Hydroxy cinnamic acid derivatives

Abstract

The invention provides a compound of formula (I) (I) wherein: A is -CHCH-, -CH2CH2- or -CH2-; B is -CO-, -O- or -NH-; C is C3-9 alkylene, C3-9 alkenylene, or C3-9 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from -C1-4 alkyl, -CF3, -CN, -OH, -O(C1-4 alkyl), -NH2, -NH(C1-4 alkyl), or -N(C1-4 alkyl)(C1-4 alkyl), and further wherein one or more -CH2- selected from the second to last -CH2 unit comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(C1-4 alkyl)-, -CO-, -CO-NH-, -NH-CO-, -S-, -SO-, or -SO2-; D is optionally substituