure 3:

[0107] (A) Western blot detection of BTK degradation in TMD8 (harbouring wt-BTK) after incubation with 0 to 10000 nM of Example 2 and Example 10-14;

[0108] (B, A-C) Western blot detection of BTK degradation in TMD8 (harbouring wt-BTK) after incubation with 0-3160 nM of Examples 20, 66, 89, 93, 94 and 95.

[0109] Figure 4:

[0110] Western blot protein expression of LCK in HSB2 cells incubated with 100 nM of Example 4 for 24 h.

[0111] Figure 5:

[0112] Western blot detection of degradation of RET in the TT cell line after exposure to Examples 117 and 123. Thin vertical line in blot A indicates digital removal of redundant samples from the same blot.

[0113] Figure 6:

[0114] (A) Western blot detection of degradation of Exon 19 deleted EGFR in the HCC-827 cell line after exposure to Example 138 for 22 h.

[0115] (B) Quantification of the intensity of the western blot signal of EGFR in panel B, relative to the ACTB (p-actin) signal. The DMSO control was set to 100%.

[0116] Detailed description of the invention

[0117] 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. Surprisingly, the inventors have found that 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. The Targeting Macrocyclic Kinase Binder (TMKB) contains a macrocyclic moiety, which is able in combination with specific pharmacophores (e.g. based on ligands for binding to specific kinases) to provide a very potent binding activity towards the kinase, in particular through improved reversible binding. Additionally, the inventors have surprisingly found that bifunctional compounds of the invention provide an enhanced degrading activity towards mutant kinase forms, such as BTK mutant forms. In exemplary embodiments 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. Based on these findings, and based on the macrocyclic moiety effect on the kinase (BTK) targeted compounds of the invention, it is anticipated that binding activity and / or degrading activity to other kinase mutants is also enhanced. 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. By limiting the number of (bioactive) conformations available to the unbound molecule, there is a lower entropic cost when the molecule interacts with its target protein as compared to a non-macrocyclic compound. 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.

[0118] Improved kinase inhibition of novel macrocyclic compounds has been demonstrated in copending applications PCT / EP2021 / 085645, PCT / EP2021 / 085641 , PCT / EP2022 / 085765 and PCT / EP2022 / 085713, which show kinase binding activity and inhibiting properties of the novel macrocyclic compounds for several kinases, including mutants of these kinases, including showing increased target residence time of the novel macrocyclic compounds.

[0119] Now, the inventors have found that 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. Additionally, 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.

[0120] Embodiments or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, wherein: the Targeting Ligase Binder (TLB) is a group that is capable of binding to a E3 ligase; the Targeting Macrocyclic Kinase Binder (TMKB) 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, wherein said compound is in embodiments as further described below.

[0121] In a first aspect of the invention is provided a bifunctional compound of of Formula (I):

[0122] Targeting Macrocyclic Kinase Binder

[0123] Formula (I), or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, wherein: the Targeting Ligase Binder (TLB) is a group that is capable of binding to a E3 ligase; the Targeting Macrocyclic Kinase Binder (TMKB) 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, 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):

[0124] (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 R1is wherein :

[0125] 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;

[0126] V is selected from the group consisting of: a direct bond, O, -OCH2- , -CH(Riv)-, -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- ;

[0127] Riv is hydrogen or (1-2C)alkyl;

[0128] R2V is hydrogen or (1-2C)alkyl;

[0129] Rsv is hydrogen or (1-2C)alkyl;

[0130] R4V is hydrogen or (1 -2C)alkyl; or

[0131] Rav and R4V form together with the carbon atom they are attached to a (3-6C)cycloalkyl;

[0132] 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 R2is selected from the group consisting of Formula (TMKB 11-1 ) to (TMKB 11-13):

[0133] (TMKB 11-1)

[0134] (TMKB II-4) (TMKB 11-5) (TMKB II-6)

[0135] 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 11-12), and Formula (TMKB 11-13) is a tertiary carbon atom (-CH-); wherein the 1 denotes the point of attachment to the Linker (DL); wherein the marks the position of R2in any one of Formula (TMKB l-a) to (TMKB l-f); wherein R3and R4together represent a macrocycle linker having Formula (TMKB 111-1 to TMKB III-60) selected from the group consisting of:

[0136] (TMKB III-1) (TMKB HI-2) (TMKB HI-3) (TMKBIII-4) (TMKBIII-5) (TMKBIII-6) (TMKB 111-7)

[0137] (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 )

[0138] (TMKB HI-22) (TMKB HI-23) (TMKB HI-25) (TMKB IH-26) (TMKB III-27) (TMKB HI-28) (TMKB HI-29)

[0139] (TMKB HI-30) (TMKB HI-31 ) (TMKB 111-32) (TMKB 111-33)

[0140]

[0141] (TMKB HI-55) (TMKB HI-56) (TMKB HI-57) (TMKB HI-58) (TMKB HI-59) (TMKB IH-60)

[0142] Wherein the ~T~ * marks the position of R3in 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 R4of 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 R4of 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 alkoxy group is optionally and independently substituted with one, two or three halogen; wherein X in Formula (TMKB 111-34) to (TMKB 111-60) is the connecting group X shown in Formula (I); and wherein R5is hydrogen, NH2 or methyl.

[0143] Targeting Macrocyclic Kinase Binder (TMKB)

[0144] Bicyclic scaffold (A)

[0145] 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):

[0146] (TMKB l-d) (TMKB l-e) (TMKB l-f)

[0147] 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):

[0148] See for compounds having a bicyclic scaffold structure of Formula (TMKB l-a): WO 2013 / 010380, W02016 / 210165;

[0149] See for compounds having a bicyclic scaffold structure of Formula (TMKB l-b): Boga S B et al (2017) Bioorg Med Chem Lett, 27, 3939-3943; Liu J et al (2016) ACS Med Chem Lett, 6 198-203;

[0150] See for compounds having a bicyclic scaffold structure of Formula (TMKB l-c): WO 2013 / 010380;

[0151] See for compounds having a bicyclic scaffold structure of Formula (TMKB l-d): BBA - General Subjects 1864 (2020) 129531 ;

[0152] See for compounds having a bicyclic scaffold structure of Formula (TMKB l-e): WO 2015 / 058084, WO2015 / 095099, WO2015 / 095102;

[0153] See for compounds having a bicyclic scaffold structure of Formula (TMKB l-f): WO 20130 / 81016;

[0154] Furthermore a review showing that various scaffolds have been used in BTK inhibitor compounds is provided in: Yifan Feng, Weiming Duan, Xiaochuan Cu, Chengyuan Liang & Minhang Xin (2019) Bruton’s tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018), Expert Opinion on Therapeutic Patents, 29:4, 217-241 . All these prior art documents demonstrate that compounds providing BTK inhibition are found for each of the bicyclic scaffold structure according to any one of Formula (TMKB l-a) to (TMKB l-f).

[0155] 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.

[0156] In preferred embodiments, the compound comprises a bicyclic scaffold A selected from:

[0157] (TMKB l-a) (TMKB l-b)

[0158] Wherein R5is hydrogen, NH2 or methyl.

[0159] In preferred embodiments, the compound comprises a bicyclic scaffold A selected from:

[0160] (TMKB l-a1 ) (TMKB l-b1 )

[0161] (R1)

[0162] In an aspect of the invention R1of the compounds of the invention has the formula: wherein :

[0163] 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;

[0164] V is selected from the group consisting of: a direct bond, O, -OCH2- , -CH(Riv)-, -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- ;

[0165] Riv is hydrogen or (1 -2C)alkyl;

[0166] R2V is hydrogen or (1 -2C)alkyl;

[0167] Rsv is hydrogen or (1 -2C)alkyl;

[0168] R4V is hydrogen or (1-2C)alkyl; or

[0169] Rsv and R4V form together with the carbon atom they are attached to a (3-6C)cycloalkyl;

[0170] 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;

[0171] In an embodiment, R1is:

[0172] 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

[0173] V is a direct bond.

[0174] In a preferred embodiment, R1is: 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

[0175] 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. 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- .

[0176] In particular embodiments, V is any one of: -OCH2- , -C(0)-N(R2v)-, -N(R2v)-C(0)-,-NH-C(0)-NH-, -NH- C(O)-C(R3V)(R4V)-C(O)-NH-,

[0177] -NH-SO2-, -NH-C(O)-O-, -CH(Riv)-NH-C(O)- and -CH(Riv)-C(O)-NH-;

[0178] Riv is hydrogen or (1 -2C)alkyl;

[0179] R2V is hydrogen or (1 -2C)alkyl;

[0180] R3V is hydrogen or (1 -2C)alkyl;

[0181] R4V is hydrogen or (1-2C)alkyl; or

[0182] R3Vand R4V form together with the carbon atom they are attached to a (3-6C)cycloalkyl.

[0183] In more preferred embodiments, 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

[0184] 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. In another preferred embodiment, R1is:

[0185] , wherein:

[0186] R1wis 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

[0187] 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.

[0188] In particular embodiments, R1is:

[0189] , wherein : wherein R1wis 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

[0190] V is a direct bond.

[0191] In another preferred embodiment, R1is:

[0192] , wherein:

[0193] W is a direct bond; and

[0194] 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. In another preferred embodiment, R1is:

[0195] , wherein :

[0196] W is a direct bond, and

[0197] 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.

[0198] In other preferred embodiments, R1is selected from the group consisting of:

[0199] R1wand R2ware 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;

[0200] V is any one of O, -C(O)-NH-, -NH-C(O)-, -CH(R1v)-NH-C(O)-, -CH(R1v)- ;

[0201] R1vis hydrogen or (1 -2C)alkyl; and

[0202] 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. In particular embodiments, R1is selected from the group consisting of: wherein:

[0203] R1wand R2ware 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;

[0204] V is any one of O, -C(O)-NH-, -NH-C(O)-, -CH(R1v)-NH-C(O)-, -CH(R1v)- ;

[0205] R1vis hydrogen or (1 -2C)alkyl; wherein R1uand R2uare 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 Xuis selected from CH and N.

[0206] In particular embodiments, V is any one of O, -C(O)-NH-, -CH(R1v)-NH-C(O)-, and -CH(R1v)-; wherein R1vis hydrogen or (1 -2C)alkyl.

[0207] In more preferred embodiments, R1is selected from the group consisting of: wherein R1wand R2ware 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 R1uand R2uare 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 Xuis selected from CH and N.

[0208] In even more preferred embodiments, R1is selected from the group consisting of: wherein R2wis 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 R3uis 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.

[0209] In most preferred embodiments, R1is: wherein R2wis selected from hydrogen, fluoro, methyl or methoxy; wherein R3uis 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.

[0210] (R2)

[0211] In an aspect of the invention the R2of the compounds is selected from the group consisting of Formula

[0212] (TMKB 11-1 ) to (TMKB 11-13):

[0213] (TMKB 11-1) (TMKB il-2) (TMKB il-3)

[0214] (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 11-12), and Formula (TMKB 11-13) is a tertiary carbon atom (-CH-); wherein the denotes the point of attachment to the Linker (DL); and wherein the marks the position of R2in any one of Formula (TMKB l-a) to (TMKB l-f).

[0215] Thus, in embodiments, in particular according to Formula (TMKB II-7) to (TMKB 11-13), R2comprises the connecting group X, which is shown in Formula (I).

[0216] 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-).

[0217] In embodiments, R2is selected from the group consisting of:

[0218] (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 R2in any one of Formula (TMKB l-a) to (TMKB l-f).

[0219] In preferred embodiments, R2is selected from the group consisting of:

[0220] (TMKB 11-1 b) (TMBK ll-1c) (TMKB ll-2b) (TMKB ll-3b)

[0221]

[0222] (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 R2in any one of Formula (TMKB l-a) to (TMKB l-f).

[0223] (Macrocycle linker represented by R3and R4)

[0224] Each of the compounds of the invention comprises the macrocycle linker (L) represented by R3and R4. In preferred embodiments, the macrocycle linker represented by R3and R4is 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.

[0225] In the given Formulas of the linkers, having Formula (111-1 ) to (HI-60): the ~T~ * (i.e. the wavy with a star) marks the position of R3in any one of Formula (TMKB l-a) to (TMKB l-f); the I (i.e. the wavy without a star) in any one of Formula (TMKB 111-1 ) to Formula (TMKB ill-33) marks the position of R4of any one of Formula (TMKB II-7) to (TMKB 11-13); the (i.e. the wavy without a star) in any one of Formula (TMKB III-34) to Formula (TMKB HI-60) marks the position of R4of any one of Formula (TMKB

[0226] 11-1) to (TMKB II-6); and the (i.e. the wavy with a hashtag) marks the point of attachment to the Linker (DL).

[0227] Thus, 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 "T™ * (i.e. the wavy with a star).

[0228] The macrocycle of the Targeting Macrocyclic Kinase Binder (TMKB) is formed by the connections between the macrocycle linker, R2and the bicyclic scaffold A of Formula (TMKB l-a) to (TMKB l-f). R2is directly connected to the macrocycle linker at the position of R4. 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 R3. In embodiments, 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.

[0229] In embodiments, in particular according to any one of Formulas (TMKB III-34) to (TMKB HI-60), 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).

[0230] In preferred embodiments, 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-).

[0231] In an embodiment, the macrocycle linker represented by R3and R4is selected from the group consisting of:

[0232] (TMKB HI-9) (TMKB 111-10) (TMKB HI-11 ) (TMKB 111-12) (TMKB 111-13) (TMKB 111-14)

[0233] (TMKB HI-15) (TMKB 111-16) (TMKB HI-17) (TMKB 111-18) (TMKB 111-19) (TMKB HI-20) (TMKB HI-21 )

[0234] (TMKB III-49C) (TMKB III-50C) (TMKB 111-51 C) (TMKB III-52C) (TMKB III-53C) (TMKB III-54C)

[0235] (TMKB HI-55C) (TMKB HI-56C) (TMKB HI-57C) (TMKB HI-58N) (TMKB HI-59C) (TMKB HI-60C) wherein the ~T" * marks the position of R3in 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 R4of 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 R4of any one of Formula (TMKB 11-1 ) to (TMKB II-6); and

[0236] # 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 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).

[0237] In a particular embodiment, the in 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 R4of any one of Formula (TMKB 11-1 ) to (TMKB II-6).

[0238] We note that in any of the Formula (TMKB III-36C), (TMKB III-40C), (TMKB III-49C), (TMKB III-50C), (TMKB 111-51 C), (TMKB III-52C), (TMKB III-53C), (TMKB III-54C), (TMKB III-55C), (TMKB III-56C), (TMKB III-57C), (TMKB lll-59C),(TMKB III-60C) the connecting group (X) is a tertiary carbon atom (-CH-) as indicated in the Formula, while in Formula (TMKB III-58N) the connecting group (X) is a tertiary amine atom (N) as indicated in the Formula.

[0239] In a preferred embodiment, the macrocycle linker represented by R3and R4is selected from the group consisting of:

[0240] (TMKB 111-1) (TMKB HI-2) (TMKB HI-3) (TMKBIII-4) (TMKBIII-5) (TMKBIH-6)

[0241] (TMKB HI-42) (TMKB IH-49C) (TMKB III-50C) (TMKB HI-51 C) (TMKB III-52C) (TMKB III-53C)

[0242] (TMKB III-55C) (TMKB III-56C) (TMKB III-57C) (TMKB III-58N) (TMKB III-59C) (TMKB III-60C) wherein the '~T~ * marks the position of R3in any one of Formula (TMKB l-a) to (TMKB l-f); wherein the in any one of Formula (TMKB 111-1 ) to Formula (TMKB III-33) marks the position of R4of any one of Formula (TMKB II-7) to (TMKB 11-13); and wherein the in any one of Formula (TMKB III-35) to Formula (TMKB III-60C) marks the position of R4of 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 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).

[0243] In a particular embodiment, 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 R4of any one of Formula (TMKB 11-7) to (TMKB 11-13).

[0244] In a particular embodiment, 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 R4of any one of Formula (TMKB 11-1 ) to (TMKB II-6).

[0245] In a more preferred embodiment, the macrocycle linker represented by R3and R4is selected from the group consisting of:

[0246] (TMKB HI-35) (TMKB IH-36C) (TMKB 111-38) (TMKB HI-39) (TMKB III-40C) (TMKB 111-41 ) wherein the ”~1 * marks the position of R3in 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 R4of any one of Formula (TMKB II-7) to (TMKB 11-13); and wherein the in any one of Formula (TMKB III-35) to Formula (TMKB III-58N) marks the position of R4of 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, hydroxy, amino, CD3, (1 -2C)alkyl, (1-2C)alkoxy, (3- 6C)cycloalkyl or (3-6C)cycloalkoxy; 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).

[0247] In a particular embodiment, 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 R4of any one of Formula (TMKB 11-7) to (TMKB 11-13).

[0248] In a particular embodiment, 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 R4of any one of Formula (TMKB 11-1 ) to (TMKB II-6).

[0249] In preferred embodiments, 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.

[0250] In preferred embodiments, a secondary amine group of the macrocycle linker represented by R3and R4is substituted by (1-6C)alkylcarbonyl, preferably by methylcarbonyl or ethylcarbonyl. In examples, 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.

[0251] In preferred embodiments, a carbon group of the macrocycle linker represented by R3and R4is substituted by (1 -4)alkyl, preferably by methyl or ethyl, thereby providing a tertiary carbon group.

[0252] Connecting group (X)

[0253] X is a connecting group of the Targeting Macrocyclic Kinase Binder (TMKB), which covalently connects the Targeting Macrocyclic Kinase Binder to the Linker (DL). In preferred embodiments, X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N). In more preferred embodiments, X is a tertiary amine atom (N).

[0254] The Targeting Macrocyclic Kinase Binder (TMKB) 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 R3and R4, in particular according to any one of Formula (TMKB III-34) to (TMKB HI-60). Alternatively, the connecting group may in embodiments be provided in the R2moiety, in particular according to any one of Formula (TMKB II-7) to (TMKB 11-13).

[0255] Linker (DL)

[0256] 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.

[0257] In embodiments, 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:

[0258] L1is independently selected from the group consisting of: a direct bond, -N(RL1)-, -O-, -C(O)-N(RL1)-, - N(RL1)-C(O)-, -N(RL1)-C(O)-O-, -C(O)-, -CEC-, -C=C-, (1-4C)alkyl, (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 or (1 -3C)alkyl; each RL1is independently -H or (1-4C)alkyl;

[0259] L2is independently selected from the group consisting of: a direct bond, -N(RL2)-, -O-, (1 -4C)alkyl, - CH2-CH2-N(RL2)-, -(CH2-CH2-O)m-, -(CH2-CH2-CH2-O)m-, -(O-CH2-CH2)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; each RL2is independently -H or (1 -4C)alkyl;

[0260] L3is independently selected from the group consisting of: a direct bond, (1 -8C)alkyl, -CHC-, -N(RL3)-, -O-, -N(RL3)-C(O)-, -C(O)-N(RL3)-, -C(O)-, -(O-CH2-CH2)n-, -(CH2-CH2-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 RL3is independently -H or (1-4C)alkyl;

[0261] L4is independently selected from the group consisting of: a direct bond, (1 -4C)alkyl , -N(RL4), -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 RL4is independently -H or (1- 4C)alkyl;

[0262] L5is independently selected from the group consisting of: a direct bond, -N(RL5)-, -N(RL5)-C(O)-, - C(O)-, (1 -4C)alkyl, -(O-CH2-CH2)q- and -(O-CH2-CH2-CH2)q-; each RL5is independently -H or (1- 4C)alkyl; each m, n, p and q is independently an integer from 1 to 3.

[0263] Thus, the linker (DL) is connected to the Targeting Ligase Binder (TLB) at Li and is connected to the Targeting Macrocyclic Kinase Binder (TMKB) at Ls.

[0264] In preferred embodiments, Li is selected from the group consisting of: a direct bond, -N(RL1)-, -O-, - C(O)-N(RL1)-, -N(RL1)-C(O)-, -C(O)-, -CHC-; each RL1is independently -H or methyl.

[0265] In preferred embodiments, L2is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -CH2- CH2-N(RL2)-, -(CH2-CH2-O)m-, -(CH2-CH2-CH2-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; each RL2is independently -H or methyl; m is an integer from 1 to 2.

[0266] In preferred embodiments, L3 is selected from the group consisting of: a direct bond, (1 -8C)alkyl, - N(RL3)-, -O-, -N(RL3)-C(O)-, -C(O)-N(RL3)-, -C(O)-, -(O-CH2-CH2)n-, -(CH2-CH2-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 RL3is independently -H or methyl; n is an integer from 1 to 2. In preferred embodiments, 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.

[0267] In preferred embodiments, Ls is selected from the group consisting of: a direct bond, -N(RL5)-, -N(RL5)- C(O)-, -C(O)-, ( 1 -4C)alkyl, -(O-CH2-CH2)qand -(O-CH2-CH2-CH2)q; each RL5is independently -H or methyl; q is independently an integer from 1 to 2.

[0268] In more preferred embodiments, Li is selected from the group consisting of: a direct bond, -NH-, -0-, - C(O)-NH-, -NH-C(O)-, -C(0)-, -CEC-.

[0269] In more preferred embodiments, 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.

[0270] In more preferred embodiments, L3 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -N(RL3)-, -O-, -N(RL3)-C(O)-, -C(O)-N(RL3)-, -C(O)-, -(O-CH2-CH2)n-, -(CH2-CH2-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 RL3is independently -H or methyl; n is an integer from 1 to 2.

[0271] In more preferred embodiments, l_4 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -N(RL4), -C(O)-, -(O-CH2-CH2)P-, -(CH2-CH2-O)P-,

[0272] 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 RL4is independently hydrogen or methyl; p is an integer from 1 to 2.

[0273] In more preferred embodiments, Ls is selected from the group consisting of: a direct bond, -N(RL5)-, - N(RL5)-C(O)-, -C(O)- and (1 -4C)alkyl; each RL5is independently hydrogen or methyl.

[0274] In even more preferred embodiments, 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

[0275] Targeting Ligase Binder (TLB) in case Li is a direct bond; and wherein the marks the point of attachment to the connecting group X; and wherein each RLis hydrogen or methyl; and wherein s is an integer from 0 to 5; and wherein t is an integer from 0 to 6.

[0276] In preferred embodiments, Li is a direct bond, and the marks the point of attachment to the

[0277] Targeting Ligase Binder (TLB).

[0278] In even more preferred embodiments, Linker (DL) is selected from the group consisting of:

[0279]

[0280] #

[0281] Wherein the marks the point of attachment to the Targeting Ligase Binder (TLB); and wherein the T~ marks the point of attachment to the connecting group X; and wherein s is an integer from 0 to 3.

[0282] Targeting Ligase Binder (TLB)

[0283] The Targeting Ligase Binder (TLB) is a group that is capable of binding to a E3 ligase.

[0284] Many groups are known to be capable of binding to a E3 ligase.

[0285] Inspired by UPS, researchers designed heterobifunctional compounds (HBC) to hijack the UPS and degrade a protein of interest (POI). 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. 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. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev. Drug. Discov. (2017) 16, 101-114). Recent HBC developments have mainly been focused on three E3 ligases, i.e. Von-Hippel-Lindau (VHL), inhibitors of apoptosis proteins (lAPs) and Cereblon (CRBN).

[0286] In embodiments, the Targeting Ligase Binder (TLB) is any one of:

[0287] wherein the marks the position of DL or L1of DL; wherein, each RTLB1is 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 CF3; t is the number of R(TLB1 ) substituents and is independently an integer from 0 to 2; each RTLB4is independently hydrogen, (1 -4C)alkyl or (1-3C)alkoxy; each RTLB5is independently hydrogen, halo, cyano or (1 -3C)alkyl;

[0288] Z is -C(RTLB6)2or -C(O)-; each RTLB6is independently hydrogen or (1 -4C)alkyl;

[0289] Z’ is a bond, -C(O)- or -CH2C(O)-;

[0290] Z” is -CH2- or -NH-;

[0291] HAr is a (1-9C)heteroaryl optionally substituted with fluoro, methyl or methoxy; and heterocyclic ring D is selected from:

[0292] In the context of the invention R(TLB1 ) and RTLB1refer to the same substituents. In the context of the invention R(TLB4) and RTLB4refer to the same substituents. In the context of the invention R(TLB5) and RTLB5refer to the same substituents.

[0293] In preferred embodiments, the Targeting Ligase Binder (TLB) is selected from the group consisting of:

[0294] wherein the marks the position of the Linker (DL) or L1of the Linker (DL); and wherein each RTLB5is independently hydrogen, fluoro or cyano;

[0295] HAr is a (1-9C)heteroaryl optionally substituted with fluoro, methyl or methoxy.

[0296] In the context of the invention R(TLB5) and RTLB5refer to the same substituents.

[0297] In more preferred embodiments, the Targeting Ligase Binder (TLB) is selected from the group consisting of:

[0298] wherein the T~ marks the position of Linker (DL) or L1of the Linker (DL).

[0299] In even more preferred embodiments, the Targeting Ligase Binder (TLB) is selected from the group consisting of: wherein the marks the position of Linker (DL) or L1of the Linker (DL). Specific Targeting Macrocyclic Kinase Binder (TMKB)

[0300] In preferred embodiments, the Targeting Macrocyclic Kinase Binder (TMKB) is selected from the group consisting of:

[0301] Wherein X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N). Note that in the following specific Targeting Macrocyclic Kinase Binder (TMKB), the connecting group is a tertiary amine atom (N):

[0302] Novel degraders containing novel Targeting Ligase Binder (TLB), which is a group that is capable of binding to a E3 ligase

[0303] In another aspect of the invention (according to clause 1) bifunctional compounds are provided of Formula (TLB-A):

[0304] 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:

[0305] Said compound according to of Formula (TLB-A) in embodiments contains parts and / or substituents as further described throughout the application as filed.

[0306] The following clauses represent further embodiments of the bifunctional compounds of Formula (TLB- A):

[0307] Clause 2. Compound according to Formula (TLB-A), wherein the Targeting Ligase Binder (TLB) is selected from the group consisting of:

[0308] wherein the marks the position of Linker (DL).

[0309] Clause 3. The bifunctional compound of Formula (TLB-A) or any one of clauses 1 - 2, wherein the Linker (DL) is -L1-L2-L3-L4-L5- , wherein:

[0310] L1is independently selected from the group consisting of: a direct bond, -N(RL1)-, -O-, -C(O)-N(RL1)-, - N(RL1)-C(O)-, -N(RL1)-C(O)-O-, -C(O)-, -C=C-, -C=C-, (1-4C)alkyl, (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 or (1 -3C)alkyl; each RL1is independently -H or (1-4C)alkyl;

[0311] L2is independently selected from the group consisting of: a direct bond, -N(RL2)-, -O-, (1 -4C)alkyl, - CH2-CH2-N(RL2)-, -(CH2-CH2-O)m-, -(CH2-CH2-CH2-O)m-, -(O-CH2-CH2)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; each RL2is independently -H or (1 -4C)alkyl;

[0312] L3is independently selected from the group consisting of: a direct bond, (1 -8C)alkyl, -C=C-, -N(RL3)-, -O-, -N(RL3)-C(O)-, -C(O)-N(RL3)-, -C(O)-, -(O-CH2-CH2)n-, -(CH2-CH2-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 RL3is independently -H or (1-4C)alkyl;

[0313] L4is independently selected from the group consisting of: a direct bond, (1 -4C)alkyl , -N(RL4), -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 RL4is independently -H or (1-4C)alkyl;

[0314] L5is independently selected from the group consisting of: a direct bond, -N(RL5)-, -N(RL5)-C(O)-, - C(O)-, (1 -4C)alkyl, -(O-CH2-CH2)q- and -(O-CH2-CH2-CH2)q-; each RL5is independently -H or (1- 4C)alkyl; each m, n, p and q is independently an integer from 1 to 3.

[0315] Clause 4. Compound according to Formula (TLB-A) or any one of clauses 1 - 3, wherein the Targeting Protein Binder (TPB) is a binder that is capable of binding to a target protein kinase.

[0316] Clause 5. Compound according to Formula (TLB-A) or clause 4, wherein the Targeting Protein Binder (TKB) is a Targeting Macrocyclic Kinase Binder (TMKB) according to the invention, which is a group that is capable of binding to a target protein kinase.

[0317] Clause 6. Compound according to Formula (TLB-A) or clause 5, wherein the compound has a subformula selected from the group consisting of:

[0318] Clause 7. Compound according to Formula (TLB-A) or the preceding clauses a pharmaceutically acceptable salt thereof, for use as a medicament.

[0319] Clause 8. Compound according to Formula (TLB-A) or any of the clauses 1 - 5 or a pharmaceutically acceptable salt thereof, for use in therapy.

[0320] Clause 9. Compound according to Formula (TLB-A) or any of the clauses 1 - 5 or a pharmaceutically acceptable salt thereof, for use in the treatment of Bruton's Tyrosine Kinase (BTK) mediated disorders.

[0321] Clause 10. Compound according to Formula (TLB-A) or any of the clauses 1 - 5 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0322] Clause 11 . Use of the compound according to Formula (TLB-A) or any of the clauses 1 - 5 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.

[0323] Clause 12. 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.

[0324] Clause 13. The pharmaceutical composition of Formula (TLB-A) or clause 11 , which further comprises at least one additional therapeutically active agent.

[0325] Clause 14. A method for treating of cancer in a subject in need thereof comprising administering to the subject the compound according to Formula (TLB-A) or any of the clauses 1 - 5 or a pharmaceutically acceptable salt thereof in an amount effective to treat cancer. In preferred embodiments of the invention, the Targeting Macrocyclic Kinase Binder (TMKB) is selected from the group consisting of: Specific bifunctional compounds

[0326] In preferred embodiments, the bifunctional compound has a sub-formula (1 - 138) selected from the group consisting of:

[0327]

[0328]

[0329]

[0330] 19 20

[0331]

[0332]

[0333]

[0334] 37 38

[0335]

[0336]

[0337]

[0338]

[0339] 109

[0340]

[0341]

[0342]

[0343] In preferred embodiments, 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).

[0344] In preferred embodiments, 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).

[0345] In preferred embodiments, 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).

[0346] In preferred embodiments, 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).

[0347] In preferred embodiments, 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).

[0348] In a preferred embodiment, 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).

[0349] In a preferred embodiment, 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).

[0350] In a preferred embodiment, 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).

[0351] Pharmaceutical composition

[0352] Pharmaceutical 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.

[0353] As used herein, “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. Preferably, 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.

[0354] Furthermore, the 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. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0355] As used herein, the term “pharmaceutical 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.

[0356] The compositions of the invention may thus comprise one or more additional ingredients. In a preferred embodiment, the composition comprises one or more carriers and / or excipients. As is known by those of average skill in the art, 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. It is within the purview of those of average skill in the art to conceive and develop suitable formulations, relying on the common general knowledge as reflected in text books such as Remington’s Pharmaceutical Sciences (Meade Publishing Co., Easton, Pa., 20.sup.th Ed., 2000), the entire disclosure of which is herein incorporated by reference, and routine development efforts.

[0357] In accordance with the various aspects of the invention, the composition is preferably provided in a unit dosage form. The term ‘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. In accordance with particularly preferred embodiments of the invention, 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.

[0358] Besides the compound according to the invention as such, pharmaceutically acceptable salts thereof may also be used. 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. For a review on suitable salts, reference is made “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0359] Pharmaceutically acceptable 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.

[0360] Medical use

[0361] The compounds and the pharmaceutical compositions of the present invention are useful as degraders of kinases, in particular tyrosine kinases. In particular, 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.

[0362] 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. 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.

[0363] 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;

[0364] (4) 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. precursor 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.

[0365] (5) diabetes, including Type I diabetes and complications from diabetes; (6) 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’s disease and / or ulcerative colitis, inflammatory bowel disease, coeliac diseases, proctitis, eosinophilic gastroenteritis, and mastocytosis; (8) neurodegenerative diseases including motor neuron disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, glutamate neurotoxicity or hypoxia; ischemic / reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia; (9) platelet aggregation and diseases associated with or caused by platelet activation, such as arteriosclerosis, thrombosis, intimal hyperplasia and restenosis following vascular injury; (10) conditions associated with cardiovascular diseases.

[0366] For the treatment of cancer a compound of the invention may be combined with one or more of an anticancer agents. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Heilman (editors), 6thedition (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.

[0367] BTK degradation

[0368] 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.

[0369] In embodiments the 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 lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’s disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto’s thyroiditis, Ord’s thyroiditis, Graves’disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barr syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture’s syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter’s syndrome, Takayasu’s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener’s granulomatosis, psoriasis, alopecia universalis, Behcet’s disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, vulvodynia, graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vulvitis, 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. In some embodiments, 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), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephrosis (PGN), endothelial / thrombotic microangiopathy injury, HIV-associated nephropathy, or fibrosis associated with exposure to a toxin, an irritant, or a chemotherapeutic agent, fibrosis associated with scleroderma, radiation induced gut fibrosis, fibrosis associated with a foregut inflammatory disorder such as Barrett’s esophagus and chronic gastritis, and / or fibrosis associated with a hindgut inflammatory disorder, such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn’s disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma.

[0370] In embodiments the 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.

[0371] 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 granulomatosis are examples of cancer, lymphoma and leukemia treatable by BTK degradation.

[0372] 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.

[0373] Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn’s disease, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’s disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto’s thyroiditis, Ord’s thyroiditis, Graves’ disease, Sjogren’s syndrome, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture’s syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter’s syndrome, Takayasu’s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener’s granulomatosis, psoriasis, alopecia universalis, Behcet’s disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, vulvodynia, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis are examples of immunological diseases treatable by BTK degradation.

[0374] Arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis are examples of an inflammatory disorder treatable by BTK degradation.

[0375] Lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord’s thyroiditis, Graves' disease, Sjogren’s syndrome, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture’s syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter’s syndrome, Takayasu’s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet’s disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia are examples of an autoimmune disease treatable by BTK degradation.

[0376] 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.

[0377] 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. In some embodiments, 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), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephrosis (PGN), endothelial / thrombotic microangiopathy injury, HIV-associated nephropathy, or fibrosis associated with exposure to a toxin, an irritant, or a chemotherapeutic agent, fibrosis associated with scleroderma, radiation induced gut fibrosis, fibrosis associated with a foregut inflammatory disorder such as Barrett's esophagus and chronic gastritis, and / or fibrosis associated with a hindgut inflammatory disorder, such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn’s disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma are examples of fibrosis treatable by BTK degradation. 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.

[0378] 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.

[0379] LCK - degradation

[0380] Known Lymphocyte-Specific Protein Tyrosine Kinase (LCK) mediated disorders include cancer, an inflammatory disease, an autoimmune disease or an pathogenic infection.

[0381] In embodiments, the compounds of the invention or a pharmaceutically acceptable salt thereof, in particular are used for treating Lymphocyte-Specific Protein Tyrosine Kinase (LCK) mediated disorders, in particular for use in the treatment of:

[0382] (i) 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;

[0383] (ii) 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.

[0384] EGFR - degradation

[0385] Known Epidermal Growth Factor Receptor (EGFR) mediated disorders include cancer.

[0386] In embodiments, the compounds of the invention or a pharmaceutically acceptable salt thereof, in particular 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. Alternatively, the compounds may be used to treat inflammatory diseases caused or aggravated on a molecular level by activity of EGFR or its ligands.

[0387] RET- degradation

[0388] Known "REarranged during Transfection" receptor tyrosine kinase (RET) mediated disorders include cancers.

[0389] In embodiments, the compounds of the invention or a pharmaceutically acceptable salt thereof, in particular 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. In other embodiments, 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.

[0390] Routes of administration

[0391] 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.

[0392] Alternatively, one may administer the compound in a local rather than a systemic manner, for example, via injection of the compound directly into an edematous site, often in a depot or sustained release formulation.

[0393] Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with endothelial cell-specific antibody.

[0394] Composition / Formulation

[0395] The pharmaceutical 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.

[0396] Pharmaceutical 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. For injection, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0397] For oral administration, 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.

[0398] Pharmaceutical preparations 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). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0399] Dragee cores are provided with 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.

[0400] Pharmaceutical preparations 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. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0401] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0402] For administration by inhalation, 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. In the case of pressurized aerosol 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.

[0403] 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.

[0404] Pharmaceutical formulations 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.

[0405] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0406] 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.

[0407] In addition to the formulations described previously, 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). Thus, for example, 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.

[0408] Synthesis of the compounds

[0409] 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 Chemistry14thEdition, 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’ 3rdEdition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.

[0410] 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.

[0411] Compounds of any one of Formula TMKB l-a to TMKB l-f, wherein R1to R5and W, V and U, Linker (DL) and Target Ligase Binder (TLB) have the previously defined meanings, can be prepared by the general synthetic route shown in any one of scheme I - VI.

[0412] Scheme I and II show a general synthetic route in relation to an exemplary compound of

[0413] Formula TMKB l-a.

[0414] Scheme I 4-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine II can be prepared from commercially available 4- chloro-1 / - / -pyrazolo[4,3-c]pyridine using A / -iodosuccinimide in a solvent such as DMF at elevated temperatures. The resulting product can then be reacted with 2,4-dimethoxybenzylamine in an appropriate solvent like n-butanol, isopropanol or 2-pentanol at high temperatures to obtain A / -[(2,4- dimethoxyphenyl)methyl]-3-iodo-1 H-pyrazolo[4,3-c]pyridin-4-amine III. 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. 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.

[0415]

[0416] Scheme II Compounds of Formula VIII can be prepared from derivatives VII using diphenylphosphorylazide in toluene or THF and a suitable alcohol such as trimethylsilylethanol, benzylalcohol or tert-butanol. Subsequent halogenation 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 IX. 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. 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 carboxyl acid deprotection using a suitable inorganic base like lithium hydroxide or sodium hydroxide. 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. 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. 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.

[0417] Alternatively compounds of Formula TMKB l-a to TMKB l-f, wherein R1to R5and W, V and U, Linker (DL) and Target Ligase Binder (TLB) have the previously defined meanings, can be prepared by the general synthetic route shown in scheme III. Scheme III shows a general synthetic route in relation to an exemplary compound of Formula TMKB l-a.

[0418] Scheme III

[0419] 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. 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. Subsequent coupling 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)3or NaBH(t-BuO)3.

[0420] Another route to obtain compounds of Formula TMKB l-a to TMKB l-f, wherein R1to R5and W,

[0421] V and U, Linker (DL) and Target Ligase Binder (TLB) have the previously defined meanings, is depicted in the general synthetic route shown in scheme IV. Scheme IV shows a general synthetic route in relation to an exemplary compound of Formula TMKB l-a.

[0422] Scheme IV

[0423] 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. Alternatively 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. Subsequent 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. 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. Subsequent coupling 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)3or NaBH(t-BuO)3.

[0424] Yet another route to obtain compounds of Formula TMKB l-a to TMKB l-f, wherein R1to R5and W, V and U, Linker (DL) and Target Ligase Binder (TLB) have the previously defined meanings, is depicted in the general synthetic route shown in scheme V. Scheme V shows a general synthetic route in relation to an exemplary compound of Formula TMKB l-a.

[0425]

[0426] Scheme V

[0427] 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. Alternatively, 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. Subsequent 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. 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. Subsequent coupling of 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.

[0428] Alternatively compounds of Formula TMKB l-a to TMKB l-f, wherein R1to R5and W, V and U, Linker (DL) and Target Ligase Binder (TLB) have the previously defined meanings, can be prepared by the general synthetic route shown in scheme VI. Scheme VI shows a general synthetic route in relation to an exemplary compound of Formula TMKB l-b.

[0429]

[0430] Scheme VI 3-Amino-6-bromo-pyrazine-2-carbonitrile (XXIX) can be prepared from commercial available 2- amino-3,5-dibromo pyrazine (XXVIII) using copper cyanide and sodium cyanide in DMF at elevated temperature. The resulting product can then be converted to 6-bromo-3-chloro-pyrazine-2-carbonitrile (XXX) under Sandmeyer conditions with copper chloride, tert-butyl nitrite in an appropriate solvent such as acetonitrile under heating. 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). This can then be reacted with an appropriately amine protected amino acid (XXXII) in a solvent such as DMF, THF or DCM in the presence of a base such as DIPEA, N-methylmorpholine, 4-DMAP or triethylamine and in the presence of a coupling reagent such as PyBOP, TBTU, EDCI or HATU to form compounds of Formula XXXIII. 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. Subsequent bromination can be accomplished using bromine or A / -bromosuccinimide in a suitable solvent like DCM or DMF at appropriate temperature to obtain compounds of Formula XXXVI. 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 dioxane and water. 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. Subsequent coupling of 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)3or NaBH(t-BuO)3.

[0431] The invention is illustrated by the following examples.

[0432] The following examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way. Reagents are either commercially available or are prepared according to procedures known in the literature.

[0433] Method LCMS (A)

[0434] LC-MS system equipped with a Waters 2998 Photodiode Array Detector, Waters Acquity QDa Detector, Waters 2767 autosampler and Waters 2545 binary gradient module was used for sample analyses with a XTerra ® MS C18 column (2.5 pm, 4.6 x 50 mm) for 10 min measurements.

[0435] 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).

[0436] Method LCMS (A): 95% A to 95% B in 7 min, then 95% A.

[0437] Method LCMS (B)

[0438] LC-MS system equipped with a Waters 2998 Photodiode Array Detector, Waters Acquity QDa Detector, Waters 2767 autosampler and Waters 2545 binary gradient module was used for sample analyses with a XTerra ® MS C18 column (2.5 pm, 4.6 x 50 mm) for 30 min measurements.

[0439] 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).

[0440] Method LCMS (B): 95% A to 95% B in 22 min, then switched to 95% A.

[0441] Method Preparative HPLC

[0442] LC-MS system equipped with a Waters 2998 Photodiode Array Detector, Waters Acquity QDa Detector, Waters 2767 autosampler and Waters 2545 binary gradient module was used for Preparative reversed phase chromatography with a Luna ® 5 pm C18(2) 100 A (150 x 21 mm).

[0443] 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).

[0444] The following abbreviations are used throughout the application with respect to chemical terminology:

[0445] TFA Trifluoracetic acid

[0446] HATU O-(7-Azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluroniumhexafluorophosphate

[0447] DMF A / ,A / -Dimethylformamide

[0448] THF Tetra hydrofuran

[0449] DCM Dichloromethane

[0450] TMS-CI Chlorotrimethylsilane

[0451] DiPEA A / ,A / -Diisopropylethylamine HPLC High Performance Liquid Chromatography

[0452] LCMS Liquid Chromatography with Mass Spectrometry detection

[0453] 4-DMAP 4-Dimethylamino pyridine

[0454] Boc tert-Butyloxycarbonyl

[0455] Cbz Benzyloxycarbonyl

[0456] LiHMDS Lithium bis(trimethylsilyl)amide

[0457] DBU 1 ,8-Diazabicyclo[5.4.0]undec-7-ene

[0458] DEAD Diethyl azodicarboxylate o / n Overnight

[0459] Pd(dppf)Ch 1 ,1'-bis(diphenylphosphino)ferrocene palladium(ll) chloride

[0460] AIBN Azobisisobutyronitril

[0461] ZrCp2(H)CI zirconocene hydrochloride (Schwartz Reagent)

[0462] 1H-NMR Proton nuclear magnetic resonance

[0463] BOC2O Di-tert-butyl decarbonate

[0464] DPPA Diphenylphosphoryl azide

[0465] T3P Propylphosphonic anhydride

[0466] NIS A / -lodosuccinimide

[0467] PyBOP benzotriazol-1 -yloxytripyrrolidinophosphonium hexafluorophosphate

[0468] TBTU 2-(1 H-Benzotriazole-1-yl)-1 ,1 ,3,3-tetramethylaminium tetrafluoroborate

[0469] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0470] 2MeTHF 2-Methyltetrahydrofuran

[0471] Z-ONSu A / -(Benzyloxycarbonyloxy)succinimide o / w Over the weekend

[0472] TCEP T ris(2-carboxyethyl)phosphine

[0473] T ris 2-Amino-2-(hydroxymethyl)propane-1 ,3-diol

[0474] The names of the final products in the intermediates and examples are generated using Biovia Draw (version 16.1). In cases were Biovia Draw could not generate a name, molecular structures are given.

[0475] Scaffold A

[0476] A / -[(2,4-dimethoxyphenyl)methyl1-3-iodo-1F / -pyrazolo[4,3-c1pyridin-4-amine

[0477] (a) 4-Chloro-3-iodo-1 / - / -pyrazolo[4,3-c]pyridine

[0478] To a solution of 4-chloro-1 F / -pyrazolo[4,3-c]pyridine (50 g, 325.6 mmol) in DMF (500 mL) was added A / -iodosuccinimide (80.6 g, 353.1 mmol) and the mixture was stirred at 100 °C for 1 h. The mixture was cooled and added slowly to a mixture of 5% sodium thiosulfate / sodium bicarbonate solution / water (1 L / 500 mL / 500 mL). The mixture was transferred to a separation funnel and extracted with ethyl acetate (total of 3.5 L). The ethyl acetate layer was separated, washed with water (750 mL) and brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure (still contains >25 mL of DMF). To the resulting suspension was added 100 mL of ethyl acetate and under stirring 250 mL of hexane. The solvent was decanted and the resulting suspension was again treated with ethyl acetate (50 mL) and hexane 250 mL. The precipitate was filtered and dried under vacuum to give 67.7 g of the title compound as a powder (Yield: 74.4%).

[0479] (b) A / -[(2,4-dimethoxyphenyl)methyl]-3-iodo-1 / - / -pyrazolo[4l3-c]pyridin-4-amine (Scaffold A)

[0480] To a suspension of 4-chloro-3-iodo-1 / - / -pyrazolo[4,3-c]pyridine (67.7 g, 242.2 mmol) in 1- butanol (675 mL) at room temperature was added 2,4-dimethoxybenzylamine (121.5 g, 726.6 mmol) and the mixture was heated at 120 °C and stirred overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The precipitate was suspended in water and extracted with ethyl acetate. The ethyl acetate layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound. The crude was suspended / dissolved in dichloromethane (350 mL) and refluxed at 50 °C. Hexane (350 mL) was added dropwise under reflux and stirred for 1 h. After cooling, the precipitate formed was filtered, washed with dichloromethane / hexane = 1 / 1 v / v% and dried under vacuum at 40 °C to give 75.82 g of the title compound as a powder (Yield: 76.3%).

[0481] Scaffold B

[0482] To an ice-cold (4 °C) suspension of A / -[(2,4-dimethoxyphenyl)methyl]-3-iodo-1 H-pyrazolo[4,3- c]pyridin-4-amine (Scaffold A) (41.02 g, 100 mmol), benzyl (1 R,5R)-5-hydroxycyclohex-3-ene-1- carboxylate (Intermediate RP1) (25.54 g, 110 mmol) and triphenylphosphine (30.14 g, 115 mmol) in toluene (400 mL) was added dropwise a solution of diisopropyl azodicarboxylate (24.07 mL, 115 mmol) in toluene (100 mL). The mixture was stirred for 30 min at 4 °C and then stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using SiOs and DCM / acetone = 97 / 3 to 95 / 5 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 50 g of benzyl (1 R,5S)-5-[4-[(2,4- dimethoxyphenyl)methylamino]-3-iodo-pyrazolo[4,3-c]pyridin-1-yl]cyclohex-3-ene-1 -carboxylate (Scaffold B) (yield 80 %).

[0483] Scaffold C

[0484] ,3-c]pyridin-1 -' ic acid (Scaffold C)

[0485] (a) benzyl (1 R,5S)-5-[4-[(2,4-dimethoxyphenyl)methylamino]-3-[4-[[4-(trifluoromethyl)-2- pyridyl]carbamoyl]phenyl]pyrazolo[4,3-c]pyridin-1-yl]cyclohex-3-ene-1 -carboxylate Benzyl (1 R,5S)-5-[4-[(2,4-dimethoxyphenyl)methylamino]-3-iodo-pyrazolo[4,3-c]pyridine-1- yl]cyclohex -3-ene- 1 -carboxylate (15.88 g, 25.43 mmol) was dissolved in dioxane / water = 4 / 1 v / v% (125 mL) and potassium carbonate (10.54 g, 76.29 mmol) was added. The solution was purged with nitrogen for 5 min and terf-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- / V-[4-(trifluoromethyl)-2- pyridyl]benzamide (10.96 g, 27.97 mmol) and Pd(dppf)Cl2.CH2Cl2 (1 .03 g, 1 .27 mmol) were added. The reaction mixture was stirred for 2 h at 80 °C. The reaction mixture was diluted with ethyl acetate and filtered over Decalite™ . The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using SiCh and ethyl acetate / heptane = 1 / 4 to 3 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 18.5 g (Yield 95.0%). (b) (1 / ?,3R)-3-r4-[(2,4-Dimethoxyphenyl)methylamino1-3-[4-r[4-(trifluoromethyl)-2-pyridvHcarba- moyl1phenyl1pyrazolo(4,3-c1pyridin-1-yl1cvclohexanecarboxylic acid ( S caf f o I d C )

[0486] To a solution of benzyl (1 R,5S)-5-[4-[(2,4-dimethoxyphenyl)methylamino]-3-[4-[[4- (trifluoromethyl)-2-pyridyl]carbamoyl]phenyl]pyrazolo[4,3-c]pyridin-1-yl]cyclohex-3-ene-1 -carboxylate (18.0 g, 23.54 mmol) in ethyl acetate / methanol = 4 / 1 v / v% (350 mL) was added 1.8 g of 10% Pd / C. Catalytic hydrogenation was performed for 16 h. at room temperature. TLC analysis indicated that the reaction was not completed. 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%).

[0487] Intermediate RP1 enzy rom e

[0488] Benzyl (1 R,5R)-5-hvdroxycvclohex-3-ene-1-carboxylate

[0489] (a) (1R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one

[0490] (R)-(+)-3-Cyclohexenecarboxylic acid (50.7 g, 402 mmol) was suspended in H2O (400 mL) under nitrogen. The mixture was cooled to 4 °C and sodium bicarbonate (101 .3 g, 1.21 mol) was added, followed by a solution of potassium iodide (333 g, 2.01 mol) and iodine (107 g, 422 mmol) in H2O (400 mL). The reaction was allowed to come to room temperature and stirred o / n and then extracted with dichloromethane (4x100 mL). The combined organic layers were washed with sat. NaHSCh-solution (2x50 mL). The organic layer was protected from light, dried over Na2SO4, filtered and concentrated (20 mbar) to afford (1R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (90.1 g, 89.0 %) as an off-white solid.

[0491] (b) (1R,5R)-6-oxabicyclo[3.2.1]oct-3-en-7-one (1 R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (90.1 g, 358 mmol) was dissolved in dry THF (650 mL). Then, DBU (77 mL, 515 mmol) was added and the mixture was refluxed for 6 h. After cooling to room temperature, the suspension was filtered through Celite™ , and concentrated in vacuo to -250 mL. This was used directly in the next step.

[0492] (c) Benzyl (1f?,5f?)-5-hydroxycyclohex-3-ene-1 -carboxylate (Intermediate RP1 )

[0493] To the THF solution of (1R,5R)-6-oxabicyclo[3.2.1]oct-3-en-7-one (0.4 mol) in methanol (300 mL) was added 2M NaOH-solution (300 mL) and the mixture was stirred for 15 min at room temperature. The reaction was quenched by addition of 3M HCI-solution (300 mL) and the water layer was saturated by addition of sodium chloride. The mixture was extracted with ethyl acetate (3x100 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in DMF (800 ml), cesium carbonate (129 g, 0.4 mol) and benzyl bromide (57 mL, 0.48 mol) were added subsequently. The mixture was stirred at room temperature for 30 min. The precipitate formed was filtered and the precipitate was washed with diethylether. The filtrate was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (heptane / ethyl acetate = 95 / 5 to 45 / 55 v / v%) to give benzyl (1R,5R)-5-hydroxycyclohex-3-ene-1-carboxylate (57.1 g, 61.5% over 3 steps) as an oil.

[0494] Intermediate RP2

[0495] Ethyl (1 R,5R)-5-hvdroxycvclohex-3-ene-1-carboxylate

[0496] (a) (1R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one

[0497] (R)-(+)-3-Cyclohexenecarboxylic acid (50.7 g, 0.4 mol) was suspended in H2O (400 mL) under nitrogen. The reaction mixture was cooled to 4 °C and sodium bicarbonate (101 g, 1 .2 mol) was added, followed by a solution of potassium iodide (333 g, 2 mol) and iodine (107 g, 0.42 mol) in H2O (400 mL). The reaction was allowed to come to room temperature and stirred o / n and then extracted with DCM (4x150 mL). The combined organic layers were washed with a solution of Na2S2Oa (120 g) in H2O (600 mL). The aqueous layer was extracted with DCM (2x150 mL). The combined organic layers were protected from light, dried over Na2SO4, filtered and concentrated (20 mbar) to afford (1 R,4R,5R)-4- iodo-6-oxabicyclo[3.2.1]octan-7-one (95.22 g, 94.5 %) as a solid.

[0498] (b) (1R,5R)-6-oxabicyclo[3.2.11oct-3-en-7-one

[0499] (1 R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (95.22 g, 377.9 mmol) was dissolved in dry THF (700 mL). Then, DBU (86.3 g, 566.9 mmol) was added and the mixture was refluxed o / n. The reaction mixture was cooled to room temperature, diluted with diethylether (500 mL) and extracted with aq. HCI (1 L, 1 M) and brine (250 mL). The aqueous layers were extracted with diethylether (2 x 480 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated (350 mbar to afford (1R,5R)-6-oxabicyclo[3.2.1]oct-3-en-7-one quantitatively as a yellowish oil which was used directly in the next step.

[0500] (c) Ethyl (1 -5-hydroxycyclohex-3-ene-1 -carboxylate (Intermediate RP2)

[0501] To a stirred solution of (1 R,5R)-6-oxabicyclo[3.2.1]oct-3-en-7-one (377.9 mmol, theor.) in ethanol (750 mL) was added potassium carbonate (10.45 g, 75.6 mmol) at room temperature and the mixture stirred o / n. The reaction mixture was filtered through a Celite pad. Removal of ethanol under reduced pressure afforded the crude product that was purified by column chromatography plug filtration (eluent 40% EtOAc / heptane) to afford the title compound (41 .38 g, 60.8% over 3 steps and column) as a yellow liquid.

[0502] Intermediate RP3

[0503] Methyl (1 R,5R)-5-hydroxycyclohex-3-ene-1-carboxylate

[0504] (a) (1R,4R,5R)-4-iodo-6-oxabicyclo(3.2.11octan-7-one

[0505] (R)-(+)-3-Cyclohexenecarboxylic acid (20.2 g, 160 mmol) was suspended in H2O (430 mL) under nitrogen. The reaction mixture was cooled to 0 °C and sodium bicarbonate (40.3 g, 480.3 mmol) was added, followed by a solution of potassium iodide (159.5 g, 961 mmol) and iodine (39.6 g, 168 mmol) in H2O (360 mL). The reaction was allowed to come to room temperature and stirred o / n and then extracted with DCM (3x150 mL). The combined organic layers were washed with a solution of Na2S20s (120 g) in H2O (600 mL). The aqueous layer was extracted with DCM (2x150 mL). The combined organic layers were protected from light, dried over Na2SO4, filtered and concentrated (20 mbar) to afford (1R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (37.88 g, 93.9 %) as an off-white solid.

[0506] (b) (1R,5R)-6-oxabicyclo[3.2.1]oct-3-en-7-one

[0507] (1 R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (37.88 g, 150.3 mmol) was dissolved in dry THF (750 mL). Then, DBU (34.3 g, 225.2 mmol) was added and the mixture was refluxed o / n. The reaction mixture was cooled to room temperature, diluted with diethylether (480 mL) and extracted with aq. HCI (1 L, 0.5 M) and brine (1 L). The aqueous layers were extracted with diethylether (2 x 480 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated (350 mbar to afford (1 R,5R)-6-oxabicyclo[3.2.1]oct-3-en-7-one quantitatively as a yellowish oil which was used directly in the next step.

[0508] (c) Methyl (1 R,5R)-5-hvdroxycvclohex-3-ene-1-carboxylate (Intermediate RP3)

[0509] Sodium bicarbonate (37.88 g, 0.451 mol) was added to a solution (1 R,5R)-6- oxabicyclo[3.2.1]oct-3-en-7-one (150.3 mmol theor.) in anhydrous MeOH (300 mL). After stirring for 1 week at room temperature the solvent was removed in vacuo (40 °C / 300 mbar). The residue was diluted with water (500 mL) and extracted with dichloromethane (3x250 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (21 .2 g, 90.3%) as a slightly coloured liquid.

[0510] Intermediate RP4 tert-Butyl A / -[(1 / ?,3S)-3-hydroxycvclohexyl]carbamate

[0511] (a) 2-Cyclohex-2-en-1 -ylisoindoline-1 ,3-dione

[0512] A mixture of potassium phthalimide (69.88 g, 377.2 mmol) and 3-bromocyclohexene (60.75 g, 377.2 mmol) in DMF (500 mL) was stirred at 30 °C and gradually warmed to 100 °C for 6 h and then o / n by room temperature. The reaction mixture was diluted with water (2 L), extracted with ethyl acetate (3x500 mL). The combined organic layers were washed with water (2x500 mL), brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane) to afford 63.29 g of the title compound (Yield: 73.8%).

[0513] (b) (±) 13-Bromo-12b-ethoxy-2,6-methano[1 indol-S-one

[0514] A / -Bromosuccinimide (61.95 g, 348 mmol) was added to a stirred solution of 2-cyclohex-2-en- 1 -ylisoindoline-1 ,3-dione (63.29 g, 278.4 mmol) in chloroform (1000 mL) and ethanol (65 mL) and the mixture was stirred at room temperature o / n. The mixture was washed with 1 M sodium thiosulphate solution (1.5 L). The organic layer was separated and dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Heptane / Ethyl acetate = 7 / 3 v / v%) to afford the title compound (97.0 g, 98.9%).

[0515] (c) 1 ,2-T rans-2,3-trans-2-Bromo-3-N-phtalimidocyclohexanol

[0516] 2M HCI-solution (150 mL) was added to a stirred solution of the orthoamide (86.44 g, 245.4 mmol) in methanol (600 mL) and the solution was stirred at room temperature for 30 min. Most of the solvent was removed and dichloromethane (300 mL) was added to the residue. This solution was then washed with water (2x50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crystalline residue was recrystallised from ethyl acetate / hexane (200 / 500 mL @ 75°C) to give the title compound (70.04 g, 88.0%)

[0517] (d) c / s-3-Phthalimidocyclohexanol

[0518] 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. Reaction proceeded slowly and additional AIBN (20 mL) and tri-n-butyltin hydride were added and the reaction mixture was stirred at reflux for 3h. Progress of the reaction was followed by TLC. The mixture was then placed under nitrogen and additional AIBN (20 mL) and tri-butyltin hydride (20 g) were added subsequently, and stirred at reflux for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with 750 mL heptane (2 x). The heptane layer was removed by suction under reduced pressure. Again 100 mL ethyl acetate and 650 mL heptane were added. The precipitate was filtered, washed with hexane and dried under vacuum at 40 °C o / n to give 49.07 g of the title compound (yield: 83.1 %).

[0519] (e) 2-[(1R,3S)-3-hydroxycvclohexyl]isoindoline-1 , 3-dione + |~(1R,3S)-3-(1 ,3-dioxoisoindolin-2- vDcyclohexyll acetate

[0520] To a solution of c / s-3-phthalimidocyclohexanol (49 g, 200 mmol) in THF (600 mL) was added Lipase Novozyme 435 (25 g) and vinyl acetate (55.3 mL, 600 mmol). The resulting mixture was shaken at room temperature and 250 rpm o / n. The progress of the reaction was monitored by LC-MS. After o / n reaction, the enzyme was filtered off, washed with THF and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using SiCte and ethyl acetate / heptane = 1 / 1 to 10 / 0 and to ethyl acetate / dichloromethane = 3 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo io give 21.21 g of 2-[(1 R,3S)-3-hydroxycyclohexyl]isoindoline- 1 ,3-dione (yield 43.3 %) and 31 g of [(1 R,3S)-3-(1 ,3-dioxoisoindolin-2-yl)cyclohexyl] acetate (yield 54.0 %).

[0521] (f) (1 S,3R)-3-aminocyclohexanol

[0522] To a solution of 2-[(1 R,3S)-3-hydroxycyclohexyl]isoidoline-1 ,3-dione (21.2 g, 86.4 mmol) in ethanol (280 mL) was added hydrazine hydrate (4.28 mL) and the reaction mixture was stirred at 100 °C o / n. The mixture was cooled to room temperature and the precipitate was filtered, washed with ethanol and the filtrate was concentrated under reduced pressure to give 9.87 g of the title compound as a yellow solid (yield: 59.9%). The crude precipitate 13.74 g still contains a lot of 2,3- dihydrophthalazine-1 , 4-dione and product (yield: 39.4%).

[0523] (g) tert- Butyl A / -[(1 R,3S)-3-hydroxycyclohexyl]carbamate (Intermediate RP4)

[0524] To a solution of (1 S,3R)-3-aminocyclohexanol (9.87 g, 51.74 mmol) in dioxane (200 mL) was added di-tert-butyl dicarbonate (11 .86 g) and the reaction mixture was stirred at room temperature o / n. 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 12.5 g of the title compound. 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.

[0525] Both batches were combined and suspended in ethyl acetate. Hexane was added and the precipitate formed was filtered, washed with hexane and dried under high vacuum at 40 °C to give 16.3 g of tert-butyl A / -[(1 R,3S)-3-hydroxycyclohexyl]carbamate (Intermediate RP4) (yield: 87.6%).

[0526] (h) [(1 S,3R)-3-(tert-butoxycarbonylamino)cyclohexyl1 (2S)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoate

[0527] To a solution of tert-butyl A / -[(1 R,3S)-3-hydroxycyclohexyl]carbamate (50 mg, 0.23 mmol) in dichloromethane (2 mL) was added triethylamine (35.6 pL, 0.26 mmol) and 4-dimethylaminopyridine (3 mg, 0.023 mmol) and the mixture was stirred for 5 min. (R)-(-)-a-methoxy-a-trifluoromethylphenylacetyl chloride (61 .6 mg, 0.24 mmol) was added and the reaction mixture was stirred at room temperature o / n. Dichloromethane was distilled off under reduced pressure, the resulting residue was purified by column chromatography (heptane / ethyl acetate = 8 / 2 v / v%) to give 71 .4 mg of the title compound (Yield: 72.0%). Both proton and fluor NMR showed that tert-butyl A / -[(1R,3S)-3-hydroxycyclohexyl]carbamate (Intermediate RP4) has a diastereoisomeric excess (d.e)of> 99.0%.

[0528] (1R,3R)-3-(Benzyloxycarbonylamino)cyclohexanecarboxylic acid

[0529] (a) Methyl (1R,5S)-5-[bis(tert-butoxycarbonyl)amino]cyclohex-3-ene-1-carboxylate

[0530] To an ice-cold (4 °C) solution of di-tert-butyl iminodicarboxylate (4.6 g, 21.2 mmol), methyl (1R,5R)-5-hydroxycyclohex-3-ene-1-carboxylate (Intermediate RP3) (3.31 g, 21.2 mmol) and triphenylphosphine (6.67 g, 25.4 mmol) in 2-MeTHF (180 mL) was added dropwise a solution of diisopropyl azodicarboxylate (6.26 mL, 31 .8 mmol) in 2-MeTHF (30 mL). The mixture was stirred for 30 min at 4 °C and then allowed to warm to room temperature and stirred for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using SiCh and heptane / ethyl acetate = 3 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 5.68 g of methyl (1R,5S)-5-[bis(tert-butoxycarbonyl)amino]cyclohex-3- ene-1 -carboxylate (yield 75.4 %).

[0531] (b) Methyl (1R,3R)-3-[bis(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

[0532] To a solution of methyl (1R,5S)-5-[bis(fert-butoxycarbonyl)amino]cyclohex-3-ene-1-carboxylate (2.48 g, 6.98 mmol) in ethanol (140 mL) was added 248 mg of 10% Pd / C. Catalytic hydrogenation was performed at room temperature for 16 h. The palladium-catalyst was filtered and the filtrate was concentrated in vacuo to give 2.6 g of the title compound (Yield: quantitative).

[0533] (c) Methyl (1 R,3R)-3-aminocvclohexanecarboxylate hydrochloride

[0534] To methyl (1 R,3R)-3-[bis(tert-butoxycarbonyl)amino]cyclohexanecarboxylate (2.6 g, 7.2 mmol) was added 4M HCI / dioxane solution (18 mL) and the mixture was stirred at room temperature o / n. The mixture was concentrated in vacuo to give 1.06 g the title compound (yield: 76%).

[0535] (d) Methyl (1R,3R)-3-(benzyloxycarbonylamino)cvclohexanecarboxylate

[0536] 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. The layers were separated and the water layer was extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with water (50 mL), 0.5N aq. HCI-solution (50 mL), water (50 mL), 5% aq. NaHCCh-solution (50 mL), water (50 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 1.78 g of the title compound (yield: quantitative, crude).

[0537] (e) (1R,3R)-3-(Benzyloxycarbonylamino)cyclohexanecarboxylic acid (Intermediate RP5)

[0538] The crude product methyl (1 R,3R)-3-(benzyloxycarbonylamino)cyclohexanecarboxylate (1.45 g, 4.98 mmol) was dissolved in THF / dioxane / water = 4 / 1 / 1 v / v% (74 mL) and subsequently lithium hydroxide (358 mg, 14.9 mmol) was added. The mixture was stirred at room temperature o / n. Ethyl acetate (50 mL) and water (were added) and the pH of the mixture was adjusted to pH < 3 by addition of 2M HCI-solution. The organic phase was separated, washed with water, brine, dried over sodium sulfate , filtered and concentrated under reduced pressure to give 800 mg of (1R,3R)-3- (benzyloxycarbonylamino)cyclohexanecarboxylic acid (Intermediate RP5) (yield:57.9%).

[0539] Intermediate RP5 (Route B)

[0540] (1R,3R)-3-(Benzyloxycarbonylamino)cvclohexanecarboxylic acid

[0541] (a) tert-Butyl A / -(4-nitrophenyl)sulfonylcarbamate

[0542] 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. To the reaction mixture was added 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. The residue was dissolved in dichloromethane and purified by plug filtration over silica (heptane to ethyl acetate = 10 / 0 to 0 / 10) to give 13.09 g of the title compound (yield: 87.5%).

[0543] (b) Methyl (1R,5S)-5-rtert-butoxycarbonyl-(4-nitrophenyl)sulfonyl-aminol-cvclohex-3-ene-1 -carboxylate

[0544] To a cold (-20 °C) solution of methyl (1 R,5R)-5-hydroxycyclohex-3-ene-1-carboxylate (15 g, 96.0 mmol), tert-butyl A / -(4-nitrophenyl)sulfonylcarbamate (29.0 g, 96.0 mmol) and triphenylphosphine (27.7 g, 105.6 mmol) in THF (300 mL) was added dropwise a solution of diisopropyl azodicarboxylate (20.8 mL, 105.6 mmol) in THF (100 mL). The reaction mixture was concentrated under reduced pressure to give a residue which was purified by column chromatography (hexane / ethyl acetate = 85 / 15 v / v%) to give 36 g of the title compound, (yield: 85.1 %).

[0545] (c) Methyl (1 R,5S)-5-(tert-butoxycarbonylamino)cvclohex-3-ene-1-carboxylate

[0546] To a stirred solution of methyl (1R,5S)-5-[fert-butoxycarbonyl-(4-nitrophenyl)sulfonyl-amino]- cyclohex-3-ene-1 -carboxylate (35.15 g, 79.8 mmol) in acetone (300 mL) was added DBU (23.85 mL, 159.6 mmol) and 2-mercaptoethanol (11.23 mL, 159.6 mmol). The reaction mixture was stirred for 3 h at room temperature. Acetone was removed under reduced pressure and the resulting residue was purified by column chromatography (hexane / ethyl acetate = 90 / 10 to 88 / 12 v / v%) to give 14.1 g of the title compound (Yield: 69.2%) as a crystalline white solid.

[0547] (d) Methyl (1R,3R)-3-(tert-butoxycarbonylamino)cvclohexanecarboxylate

[0548] To a solution of methyl (1R,5S)-5-(tert-butoxycarbonylamino)cyclohex-3-ene-1 -carboxylate (14.9 g, 58.36 mmol) in methanol (300 ml_) was added 1.5 g of 10% Pd / C. Catalytic hydrogenation was performed for 3 h at room temperature. The palladium-catalyst was filtered and the filtrate was concentrated in vacuo to afford the title compound in quantitative crude yield.

[0549] (e) Methyl (1R,3R)-3-aminocvclohexanecarboxylate hydrochloride

[0550] To a cooled (4 °C) solution of methyl (1 R,3R)-3-(tert-butoxycarbonylamino)cyclo- hexanecarboxylate (15.2 g, 58.36 mmol) in methanol (300 mL) was added drop-wise acetyl chloride (42 m L, 583.6 mmol). The reaction mixture was stirred for 1 h. The mixture was concentrated under reduced pressure and dried in vacuo to give the title compound in quantitative crude yield.

[0551] (f) Methyl (1 R,3R)-3-(benzyloxycarbonylamino)cvclohexanecarboxylate

[0552] To a cooled (4 °C) solution of methyl (1 R,3R)-3-aminocyclohexanecarboxylate hydrochloride (58.36 mmol) in dioxane / water = 1 / 1 v / v% (200 mL) was added portion-wise sodium bicarbonate (14.7 g, 175 mmol). To the resulting suspension was added drop-wise a solution of N- (benzyloxycarbonyloxy)succinimide (14.8 g, 59.02 mmol) in dioxane (150 mL) and the resulting mixture was stirred at room temperature o / w. LC-MS showed some starting material present. Additionally, 1.5 g of Z-ONSu was added as a solution in dioxane. The mixture was stirred at room temperature o / n. Ethyl acetate was added and the resulting mixture was washed with 0.5M HCI solution, water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure and dried in vacuo to give the title compound in quantitative crude yield.

[0553] (g) (1 R,3R)-3-(benzyloxycarbonylamino)cyclohexanecarboxylic acid (Intermediate RP5)

[0554] To a solution of methyl (1 R,3R)-3-(benzyloxycarbonylamino)cyclohexanecarboxylate (58.36 mmol) in THF / water = 4 / 1 v / v% (375 mL) was added lithium hydroxide (4.21 g, 175 mmol) and the reaction mixture was stirred at room temperature o / n. Ethyl acetate (300 mL) and water (300 mL) were added to the mixture and the aqueous phase was separated. The ethyl acetate layer washed extracted with water (100 mL). The combined aqueous phases were washed with dichloromethane (100 mL) and acidified (pH < 2) by addition of 2M HCI-solution (90 mL). The water layer was extracted with ethyl acetate (3x250 mL). The combined ethyl acetate layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure and dried in vacuo to give 15.72 g of the title compound (Yield: 96.7% over 4 steps). Intermediate RP5b (Route C)

[0555] (1R,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid

[0556] (a) Ethyl (1R,5S)-5-(1 ,3-dioxoisoindolin-2-yl)cyclohex-3-ene-1 -carboxylate

[0557] To an ice-cold (0 °C) solution of ethyl (1 R,5R)-5-hydroxycyclohex-3-ene-1-carboxylate (Intermediate RP2, 15.0 g, 88.13 mmol), phthalimide (14.26 g, 96.94 mmol) and triphenylphosphine (34.67 g, 132.2 mmol) in toluene (264 ml_) was added dropwise diisopropyl azodicarboxylate (26.02 mL, 132.2 mmol) in 10 min. The reaction mixture was stirred at 0 °C for 30 min and then allowed to come to room temperature and stirred for 3 h. The mixture was concentrated under reduced pressure to give a yellow oil. Heptane / ethyl acetate = 7 / 3 v / v% (500 mL) was added and the mixture was heated to 70 °C. After cooling, the mixture was stirred for 72 h at room temperature. The solids were filtered, washed with heptane / ethyl acetate = 9 / 1 v / v% (2x50 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (heptane / ethyl acetate = 9 / 1 to 6 / 4 v / v%) to give 21 .96 g of the title compound (Yield: 83.0%) as fluffy off-white solids.

[0558] (b) Ethyl (1R,3R)-3-(1 ,3-dioxoisoindolin-2-yl)cvclohexanecarboxylate

[0559] To a solution of ethyl (1R,5S)-5-(1 ,3-dioxoisoindolin-2-yl)cyclohex-3-ene-1-carboxylate (27.73 g, 97.19 mmol) in methanol (975 mL) was added 2.7 g of 10% Pd / C. Catalytic hydrogenation was performed for 3 h at room temperature. The palladium-catalyst was filtered and the filtrate was concentrated in vacuo to afford 27.52 g the title compound (Yield: 94%).

[0560] (c) Ethyl (1 R,3R)-3-aminocyclohexanecarboxylate

[0561] To a solution of ethyl (1 R,3R)-3-(1 ,3-dioxoisoindolin-2-yl)cyclohexanecarboxylate (26.5 g, 87.95 mmol) in ethanol (440 mL) was added drop-wise hydrazine hydrate (64% in water, 4.68 mL, 96.74 mmol). The reaction mixture was stirred for 30 min. at room temperature and then refluxed for 3 h. Additional hydrazine hydrate (425 pL) was added and stirring under reflux was continued for 2 h. The mixture was concentrated under reduced pressure and dried in vacuo to give the title compound in quantitative crude yield.

[0562] (d) Ethyl (1R,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylate

[0563] To a cold (0 °C) stirred suspension of ethyl (1 R,3R)-3-aminocyclohexanecarboxylate (91.27 mmol, theoretical) in dichloromethane (456 mL) was added portion-wise di-tert-butyl dicarbonate (21.91g, 100.4 mmol). The reaction mixture was stirred for 15 min at 0 °C, then allowed to come to room temperature. The mixture was washed with cold 0.5N NaOH-solution, water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (heptane / ethyl acetate = 8 / 2 to 6 / 4 v / v%) to give 20.5 g of the title compound (Yield: 83.0% over two steps) as an off-white solid.

[0564] (e) (1R,3R)-3-(tert-butoxycarbonylamino)cvclohexanecarboxylic acid

[0565] To a solution of ethyl (1R,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylate (20.5 g, 75.56 mmol) in THF (300 mL) was added a solution of lithium hydroxide (1.8 g, 75.56 mmol) in water (150 mL) and the reaction mixture was stirred at room temperature o / n. Additional lithium hydroxide (0.9 g) was added and stirring was continued for 24 h at room temperature. The mixture was acidified (pH < 2) by addition of 1 M HCI-solution (131 mL). The water layer was separated and extracted with dichloromethane (2x100 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure and dried in vacuo to give 16.81 g (91 %) of (1R,3R)-3-(tert-butoxycarbonylamino)cyclo-hexanecarboxylic acid (Intermediate RP5b).

[0566] Intermediate RP6

[0567] T3P DiPEA tert-Butyl A / -[(1 R,3S)-3-hydroxy-1 -methyl-butyl]carbamate

[0568] (a) tert-Butyl A / -[(1 R)-3-[methoxy(methyl)amino1-1-methyl-3-oxo-propyl1carbamate

[0569] DiPEA (22.3 mL, 132 mmol) followed by T3P (50 wt% in EtOAc, 34 mL, 57 mmol) and N,O- dimethylhydroxylamine (6.43 g, 66 mmol) were added sequentially to a solution of (R)- / V-Boc-3- aminobutyric acid (8.94 g, 44 mmol) in DMF (90 mL). The reaction mixture was stirred at room temperature o / n. Water (50 mL) was added and the aqueous mixture was stirred for 1 h. and then extracted with ethyl acetate. The organic extracts were combined, washed with 5% aq. NaHCCh- solution, water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 10.84 g (100%) of the title compound.

[0570] (b) tert-Butyl A / -[(1 R)-1-methyl-3-oxo-butyl]carbamate

[0571] 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. The aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography using SiO2 and heptane / ethyl acetate = 1 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 3.3 g of tert-butyl / V-[(1 R)-1-methyl-3-oxo-butyl]carbamate (yield 37%).

[0572] (c) tert-Butyl A / -[(1R,3S)-3-hydroxy-1-methyl-butyl1carbamate (Intermediate RP6)

[0573] Sodium borohydride (744 mg, 19.68 mmol) was added to a cold (0 °C) solution of tert-butyl N- [(1R)-1-methyl-3-oxo-butyl]carbamate (3.3 g, 16.4 mmol) in ethanol (82 mL) under nitrogen. After stirring at this temperature for 5 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. NHUCI-solution was added carefully. The aqueous mixture was extracted with ethyl acetate. The organic extracts were combined, washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography using SiOz and dichloromethane / TBME = 10 / 0 to 6 / 4 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 1.93 g (50%) of tertbutyl A / -[( 1 R,3S)-3-hydroxy-1 -methyl-butyl]carbamate (Intermediate RP6) and 1 .82 g (47%) of tert-butyl A / -[(1 R,3R)-3-hydroxy-1 -methyl-butyl]carbamate.

[0574] Intermediate RP7

[0575] (1R,3R)-3-(tert-butoxycarbonylamino)cvclopentanecarboxylic acid

[0576] The title compound was prepared according to procedures described in WO2019 / 236631 starting from (1 S)-(+)-2-azabicyclo[2.2.1]hept-5-en-3-one (10 g.) to give 7.79 g (37.1% over 4 steps) of (1R,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (Intermediate RP7).

[0577] Intermediate RP8

[0578] NaH THF

[0579] Grubbs methatesis 0 C to rT DCM, rT, o / n tert-Butyl A / -[(3S,5R)-5-hydroxytetrahydropyran-3-yl]carbamate

[0580] (a) 1-Allyloxybut-3-en-2-ol

[0581] To a cold (0 °C) solution of 2-vinyloxirane (2 mL, 25 mmol) and prop-2-en-1-ol (3.4 mL, 50 mmol) in DMF (50 mL) was added carefully portion-wise sodium hydride (60% in mineral oil, 2 g, 50 mmol). After stirring at 0 °C for 30 min, the mixture was stirred at 50 °C o / n. The mixture was cooled to 0 °C and quenched by addition of 1 N HCI-solution (100 mL) and stirred for 1 h, allowing the temperature to come to room temperature. The mixture was extracted with diethyl ether (3x100 mL). The combined organic extracts were washed with 10% w / w LiCI-solution (100 mL) and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure (bath temperature 35 °C, 600 mbar). The resulting residue was purified by column chromatography (pentane / diethyl ether = 95 / 5 to 1 / 1 v / v%) to give 1.38 g of the title compound (Yield: 43.0%) as a colourless oil.

[0582] (b) 3,6-Dihvdro-2H-pyran-3-ol

[0583] To a solution of 1-allyloxybut-3-en-2-ol (1.38 g, 10.8 mmol) in dichloromethane (100 mL) was added Grubbs 1stgeneration catalyst (178 mg, 0.22 mmol) and the reaction mixture was stirred at room temperature o / n. The mixture was concentrated under reduced pressure (bath temperature 35 °C, 600 mbar). The resulting residue was purified by column chromatography (pentane / diethyl ether = 95 / 5 to 1 / 1 v / v%) to give 566 mg of the title compound (Yield: 52.0%) as a colourless oil.

[0584] (c) 2-(3,6-Dihvdro-2 / - / -pyran-3-yl)isoindoline-1 ,3-dione To a cold (0 °C) solution of 3,6-dihydro-2 / - / -pyran-3-ol (380 mg, 3.8 mmol), phthalimide (373 mg, 2.53 mmol) and triphenylphosphine (798 mg, 3.03 mmol) in THF (15 mL) was added dropwise a solution of di-fert-butyl azodicarboxylate (698 mg, 3.03 mmol) in THF (4 mL). The reaction mixture was stirred at 0 °C for 30 min and then allowed to come to room temperature and stirred for 3 h. The mixture was concentrated under reduced pressure to give a yellow oil. The resulting residue was purified by column chromatography (dichloromethane / ethyl acetate = 10 / 0 to 1 / 9 v / v%) to give 456 mg of the title compound (Yield: 79%).

[0585] (d) tert- Butyl A / -[(3S,5F?)-5-hydroxytetrahydropyran-3-yl]carbamate (Intermediate RP8)

[0586] This compound was prepared in an analogous manner as described Intermediate RP4 steps b to h, using 2-(3,6-dihydro-2F / -pyran-3-yl)isoindoline-1 , 3-dione to afford 220 mg of the title compound (-90% e.e.).

[0587] Intermediate BP1

[0588] 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-A / -[4-(trifluoromethyl)-2-pyridyl]benzamide (Intermediate BP1)

[0589] (a) 4-(4,4l5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoyl chloride

[0590] To a cold (0 °C) solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (24.8 g, 100 mmol) in dichloromethane (300 mL) was added a catalytic amount of DMF. A solution of oxalyl chloride (12.9 mL, 150 mmol) was added dropwise. After stirring for 60 min at 0 °C, the reaction mixture was allowed to warm to room temperature and the mixture was stirred o / n. The reaction mixture was concentrated to give 26.33 g of crude 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoyl chloride (yield: 99%).

[0591] (b) 4-(4,4l5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-A / -[4-(trifluoromethyl)-2-pyridyl1benzamide (Intermediate BP1)

[0592] To a cold (0 °C) solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoyl chloride (26.33 g, 100 mmol) in acetonitrile (300 mL) was subsequently added 4-(trifluoromethyl)pyridin-2-amine (19.45 g, 120 mmol) and 4-DMAP (14.66 g, 120 mmol) The mixture was stirred under nitrogen atmosphere at 0°C and allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo. The crude oily solids were then dissolved in dichloromethane (300 mL) and washed with 5% citric acid (3x, 300 mL), 5% NaHCOa (2x300 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue triturated in refluxing heptane (300 mL) for 1-2 hours. The mixture was filtrated and evaporated under reduced pressure. The residue was stirred in 6 N NaOH (140 mL) and THF (140 mL) at room temperature for 4 hrs. Then 250 mL EtOAc was added and the layers were separated. The organic layer was washed with water, 5% citric acid and brine, dried over sodium sulfate and concentrated in vacuo to give 24.4 g of 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-A / -[4-(trifluoromethyl)-2-pyridyl]benzamide (Intermediate BP1 ) (yield: 62%) as off-white solids.

[0593] Intermediate BP2

[0594] 3-Fluoro-4-(4,4,5,5-l 1-1 ,3,2-dioxaborolan-2-yl)-A / -|

[0595] (Intermediate BP2)

[0596] This compound was prepared in an analogous manner as described in Intermediate BP1 , starting from 4-(trifluoromethyl)pyridine-2-amine and 3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoic acid, to afford the title compound (5.01 g, 69,7%).

[0597] Intermediate BP3

[0598] 2-Methoxv-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-vl)- / V-[4-i

[0599] (Intermediate BP3)

[0600] (a) 4-Bromo-2-methoxybenzoyl chloride

[0601] This compound was prepared in an analogous manner as described in Intermediate BP1 step a, starting from 4-bromo-2-methoxybenzoic acid to afford the title compound (5.75 g, quant, crude).

[0602] (b) 4-Bromo-2-methoxy-A / -[4-(trifluoromethyl)-2-pyridyl]benzamide

[0603] This compound was prepared in an analogous manner as described in Intermediate BP1 step b, starting from 4-bromo-2-methoxybenzoyl chloride and 4-(trifluoromethyl)pyridine-2-amine to afford the title compound (6.6 g, 81 %).

[0604] (c) 2-Methoxy-4-(4,4,5,5-tetramethyl-1 ,312-dioxaborolan-2-yl)-A / -[4-(trifluoromethyl)-2- pyridyllbenzamide (Intermediate BP3) To a solution of 4-bromo-2-methoxy-A / -[4-(trifluoromethyl)-2-pyridyl]benzamide (6.15 g, 16.4 mmol) in dioxane (100 mL) was added b / s(pinacolato)diboron (5.4 g, 21 .3 mmol) and potassium acetate (3.22 g, 32.8 mmol). The reaction mixture was degassed with nitrogen. Subsequently Pd(dppf)Cl2.CH2Cl2 complex (670 mg, 0.82 mmol) was added and the reaction mixture was stirred at 80 °C for 8 h. The mixture was cooled to room temperature and after addition of water extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using SiO2 and ethyl acetate / heptane = 1 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 6.13 g of 2-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- A / -[4-(trifluoromethyl)-2-pyridyl]benzamide (Intermediate BP3) (yield: 88%).

[0605] Intermediate BP4

[0606] [4-(2-Pyridylcarbamoyl)phenyl]boronic acid (Intermediate BP4)

[0607] 4-Carboxyphenylboronic acid (15.0 g, 90.4 mmol) was suspended in toluene (180 mL) and DMF (277 pL, 3.61 mmol) was added. The reaction mixture was heated to 50 °C, at which point thionyl chloride (19.63 mL, 271 mmol) was added slowly (<5min). The reaction mixture was heated to 60 °C and stirred for 8 h. After cooling to room temperature a white suspension occurred. The mixture was then concentrated under vacuum to remove solvent. Toluene was added and the mixture was concentrated to remove excess thionyl chloride. Pyridine (75 mL) was added and the slurry was cooled to 5°C. A solution of 2-aminopyridine (17.0 g, 180.8 mmol) in pyridine (30 mL) was added and the reaction mixture was slowly heated to 65°C to 70°C and stirred for 8h. The reaction mixture was concentrated under vacuum to remove solvent. The residue was heated to 70°C and water (10 mL) was added. After 1.5 h toluene (20 mL) was added followed by water (80 mL). The reaction mixture was cooled to 20°C, stirred for 72 h at room temperature. The suspension formed was filtered and washed with water (50 mL). The solids were re-suspended in water (50 mL) and stirred. The solids were filtered and washed with water (50 mL), dried in a vacuum oven at 40°C yielding 12.7 g of [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Intermediate BP4) as white solids (yield: 58%). Intermediate BP5 r4-[r(5-fluoro-2-methoxy-benzoyl)amino1methyl1phenyl1boronic acid (Intermediate BP5)

[0608] To a suspension of 4-aminomethylphenylboronic acid hydrochloride (4.41 g, 23.5 mmol) and 5- fluoro-2-methoxybenzoic acid (4 g, 23.5 mmol) in anhydrous THF (100 mL), under a nitrogen atmosphere, was added successively, A / . / V-diisopropylethylamine (19.4 mL, 118 mmol) and 1- propanephosphonic acid cyclic anhydride (50 wt% in EtOAc, 23 mL, 35.3 mmol). The reaction mixture was heated under reflux at 70 °C o / n. The mixture was diluted with water and dichloromethane, then partitioned. The aqueous layer was extracted with DCM (2x). The combined organic extracts were filtered over a PE-filter and concentrated under reduced pressure. The residue was purified by column chromatography using SiO2 and dichloromethane / methanol = 99 / 1 to 95 / 5 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 5.07 g of [4-[[(5-fluoro-2-methoxy- benzoyl)amino]methyl]phenyl]boronic acid (Intermediate BP5) (Yield 71 %).

[0609] Intermediate BP6 r4-[(4-cyano-2-pyridyl)carbamoyl1phenyl1boronic acid (Intermediate BP6)

[0610] This compound was prepared in an analogous manner as described in Intermediate BP1 , starting from 2-aminopyridine-4-carbonitrile and 4-carboxyphenylboronic acid, to afford the title compound (4.8 g, 39%). Intermediate BP7

[0611] A / -(4-Fluoro-2-pyridyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide (Intermediate BP7)

[0612] This compound was prepared in an analogous manner as described in Intermediate BP1 , starting from 4-fluoropyridin-2-amine and 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid, to afford the title compound (3.48 g, 33%).

[0613] Intermediate BP8 A / -[4-(difluoromethyl)-2-pyridyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide (Intermediate BP8)

[0614] This compound was prepared in an analogous manner as described in Intermediate BP3, starting from 4-(difluoromethyl)pyridin-2-amine and 4-bromobenzoic acid, to afford the title compound (45 mg, 59%).

[0615] Intermediate BP9

[0616] A / -(4-Methyl-2-pyridyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide (Intermediate BP9) This compound was prepared in an analogous manner as described in Intermediate BP1 , starting from 2-amino-4-methylpyridine and 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid, to afford the title compound (822 mg, 49%).

[0617] Intermediate BP10

[0618] (Intermediate BP10)

[0619] This compound was prepared in an analogous manner as described in Intermediate BP3, starting from 4-(difluoromethoxy)pyridin-2-amine and 4-bromobenzoic acid, to afford the title compound (144 mg, 100%).

[0620] Intermediate BP11

[0621] A / .(4-i l-2-pyridyl)-4-(4,4,5,5-1 1-1 ,3,2-dioxaborolan-2-' (Intermediate

[0622] BP11)

[0623] This compound was prepared in an analogous manner as described in Intermediate BP3, starting from 4-cyclopropylpyridin-2-amine and 4-bromobenzoic acid, to afford the title compound (69 mg, 100%). Intermediate BP12

[0624] A / -(4-Methoxy-2-pyridyl)-4-(4,4,5,5-1 1-1 ,3,2-dioxaborolan-2-' (Intermediate

[0625] BP12)

[0626] 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 %).

[0627] Intermediate BP13

[0628] A / -[1 -Methyl-5-i l-3-yll-4-(4,4,5,5-1 1-1 ,3,2-dioxaborolan-2-'

[0629] (Intermediate BP13)

[0630] This compound was prepared in an analogous manner as described in Intermediate BP1 , starting from 1-methyl-5-(trifluoromethyl)-1f / -pyrazol-3-amine and 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoic acid, to afford the title compound (1.9 g, 80%).

[0631] Intermediate BPM 4-Methoxy-A / -[2-methoxy-4-(4,4l5,5-tetramethyl-1 ,3l2-dioxaborolan-2-yl)phenyl1-1-methyl-indole-2- carboxamide (Intermediate BPM)

[0632] To 4-methoxy-1-methyl-1H-indole-2-carboxylic acid (24.4 mmol, 5 g) and oxalyl chloride (24.4 mmol, 2.3 mL) in dichloromethane (60 mL) A / ,A / -dimethylformamide (1.22 mmol, 95 pL) was added and the mixture was stirred at room temperature until it formed a clear solution (approximately 4 hours). The mixture was concentrated in vacuo. The residue, 4-methoxy-1-methyl-1 H-indole-2-carbonyl chloride, was added to a solution of 4-amino-3-methoxyphenylboronic acid pinacol ester (24.2 mmol, 6.03 g) and 4-dimethylaminopyridine (2.419 mmol, 0.296 g) in pyridine (30 mL) and dichloromethane (30 mL). After stirring at room temperature overnight the reaction mixture was diluted with dichloromethane and 2N hydrochloric acid. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo to give 10.55 g of the title compound.

[0633] Intermediate BP15

[0634] A / -(4-lsopropyl-3-methyl-phenyl)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide

[0635] (Intermediate BP15)

[0636] A solution of 4-DMAPcat (33 mg, 0.27 mmol), EDCI.HCI (516 mg, 191.71 mmol), 3- carboxyphenylboronic acid, pinacol ester (635 mg, 2.56 mmol) and 4-isopropyl-3-methylaniline hydrochloride (500 mg, 2.69 mmol) in DCM (25 mL) was stirred at room temperature o / n. 3% aq. Citric acid solution (25 mL) and ethyl acetate (25 mL) were added to the reaction mixture and the mixture was stirred for 5 min at room temperature. The organic layer was separated, washed with 1% aq. citric acid solution (25 mL) and brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using SiO2 and ethyl acetate / heptane = 1 / 4 to 1 / 1 v / v%. All fractions containing the title compound were collected and concentrated under reduced pressure to give 630 mg (Yield 61.7%). Intermediate BP16

[0637] 1-(5-tert-Butylisoxazol-3-yl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]urea

[0638] (Intermediate BP16)

[0639] (a) 2,2,2-Trichloroethyl A / -(5-fert-butylisoxazol-3-yl)carbamate

[0640] To a cold (0 °) solution of 3-amino-5-tert-butylisoxazole ( 1.o g, 7.13 mmol) and pyridine (632 pL, 7.84 mmol) in THF (40 mL) was added 2,2,2-trichloroethyl chloroformate (1.08 mL, 7.84 mmol) was added drop-wise within 10 minutes. The resulting suspension was stirred 1 h at 0 °C and further 4 h at room temperature. The mixture was diluted with ethyl acetate (20 mL) and water (20 mL) was added. The resulting bi-phasic system was stirred 30 min at room temperature. After separation of the layers, the water layer was extracted with ethyl EtOAc (2x20 mL). The combined organic layers were washed with water (2x50 mL), 50 mL sat. aq. NaHCOa-solution and brine (25 mL), dried (Na2SO4), filtered and concentrated to give 2.27 g of the title compound (yield >95%). This was used without further purification.

[0641] (b) 1-(5-tert-Butylisoxazol-3-yl)-3-r4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl1urea (Intermediate BP16)

[0642] 4-Aminophenylboronic acid pinacol ester (183 mg, 0.83 mmol) and A / , / V-diisopropylethylamine (533 pL, 3.0 mmol) were added to a solution of 2,2,2-trichloroethyl A / -(5-fert-butylisoxazol-3-yl)carba- mate (315 mg, 1.0 mmol) in DMSO (20 mL). The reaction mixture was stirred at 100 °C for 24 h. The mixture was poured in a stirred mixture of water (100 mL), brine (100 mL) and EtOAc (50 mL). The resulting bi-phasic system was stirred 30 min at room temperature. After separation of the layers, the water layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with water / brine = 1 / 1 v / v% (100 mL), 0.2N HCI-solution (2x100 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was triturated with dichloromethane (10 mL) to give 100 mg of the title compound (yield: 25%). Intermediate BP17

[0643] 1-(3-Fluorophenyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl1urea (Intermediate BP17)

[0644] This compound was prepared in an analogous manner as described in Intermediate BP16 starting from 3-fluoroaniline to afford the title compound (42 mg, 28.9%).

[0645] Intermediate BP18

[0646] / \ / 1-(4-fluorophenyl)-A / 1'-[3-fluoro-4-(4l4,5,5-tetramethyl-1l3,2-dioxaborolan-2-yl)phenyl1cyclopropane- 1 ,1 -dicarboxamide (Intermediate BP18)

[0647] This compound was prepared in an analogous manner as described in Bioorg. Med. Chem. (2015), 23(3), 564-578 starting from commercially available 1-((4-fluorophenyl)carbamoyl)cyclo- propanecarboxylic acid and 4-amino-2-fluorophenylboronic acid pinacol ester to afford the title compound (587 mg, quantitative).

[0648] Intermediate BP19

[0649] / \Z-[4-(4,4l5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl1-3-(trifluoromethyl)benzamide (Intermediate

[0650] BP19) This compound was prepared in an analogous manner as described in Bioorg. Med. Chem. (2015), 23(3), 564-578 starting from commercially available 3-(frifluoromethyl)benzoic acid and 4- aminophenylboronic acid pinacol ester to afford the title compound (393 mg, 90%). Intermediate BP20

[0651] / \ / -(5-fe / 't-butylisoxazol-3-yl)-2-[4-(4l4,5l5-tetramethyl-1 ,3l2-dioxaborolan-2-yl)phenyl1acetamide

[0652] (Intermediate BP20)

[0653] This compound via an HATU coupling starting from commercially available phenylacetic acid- 4-boronic acid pinacol ester and 3-amino-5-ferf-butylisoxazole to afford the title compound (139 mg,

[0654] 28%).

[0655] Intermediate L1

[0656] Swartz-rea ent tert-Butyl A / -[(E)-6-(4,4,5,5-tetramethyl-1 ,3l2-dioxaborolan-2-yl)hex-5-enyl]carbamate (Intermediate L1)

[0657] (a) tert-Butyl A / -hex-5-ynylcarbamate

[0658] A solution of 6-heptynoic acid (0.800 mL, 6.32 mmol), diphenylphosphoryl azide (1.65 mL, 7.66 mmol), and EtsN (1 .75 mL, 12.6 mmol) in tert-BuOH (6.3 mL) was stirred at reflux for 48 h. The reaction mixture was cooled to rt and diluted with Et2O (50 mL) and H2O (50 mL). The layers were separated and the aqueous phase was extracted with Et20 (2 x 50 mL). The combined organic extracts were washed with H2O (100 mL) and brine (100 mL), dried over MgSCX filtered, and concentrated under reduced pressure to give a dark yellow oil. The oil was purified by chromatography on SiCh (15% EtOAc in hexanes) to give tert-butyl A / -hex-5-ynylcarbamate (0.54 g, 43.3%) as a clear, colourless oil.

[0659] (b) tert-Butyl A / -[(E)-6-(4,4l5,5-tetramethyl-1l3,2-dioxaborolan-2-yl)hex-5-enyl1carbamate (Intermediate L1)

[0660] A solution of tert-butyl A / -hex-5-ynylcarbamate (0.54 g, 2.74 mmol), ZrCp2(H)CI (211 mg, 0.82 mmol), EtaN (385 pL, 2.76 mmol), and pinacolborane (596 pL, 4.11 mmol) in dichloromethane (2.75 mL) was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature and quenched by dropwise addition of methanol (3.15 mL). The organic solvents were evaporated under reduced pressure to give a cloudy white oil which was taken up in diethyl ether (5 mL) and filtered through a thin pad of boron-doped SiCh. After “rinsing” with diethyl ether (25 mL) the filtrate was concentrated under reduced pressure to give 0.79 g (88.7%) a clear, colorless oil. The crude product was purified by flash chromatography on boron-doped silica gel in hexane / ethyl acetate = 95 / 5 to 8 / 2 v / v% as eluent. The fractions containing the title compound were pooled and concentrated to obtain 481 mg of the title compound (yield: 54%).

[0661] Intermediate L2 tert-Butyl / V-[(E)-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)hept-6-enyl]carbamate (Intermediate

[0662] L2)

[0663] This compound was prepared in an analogous manner as described in Intermediate L1 starting from 7-heptynoic acid to afford the title compound (742.6 mg, 28.9%). Intermediate L3

[0664] Schwartz-reagent

[0665] Pinacolborane DCM reflux, 3 h tert-Butyl A / -[2-[methyl-[(E)-3-(4,4,5l5-tetramethyl-1l3,2-dioxaborolan-2-yl)allyl1amino1ethyl]-carbamate (Intermediate L3)

[0666] (a) tert-Butyl M-[2-[methyl(prop-2-ynyl)amino]ethyr|carbamate

[0667] To a solution of propargyl p-toluenesulfonate (1.05 g, 4.98 mmol) in acetonitril (25 mL) was subsequently added N-tert-butoxycarbonyl-2-methylamino-ethylamine hydrochloride (4.75 mmol) and potassium carbonate (1.31 g, 9.49 mmol) and the reaction mixture was refluxed for 4 h. Water and 5% sodium bicarbonate solution were added to the mixture and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by chromatography on SiOs (ethyl acetate) to give tert-butyl A / -[2-[methyl(prop-2- ynyl)amino]ethyl]carbamate (0.88 g, 87.3%) as a clear, yellow oil.

[0668] (b) tert-Butyl A / -[2-rmethyl-r(E)-3-(4,4l5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl1amino1ethyl1- carbamate (Intermediate L3)

[0669] A solution of tert-Butyl A / -[2-[methyl(prop-2-ynyl)amino]ethyl]carbamate (0.88 g, 4.15 mmol), ZrCp2(H)CI (321 mg, 1.24 mmol), EtaN (584 pL, 4.19 mmol), and pinacolborane (902 pL, 4.19 mmol) in dichloromethane (5 mL) was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature and quenched by dropwise addition of methanol (5.3 mL). The organic solvents were evaporated under reduced pressure to give a cloudy white oil which was taken up in diethyl ether (5 mL) and filtered through a thin pad of boron-doped SiOa. After “rinsing” with diethyl ether (25 mL) the filtrate was concentrated under reduced pressure to give a clear, yellow oil. The crude product was purified by flash chromatography on boron-doped silica gel in ethyl acetate as eluent. The fractions containing the title compound were pooled and concentrated to obtain 0.88 g of the title compound. (Yield: 62.4%)

[0670] Intermediate L4 tert-Butyl A / -[2-[methyl-[(E)-4-(4,4,5l5-tetramethyl-1l3,2-dioxaborolan-2-yl)but-3-enyl]amino1- ethyllcarbamate (Intermediate L4) This compound was prepared in an analogous manner as described in Intermediate L3, starting from M-tert-butoxycarbonyl-2-methylamino-ethylamine hydrochloride and 3-butynyl p- toluenesulfonate to afford the title compound (1.07 g, 52.6%).

[0671] Intermediate L5

[0672] Schwartz-reagent O

[0673] Et3N

[0674] -

[0675] Pinacolborane

[0676] □CM reflux, 3 h

[0677] Methyl 2-[(E)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3-enoxy]acetate (Intermediate L5)

[0678] (a) Methyl 2-but-3-ynoxyacetate

[0679] To a cold (0 °C) suspension of NaH (60% dispersion in mineral oil, 428 mg, 10.7 mmol) in THF (7 mL) was added but-3-yn-1-ol (624 mg, 8.92 mmol mmol) in THF (1 mL). After stirring at room temperature for 30 min, the mixture was cooled to 0 °C and a solution of methyl 2-bromoacetate (1.36 g, 8.92 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred o / n allowing the temperature to come to room temperature. Diethyl ether (25 mL) was added to the mixture and washed with water (25 mL). The water layer was extracted with diethyl ether (2x25 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiOz (pentanes / diethyl ether = 10 / 0 to 1 / 1 v / v%) to give methyl 2-but-3-ynoxyacetate (620 mg, 48%) as a clear, colourless oil.

[0680] (b) Methyl 2-[(E)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3-enoxy1acetate (Intermediate

[0681] L5)

[0682] This compound was prepared in an analogous manner as described in Intermediate L1 step b, starting from methyl 2-but-3-ynoxyacetate to afford the title compound (480 mg, 42%).

[0683] Intermediate L6

[0684] Methyl (E)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)hex-5-enoate (Intermediate L6)

[0685] This compound was prepared in an analogous manner as described in Intermediate L1 step b, starting from methyl 5-hexynoate to afford the title compound (558 mg, 44%).

[0686] -[(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl]amino1acetate no)acetate pargylamine (2.0 mL, 31.2 mmol) and triethylamine (4.8 mL, 34.4 mmol) moacetate (3.25 mL, 34.4 mmol). The reaction mixture was stirred at 50 uct, obtained after concentration of the mixture in vacuo, was purified by chloromethane / methanol = 10 / 0 to 95 / 5 v / v%) to give methyl 2-(prop-2- 7%) as an oil.

[0687] (b) Methyl 2-[terf-butoxycarbonyl(prop-2-ynyl)amino]acetate

[0688] To a cold (0 °C) solution of methyl 2-(prop-2ynylamino)acetate (1 .50 g, 11 .8 mmol) and DiPEA (3.90 mL, 23.6 mmol) in DCM (40 mL) was added BOC2O (2.32 g, 10.6 mmol) and the mixture was stirred o / n. The mixture was washed with 1 N KHSO4 (2x60 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound (2.42 g, 86%).

[0689] (c) Methyl 2-[tert-butoxycarbonyl-[(E)-3-(4l4l5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)allyl1amino]acetate (Intermediate L7)

[0690] This compound was prepared in an analogous manner as described in Intermediate L1 step b, starting from methyl 2-[tert-butoxycarbonyl(prop-2-ynyl)amino]acetate to afford the title compound (831 mg, 53%).

[0691] Methyl 2-[methyl-[(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl]amino]acetate (Intermediate

[0692] L8) This compound was prepared in an analogous manner as described in Intermediate L7, starting from A / -methyl-A / -prop-2ynyl-amine and methyl bromoacetate to afford the title compound (1.22 g, 64%).

[0693] Intermediate L9

[0694] Schwartz-reagent

[0695] (Intermediate L9)

[0696] This compound was prepared in an analogous manner as described in Intermediate L7, starting from A / -methyl-A / -prop-2ynyl-amine and methyl 4-bromobutyrate to afford the title compound (344 mg, 16%).

[0697] Intermediate L10 - enoate (Intermediate L10)

[0698] (a) Methyl 6-oxo-8-trimethylsilyl-oct-7-vnoate

[0699] A solution of bis(trimethylsilyl)acetylene (12.8 g, 96 mmol) and methyl 6-chloro-6-oxo- hexanoate (80 mmol) in dichloromethane (100 mL) was added dropwise to a suspension of aluminium chloride (12.8 g, 96 mmol) in dichloromethane (100 mL) at 0 °C and stirred for 2 h allowing the temperature to come to room temperature. The reaction mixture was quenched with ice and saturated aq. citric acid (100 mL) and extracted with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The brown residue was purified by column chromatography (hexane / ethyl acetate = 99:1 to 9 / 1 v / v%) on silica gel to afford the title compound (4.86 g, 25.3%) as a yellowish oil. Crude fractions were again purified by column chromatography (hexane / ethyl acetate = 99:1 to 95 / 5 v / v%) on silica gel to afford the title compound (5.37 g, 27.9%) as a yellowish oil.

[0700] (b) Methyl (6S)-6-hydroxy-8-trimethylsilyl-oct-7-vnoate

[0701] A mixture of (1 S,2S)-(+)-A / -(4-toluenesulfonyl)-1 ,2-diphenylethylenediamine (295 mg, 0.806 mmol), dichloro(p-cymene)ruthenium(ll)dimer (248 mg, 0.40 mmol) and potassium hydroxide (363 mg, 6.47 mmol) in dichloromethane (10 mL) was stirred at room temperature for 10 min. The solution was treated with water (10 mL) and the colour changed from orange to deep purple. The organic layer was separated and dried over MgSCh, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (2 mL) and added to a solution of methyl 6-oxo-8-trimethylsilyl-oct-7-ynoate (4.86 g, 20.22 mmol) in degassed isopropanol (50 mL) at room temperature. After stirring o / n, the solution was recharged with same amount of pre-treaded Ru-cat. and stirred at room temperature for 2 h, concentrated under reduced pressure and the residue was filtered on silica gel (hexane / ethyl acetate = 98 / 2 to 9 / 1 v / v%) to afford the title compound (4.27 g, 87.1 %) as a yellow / orange oil.

[0702] (c) Methyl (6S)-6-hydroxyoct-7-ynoate

[0703] 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. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 6 / 4 v / v%) affording methyl (6S)-6-hydroxyoct-7-ynoate (2.4 g, 80.0%) as a yellowish oil.

[0704] (d) Methyl (6S)-6-[te / 't-butyl(dimethyl)silyl]oxyoct-7-ynoate

[0705] To a solution of methyl (6S)-6-hydroxyoct-7-ynoate (2.4 g, 14.1 mmol) in dichloromethane (25 mL) under nitrogen atmosphere was added at 0 °C fert-butyldimethylsilyl chloride (2.34 g, 15.51 mmol) and imidazole (1.92 g, 28.2 mmol). The mixture was stirred at room temperature o / n and water was added. The aqueous layer was separated over a PE-filter and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 99 / 1 to 9 / 1 v / v%) affording methyl (6S)-6-[tert-butyl(dimethyl)silyl]oxyoct-7-ynoate (3.79 g, 75.6% over two steps) as a colourless oil.

[0706] (e) Methyl (E,6S)-6-[tert-butyl(dimethyl)silyl1oxy-8-(4l4,5,5-tetramethyl-1l3,2-dioxaborolan-2-yl)oct-7- enoate (Intermediate L10)

[0707] To an oven-dried 10 mL Schlenk-tube equipped with a magnetic stirring bar were added Schwartz’s reagent (90.6 mg, 0.35 mmol), methyl (6S)-6-[tert-butyl(dimethyl)silyl]oxyoct-7-ynoate (1 g, 3.51 mmol), EtsN (49 pL, 0.35 mmol) and pinacolborane (552 pL, 3.69 mmol), under an inert nitrogen atmosphere. The tube was then sealed and the mixture was stirred at 60 °C for 24 hours. The reaction was allowed to cool to room temperature, diluted with diethyl ether, passed through a pad of silica gel and concentrated under reduced pressure at room temperature. The crude mixture was purified by column chromatography using SiOs and hexane / ethyl acetate = 99 / 1 to 9 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 311.6 mg of the title compound (yield: 21.5%).

[0708] Intermediate L11 1 ,3,2-dioxaborolan-2-yl)oct-7- enoate (Intermediate L11)

[0709] This compound was prepared in an analogous manner as described in Intermediate L10, starting from methyl 6-oxo-8-trimethylsilyl-oct-7-ynoate and of (1R,2R)-(+)- / \ / -(4-toluenesulfonyl)-1 ,2- diphenylethylenediamine to afford the title compound (295 mg, 20.4%).

[0710] Intermediate L12 -1 ,3,2-dioxaborolan-2-yl)hept-6- enoate (Intermediate L12)

[0711] This compound was prepared in an analogous manner as described in Intermediate L10, starting from methyl 5-oxo-7-trimethylsilyl-hept-6-ynoate and of (1 S,2S)-(+)- / \ / -(4-toluenesulfonyl)-1 ,2- diphenylethylenediamine to afford the title compound (367.6 mg, 20.1%).

[0712] Intermediate L13 -1 ,3,2-dioxaborolan-2-yl)hept-6- enoate (Intermediate L13)

[0713] This compound was prepared in an analogous manner as described in Intermediate L10, starting from methyl 5-oxo-7-trimethylsilyl-hept-6-ynoate and of (1R,2R)-(+)-A / -(4-toluenesulfonyl)-1 ,2- diphenylethylenediamine to afford the title compound (400.9 mg, 21 .8%). Intermediate L14

[0714] Methyl 4-[tert-butoxycarbonyl-|'(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl]amino]- butanoate (Intermediate L14)

[0715] (a) 2-Nitro-A / -prop-2-vnyl-benzenesulfonamide

[0716] To a solution of propargylamine (3.2 ml_, 50 mmol) and triethylamine (17.5 mL, 125 mmol) in dichloromethane (100 mL) was added 2-nitrophenylsulfonyl chloride (10.5 g, 47.2 mmol). The reaction mixture was stirred at room temperature o / n. The mixture was washed, after addition of dichloromethane (100 mL), with 1 N HCI-solution, water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate / heptane to give 2-nitro-A / -prop-2-ynyl- benzenesulfonamide (9.57 g, 79%).

[0717] (b) Methyl 4-[(2-nitrophenyl)sulfonyl-prop-2-ynyl-amino]butanoate

[0718] To a solution of 4-nitro-A / -prop-2-ynyl-benzenesulfonamide (1 g, 4.16 mmol) and K2CO3 (1.15 g, 8.32 mmol) in DMF (12 mL) was added t-butyl-3-bromopropionate (0.9 g, 5 mmol) and the mixture was stirred at 40 °C for 4 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3x100 mL), brine and dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography using SiCh and heptane / ethyl acetate = 1 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 1.5 g of the title compound (yield: 85%).

[0719] (c) Methyl 4-[tert-butoxycarbonyl(prop-2-vnyl)amino]butanoate

[0720] To a solution of methyl 4-[(2-nitrophenyl)sulfonyl-prop-2-ynyl-amino]butanoate (0.950 g, 2.79 mmol) and cesium carbonate (1 .82 g, 5.58 mmol) in MeCN (15 mL) was added 2-mercaptoethanol (235 pL, 3.35 mmol) This was heated to 40°C for 1 d. Subsequently di-tert-butyl bicarbonate (0.245 g, 1.12 mmol) was added and stirred at rt for 1 h. After addition of ethyl acetate (100 mL) the mixture was washed with 5% aq. NaHCOa-solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography using SiO2 and heptane / ethyl acetate = 1 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 0.73 g of the title compound (yield: 72%).

[0721] (d) Methyl 4-[tert-butoxycarbonyl-[(E)-3-(4l4l5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl]- aminolbutanoate (Intermediate L14)

[0722] This compound was prepared in an analogous manner as described in Intermediate L1 step b, starting from methyl 4-[tert-butoxycarbonyl(prop-2-ynyl)amino]butanoate to afford the title compound (304 mg, 28%). Intermediate L15

[0723] Methyl (E)-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)oct-7-enoate (Intermediate L15)

[0724] (a) Methyl oct-7-ynoate

[0725] To a solution of oct-7-ynoic acid (1.82 g, 13 mmol) in methanol (15 ml) was added conc.-FbSOd (4 drops). The reaction mixture was stirred for 5 h. at 70 °C. After cooling of the mixture, ethyl acetate (150 mL) was added and the organic phase was washed with sat. aq. NaHCOa-solution, water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.86 g of methyl oct-7-ynoate (yield: 93%).

[0726] (b) Methyl 2-[(E)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3-enoxy]acetate (Intermediate L15)

[0727] This compound was prepared in an analogous manner as described in Intermediate L10 step e, starting from methyl oct-7-ynoate to afford the title compound (881 mg, 47%).

[0728] Intermediate L16 e (Intermediate L16)

[0729] This compound was prepared in an analogous manner as described in Intermediate L15, starting from non-8-ynoic acid to afford the title compound (785 mg, 45%).

[0730] Intermediate L17 re ux

[0731] (Intermediate L17)

[0732] (a) Ethyl 3-[methyl(prop-2-ynyl)amino]propanoate A / -methyl propargylamine (1.0 g, 18.15 mmol) was added to ethyl acrylate (1.21 g, 12.1 mmol) followed by addition of acidic alumina (24.2 mmol, 2 eq.) and the mixture was stirred at 75°C in a sealed tube for 3 h. The mixture was purified directly by column chromatography using SiO2 and heptane / ethyl acetate = 10 / 0 to 3 / 7 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 2.41 g of the title compound (yield: 106%).

[0733] (b) Ethyl 3-[methyl-[(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl]amino]propanoate (Intermediate L17)

[0734] This compound was prepared in an analogous manner as described in Intermediate L10 step e, starting from ethyl 3-[methyl(prop-2-ynyl)amino]propanoate to afford the title compound (112 mg, 24%).

[0735] Intermediate L18

[0736] Schwartz-reagent

[0737] Pinacolborane reflux

[0738] Methyl 2-r(E)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pent-4-enoxy]acetate (Intermediate L18)

[0739] (a) Methyl 2-pent-4-ynoxyacetate

[0740] Sodium hydride (60% dispersion in mineral oil, 428 mg, 10.7 mmol) was suspended in THF (7 mL) and cooled to 0 °C. Next, a solution of the 4-pentyn-1-ol (750 mg, 8.92 mmol) in THF (1 mL) was added dropwise. The reaction mixture was allowed to come to room temperature and stirred for 30 min. The resulting suspension was cooled to 0 °C again and methyl 2-bromoacetate (1.36 g, 8.92 mmol) in THF (1 mL) was added dropwise. The resulting mixture was allowed to come to room temperature and stirred o / n. The reaction mixture was diluted with diethyl ether (25 mL) followed by addition of sat. aq. ammonium chloride solution (10 mL). The aqueous layer was extracted twice with diethyl ether (10 mL). The combined organic layers were, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, (first 46 °C, 750 mbar, followed by rt, 70 mbar for 15 minutes) to give an orange / brown liquid. The mixture was purified directly by column chromatography using SiCte and pentanes / diethyl ether = 95 / 5 to 1 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 480 mg of the title compound (yield: 34%).

[0741] (b) Methyl 2-[(E)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pent-4-enoxy]acetate (Intermediate L18)

[0742] This compound was prepared in an analogous manner as described in Intermediate L10 step e, starting from methyl 2-pent-4-ynoxyacetate to afford the title compound (430 mg, 49%).

[0743] Intermediate L19

[0744] (Intermediate L19)

[0745] This compound was prepared in an analogous manner as described in Intermediate L9, starting from A / -methylprop-2-yn-1 -amine and ethyl 5-bromopentanoate to afford the title compound (550 mg, 30%).

[0746] Intermediate L20

[0747] (Intermediate L20)

[0748] This compound was prepared in an analogous manner as described in Intermediate L17 step a and Intermediate 7 step b and c, starting from propargylamine and ethyl acrylate to afford the title compound (594 mg, 19%).

[0749] Intermediate L21

[0750] (Intermediate L21)

[0751] This compound was prepared in an analogous manner as described in Intermediate L14, starting from propargylamine and ethyl 5-bromopentanoate to afford the title compound (537 mg, 25%).

[0752] Intermediate L22 oate (Intermediate L22)

[0753] This compound was prepared in an analogous manner as described in Intermediate L15, starting from 6-heptynoic acid to afford the title compound (2.15 g, 25%). Intermediate L23

[0754] Methyl 3-[(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyloxy]propanoate (Intermediate L23)

[0755] (a) tert-Butyl 3-prop-2-ynoxypropanoate

[0756] To a solution of propargyl alcohol (1.36 mL, 23.4 mmol) in THF (20 mL) was added a small lump of sodium (-20.08 mg, 0.874 mmol) and the reaction mixture was heated at 60°C until complete solubilization (30-45 min) of sodium. The reaction mixture was cooled to room temperature and tertbutyl acrylate (2.29 mL, 15.6 mmol) in THF (3 mL) was added dropwise over 10 minutes. After completion of addition, the reaction mixture was stirred 3 h at room temperature. Water (25 mL) was added to the reaction mixture and the bi-phasic system was stirred 30 minutes at room temperature. The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (2x20 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.2 g (yield: 76%) of tert-butyl 3-prop-2-ynoxypropanoate as a colourless oil.

[0757] (b) Methyl 3-prop-2-ynoxypropanoate

[0758] To a solution of tert-butyl 3-prop-2-ynoxypropanoate (2.2 g, 11.9 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (8 mL, 119 mmol). The reaction mixture was stirred at room temperature o / n. The mixture was concentrated and traces of trifluoroacetic acid were co-evaporated with toluene and DCM. The residue was purified by flash column chromatography using SiO2 and dichloromethane / methanol = 10 / 0 to 9 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo. The residue was dissolved in methanol (5 mL) and cone. H2SO4 (4 drops) was added. The reaction mixture was stirred at 70 °C o / n. After cooling of the mixture, ethyl acetate (150 mL) was added and the organic phase was washed with sat. aq. NaHCOa-solution, water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1 .34 g of methyl 3- prop-2-ynoxypropanoate (yield: 91 %).

[0759] (c) Methyl 3-[(E)-3-(4,4l5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyloxy]propanoate (Intermediate L23)

[0760] This compound was prepared in an analogous manner as described in Intermediate L10 step e, starting from methyl 3-prop-2-ynoxypropanoate to afford the title compound (920 mg, 37%). Intermediate L24

[0761] Methyl 3-[(E)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3-enoxy]propanoate (Intermediate

[0762] L24)

[0763] This compound was prepared in an analogous manner as described in Intermediate L23, starting from but-3-yn-1-ol and ferf-butyl acrylate to afford the title compound (1.32 g, 38%).

[0764] Intermediate L25

[0765] Ethyl 4-[(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyloxy]butanoate (Intermediate L25)

[0766] (a) 3-(2-Bromoethoxy)prop-1 -yne

[0767] Triphenylphosphine (3.93 g, 15 mmol) was added at room temperature, portion-wise to a stirred solution of carbon tetrabromide (4.97 g, 15 mmol) and 2-prop-2-ynoxyethanol (1.00 g, 10 mmol) in DCM (33 mL). The reaction mixture was stirred at room temperature o / n. The mixture was concentrated and the residue was purified by column chromatography using SiOz and pentanes / diethyl ether = 95 / 5 to 8 / 2 v / v%. All fractions containing the title compound were collected and concentrated in vacuo (500 mbar) to give 730 mg of the title compound (yield: 46%).

[0768] (b) Diethyl 2-(2-prop-2-ynoxyethyl)propanedioate

[0769] NaH (60% dispersion in mineral oil, 122 mg, 3.0 mmol) was added carefully to a stirred solution of diethyl malonate (418 pL, 2.75 mmol) in THF (23 mL) at room temperature. The reaction mixture was stirred for 30 min after which a solution of 3-(2-bromoethoxy)prop-1-yne (450 mg, 2.75 mmol) in THF (4.5 mL) was added dropwise, followed by sodium iodide (405 mg, 2.75 mmol). The resulting mixture was stirred at 54 °C for 24 h. The mixture was diluted with water (25 mL) and diethyl ether (25 mL) was added. The organic phase was separated and the water layer was extracted with diethyl ether (2x20 mL). The combined organic extracts were washed with water (2x30 mL), brine (15 mL), dried (Na2SO4) filtered and concentrated in vacuo to give 500 mg of the title compound which was used directly in the next step.

[0770] (c) Ethyl 4-prop-2-vnoxybutanoate

[0771] To a solution of diethyl 2-(2-prop-2-ynoxyethyl)propanedioate (635 mg, 2.62 mmol) in DMSO (1.3 mL) was added water (94 pL, 5.24 mmol) and lithium chloride (331 mg, 7.87 mmol). The resulting mixture was stirred at 170 °C for 3 h. Water (50 mL), brine (50 mL) and diethyl ether (50 mL) were added to the cooled mixture. After stirring 30 minutes at room temperature, the mixture was filtered over Decalite ® and the layers of the filtrate were separated. The water layer was extracted with diethyl ether (2x25 mL). The combined organic extracts were washed with water (100 mL), brine (25 mL), dried (Na2SO4) filtered and concentrated in vacuo (500 mbar). The mixture was concentrated and the residue was purified by column chromatography using SiO2 and pentanes / diethyl ether = 99 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo (300 mbar) to give 103 mg of the title compound (yield: 46% taking into account content of 50%).

[0772] (d) Ethyl 4-[(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyloxy1butanoate (Intermediate L25) This compound was prepared in an analogous manner as described in Intermediate L10 step e, starting from ethyl 4-prop-2-ynoxybutanoate to afford the title compound (50 mg, 28%).

[0773] Intermediate L26

[0774] Methyl (2F?)-2-r(E)-3-(4,4,5,5-tetramethyl-1 ,312-dioxaborolan-2-yl)allyloxy1propanoate (Intermediate

[0775] L26)

[0776] This compound was prepared in an analogous manner as described in Intermediate L18, starting from propargyl bromide and (R)-(+)-methyl lactate to afford the title compound (380 mg, 44%).

[0777] Intermediate L27

[0778] Methyl 2-rmethyl-r(E)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3-enyl1amino1acetate (Intermediate L27)

[0779] This compound was prepared in an analogous manner as described in Intermediate L3, starting from 3-butynyl p-toluenesulfonate and sarcosine methyl ester, HCI to afford the title compound (372 mg, 37%).

[0780] Intermediate L28

[0781] Methyl 2-7ert-butoxycarbonyl-[(E)-5-(4,4,5l5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pent-4- enyllaminolacetate (Intermediate L28) This compound was prepared in an analogous manner as described in Intermediate L14, starting from 4-pentyn-1-ol and glycine methyl ester hydrochloride to afford the title compound (1.18 g, 88%).

[0782] Intermediate L29 aborolan-2-yl)but-3- (Intermediate L29)

[0783] This compound was prepared in an analogous manner as described in Intermediate L14, starting from but-3-yn-1-ol and glycine methyl ester hydrochloride to afford the title compound (615 mg, 65%).

[0784] Intermediate L30

[0785] This compound was prepared in an analogous manner as described in Intermediate L14, starting from but-3-yn-1-ol and methyl 3-aminopropanoate hydrochloride to afford the title compound (544 mg, 47%).

[0786] Intermediate L31

[0787] Methyl (2S)-1-[(E)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3-enyl]azetidine-2-carboxylate (Intermediate L31)

[0788] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from methyl (2S)-azetidine-2-carboxylate hydrochloride and but- 3-ynyl 4-methylbenzenesulfonate to afford the title compound (348 mg, 36%).

[0789] Intermediate L32

[0790] (Intermediate L32)

[0791] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from methyl 3-(methylamino)propanoate and but-3-ynyl 4- methylbenzenesulfonate to afford the title compound (574 mg, 40%).

[0792] Intermediate L33

[0793] This compound was prepared in an analogous manner as described in Intermediate 7 and Intermediate L10, starting from the Weinreb amide of Boc-Gly-OH and TMS-acetylene to afford the title compound (241 mg, 35%).

[0794] Intermediate L34

[0795] Swartz-reagent ,3,2-dioxaborolan-2-yl)but-3-enyllaminol-butanoate

[0796] (Intermediate L34)

[0797] (a) Methyl (3 / ?)-3-[(2-nitrophenyl)sulfonylamino]butanoate

[0798] To a solution of (R)-3-amino-butyric acid methyl ester hydrochloride (3 g, 25.6 mmol) and triethylamine (8.5 ml_, 64 mmol) in dichloromethane (75 ml_) was added 2-nitrophenylsulfonyl chloride (5.8 g, 26.2 mmol). The reaction mixture was stirred at room temperature o / n. The mixture was washed, after addition of dichloromethane (75 mL), with 0.1 N HCI-solution, 5% aq. NaHCOa-solution, water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography using SiO? and heptane / ethyl acetate = 9 / 1 to 4 / 6 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give methyl (3R)- 3-[(2-nitrophenyl)sulfonylamino]butanoate (5.6 g, 95%).

[0799] (b) Methyl (3R)-3-[methyl-(2-nitrophenyl)sulfonyl-amino]butanoate

[0800] To a solution of methyl (3R)-3-[(2-nitrophenyl)sulfonylamino]butanoate (4.09 g, 12.9 mmol) and K2CO3 (3.57 g, 25.8 mmol) in acetonitrile (44 mL) was added methyl iodide (0.84 mL, 13.5 mmol) and the mixture was stirred at 50 °C for 2 d. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3x100 mL), brine and dried over sodium sulfate, filtered and concentrated in vacuo to give 4.13 g of the title compound (yield: 101 %).

[0801] (c) Methyl (3R)-3-(methylamino)butanoate

[0802] To a solution of methyl (3R)-3-[methyl-(2-nitrophenyl)sulfonyl-amino]butanoate (1.69 g, 5.34 mmol) and cesium carbonate (3.49 g, 10.7 mmol) in acetonitrile (20 mL) was added 2-mercaptoethanol (1.1 mL, 15.66 mmol) This was heated to 40°C o / n. The reaction mixture was filtered and acidified with 2 N HCI-solution until pH 1 was reached. Then mixture was then loaded over a SCX-2 column (20 g). The column was washed with acetonitrile until the column was colourless, followed by a solvent switch to methanol and then the product was eluted with 2 N NHa / MeOH to yield methyl (3R)-3- (methylamino)butanoate (0.569 g, 81 % ).

[0803] (d) Methyl (3R)-3-[methyl-[(E)-4-(4,4,5l5-tetramethyl-1 ,312-dioxaborolan-2-yl)but-3-enyl1amino1- butanoate (Intermediate L34)

[0804] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from methyl (3R)-3-(methylamino)butanoate and but-3-ynyl 4- methylbenzenesulfonate to afford the title compound (980 mg, 57%).

[0805] Intermediate L35

[0806] Methyl 2-rmethyl-r(E)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pent-4-envHamino]acetate (Intermediate L35)

[0807] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from sarcosine methyl ester hydrochloride and pent-4-ynyl methanesulfonate to afford the title compound (760 mg, 37%). Intermediate L36

[0808] (Intermediate L36)

[0809] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from methyl (2R)-azetidine-2-carboxylate hydrochloride and but- 3-ynyl 4-methylbenzenesulfonate to afford the title compound (1.1 g, 91 %).

[0810] Intermediate L37 butanoate (Intermediate L37)

[0811] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from methyl 4-(methylamino)butanoate hydrochloride and [(1 R)-1 - methylprop-2-ynyl] 4-methylbenzenesulfonate to afford the title compound (78 mg, 23%).

[0812] Intermediate L38

[0813] (Intermediate L38)

[0814] This compound was prepared in an analogous manner as described in Intermediate L34, starting from methyl (3R)-3-(methylamino)butanoate and propargyl p-toluenesulfonate to afford the title compound (215 mg, 24%).

[0815] Intermediate L39 Methyl (3R)-3-[tert-butoxycarbonyl-[(E)-4-(4l4,5l5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3- enyl]amino]butanoate (Intermediate L39)

[0816] This compound was prepared in an analogous manner as described in Intermediate L14, starting from but-3-yn-1-ol and (R)-3-amino-butyric acid methyl ester hydrochloride to afford the title compound (759 mg, 55%).

[0817] Intermediate L40 (Intermediate L40)

[0818] This compound was prepared in an analogous manner as described in Intermediate L18, starting from propargyl alcohol and methyl bromoacetate to afford the title compound (359 mg, 41%).

[0819] Intermediate L41

[0820] Methyl (2S)-1-[(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl]azetidine-2-carboxylate (Intermediate L41)

[0821] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from methyl (2S)-azetidine-2-carboxylate hydrochloride and prop- 2-ynyl 4-methylbenzenesulfonate to afford the title compound (1 .86 g, 80%).

[0822] Intermediate L42 te L42)

[0823] (a) 2-prop-2-ynylsulfanylacetic acid

[0824] A solution of propargyl bromide in toluene (18.4 mL, 213 mmol) was added to a cold (0 °C) solution of mercaptoacetic acid (13.08 g, 142 mmol) in aqueous ammonia (24%, 250 mL). The reaction mixture was stirred at 0 °C for 40 min. The solution was concentrated, filtered and a sat. aq. NaHCCh- solution was added. The solution was washed with dichloromethane. The aqueous phase was carefully acidified with concentrated HCI and extracted with dichloromethane. The organic phase was separated over a PE-filter and concentrated under reduced pressure giving 13.53 g of 2-prop-2-ynylsulfanylacetic acid as a slightly green oil which crystalized slowly to form off-white crystals (Yield: 73.2%).

[0825] (b) 2-prop-2-vnylsulfanylacetic acid

[0826] To a solution of 2-prop-2-ynylsulfanylacetic acid (13.53 g, 104 mmol) in methanol (150 mL) was added 10 drops of H2SO4 (cone). The reaction mixture was stirred at reflux for 3 h. The mixture was concentrated under reduced pressure and ethyl acetate was added. The organic was washed carefully with 5% aq. NaHCCh-solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 14.11 g of the title compound as a slightly brown oil (yield: 94.1 %).

[0827] (c) Methyl 2-[(E)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)allyl]sulfanylacetate (Intermediate

[0828] L42)

[0829] This compound was prepared in an analogous manner as described in Intermediate 10 step e, starting from 2-prop-2-ynylsulfanylacetic acid to afford the title compound (455 mg, 25%).

[0830] Intermediate L43

[0831] Methyl (E)-10-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)dec-9-enoate (Intermediate L43)

[0832] This compound was prepared in an analogous manner as described in Intermediate L15, starting from dec-9-ynoic acid to afford the title compound (801 mg, 39%).

[0833] Intermediate L44

[0834] Methyl (E)-11 -(4,4,5,5-tetramethyl-1l3,2-dioxaborolan-2-yl)undec-10-enoate (Intermediate L44)

[0835] This compound was prepared in an analogous manner as described in Intermediate L15, starting from undec-10-ynoic acid to afford the title compound (278 mg, 14%).

[0836] Intermediate L45

[0837] Ethyl 3-[(E)-1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3-enoxy]propanoate (Intermediate L45)

[0838] This compound was prepared in an analogous manner as described in Intermediate L23, starting from 4-pentyn-2-ol and fert-butyl acrylate to afford the title compound (1.08 g, 87%).

[0839] Intermediate L46 Methyl (E,7S)-7-|~tert-butyl(dimethyl)silyl1oxy-9-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)non-8- enoate (Intermediate L46)

[0840] This compound was prepared in an analogous manner as described in Intermediate L10, starting from ethyl 7-chloro-7-oxo-heptanoate and of (1 S,2S)-(+)- / V-(4-toluenesulfonyl)-1 ,2- diphenylethylenediamine to afford the title compound (477 mg, 22.2%).

[0841] Intermediate L47

[0842] Ethyl (E)-6,6-dideuterio-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)oct-7-enoate (Intermediate L47)

[0843] (a) Methyl 6,6-dideuterio-6-hydroxy-hexanoate

[0844] To a cold (0 °C) solution of adipic acid monomethyl ester (958 mg, 5.98 mmol) and triethylamine (917 pL, 6.58 mmol) in THF (9.5 mL) was added drop-wise solution of ethyl chloroformate (629 pL, 6.58 mmol) in THF (7.0 mL). The mixture was stirred for 1 h allowing the temperature to come to room temperature. The mixture was filtrated and the residue washed with THF (5 mL). The combined filtrates were added dropwise to a solution of NaBD4 (500 mg, 11 .9 mmol) in water (14 mL) at 0 °C. The reaction mixture was stirred for 1 h. The mixture was acidified with 2N aq. HCI-solution (10 mL) to adjust the pH to 3-4 and diethyl ether was added (20 mL). The resulting mixture was stirred 30 minutes at room temperature. The water layer was separated and extracted with diethyl ether (2x10 mL). The combined organic layers were washed with 0.5N NaOH (2x20 mL), water (20 mL) and brine (5.0 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography using SiCh and pentane / diethyl ether = 4 / 1 to 0 / 10 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give methyl 6,6-dideuterio-6-hydroxy- hexanoate (280 mg, 32%).

[0845] (b) 6,6-Dideuterio-6-hydroxy-hexanoic acid

[0846] Methyl 6,6-dideuterio-6-hydroxy-hexanoate (280 mg, 1 .89 mmol) was dissolved in THF / water = 1 / 1 v / v% (18 mL) and subsequently lithium hydroxide (50 mg, 2.08 mmol) was added. The mixture was stirred at room temperature o / n. Ethyl acetate (50 mL) and water (were added) and the pH of the mixture was adjusted to pH < 3 by addition of 2M HCI-solution. The organic phase was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 230 mg of 6,6-dideuterio-6-hydroxy-hexanoic acid (yield: 91 %).

[0847] (c) 6-Bromo-6,6-dideuterio-hexanoic acid

[0848] 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. Next, 6,6-dideuterio-6-hydroxy-hexanoic acid (230 mg, 1.72 mmol) dissolved in dichloromethane (8 mL) was added dropwise and the mixture was stirred for 45 min at - 78 °C allowing to come to room temperature. The mixture was diluted with water and thoroughly stirred, 15 minutes at rt. The layers were separated and the water layer was extracted with dichloromethane (2x10 mL). The organic layers were combined and washed with 10% aq. Na2S2O4- solution (20 mL), 0.2N aq. NaOH-solution. 2N aq. HCI-solution was added to the alkaline water layer to adjust pH < 3. This water layer was extracted with dichloromethane. The combined organic layers were filtered over a PE filter and concentrated under reduced pressure to afford 230 mg of the title compound (yield: 54%).

[0849] (d) 6,6-Dideuteriooct-7-ynoic acid

[0850] A solution of 6-bromo-6,6-dideuterio-hexanoic acid (405 mg, 2.05 mmol) in DMSO (1 mL) was added dropwise to a cold (0 °C) suspension of lithium acetylide ethylenediamine complex (560 mg, 6.09 mmol) in DMSO (2 mL). The resulting mixture was allowed to come to room temperature and stirred 1 .5 h. The mixture was cautiously poured, at 0 °C, in a mixture of ice-water (35 mL) and brine (20 mL) and stirred 30 min at 0 °C. At this temperature, 2 N aq. HCI-solution (10 mL) was added followed by ethyl acetate (20 mL) and after stirring 30 minutes at room temperature, the layers were separated. The water layer was extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography using SiO2 and heptane / ethyl acetate = 95 / 5 to 1 / 4 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 6,6-dideuteriooct-7-ynoic acid (200 mg, 69%).

[0851] (e) Ethyl (E)-6,6-dideuterio-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)oct-7-enoate (Intermediate L47)

[0852] This compound was prepared in an analogous manner as described in Intermediate L10, starting from ethyl 6,6-dideuteriooct-7-ynoate to afford the title compound (320 mg, 86%).

[0853] Intermediate L48

[0854] [(E)-3,3-Difluoro-7-methoxy-7-oxo-hept-1 -enyllboronic acid (Intermediate L48)

[0855] This compound was prepared according to procedures described in Org. Lett. (2020) 22, 2991 -2994 afford the title compound. Intermediate L49

[0856] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from 1 -tert-butyl 2-methyl (2R)-piperazine-1 ,2-di carboxyl ate and propargyl p-toluenesulfonate to afford the title compound (300 mg, 72%).

[0857] Intermediate L50 propanoate (Intermediate L50)

[0858] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from Boc-D-Ala-OMe and propargyl bromide to afford the title compound (520 mg, 40%).

[0859] Intermediate L51

[0860] (Intermediate L51)

[0861] This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from methyl (3R)-pyrrolidine-3-carboxylate hydrochloride and propargyl p-toluenesulfonate to afford the title compound (410 mg, 40%).

[0862] Intermediate L52 tert-Butyl A / -[(2R)-2-[(E)-3-(4,4,5,5-1 1-1 ,3,2-dioxaborolan-2-' i-mate

[0863] (Intermediate L52) This compound was prepared in an analogous manner as described in Intermediate L3 step a and Intermediate 10 step e, starting from A / -Boc-(R)-1-amino-2-propanol and propargyl bromide to afford the title compound (578 mg, 41 %).

[0864] Intermediate L53 ioxaborolan-2-yl)but-3- enyl]amino]butanoate (Intermediate L53)

[0865] This compound was prepared in an analogous manner as described in Intermediate L14, starting from but-3-yn-1-ol and (S)-3-amino-butyric acid methyl ester hydrochloride to afford the title compound (600 mg, 50%).

[0866] Intermediate L54

[0867] (Intermediate L54)

[0868] This compound was prepared in an analogous manner as described in Intermediate L34, starting from (S)-3-amino-butyric acid methyl ester hydrochloride and propargyl p-toluenesulfonate to afford the title compound (630 mg, 95%).

[0869] Intermediate L55 i-tanoate

[0870] (Intermediate L55)

[0871] This compound was prepared in an analogous manner as described in Intermediate L34, starting from (S)-3-amino-butyric acid methyl ester hydrochloride and 3-butynyl p-toluenesulfonate to afford the title compound (350 mg, 35%). Intermediate L56 tert-Butyl A / -[(2R)-2-| 1-1 ,3,2-dioxaborolan-2-' pyllcarbamate (Intermediate L56)

[0872] This compound was prepared in an analogous manner as described in Intermediate L10 step e, starting from tert-butyl A / -[(2R)-2-[methyl(prop-2-ynyl)amino]propyl]carbamate to afford the title compound (272 mg, 87%).

[0873] Intermediate L57 (Intermediate L57)

[0874] This compound was prepared in an analogous manner as described in Intermediate L23, starting from but-3-yn-1-ol and tert-butyl crotonate to afford the title compound (380 mg, 34%).

[0875] Intermediate L58

[0876] This compound was prepared in an analogous manner as described in Intermediate L34, starting from but-3-yn-1-ol and (R)-3-aminobutyric acid methyl ester hydrochloride to afford the title compound (387 mg, 16%).

[0877] Intermediate L59 This compound was prepared in an analogous manner as described in Intermediate L14, starting from but-3-yn-1-ol and glycine ethyl ester hydrochloride to afford the title compound (190 mg, 91%).

[0878] Intermediate L60 tert-Butyl 2-[benzyloxycarbonyl-[(E)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)but-3-

[0879] (Intermediate L60)

[0880] This compound was prepared in an analogous manner as described in Intermediate L3, starting from 3-butynyl p-toluenesulfonate and glycine tert-butyl ester hydrochloride to afford the title compound (1.61 g, 4%).

[0881] Intermediate L61 tert-Butyl 2-[benzyloxycarbonyl-[(E)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pent-4-

[0882] (Intermediate L61)

[0883] This compound was prepared in an analogous manner as described in Intermediate L3, starting from pent-4-ynyl 4-methylbenzenesulfonate and glycine tert-butyl ester hydrochloride to afford the title compound (38.78 g, 68.5%).

[0884] Intermediate L62 tert-Butyl 3- l-1 ,3,2-dioxaborolan-2-yl)but-3- enyl]amino]propanoate (Intermediate L62)

[0885] This compound was prepared in an analogous manner as described in Intermediate L3, starting from pent-4-ynyl 4-methylbenzenesulfonate and glycine tert-butyl ester hydrochloride to afford the title compound (5.88 g, 57%). Intermediate TLB1

[0886] (2,3,4,5,6-Pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoate (Intermediate TLB1)

[0887] (a) 3-(2,4-Dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoic acid

[0888] 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). After stirring, the resulting beige suspension was stored o / n in the fridge at 5 °C, and then filtered. The residue was washed with water and dried to afford a brown solid. The solid was taken up in a 0.05M aq. HCI-solution and filtered. The residue was washed with TBME (3x25 mL) and dried at 40 °C under reduced pressure to afford 6.05 g of the title compound as a beige solid (Yield: 76.6%).

[0889] (b) (2,3,4,5,6-Pentafluorophenyl) 3-(2l4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoate (Intermediate TLB1)

[0890] To a cold (0 °C) suspension of 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoic acid (2 g, 7.57 mmol) and pentafluorophenyl 2,2,2-trifluoroacetate (2.54 g, 9.08 mmol) was added dropwise DIPEA (5 mL, 30.2 mmol) and the reaction mixture was stirred o / n allowing the temperature to come to room temperature. The mixture was diluted with water (50 mL). Then the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filetred and concentrated under reduced pressure to give 2.93 g of the title compound (yield: 89.9%).

[0891] Intermediate TLB2

[0892] (2,3,4,5,6-Pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-benzoate (I ntermed iate

[0893] TLB2) This compound was prepared in an analogous manner as described in Intermediate TLB1 , starting from 3-amino-4-methyl-benzoic acid and acrylic acid to afford the title compound (5.09 g, 79%).

[0894] Intermediate DL1

[0895] H — Cl H-CI tert-Butyl 3-piperazin-1-ylpropanoate dihydrochloride (Intermediate DL1 )

[0896] (a) Benzyl 4-(3-tert-butoxy-3-oxo-propyl)piperazine-1 -carboxylate

[0897] To a solution of benzyl piperazine-1 -carboxylate (5 mL, 25.92 mmol) in ethanolabs (15 mL) was added tert-butyl acrylate (5 mL, 45.84 mmol) and the reaction mixture was stirred at 100 °C for 5 h. Diethylether (35 mL) water (15 mL) and 1 M HCI-solution (35 mL) were added subsequently to the mixture and the water layer was separated. Ethyl acetate (150 mL) and 1 M NaOH-solution (35 mL) were added to the water layer, the organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Yield: 8.25 g (91.3%, crude)

[0898] (b) tert- Butyl 3-piperazin-1-ylpropanoate dihydrochloride (Intermediate DL1)

[0899] To a solution of benzyl 4-(3-fert-butoxy-3-oxo-propyl)piperazine-1 -carboxylate (8.1 g, 23.25 mmol) in methanol (150 mL) was added 4M HCI-solution (11.62 mL, 46.5 mmol) and a suspension of 10% Pd on charcoal (800 mg) in ethanol (5 mL). Catalytic hydrogenation was perfomed for 2 h at room temperature. The palladium-catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give of the title compound in quantitative crude yield.

[0900] Intermediate DL2 tert-Butyl 2-[(3 / ?)-pyrrolidin-3-yl]oxyacetate (Intermediate DL2)

[0901] (a) Benzyl (3f?)-3-(2-tert-butoxy-2-oxo-ethoxy)pyrrolidine-1 -carboxylate

[0902] To a cold (0 °C) solution of benzyl (3R)-3-hydroxypyrrolidine-1 -carboxylate (221 mg, 1 mmol) in THF (9 mL) was added sodium hydride (60% dispersion in mineral oil, 60 mg, 1 .5 mmol). The mixture was stirred at 0 °C for 1 h, then a solution of tert-butyl bromoacetate (390 mg, 2 mmol) in THF (1 mL) and the reaction mixture is stirred for 3 h allowing the temperature to reach room temperature. Saturated ammoniumchloride solution and ethyl acetate were added. The ethyl acetate layers was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (heptane / ethyl acetate = 10 / 0 to 0 / 10 v / v%) to give 169 mg of the title compound (yield: 50%).

[0903] (b) tert-Butyl 2-[(3F?)-pyrrolidin-3-yl]oxyacetate (Intermediate DL2) To a solution of benzyl (3R)-3-(2-tert-butoxy-2-oxo-ethoxy)pyrrolidine-1-carboxylate (219 mg, 0.65 mmol) in ethanol (30 mL) was added 10% Pd on charcoal (35 mg). Catalytic hydrogenation was perfomed for 2 h at room temperature. The palladium-catalyst was removed by filtration and the filtrate was concentrated in vacuo to give of the title compound in quantitative crude yield.

[0904] Intermediate TLB-DL1

[0905] 3-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1l3-dioxo-isoindolin-4-yl1amino1ethoxy1ethoxy1ethoxy1propanoic acid (Intermediate TLB-DL1)

[0906] (a) tert-Butyl 3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]- ethoxylpropanoate

[0907] A solution of 2-(2,6-dioxo-piperidin-3-yl)-4-fluoroisoindoline-1 ,3-dione (200 mg, 0.72 mmol), tert-butyl 12-amino-4,7,10-trioxadodecanoate (241 mg, 0.87 mmol) and DiPEA (480 pL, 2.90 mmol) in DMF (5 mL) was stirred at 80 °C o / n. The mixture was concentrated under vacuum at 60 °C. Purification was performed using preparative LCMS. Fractions containing the title compound were collected and lyophylised to afford 116.0 mg (30.0%) as a yellow oil.

[0908] (b) 3-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]propa- noic acid (Intermediate TLB-DL1)

[0909] To a solution of tert-butyl 3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-4-yl]amino]- ethoxy]ethoxy]ethoxy]propanoate (116 mg, 0.22 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperatur for 1 h and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (dichloromethane / methanol = 10 / 0 to 8 / 2 v / v%) to give 98.4 mg of the title compound (yield: 94.8%).

[0910] Intermediate TLB-DL2

[0911] 3-r2-[2-r[2-(2,6-Dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-4-yllamino1ethoxy1ethoxy1propanoic acid

[0912] (Intermediate TLB-DL2)

[0913] This compound was prepared in an analogous manner as described in Intermediate TLB-DL1 , starting from 2-(2,6-dioxo-piperidin-3-yl)-4-fluoroisoindoline-1 , 3-dione and H2N-PEG2-CO-OtBu to afford the title compound (86.7 mg, 92.3%). Intermediate TLB-DL3

[0914] 3- 6-dioxo-3-pi i-1 ,3-dioxo-isoindolin-4-' acid (Intermediate TLB-DL3)

[0915] This compound was prepared in an analogous manner as described in Intermediate TLB-DL1 , starting from 2-(2,6-dioxo-piperidin-3-yl)-4-fluoroisoindoline-1 ,3-dione and tert-butyl 3-amino- (PEG4)propionate to afford the title compound (110.3 mg, 88.6%).

[0916] Intermediate TLB-DL4

[0917] 1-1 ,3-dioxo-isoindolin-4-' ermediate TLB-DL4)

[0918] This compound was prepared in an analogous manner as described in Intermediate TLB-DL1 , starting from 2-(2,6-dioxo-piperidin-3-yl)-4-fluoroisoindoline-1 ,3-dione and HzN-PEG6-CO-OtBu to afford the title compound (125.3 mg, quant.).

[0919] Intermediate TLB-DL5

[0920] 3- 6-Dioxo-3-pi l-1 ,3-dioxo-isoindolin-5-' ic acid (Intermediate

[0921] TLB-DL5)

[0922] (a) tert-Butyl 3-[4-[2-(2,6-dioxo-3-piperidyl)-1l3-dioxo-isoindolin-5-yl1piperazin-1-yl1propanoate

[0923] A solution of 2-(2,6-dioxo-piperidin-3-yl)-5-fluoroisoindoline-1 ,3-dione (750 mg, 2.72 mmol), tert-butyl 3-piperazin-1-ylpropanoate dihydrochloride (764 mg, 2.66 mmol) and DiPEA (1.35 ml_, 8.15 mmol) in DMF (3 mL) was stirred at 80 °C o / n. The mixture was concentrated under vacuum at 60 °C. The residue was purified by column chromatography (dichloromethane / methanol = 99 / 1 to 97 / 3 v / v%) to afford tert-butyl 3-[4-[2-(2,6-dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl]piperazin-1-yl]propanoate (601.9 mg, 48.1 %).

[0924] (b) 3-[4-[2-(2,6-Dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl1piperazin-1 -yllpropanoic acid (Intermediate TLB-DL5) To a solution of tert-butyl 3-[4-[2-(2,6-dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl]piperazin-1- yl]propanoate (255.6 mg, 0.54 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the mixture was stirred for 2 h at room temperature. The mixture was concentrated in vacuo. The residue was triturated with dichloromethane and dried in vacuo to give 246 mg of the title compound (Yield: quant).

[0925] Intermediate TLB-DL6

[0926] (3R)-1-r2-(2,6-Dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl1pyrrolidine-3-carbaldehyde (Intermediate TLB-DL6)

[0927] (a) 2-(2,6-Dioxo-3-piperidyl)-5-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]isoin-doline-1 , 3-dione

[0928] A solution of 2-(2,6-dioxo-piperidin-3-yl)-5-fluoroisoindoline-1 , 3-dione (750 mg, 2.72 mmol), (R)-pyrrolidin-3-ylmethanol (269 mg, 2.66 mmol) and DiPEA (1.35 mL, 8.15 mmol) in DMF (3 mL) was stirred at 80 °C o / n. The mixture was concentrated under vacuum at 60 °C. The residue was purified by column chromatography (dichloromethane / methanol = 99 / 1 to 96 / 4 v / v%) to afford 2-(2,6-dioxo-3- piperidyl)-5-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]isoin-doline-1 , 3-dione (651 .9 mg, 63.5%).

[0929] (b) (3R)-1-[2-(2,6-Dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl]pyrrolidine-3-carbaldehvde (Intermediate TLB-DL6

[0930] Dess-Martin periodinane (1.14 g, 2.69 mmol) was added to a solution of 2-(2,6-dioxo-3- piperidyl)-5-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]isoin-doline-1 , 3-dione (480 mg, 1.34 mmol) in dichloromethane (15 mL). The mixture was allowed to stir at room temperature for one hour. Dichloromethane and aqueous NazSOa were added. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate) to afford (3R)-1-[2-(2,6- dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl]pyrrolidine-3-carbaldehyde (444.4 mg, 93.1 %).

[0931] Intermediate TLB-DL7

[0932] 3-[4-[3-(2,4-Dioxohexahvdropyrimidin-1-yl)-4-methoxy-benzoyl1piperazin-1-yl1propanoic acid

[0933] (Intermediate TLB-DL7)

[0934] (a) tert-Butyl 3-[4-[3-(2,4-dioxohexahvdropyrimidin-1-yl)-4-methoxy-benzoyl]piperazin-1-yl]propanoate

[0935] To a solution of (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy- benzoate (Intermediate TLB1 , 250 mg, 0.58 mmol) in DMF (3 mL) was added subsequently N,N- diisopropylethylamine (288 pL, 1.74 mmol) and fert-butyl 3-piperazin-1-ylpropanoate (131 mg, 0.61 mmol). The reaction mixture was stirred at room temperature o / n. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography using SiCte and dichloromethane / methanol = 99 / 1 to 95 / 5 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 242 mg of the title compound (Yield 90.5%).

[0936] (b) 3-[4-[3-(2,4-Dioxohexahvdropyrimidin-1-yl)-4-methoxy-benzoyl]piperazin-1-yl]propanoic acid (Intermediate TLB-DL7)

[0937] To a solution of tert-butyl 3-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoyl]pipe- razin-1-yl]propanoate (151 mg, 0.33 mmol) in dioxane (1 mL) was added 4M HCI / dioxane solution (3 mL) and the reaction mixture was stiired at room temperature for 3 h. The mixture was concentrated in vacuo. The residue was triturated with dichloromethane and dried in vacuo to give the title compound in quantitative crude yield.

[0938] Intermediate TLB-DL8

[0939] 3-[2-[[3-(2,4-Dioxohexahvdropyrimidin-1-yl)-4-methoxy-benzoyl]aminolethoxy]propanoic acid (Intermediate TLB-DL8)

[0940] This compound was prepared in an analogous manner as described in Intermediate TLB-DL7, starting from (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoate (Intermediate TLB1) and tert-butyl 3-(2-aminoethoxy)propanoate to afford the title compound (107 mg, 79%).

[0941] Intermediate TLB-DL9

[0942] 3-[2-[[3-(2,4-Dioxohexahydropyrimidin-1-yl)-4-methyl-benzoyl]amino]ethoxy]propanoic acid (Intermediate TLB-DL9)

[0943] This compound was prepared in an analogous manner as described in Intermediate TLB-DL7, starting from (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1 -yl)-4-methyl-benzoate (Intermediate TLB2) and tert-butyl 3-(2-aminoethoxy)propanoate to afford the title compound (93 mg, 85%).

[0944] Intermediate TLB-DL10

[0945] 3-[2-[2-[[3-(2,4-Dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoyl]amino]ethoxy]ethoxy]propanoic acid (Intermediate TLB-DL10)

[0946] This compound was prepared in an analogous manner as described in Intermediate TLB-DL7, starting from (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoate (Intermediate TLB1) and tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propanoate to afford the title compound (1 g, 70%).

[0947] Intermediate TLB-DL11

[0948] 3-[2-[2-[[3-(2,4-Dioxohexahydropyrimidin-1-yl)-4-methyl-benzoyl]amino]ethoxy]ethoxy]propanoic acid (Intermediate TLB-DL11)

[0949] This compound was prepared in an analogous manner as described in Intermediate TLB-DL7, starting from (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1 -yl)-4-methyl-benzoate (Intermediate TLB2) and tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propanoate to afford the title compound (258 mg, 63%).

[0950] Intermediate TLB-DL12

[0951] 2-[(3 / ?)-1-[2-(2,6-Dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl]pyrrolidin-3-yl]oxyacetic acid

[0952] (Intermediate TLB-DL12)

[0953] This compound was prepared in an analogous manner as described in Intermediate TLB-DL5, starting from tert-butyl 2-[(3R)-pyrrolidin-3-yl]oxyacetate_(lntermediate DL2) and 2-(2,6-dioxopiperidin-

[0954] 3-yl)-5-fluoroisoindoline-1 ,3-dione to afford 125 mg of the title compound.

[0955] Intermediate TLB-DL13

[0956]

[0957] 7-[2-(2,6-Dioxo-3-piperidyl)-1 -oxo-isoindolin-5-yl]hept-6-ynoic acid (Intermediate TLB-DL13)

[0958] (a) 3-(5-Bromo-1-oxo-isoindolin-2-yl)piperidine-2, 6-dione

[0959] A / ,A / -diisopropylethylamine (12.5 mL, 75.63 mmol) was added to methyl 4-bromo-2- (bromomethyl)benzoate (7.32 g, 23.77 mmol) and 3-aminopiperidine-2, 6-dione hydrochloride (5.87 g, 35.66 mmol) in acetonitrile (100 mL). The resulting suspension was stirred at 80 °C for 48 hours. The reaction mixture was cooled to room temperature and filtered. The solid was washed with acetonitrile (30 mL), acetonitrile:diethyl ether (50 mL [2:3]) and diethylether (2x50 mL) to afford 3-(5-bromo-1-oxo- isoindolin-2-yl)piperidine-2, 6-dione (7.38 g, 95.8%) as a dark purple solid.

[0960] (b) tert- Butyl hept-6-ynoate

[0961] To a cold (0 °C) solution of 6-heptynoic acid (3.03 g, 24 mmol) in THF (48 mL) was added trifluoroacetic acid anhydride (6.68 mL, 48 mmol) and the reaction mixture was stirred for 1 h at room temperature. tert-BuOH (24 mL) was added and the mixture was stirred overnight. The reaction mixture was quenched with 5% NaHCOa-solution (200 mL) and extracted with heptane:ethyl acetate=1 :1 (3x50 mL). The combined organic layers were washed with sat. NaHCOa-solution (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound in quantitative crude yield.

[0962] (c) tert- Butyl 7-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl1hept-6-ynoate

[0963] A solution of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2, 6-dione (1 g, 3.1 mmol) and triethylamine (2.6 mL) in DMF (10 mL) was purged with nitrogen for 5 minutes, followed by addition of copper iodide (29 mg, 0.155 mmol) and bis(triphenylphosphine)palladium chloride (108 mg, 0.155 mmol). Finally tert-butyl hept-6-ynoate (620 mg, 3.4 mmol) was added and the mixture was stirred at 80°C for 5 h. The reaction mixture was recharged with the same amounts of copper iodide (29 mg, 0.155 mmol), bis(triphenylphosphine)palladium chloride (108 mg, 0.155) and tert-butyl hept-6-ynoate (620 mg, 3.4 mmol) and again stirred at 80°C for 5 h. The reaction mixture was added dropwise to ethyl acetate (100 mL) / 10% citric acid (100 mL) under heavy stirring. The dark black mixture was filtered over a Celite™ and rinsed with ethyl acetate (60 mL) until the filtrate was colorless. The dark black layers were seperated and the aqueous layer was extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using SiCh and heptane / ethyl acetate = 9 / 1 to 1 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 853 mg of the title compound (yield 65%).

[0964] (d) 7-[2-(2,6-Dioxo-3-piperidyl)-1 -oxo-isoindolin-5-yl1hept-6-ynoic acid (Intermediate TLB-DL13) To a solution of tert-butyl 7-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]hept-6-ynoate (853 mg, 2.05 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL) and the mixture was stirred at room temperature o / n. The mixture added dropwise to diethyl ether (80 mL) and the precipitate formed was filtered. The precipitate was dried in vacuo to give 485 mg of the title compound (yield: 65%).

[0965] Intermediate TLB-DL14

[0966] 6-[2-(2,6-Dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]hex-5-ynoic acid (Intermediate TLB-DL14)

[0967] This compound was prepared in an analogous manner as described in Intermediate TLB- DL13, starting from 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2, 6-dione and fert-butyl hex-5-ynoate to afford 459 mg of the title compound (yield: 98%).

[0968] Intermediate TLB-DL15

[0969] 5-[2-(2,6-Dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]pent-4-ynoic acid (Intermediate TLB-DL15)

[0970] This compound was prepared in an analogous manner as described in Intermediate TLB- DL13, starting from 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2, 6-dione and tert-butyl pent-4-ynoate to afford 124 mg of the title compound (yield: 42%).

[0971] Intermediate TLB-DL16

[0972] 3-[[6-[3-(2,4-Dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carbonyl]amino]propanoic acid (Intermediate TLB-DL16)

[0973] (a) tert-Butyl 3-[(3-amino-3-oxo-propyl)amino]azetidine-1 -carboxylate

[0974] Acrylamide (7.43 g, 104.5 mmol) and triethylamine (9.71 mL, 69.7 mmol) were successively added to a solution of 3-amino-1-A / -Boc-azetidine (6 g, 34.8 mmol) in ethanol (40 mL). The reaction mixture was stirred at 65°C for 24 hrs. The reaction mixture was concentrated in vacuo to give 13.6 g of crude tert-butyl 3-[(3-amino-3-oxo-propyl)amino]azetidine-1 -carboxylate which was used directly in the next step.

[0975] (b) tert-Butyl 3-[(3-amino-3-oxo-propyl)-(2, 2, 2-trichloroethoxycarbonyl)-amino]azetidine-1 -carboxylate

[0976] 2,2,2-Trichloroethyl chloroformate (4.79 mL, 34.8 mmol) was slowly added to a cooled solution of tert-butyl 3-[(3-amino-3-oxo-propyl)amino]azetidine-1 -carboxylate (13.6 g, 34.8 mmol, theor.) and triethylamine (4.85 mL, 34.8 mmol) in dichloromethane (50 mL). The reaction mixture was stirred for 4 h allowing the mixture to come to room temperature. The organic layer was washed with water (3x50 mL) and filtered over a PE filter. The filtrate was concentrated in vacuo. The residue (thick oil) was again dissolved in dichloromethane, washed with 5% citric acid solution, brine and filtered over a PE filter. The filtrate was concentrated in vacuo, to give 12.75 g of the title compound as a white foam (yield: 87.5%).

[0977] (c) tert-Butyl 3-(2,4-dioxohexahydropyrimidin-1 -yl)azetidine-1 -carboxylate

[0978] Sodium methoxide (4.93 g, 91.35 mmol) was added to a solution of tert-butyl 3-[(3-amino-3- oxo-propyl)-(2,2,2-trichloroethoxycarbonyl)amino]azetidine-1-carboxylate (12.75 g, 30.45 mmol) in methanol (150 mL) under inert atmosphere. The reaction mixture was stirred at 65 °C for 1 h. After cooling, the reaction mixture was concentrated to a small volume. MTBE (300 mL) was added and after cooling, the mixture was acidified to pH 5-6 by adding 5% citric acid solution dropwise. The aqueous layer was separated and extracted with dichloromethane. De combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography using SiO? and dichloromethane / methanol = 99 / 1 to 95 / 5 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 9.05 g of the title compound (Yield : 71.0%) as a white solid.

[0979] (d) 1 -(Azetidin-3-yl)hexahydropyrimidine-2, 4-dione 2,2,2-trifluoroacetic acid

[0980] A solution of tert-butyl 3-(2,4-dioxohexahydropyrimidin-1-yl)azetidine-1 -carboxylate (9.05 g, 30.45 mmol) in DCM / TFA = 1 / 1 v / v% (30 mL) was stirred for 1 h. at room temperature. The mixture was partially concentrated (10 mL) and carefully added dropwise to diethylether (400 mL) and stirred for 24 h at room temperature. The precipitate formed was filtered, washed with diethylether and dried under vacuum at 40 °C to give 6.4 g of the title compound as a white powder in a quantitative yield.

[0981] (e) tert-Butyl 6-[3-(2l4-dioxohexahvdropyrimidin-1-yl)azetidin-1-yl1pyridine-3-carboxylate

[0982] To a solution of 1-(azetidin-3-yl)hexahydropyrimidine-2, 4-dione 2,2,2-trifluoroacetic acid (1.2 g, 4.2 mmol) in acetonitrile (12 mL) was added subsequently triethylamine (1.2 mL, 12.0 mmol) and 6- chloronicotinic acid tert-butyl ester (943 mg, 4.4 mmol) and the reaction mixture was stirred at 80 °C for o / n. After cooling, the mixture was concentrated under reduced pressure and the residue dissolved in dichloromethane / methanol = 9 / 1 v / v%, and washed with 5% citric acid solution, water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 833 mg (57%) of the title product.

[0983] (f) 6-[3-(2,4-Dioxohexahydropyrimidin-1 -yl)azetidin-1 -yllpyridine-3-carboxylic acid

[0984] A solution of tert-butyl 6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carbo- xylate (803 mg, 2.3 mmol) in DCM / TFA = 1 / 1 v / v% (10 mL) was stirred for room temperature o / n. The mixture added dropwise to diethylether (100 mL) and stirred for 24 h at room temperature. The precipitate was filtered off, washed with diethyl ether, and dried in vacuo to afford the title compound (761 mg, 81%) as an off-white solid.

[0985] (g) tert-Butyl 3-[[6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl1pyridine-3-carbonyl1amino]propa- noate

[0986] 6-[3-(2,4-Dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carboxylic acid (50 mg, 0.124 mmol) and tert-butyl 3-aminopropanoate (20.3 pL, 0.137 mmol) were suspended in DCM (1 mL). HATU (49.6 mg, 0.13 mmol) and DiPEA (60.5 pL, 0.868 mmol) were added subsequently and the mixture stirred at room temperature o / n. The mixture was washed with 5% NaHCCh-solution and 5% citric acid solution. The organic layer was separated over a PE-filter. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography (dichloromethane to methanol = 98 / 2 to 9 / 1 v / v%) to afford 34.3 mg of the title compound (yield: 66.9%).

[0987] (h) 3-[[6-[3-(2l4-Dioxohexahvdropyrimidin-1-yl)azetidin-1-yl1pyridine-3-carbonyl1amino]propanoic acid

[0988] (Intermediate TLB-DL16) A solution of tert-butyl 3-[[6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3- carbonyl]amino]propanoate (34.3 mg, 0.08 mmol) in DCM / TFA = 1 / 1 v / v% (3 mL) was stirred for room temperature o / n. The mixture added dropwise to diethylether (20 mL) and stirred for 24 h. at room temperature. The supernatant was decanted and the residue dried in vacuo to afford the title compound (32.7 mg, 82.9%) as an off-white solid.

[0989] Intermediate TLB-DL17

[0990] 3-[2-[[6-[3-(2,4-Dioxohexahvdropyrimidin-1-yl)azetidin-1-yl]pyridine-3carbonyl]amino]ethoxy] propanoic acid (Intermediate TLB-DL17)

[0991] This compound was prepared in an analogous manner as described in Intermediate TLB- DL16, starting from 6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carboxylic acid and tert-butyl 3-(2-aminoethoxy)propanoate to afford 48.5 mg of the title compound (yield: 99%).

[0992] Intermediate TLB-DL18

[0993] 3-[2-[2-[[6-[3-(2,4-Dioxohexahvdropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carbonyl]amino]ethoxy]- ethoxylpropanoic acid (Intermediate TLB-DL18)

[0994] This compound was prepared in an analogous manner as described in Intermediate TLB- DL16, starting from 6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carboxylic acid and tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propanoate to afford 50.5 mg of the title compound (yield: 92%). Intermediate TLB-DL19

[0995] 3-1 ,4-Dii in-1 -vl)azetidin-1 -yllpyridine-3-i ic acid (Intermediate TLB-DL19)

[0996] This compound was prepared in an analogous manner as described in Intermediate TLB- DL16, starting from 6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carboxylic acid and tert-butyl 3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propanoate to afford 39.2 mg of the title compound (yield: 71 %).

[0997] Intermediate TLD-DL20

[0998] This compound was prepared in an analogous manner as described in Intermediate TLB- DL16, starting from 6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carboxylic acid and tert-butyl 3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]propanoate to afford 38.6 mg of the title compound (yield: 70%).

[0999] Intermediate TLB-DL21 6-[6-[3-(2,4-dioxohexahvdropyrimidin-1-yl)azetidin-1-yl]-3-pyridyl]hex-5-ynoic acid (Intermediate TLB- DL21)

[1000] To 1-(azetidin-3-yl)hexahydropyrimidine-2, 4-dione 2,2,2-trifluoroacetic acid (150 mg, 0.5 mmol) was added 6-(6-chloro-3-pyridyl)hex-5-ynoic acid (90.6 mg, 0.4 mmol) followed by CS2CO3 (727 mg, 2.2 mmol). Under an inert atmosphere, dry dioxane (6.0 mL) was added, followed by tBuXPhos Pd G3 (32.2 mg, 0.04 mmol). The mixture was degassed and stirred at 105 °C for 20 hours. The solvent was removed under a stream of nitrogen and the residue was dissolved in water. The pH was adjusted to 4 and the mixture was filtered through a C18 column. The fractions containing product were lyophilized and the residue was purified by HPLC to afford the title compound (6.0 mg, 4.1 %) as an orange solid. A second batch of the title compound was made on a one-third scale (5.3 mg, 1 1 %)

[1001] Intermediate TLB-DL22

[1002] 4-H(1 S)-1-[(2S,4f?)-4-hvdroxy-2-r[4-(4-methylthiazol-5-yl)phenyllmethylcarbamoyllpyrrolidine-1- carbonyl1-2,2-dimethyl-propyl1amino1-4-oxo-butanoic acid (Intermediate TLB-DL22)

[1003] Succinic anhydride (46.5 mg, 0.46 mmol) was added to a stirred suspension of (2S,4R)-1-((S)- 2-amino-3,3-dimethylbutanoyl)-4-hydroxy-A / -(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (100 mg, 0.21 mmol) in pyridine (0.5 mL) and the reaction mixture was stirred for 3 d. at room temperature. The mixture was concentrated under reduced pressure. Purification was performed using preparative LCMS. Fractions containing the title compound were lyophilised to afford 84 mg (yield: 75%) of the title compound.

[1004] Intermediate TLB-DL23

[1005] 3-1 idin-1 -yl)-4- ic acid (Intermediate TLB-DL23)

[1006] (a) tert-Butyl 4-(4-pyridyloxy)piperidine-1 -carboxylate

[1007] To an ice-cold (4 °C) solution of tert-butyl 4-hydroxypiperidine-1 -carboxylate (2.12 g, 10.5 mmol), pyridin-4-ol (1 g, 10.5 mmol) and triphenylphosphine (4.14 g, 15.8 mmol) in THF (20 mL) was added dropwise a solution of diisopropyl azodicarboxylate (3.1 mL, 15.8 mmol) in THF (10 mL). The mixture was stirred for 30 min at 4 °C and then stirred at room temperature o / n. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using SiO2 and heptane / ethyl acetate = 4 / 1 to 0 / 10 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 1 .41 g of fert-butyl 4-(4-pyridyloxy)piperidine-1 -carboxylate (yield: 48 %).

[1008] (b) tert-Butyl 4-(1-benzylpyridin-1-ium-4-yl)oxypiperidine-1 -carboxylate bromide

[1009] To a solution of tert-butyl 4-(4-pyridyloxy)piperidine-1 -carboxylate (750 mg, 2.69 mmol) in DCM (8 mL) was added benzyl bromide (644 pL, 5.38 mmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated to a small volume and diethyl ether (15 mL) was added. The precipitate formed was filtered, washed with diethyl ether and dried in vacuo to give 1.18 g of the title compound (yield: 98%).

[1010] (c) tert-Butyl 4-r(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy1piperidine-1 -carboxylate

[1011] To an ice-cold (4 °C) solution of tert-butyl 4-(1-benzylpyridin-1-ium-4-yl)oxypiperidine-1- carboxylate bromide (1.17 g, 2.60 mmol) in methanol (6 mL) was added sodium borohydride (197 mg, 5.20 mmol). The reaction mixture was stirred for 30 min allowing the temperature to come to room temperature. After quenching with acetone (2 mL), the mixture was stirred for 15 min. The mixture was concentrated and the residue dissolved in ethyl acetate, washed with 5% aq. HCOa-solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 970 mg of the title compound (quantitative yield).

[1012] (d) tert-Butyl 4-(4-piperidyloxy)piperidine-1 -carboxylate

[1013] To a stirred solution of tert-butyl 4-[(1-benzyl-3,6-dihydro-2 / - / -pyridin-4-yl)oxy]piperidine-1- carboxylate (870 mg, 2.34 mmol) in methanol (11 mL) was added a suspension of 10% Pd on charcoal (124 mg) in ethanol (4 mL). The reaction mixture was stirred at room temperature for 15 min under a nitrogen atmosphere. Then, ammonium formate (1.48 g, 23.4 mmol) was added and the reaction mixture was heated to reflux temperature for 15 min. The reaction mixture was cooled, filtered over Decalite® and concentrated in vacuo to give the title compound (744 mg, quantitative).

[1014] (e) Benzyl 4-r(1-tert-butoxycarbonyl-4-piperidyl)oxy1piperidine-1-carboxylate

[1015] To an ice-cold (4 °C) solution of tert-butyl 4-(4-piperidyloxy)piperidine-1 -carboxylate (744 mg, 2.34 mmol) in THF (7.5 mL) was added triethylamine (652 pL, 4.68 mmol). To the mixture was added drop-wise a solution of A / -(benzyloxycarbonyloxy)succinimide (641 mg, 2.57 mmol) in THF (2.5 mL) and the resulting mixture was stirred at room temperature o / n. Ethyl acetate was added and the resulting mixture was washed with 5% citric acid solution, water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using SiO2 and heptane / ethyl acetate = 10 / 0 to 0 / 10 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 849 mg of benzyl 4-[(1- tert-butoxycarbonyl-4-piperidyl)oxy]piperidine-1-carboxylate (yield: 87%).

[1016] (f) Benzyl 4-(4-piperidyloxy)piperidine-1 -carboxylate

[1017] To a stirred solution of benzyl 4-[(1-fert-butoxycarbonyl-4-piperidyl)oxy]piperidine-1-carboxylate (849 mg, 2.02 mmol) in dichloromethane (6 mL) was added TFA (1 .5 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography using SiO2 and dichloromethane / 7N NH3 in methanol = 9 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 602 mg of the title compound (yield: 94%).

[1018] (g) Benzyl 4-[[1-(3-tert-butoxy-3-oxo-propyl)-4-piperidyl]oxy]piperidine-1-carboxylate

[1019] To a solution of benzyl 4-(4-piperidyloxy)piperidine-1-carboxylate (600 mg, 1.88 mmol) and triethylamine (524 pL, 3.76 mmol) in ethanolabs (9.5 mL) was added fert-butyl acrylate (682 pL, 4.7 mmol) and the reaction mixture is stirred at room temperature o / n. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography using SiCte and dichloromethane / methanol = 9 / 1 to 85 / 15 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 645 mg of the title compound (yield: 77%).

[1020] (h) tert-Butyl 3-[4-(4-piperidyloxy)-1 -piperidyllpropanoate

[1021] To a solution of benzyl 4-[[1-(3-tert-butoxy-3-oxo-propyl)-4-piperidyl]oxy]piperidine-1- carboxylate (645 mg, 1.44 mmol) in methanol (7 mL) was added 10% Pd on charcoal (76 mg). Catalytic hydrogenation was performed for 2 h. at room temperature. The palladium-catalyst was filtered and the filtrate was evaporated to give of the title compound in quantitative crude yield. (i) tert-Butyl 3-[4-[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoyl]-4-piperidyl]oxy]-1- piperidyllpropanoate

[1022] To a solution of (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy- benzoate (Intermediate TLB1 , 124 mg, 0.29 mmol) in DMC / DMF=3 / 1 v / v% (6 mL) was added subsequently A / ,A / -diisopropylethylamine (151 pL, 0.86 mmol) and tert-butyl 3-[4-(4-piperidyloxy)-1- piperidyl]propanoate (90 mg, 0.29 mmol). The reaction mixture was stirred at room temperature o / n. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography using SiO2 and dichloromethane / methanol = 95 / 5 to 9 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 120 mg of the title compound (Yield 74%).

[1023] (j) 3-[4-r[1-r3-(2,4-dioxohexahvdropyrimidin-1-yl)-4-methoxy-benzoyll-4-piperidyl1oxyl-1-piperidyl1pro- panoic acid (Intermediate TLB-DL23)

[1024] To a solution of tert-butyl 3-[4-[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methoxy-benzoyl]-4- piperidyl]oxy]-1-piperidyl]propanoate (120 mg, 0.21 mmol) in dioxane (1 mL) was added 4M HCI / dioxane solution (3 mL) and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was triturated with dichloromethane and dried in vacuo to give the title compound in quantitative crude yield.

[1025] Intermediate TLB-DL24

[1026] 3-[4-[[1-[3-(2,4-Dioxohexahvdropyrimidin-1-yl)-4-methyl-benzoyl]-4-piperidyl1oxy1-1-piperidyl]propanoic acid (Intermediate TLB-DL24)

[1027] This compound was prepared in an analogous manner as described in Intermediate TLB- DL24, starting using (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl- benzoate (Intermediate TLB2) in the last sequences of steps to afford 136 mg of the title compound (yield: quantitative).

[1028] Intermediate TLB-DL25 2-[1-[[6-[3-(2,4-Dioxohexahvdropyrimidin-1-yl)azetidin-1-yl]-3-pyridyl]methyl]-4-piperidyHacetic acid (Intermediate TLB-DL25)

[1029] (a) 6-[3-(2,4-Dioxohexahvdropyrimidin-1-yl)azetidin-1-yl1pyridine-3-carbaldehyde

[1030] To a flask charged with 1-(azetidin-3-yl)hexahydropyrimidine-2, 4-dione 2,2,2-trifluoroacetic acid (1.0 g, 3.6 mmol) in acetonitrile (35 ml_) was added triethylamine (1.1 mL, 10.6 mmol) followed by 6- chloropyridine-3-carbaldehyde (560 mg, 4.0 mmol). The mixture was stirred and heated to 95 °C overnight. After cooling to room temperature, the solvent was concentrated in vacuo and DCM / MeOH = 9 / 1 v / v% (80 mL) was added to the residue, followed by the addition of water (30 mL). The layers were separated and the aqueous layer was extracted with DCM / MeOH = 9 / 1 v / v% (3 x 25 mL). The combined organic layers were filtered over a PE filter and concentrated in vacuo. The residue was purified by column chromatography using SiOz and dichloromethane / methanol = 99 / 1 to 9 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 460 mg of the title compound (Yield 46%).

[1031] (b) tert-Butyl 3-[4-[[6-[3-(2l4-dioxohexahvdropyrimidin-1-yl)azetidin-1-yl]-3-pyridyl]methyl]piperazin-1- yllpropanoate

[1032] To a tube charged with 6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3- carbaldehyde (40 mg, 0.15 mmol) in THF / DMF = 1 / 1 v / v% (2 mL) was added tert-butyl piperidine-4- carboxylate (22.6 pL, 0.15 mmol) followed by acetic acid (8.6 pL, 0.15 mmol). The mixture was stirred for 15 minutes, after which NaBHaCN (13.2 mg, 0.22 mmol) was added. The mixture was stirred o / w. The mixture was recharged with AcOH, NaBHaCN, and amine as needed. The solvent was concentrated in vacuo and the residue was dissolved in DCM / MeOH = 9 / 1 v / v% (5 mL) and washed with sat. aq. NaHCOa-solution (2 x 2 mL). The combined aqueous phases were extracted with DCM / MeOH = 9 / 1 v / v% (2 mL). The combined organic phases were filtered through a PE filter and concentrated in vacuo. The residue was purified by column chromatography using SiOz and dichloromethane / 7N NH3 in methanol = 10 / 0 to 9 / 1 v / v%. All fractions containing the title compound were collected and concentrated in vacuo to give 29.2 mg of the title compound (Yield 43%).

[1033] (c) 2-[1-[[6-[3-(2,4-Dioxohexahvdropyrimidin-1-yl)azetidine-1-yl]-3-pyridyl1methyl1-4-piperidyl]acetic acid (Intermediate TLB-DL25)

[1034] To a flask charged with tert-butyl 3-[4-[[6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]-3- pyridyl]methyl]piperazin-1-yl]propanoate (28 mg, 0.06 mmol) was added DCM / TFA = 1 / 1 v / v% (2 mL). The mixture was stirred for 1 hour. Diethyl ether (5 mL) was added and the mixture was concentrated in vacuo to afford 2-[1-[[6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidine-1-yl]-3-pyridyl]methyl]-4- piperidyl]acetic acid (Intermediate TLB-DL25) (50 mg, quant) which was used directly for coupling to the TMKB-intermediates. Intermediate TLB-DL26

[1035] / V-(2,6-dioxo-3-piperidyl)-5-(4-formyl-1-piperidyl)pyridine-2-carboxamide (Intermediate TLB-DL26)

[1036] (a) Benzyl 4-(dimethoxymethyl)piperidine-1 -carboxylate

[1037] A solution of 4-formyl-A / -Cbz-piperidine (5 g, 20.22 mmol) in methanol :trimethylorthoformate (3:1 v / v%, 80 mL) containing a trace amount of p-toluenesulfonic acid was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo to provide of the title compound in quantitative crude yield.

[1038] (b) 4-(Dimethoxymethyl)piperidine

[1039] To a solution of benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate (6.23 g, 21.2 mmol) in methanol (100 mL) was added a slurry of 20% Pd(OH)z on charcoal (500 mg) in methanol (5 mL). Catalytic hydrogenation was performed for 4 h. at room temperature. The palladium-catalyst was filtered and the filtrate was evaporated to afford the title compound (3.09 g, 92%) as an oil.

[1040] (c) Methyl 5-[4-(dimethoxymethyl)-1-piperidyl]pyridine-2-carboxylate

[1041] To a vial charged with methyl 5-fluoropicolinate (974 mg, 6.28 mmol) in DMSO (6.3 mL) was added 4-(dimethoxymethyl)piperidine (1.0 g, 6.28 mmol) followed by DIPEA (2.18 mL, 12.6 mmol). The mixture was heated to 100 °C and stirred overnight. The mixture was cooled to room temperature and water (8.0 mL) was added. The solids were filtered and the residue was dried in vacuo to afford the title compound (1.31 g, 71 %) as a beige solid.

[1042] (d) Lithium 5-[4-(dimethoxymethyl)-1-piperidyl]pyridine-2-carboxylate

[1043] To a solution of methyl 5-[4-(dimethoxymethyl)-1-piperidyl]pyridine-2-carboxylate (1.31 g, 4.45 mmol) in THF / water=4 / 1 v / v% (45 mL) was added lithium hydroxide (118 mg, 4.89 mmol) and the reaction mixture was stirred overnight. Water (30 mL) was added, followed by the removal of volatiles in vacuo. The residue was lyophilised to afford the title compound (1 .34 g, 105%) as a beige solid.

[1044] (e) 5-[4-(Dimethoxymethyl)-1-piperidyl1-A / -(2l6-dioxo-3-piperidyl)pyridine-2-carboxamide

[1045] Lithium 5-[4-(dimethoxymethyl)-1-piperidyl]pyridine-2-carboxylate (1.34 g, 4.68 mmol) and 3- aminopiperidine-2, 6-dione hydrochloride (770 mg, 4.68 mmol) were dissolved in DMF (25 mL). HATU (3.55 g, 9.36 mmol) and DiPEA (2.02 mL, 11 .7 mmol) were added subsequently and the mixture stirred at room temperature for 1 h. To the mixture was added dichloromethane / methanol=1 / 1 v / v% (100 mL) and the mixture was washed with 5% NaHCCh-solution and 5% citric acid solution. The organic layer was separated over a PE-filter. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography (dichloromethane to methanol = 10 / 0 to 9 / 1 v / v%) to afford 1 .2 g of the title compound (yield: 66%).

[1046] (f) A / -(2,6-dioxo-3-piperidyl)-5-(4-formyl-1-piperidyl)pyridine-2-carboxamide (Intermediate TLB-DL26)

[1047] To a solution of 5-[4-(dimethoxymethyl)-1-piperidyl]-N-(2,6-dioxo-3-piperidyl)pyridine-2-carbox- amide (200 mg, 0.52 mmol) in THF (4 mL) was added 2N aq. HCI (2 mL). The mixture was stirred for 2 hours. The mixture was neutralized with 5% aq. sodium bicarbonate and the aqueous phase was extracted with dichloromethane / methanol=9 / 1 v / v% (2 x 10 mL). The organic phase was concentrated in vacuo to afford the intermediate aldehyde (Intermediate TLB-DL26) (140 mg, 77%) which was used directly for reductive amination reactions with the TMKB-intermediates.

[1048] Intermediate TLB-DL27

[1049] 2-[1-[[1-[6-[(2,6-Dioxo-3-piperidyl)carbamoyl]-3-pyridyl1-4-piperidyl1methyl]-4-piperidyl1acetic acid

[1050] (Intermediate TLB-DL27)

[1051] (a) tert- Butyl 2-[1-[[1-[6-[(2,6-dioxo-3-piperidyl)carbamoyl1-3-pyridyl1-4-piperidyl1methyl1-4- piperidyllacetate

[1052] To a tube charged with A / -(2,6-dioxo-3-piperidyl)-5-(4-formyl-1-piperidyl)pyridine-2-carbox- amide (66 mg, 0.19 mmol) in DCM (2 mL) was added tert-butyl piperidine-4-carboxylate (49.6 pL, 0.23 mmol) followed by acetic acid (10.9 pL, 0.15 mmol). The mixture was stirred for 15 minutes at room temperature, after which sodium cyanoborohydride (7.2 mg, 0.116 mmol) was added and stirring was continued for 4 hours. The mixture was quenched by addition of methanol (0.5 mL). Dichloromethane (4.5 mL) was and added and the mixture was washed with saturated aqueous NaHCOa-solution (2 x 2 mL). The organic phase was filtered over a PE filter and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were pooled and lyophilised to afford the title compound (32.6 mg) as a beige solid.

[1053] (b) 2-[1-[[1-[6-[(2l6-Dioxo-3-piperidyl)carbamoyl1-3-pyridyl1-4-piperidyl1methyl1-4-piperidyl1acetic acid

[1054] (Intermediate TLB-DL27) To a flask charged with tert-butyl 2-[1-[[1-[6-[(2,6-dioxo-3-piperidyl)carbamoyl]-3-pyridyl]-4- piperidyl]methyl]-4-piperidyl]acetate (32.6 mg) was added DCM / TFA = 1 / 1 v / v% (2 mL). The mixture was stirred for 1 hour. Diethyl ether (5 mL) was added and the mixture was concentrated in vacuo to afford 2-[1 -[[1 -[6-[(2,6-dioxo-3-piperidyl)carbamoyl]-3-pyridyl]-4-piperidyl]methyl]-4-piperidyl]acetic acid (Intermediate TLB-DL27) quantitatively, which was used directly for coupling to the TMKB- intermediates.

[1055] Intermediate DL3 tert-Butyl 2-[1-(4-piperidylmethyl)-4-piperidyl]acetate (Intermediate DL3)

[1056] (a) Benzyl 4-[[4-(2-tert-butoxy-2-oxo-ethyl)-1-piperidyl]methyl]piperidine-1-carboxylate

[1057] To a solution of tert-butyl 2-(4-piperidyl)acetate (0.5 g, 2.51 mmol) and 4-formyl- / V-Cbz- piperidine in THF (7.5 mL) was added acetic acid (180 pL) and the reaction mixture was stirred at room temperature o / n. After cooling to 0 °C sodium cyanoborohydride (0.189 g, 3.0 mmol) was added and the mixture was stirred for 1 h allowing the mixture to reach room temperature. 5% aq. NaHCCh-solution was added and the mixture was extracted with ethyl acetate. The ethyl acetate layers was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (heptane / ethyl acetate = 10 / 0 to 0 / 10 v / v%) to give 606 mg of the title compound (yield: 56%).

[1058] (b) tert-Butyl 2-[1-(4-piperidylmethyl)-4-piperidyl]acetate (Intermediate DL3)

[1059] To a solution of benzyl 4-[[4-(2-tert-butoxy-2-oxo-ethyl)-1-piperidyl]methyl]piperidine-1 -carboxylate (606 mg, 1.41 mmol) in ethanol (7.5 mL) was added 10% Pd on charcoal (60 mg). Catalytic hydrogenation was performed for 2 h at room temperature. The palladium-catalyst was removed by filtration and the filtrate was concentrated in vacuo to give tert-butyl 2-[1-(4-piperidylmethyl)-4- piperidyl]acetate (Intermediate DL3) in quantitative crude yield.

[1060] Intermediate TLB-DL28

[1061] 2-[1-[[1-[2-(2,6-Dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]acetic acid (Intermediate TLB-DL28)

[1062] This compound was prepared in an analogous manner as described in Intermediate TLB-DL5, starting from 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1 ,3-dione and tert-butyl 2-[1 -(4-piperidyl- methyl)-4-piperidyl]acetate (Intermediate DL3) to afford the title compound (22.4 mg, 53%).

[1063] Intermediate TLD-DL29

[1064] 3-[1-[[1-[6-[(2,6-dioxo-3-piperidyl)carbamoyl1-3-pyridyl1-4-piperidyl]methyl]-4-piperidyl1propanoic acid (Intermediate TLB-DL29)

[1065] This compound was prepared in an analogous manner as described in Intermediate TLB- DL27, starting from A / -(2,6-dioxo-3-piperidyl)-5-(4-formyl-1-piperidyl)pyridine-2-carbox-amide (Intermediate 26) and tert-butyl 3-(4-piperidyl)propanoate to afford 50.3 mg of the title compound (quant, yield).

[1066] Intermediate TLB-DL30

[1067] 2-[3-[3-(2,4-dioxohexahvdropyrimidin-1-yl)-4-methyl-benzoyl1-3,9-diazaspiro[5.51undecan-9-yl]acetic acid (Intermediate TLB-DL30)

[1068] This compound was prepared in an analogous manner as described in Intermediate TLB- DL24, starting from (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-ben- zoate (Intermediate TLB2) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate to afford 318 mg of the title compound (yield: 92%).

[1069] Intermediate TLB-DL31 3-[3-[3-(2,4-dioxohexahvdropyrimidin-1-yl)-4-methyl-benzoyl]-3,9-diazaspiro[5.5]undecan-9- yllpropanoic acid (Intermediate TLB-DL31)

[1070] This compound was prepared in an analogous manner as described in Intermediate TLB- DL24, starting from (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-ben- zoate (Intermediate TLB2) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate to afford 330 mg of the title compound (yield: 89%).

[1071] Intermediate TLB-DL32

[1072] 3-ri-fr6-f3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]-3-pvridyl]methyl]-4-piperidyl]propanoic acid (Intermediate TLB-DL32)

[1073] This compound was prepared in an analogous manner as described in Intermediate TLB- DL25, starting from 6-[3-(2,4-dioxohexahydropyrimidin-1-yl)azetidin-1-yl]pyridine-3-carbaldehyde and tert-butyl 3-(4-piperidyl)propanoate to afford 83.2 mg of the title compound.

[1074] Intermediate TLB-DL33

[1075] 2-[4-(2,6-dioxo-3-i :ic acid (Intermediate TLB-DL33)

[1076] This compound was prepared in an analogous manner as described in Angew. Chem. Int. Ed.

[1077] 2021 , 60, 26663 to afford 1.31 g of the title compound (yield: 88%).

[1078] Intermediate TLB3

[1079] 3,4,5,6-i 2-[4-(2,6-dioxo-3- (Intermediate TLB3)

[1080] This compound was prepared in an analogous manner as described in Intermediate TLB1, starting from 2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetic acid (Intermediate TLB-DL33) to afford the title compound (352 mg, 17%). Intermediate TLB-DL34

[1081] 3- [2-(2,6-dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-vH-4-piperidyl1oxyl-1-piperidyl1propanoic acid (Intermediate TLB-DL34)

[1082] This compound was prepared in an analogous manner as described in Intermediate TLB-DL5, starting from 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1 , 3-dione and tert-butyl 3-[4-(4-piperidyloxy)-

[1083] 1-piperidyl]propanoate (Intermediate TLB-DL23-h) to afford the title compound (160 mg, quant.).

[1084] Intermediate TLB-DL35

[1085] 2- [3-(2,4-dioxohexahvdropyrimidin-1-yl)-4-methyl-benzoyll-4-piperidyl1methyll-4-piperidyl1acetic acid (Intermediate TLB-DL35)

[1086] This compound was prepared in an analogous manner as described in Intermediate TLB- DL24, starting from (2,3,4,5,6-pentafluorophenyl) 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-ben- zoate (Intermediate TLB2) and tert-butyl 2-[1-(4-piperidylmethyl)-4-piperidyl]acetate (Intermediate DL3) to afford 108 mg of the title compound (yield: quantitative).

[1087] Intermediate TLB-DL36

[1088] 3-[2-[[6-(2,4-Dioxo-1 ,3,8-triazaspiro[4.5]decan-8-yl)pyridine-3-carbonyl]amino]ethoxy1propanoic acid

[1089] (Intermediate TLB-DL36)

[1090] (a) tert-Butyl 6-(2,4-dioxo-1 ,3,8-triazaspiror4.51decan-8-yl)pyridine-3-carboxylate

[1091] To a solution of 1 , 3, 8-triazaspiro[4.5]decane-2, 4-dione 2,2,2-trifluoroacetic acid salt (283 mg, 1 mmol) and tert-butyl 6-chloropyridine-3-carboxylate (230 mg, 1.08 mmol) in DMF (5 rciL) was added DiPEA (696 pl, 4 mmol) and the reaction mixture was stirred at 120 °C overnight. Water / brine=1 / 1 v / v% (75 mL) was added and the mixture was extracted with ethyl acetate. The ethyl acetate layers was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (dichloromethane / methanol = 98 / 2 to 9 / 1 v / v%) to give 198 mg of the title compound (yield: 57%).

[1092] (b) 6-(2,4-Dioxo-1 ,3l8-triazaspiror4.51decan-8-yl)pyridine-3-carboxylic acid

[1093] To a stirred solution of tert-butyl 6-(2,4-dioxo-1 ,3,8-triazaspiro[4.5]decan-8-yl)pyridine-3- carboxylate (195 mg, 0.56 mmol) in dichloromethane (1.5 mL) was added TFA (1.5 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and traces of trifluoroacetic acid were removed by co-evaporation twice with dichloromethane to give 286 mg of the title compound as the trifluoroacetic acid salt in quantitative crude yield.

[1094] (c) tert-Butyl 3-r2-r[6-(2,4-dioxo-1 ,3,8-triazaspiro[4.51decan-8-yl)pyridine-3-carbonyllamino1ethoxylpro- panoate

[1095] 6-(2,4-Dioxo-1 ,3,8-triazaspiro[4.5]decan-8-yl)pyridine-3-carboxylic acid (52 mg, 0.1 mmol) and tert-butyl 3-(2-aminoethoxy)propanoate (19.1 pL, 0.11 mmol) were dissolved in DMF (1.2 mL). HATU (40 mg, 0.105 mmol) and DiPEA (0.12 mL, 0.7 mmol) were added subsequently and the mixture stirred at room temperature for 1 h. To the mixture was added to water / brine / ethyl acetate=1 / 1 / 1 v / v% (30 mL) and the mixture was stirred for 15 min. The ethyl acetate layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane to methanol = 10 / 0 to 9 / 1 v / v%) to afford 34 mg of the title compound (yield: 75%).

[1096] (d) 3-[2-r[6-(2l4-Dioxo-1l3,8-triazaspiro[4.51decan-8-yl)pyridine-3-carbonyl1amino1ethoxy1propanoic acid (Intermediate TLB-DL36)

[1097] To a stirred solution of tert-butyl 3-[2-[[6-(2,4-dioxo-1 ,3,8-triazaspiro[4.5]decan-8-yl)pyridine-3- carbonyl]amino]ethoxy]propanoate (34 mg, 0.074 mmol) in dichloromethane (1 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and traces of trifluoroacetic acid were removed by co-evaporation twice with dichloromethane to give 37 mg of the title compound as the trifluoroacetic acid salt in quantitative crude yield.

[1098] Intermediate DL4 terf-Butyl 2-(azetidin-3-' (Intermediate DL4)

[1099] This compound was prepared in an analogous manner as described in Intermediate DL2, starting from benzyl 3-hydroxyazetidine-1 -carboxylate and tert-butyl bromoacetate to afford 160 mg of the title compound (yield: quantitative).

[1100] Intermediate TLB-DL37

[1101] 2-[1-[2-(2,6-Dioxo-3-piperidyl)-1 ,3-dioxo-isoindolin-5-yl]azetidin-3-yl]oxyacetic acid (Intermediate TLB- DL37)

[1102] This compound was prepared in an analogous manner as described in Intermediate TLB-DL5, starting from 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1 ,3-dione and tert-butyl 2-(azetidin-3- yloxy)acetate (Intermediate DL4) to afford the title compound (50 mg, 20%).

[1103] Intermediate TLB-DL38

[1104] 3-r4-[6-(2,4-Dioxo-1l3,8-triazaspiror4.51decan-8-yl)pyridine-3-carbonyl1piperazin-1-yl1propanoic acid (Intermediate TLB-DL38)

[1105] This compound was prepared in an analogous manner as described in Intermediate TLB- DL37, starting from 6-(2,4-dioxo-1 ,3,8-triazaspiro[4.5]decan-8-yl)pyridine-3-carboxylic acid (Intermediate TLB-DL37-b) and tert-butyl 3-piperazin-1-ylpropanoate dihydrochloride (Intermediate DL1) to afford the title compound (53 mg, 97%).

[1106] Intermediate TLB-DL39

[1107] 2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino1-3,3-dimethyl- butanoyl]-3-[r(1 R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1 / - / -isoquinolin-7-yl]oxy1ethoxy]ethoxy]acetic acid (Intermediate TLB-DL39)

[1108] (a) tert-Butyl A / -[(1 S)-2-[r(1 S)-1-[(3S)-7-hydroxy-3-[[(1 R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1 / - / - isoquinoline-2-carbonyl1-2,2-dimethyl-propyl1amino1-1-methyl-2-oxo-ethyl1-A / -methyl-carbamate

[1109] This compound was prepared from subsequent HATU-coupling and acid-deprotection reactions starting from commercially available (R)-1 ,2,3,4-tetrahydronaphthalen-1-amine, Boc-7-hydroxy-(S)- 1.2.3.4-tetrahydroisoquinoline-3-carboxylic acid, Boc-Tle-OH and Boc-N-Me-Ala-OH to give 150 mg of the title compound.

[1110] (b) Methyl 2-[2-r2-[[(3S)-2-[(2S)-2-r[(2S)-2-rfert-butoxycarbonyl(methyl)amino1propanoyl1amino1-3,3- dimethyl-butanoyl1-3-[[(1R)-tetralin-1-yl]carbamoyl1-3,4-dihydro-1 / - / -isoquinolin-7- ylloxylethoxylethoxylacetate

[1111] To a solution of tert-butyl A / -[(1 S)-2-[[(1 S)-1-[(3S)-7-hydroxy-3-[[(1 R)-tetralin-1-yl]carbamoyl]-

[1112] 3.4-dihydro-1 / - / -isoquinoline-2-carbonyl]-2,2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-A / -methyl- carbamate (136 mg, 0.22 mmol) in DMF (3.9 mL) was added a solution of methyl 2-[2-(2- chloroethoxy)ethoxy]acetate (47 mg, 0.24 mmol) in DMF (0.5 mL) followed by potassium carbonate (91 mg, 0.66 mmol). The reaction mixture was stirred at ...

Claims

CLAIMS1 . A bifunctional compound of Formula (I):Targeting Macrocyclic Kinase BinderFormula (I), or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, wherein: the Targeting Ligase Binder (TLB) is a group that is capable of binding to a E3 ligase; the Targeting Macrocyclic Kinase Binder (TMKB) 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):(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 R1is wherein :5 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;10 V is selected from the group consisting of: a direct bond, O, -OCH2- , -CH(Riv)-, -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;15 Rav is hydrogen or (1 -2C)alkyl;R4V is hydrogen or (1-2C)alkyl; orRav and R4v form together with the carbon atom they are attached to a (3-6C)cycloalkyl;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 is20 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 R2is selected from the group consisting of Formula (TMKB 11-1 ) to (TMKB 11-13):510wherein Q is a monocyclic ring selected from a (3-7C)cycloalkyl and a (3-6C)heterocycloalkyl, wherein15 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;20 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 carbon atom (-CH-); w wherein the denotes the point of attachment to the Linker (DL); wherein the '~1 marks the position of R2in any one of Formula (TMKB l-a) to (TMKB l-f);25 wherein R3and R4together represent a macrocycle linker having Formula (TMKB 111-1 to TMKB III-60) selected from the group consisting of:30(TMKB IH-1 ) (TMKB HI-2) (TMKB HI-3) (TMKBIII-4) (TMKBIII-5) (TMKBIH-6) (TMKB HI-7)(TMKB HI-55) (TMKB HI-56) (TMKB HI-57) (TMKB HI-58) (TMKB HI-59) (TMKB IH-60) wherein the I * marks the position of R3in 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 R4of 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 R4of any one of Formula (TMKB 11-1 ) to (TMKB II-6); and wherein thedenotes 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 alkoxy group is optionally and independently substituted with one, two or three halogen; wherein X in Formula (TMKB III-34) to (TMKB IH-60) is the connecting group X shown in Formula (I); and wherein R5is hydrogen, NH2 or methyl.

2. The bifunctional compound of any one of the preceding claims, wherein the Linker (DL) is -L1-L2-L3- L4-L5- , wherein Li is connected to the Targeting Ligase Binder (TLB) and the L5 is connected to the Targeting Macrocyclic Kinase Binder (TMKB), wherein:Li is independently selected from the group consisting of: a direct bond, -N(RL1)-, -O-, -C(O)-N(RL1)-, - N(RL1)-C(O)-, -N(RL1)-C(O)-O-, -C(O)-, -C=C-, -C=C-, -OCH2C(O)-, (1-4C)alkyl, (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 or (1 -3C)alkyl; each RL1is independently -H or (1-4C)alkyl;L2is independently selected from the group consisting of: a direct bond, -N(RL2)-, -O-, (1 -4C)alkyl, - CH2-CH2-N(RL2)-, -(CH2-CH2-O)m-, -(CH2-CH2-CH2-O)m-, -(O-CH2-CH2)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; each RL2is independently -H or (1 -4C)alkyl; l_3 is independently selected from the group consisting of: a direct bond, (1 -8C)alkyl, -CHC-, -N(RL3)-, -O-, -N(RL3)-C(O)-, -C(O)-N(RL3)-, -C(O)-, -(O-CH2-CH2)n-, -(CH2-CH2-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 RL3is independently -H or (1-4C)alkyl; l_4 is independently selected from the group consisting of: a direct bond, (1 -4C)alkyl , -N(RL4), -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 RL4is independently -H or (1- 4C)alkyl; l_5 is independently selected from the group consisting of: a direct bond, -N(RL5)-, -N(RL5)-C(O)-, - C(O)-, (1 -4C)alkyl, -(O-CH2-CH2)q- and -(O-CH2-CH2-CH2)q-; each RL5is independently -H or (1- 4C)alkyl; each m, n, p and q is independently an integer from 1 to 3.

3. The bifunctional compound of any one of the preceding claims, wherein the Targeting Ligase Binder (TLB) is any one of:wherein the marks the position of DL or L1of DL; wherein, each RTLB1is 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 CF3; t is the number of R(TLB1 ) substituents and is independently an integer from 0 to 2; each RTLB4is independently hydrogen, (1-4C)alkyl or (1-3C)alkoxy; each RTLB5is independently hydrogen, halo, cyano or (1 -3C)alkyl;Z is -C(RTLB6)2or -C(O)-; each RTLB6is independently hydrogen or (1 -4C)alkyl; Z’ is a bond, -C(O)- or -CH2C(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:

4. Compound according to any one of the preceding claims, wherein the macrocycle linker represented by R3and R4is 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 HI-530) (TMKB III-54C)(TMKB HI-55C) (TMKB HI-56C) (TMKB HI-57C) (TMKB HI-58N) (TMKB HI-59C) (TMKB HI-60C) wherein the * marks the position of R3in 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 R4of 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 R4of any one of Formula (TMKB 11-1 ) to (TMKB II-6); and# wherein thedenotes 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 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).

5. Compound according to any one of the preceding claims, wherein the macrocycle linker represented by R3and R4is selected from the group consisting of:(TMKB 111-9) (TMKB 111-10) (TMKB 111-11 ) (TMKB 111-12) (TMKB 111-13)(TMKB HI-42) (TMKB IH-49C) (TMKB III-50C) (TMKB HI-51 C) (TMKB III-52C) (TMKB III-53C)(TMKB HI-55C) (TMKB HI-56C) (TMKB HI-57C) (TMKB HI-58N) (TMKB HI-59C) (TMKB HI-60C) wherein the ”T~ * marks the position of R3in 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 R4of 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 R4of any one of Formula (TMKB 11-1 ) to (TMKB II-6); and# wherein thedenotes 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 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).

6. Compound according to any one of the preceding claims, wherein the macrocycle linker represented by R3and R4is selected from the group consisting of:(TMKB HI-9) (TMKB 111-10) (TMKB 111-11 ) (TMKB 111-12) (TMKB 111-13)wherein the '~T~ * marks the position of R3in any one of Formula (TMKB l-a) to (TMKB l-f); wherein the in any one of Formula (TMKB 111-1 ) to Formula (TMKB III-33) marks the position of R4of any one of Formula (TMKB H-7) to (TMKB 11-13); andwherein the ™T in any one of Formula (TMKB 111-35) to Formula (TMKB III-58N) marks the position of R4of any one of Formula (TMKB 11-1 ) to (TMKB II-6); and wherein thedenotes 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, hydroxy, amino, CD3, (1 -2C)alkyl, (1-2C)alkoxy, (3- 6C)cycloalkyl or (3-6C)cycloalkoxy; 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).

7. Compound according to any of the preceding claims, wherein R2is selected from the group consisting of:(TMKB 11-11 C) (TMKB 11-12C) 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 R2in any one of Formula (TMKB l-a) to (TMKB l-f).

8. Compound according to any of the preceding claims, wherein R2is selected from the group consisting of:(TMKB ll-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 R2in any one of Formula (TMKB l-a) to (TMKB l-f).

9. Compound according to any one of the preceding claims, wherein the compound comprises a bicyclic scaffold selected from:(TMKB l-a) (TMKB l-b)Wherein R5is hydrogen, NH2 or methyl.

10. Compound according to any one of the preceding claims, wherein the compound comprises a bicyclic scaffold selected from:(TMKB l-a1 ) (TMKB l-b1 )11 . Compound according to any one of the preceding claims 1 - 10, wherein R1is:, wherein: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; andV is a direct bond.

12. Compound according to any one of the preceding claims 1 - 11 , wherein R1is: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; andU 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.

13. Compound according to any one of the preceding claims 1 - 10 and 12, wherein V is any one of: -OCH2- , -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)- and -CH(Riv)-C(O)-NH-;Riv is hydrogen or (1 -2C)alkyl; hydrogen or (1 -2C)alkyl;Rsv is hydrogen or (1 -2C)alkyl; hydrogen or (1-2C)alkyl; or form together with the carbon atom they are attached to a (3-6C)cycloalkyl.

14. Compound according to any one of the preceding claims 1 - 10 and 12 - 13, wherein R1is 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; andU 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.

15. Compound according to any one of the preceding claims 1 - 10, wherein R1is:, wherein:R1wis 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; andV 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.

16. Compound according to any one of the preceding claims 1 - 10 and 15, wherein R1is:, wherein :wherein R1wis 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; andV is a direct bond.

17. Compound according to any one of the preceding claims 1 - 10, wherein R1is:, wherein:W is a direct bond; andU 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.

18. Compound according to any one of the preceding claims 1 - 10, wherein R1is:, wherein :W is a direct bond, andU 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.

19. Compound according to any one of the preceding claims 1 - 10, wherein R1is selected from the group consisting of:wherein:R1wand R2ware 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(R1v)-NH-C(O)-, -CH(R1v)- ;R1vis hydrogen or (1 -2C)alkyl; andU 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.

20. Compound according to any one of the preceding claims 1 - 10 and 19, wherein R1is selected from the group consisting of:wherein:R1wand R2ware 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(R1v)-NH-C(O)-, -CH(R1v)- ;R1vis hydrogen or (1 -2C)alkyl; wherein R1uand R2uare 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 Xuis selected from CH and N.21 . Compound according to any one of the preceding claims 1 - 10 and 19 - 20, wherein V is any one of O, -C(O)-NH-, -CH(R1v)-NH-C(O)-, and -CH(R1v)-; wherein R1vis hydrogen or (1 -2C)alkyl.

22. Compound according to any one of the preceding claims 1 - 10 and 19 - 21 , wherein R1is selected from the group consisting of:wherein R1wand R2ware 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 R1uand R2uare 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 Xuis selected from CH and N.

23. Compound according to any one of the preceding claims 1 - 10 and 19 - 22, wherein R1is selected from the group consisting of:wherein R2wis 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 R3uis 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.

24. Compound according to any one of the preceding claims 1 - 10 and 19 - 23, wherein R1is:wherein R2wis selected from hydrogen, fluoro, methyl or methoxy; wherein R3uis 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.

25. Compound according to any one of the preceding claims 1-24, wherein Li is selected from the group consisting of: a direct bond, -N(RL1)-, -O-, -C(O)-N(RL1)-, -N(RL1)-C(O)-, -C(O)-, -C=C-, -OCH2C(O)-, (1-4C)alkyl; each RL1is independently -H or methyl;26. Compound according to any one of the preceding claims 1-25, wherein L2 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -CH2-CH2-N(RL2)-, -(CH2-CH2-O)m-, -(CH2-CH2-CH2- 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; each RL2is independently -H or methyl; m is an integer from 1 to 2.

27. Compound according to any one of the preceding claims 1-26, wherein L3 is selected from the group consisting of: a direct bond, (1 -8C)alkyl, -N(RL3)-, -O-, -N(RL3)-C(O)-, -C(O)-N(RL3)-, -C(O)-, -(O-CH2-CH2)n-, -(CH2-CH2-O)n- and (3-12C)heterocycloalkyl; wherein any of said or heterocycloalkyl group is optionally and independently substituted with one, two or three halogen, oxo, hydroxy, (1 -3C)alkyl or (1-3C)alkoxy; each RL3is independently -H or methyl; n is an integer from 1 to 2.

28. Compound according to any one of the preceding claims 1-27, wherein L4 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -(O-CH2-CH2)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.

29. Compound according to any one of the preceding claims 1-28, wherein Ls is selected from the group consisting of: a direct bond, -N(RL5)-, -N(RL5)-C(O)-, -C(O)-, (1-4C)alkyl, -(O-CH2-CH2)q and - (O-CH2-CH2-CH2)q; each RL5is independently -H or methyl; q is independently an integer from 1 to 2.

30. Compound according to any one of the preceding claims 1-29, 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.31 . Compound according to any one of the preceding claims 1-30, wherein 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. Compound according to any one of the preceding claims 1-31 , wherein L3 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -N(RL3)-, -O-, -N(RL3)-C(O)-, -C(O)-N(RL3)-, -C(O)-, -(O-CH2-CH2)n-, -(CH2-CH2-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 RL3is independently -H or methyl; n is an integer from 1 to 2. Compound according to any one of the preceding claims 1-32, wherein L4 is selected from the group consisting of: a direct bond, (1 -4C)alkyl, -N(RL4), -C(O)-, -(O-CH2-CH2)P-, -(CH2-CH2-O)P-,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 RL4is independently hydrogen or methyl; p is an integer from 1 to 2. Compound according to any one of the preceding claims 1-33, wherein Ls is selected from the group consisting of: a direct bond, -N(RL5)-, -N(RL5)-C(O)-, -C(O)- and (1 -4C)alkyl; each RL5is independently hydrogen or methyl. Compound according to any one of the preceding claims 1-34, wherein the Linker (DL) is -L1-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:1wherein themarks the point of attachment to Li or marks the point of attachment to theTargeting Ligase Binder (TLB) in case Li is a direct bond; and wherein the marks the point of attachment to the connecting group X; and wherein each RLis hydrogen or methyl; and wherein s is an integer from 0 to 5; and wherein t is an integer from 0 to 6.Compound according to any one of the preceding claims 1-35, wherein Linker (DL) is selected from the group consisting of:# wherein themarks the point of attachment to the Targeting Ligase Binder (TLB); and wherein the I marks the point of attachment to the connecting group X; and wherein s is an integer from 0 to 3.

37. Compound according to any one of the preceding claims 1-36, wherein the Targeting Ligase Binder (TLB) is selected from the group consisting of:wherein the marks the position of the Linker (DL) or L1of the Linker (DL); and wherein each RTLB5is independently hydrogen, fluoro or cyano;HAr is a (1-9C)heteroaryl optionally substituted with fluoro, methyl or methoxy.

38. Compound according to any one of the preceding claims 1-37, wherein the Targeting Ligase Binder (TLB) is selected from the group consisting of:wherein the marks the position of Linker (DL) or Li of the Linker (DL).

39. Compound according to any one of the preceding claims 1-38, wherein the Targeting Ligase Binder (TLB) is selected from the group consisting of:wherein the marks the position of Linker (DL) or L1of the Linker (DL).

40. Compound according to any one of the preceding claims 1-39, wherein the Targeting Macrocyclic Kinase Binder (TMKB) is selected from the group consisting of:Wherein X is a tertiary carbon atom (-CH-) or a tertiary amine atom (N).Compound according to any one of the preceding claims 1-40, wherein the Targeting Macrocyclic Kinase Binder (TMKB) is selected from the group consisting of:Compound according to claim 1, wherein the compound has a sub-formula 1 - 138 selected from the group consisting of:37 3879 80136 137 138 Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading Bruton's Tyrosine Kinase (BTK), wherein said bifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 18, 20, 22, 23, 44, 48, 60, 66, 68, 69, 87, 89, 90, 93, 94, 95 and 105. Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading Bruton’s Tyrosine Kinase C481S mutant (BTK C481S), wherein said bifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 18, 20, 22, 44, 66, 68, 69, 87, 93, 94 and 95. Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading Bruton's Tyrosine Kinase C481 S / T474I mutant (BTK C481 S / T474I), wherein said bifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 18, 20, 22, 44, 48, 66, 68, 69, 87, 89, 93, 94 and 95. Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading Bruton’s Tyrosine Kinase T474I mutant (BTK T474I), wherein said bifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 18, 20, 22, 34, 44, 45, 48, 66, 67, 68, 87, 89, 93, 94 and 95. Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading Bruton’s Tyrosine Kinase V416L mutant (BTK V416L), wherein saidbifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 2, 4, 20, 22, 45, 66, 89, 93, 94 and 95.

48. Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading Bruton's Tyrosine Kinase L528W mutant (BTK L528W), wherein said bifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 2, 4, 20, 22, 45, 66, 89, 93 and 95.

49. Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading Lymphocyte-Specific Protein Tyrosine Kinase (LCK), wherein said bifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 4.

50. Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading "REarranged during Transfection" receptor tyrosine kinase (RET), wherein said bifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 111 , 112, 115, 117, 118, 120, 123, 124 and 127 - 135.51 . Compound according to any one of the preceding claims wherein said compound is preferable suitable for degrading Epidermal Growth Factor Receptor (EGFR), wherein said bifunctional compound has a sub-formula as shown in claim 42 selected from the group consisting of: 137 and 138.

52. Compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, for use as a medicament.

53. Compound according to any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof, for use in therapy.

54. Compound according to any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof, for use in the treatment of Bruton’s Tyrosine Kinase (BTK) mediated disorders.

55. Compound according to any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

56. Compound according to any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof, for use in the treatment of Bruton’s Tyrosine Kinase (Btk) mediated disorders, wherein the Btk mediated disorder is selected from the group consisting of an allergic disease, an immunological disease, an autoimmune disease, an inflammatory disease, heteroimmune condition, fibrosis, a thromboembolic disease, a bone-related disease, and cancer.

57. Compound according to any of the claims 1 - 51 or claim 54, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease selected from the group consisting of 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, 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, lymphomatoid granulomatosis.

58. Compound according to any of the claims 1 - 51 or claim 54, or a pharmaceutically acceptable salt thereof, for use in the treatment of Bruton’s Tyrosine Kinase (Btk) mediated disorders, wherein the Btk mediated disorder is selected from the group consisting of arthritis, rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter’s syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis (with or without nephrotic syndrome), autoimmune hematologic disorders, hemolytic anemia, aplasic anemia, idiopathic thrombocytopenia, and neutropenia, autoimmune gastritis, and autoimmune inflammatory bowel diseases, ulcerative colitis, Crohn’s disease, host versus graft disease, allograft rejection, chronic thyroiditis, Graves’ disease, schleroderma, diabetes (type I and type II), active hepatitis (acute and chronic), pancreatitis, primary billiary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosis, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, vasculitis (e.g. Behcet’s disease) chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic sprue, cachexia, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, kerato conjunctivitis, otitis media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease, and chronic obstructive pulmonary disease.

59. Compound according to any of the claims 1 - 51 , in particular claim 49, or a pharmaceutically acceptable salt thereof, for use in the treatment of Lymphocyte-Specific Protein Tyrosine Kinase (LCK) mediated disorders.

60. Compound according to any of the claims 1 - 51 , in particular claim 49, or a pharmaceutically acceptable salt thereof, for use in the treatment of 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, atherosclerosis, 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.61 . Compound according to any of the claims 1 - 51 , in particular claim 49, or a pharmaceutically acceptable salt thereof, for use in the treatment of 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.

62. Compound according to any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof, for use in the treatment of "REarranged during Transfection" receptor tyrosine kinase (RET) mediated disorders.

63. Compound according to any of the claims 1 - 51 or claim 62, or a pharmaceutically acceptable salt thereof, for use in the treatment of “REarranged during Transfection” receptor tyrosine kinase (RET) mediated disorders, preferably for use in the treatment of cancer, wherein the RET mediated disorder is selected from the group consisting of 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.

64. Compound according to any of the claims 1 - 51 or claim 62, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in familial RET-mediated disorders, such as multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.

65. Compound according to any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof, for use in the treatment of Epidermal Growth Factor Receptor (EGFR) mediated disorders.

66. Compound according to any of the claims 1 - 51 or claim 65, or a pharmaceutically acceptable salt thereof, for use in the treatment of Epidermal Growth Factor Receptor (EGFR) mediated disorders, preferably for use in the treatment of cancer or in the treatment of an inflammatory disease, wherein the EGFR mediated disorder is selected from the group consisting of a lung cancer, nonsmall 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, or an inflammatory disease caused or aggravated on a molecular level by activity of EGFR or its ligands.thereof, for the manufacture of a medicament.

68. A pharmaceutical composition which comprises the compound according to any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

69. The pharmaceutical composition of claim 68, which further comprises at least one additional therapeutically active agent.

70. A method for treating of cancer in a subject in need thereof comprising administering to the subject the compound according to any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof in an amount effective to treat cancer.71 . A method for treating a subject suffering with a Bruton's Tyrosine Kinase (BTK) mediated disorder comprising administering to the subject the compound of any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof in an amount effective to treat the BTK mediated disorder.

72. 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 any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof in an amount effective to treat the LCK mediated disorder.

73. A method for treating a subject suffering with a “REarranged during Transfection” receptor tyrosine kinase (RET) mediated disorder comprising administering to the subject the compound of any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof in an amount effective to treat the RET mediated disorder.

74. A method for treating a subject suffering with a Epidermal Growth Factor Receptor (EGFR) mediated disorder comprising administering to the subject the compound of any of the claims 1 - 51 or a pharmaceutically acceptable salt thereof in an amount effective to treat the EGFR mediated disorder.

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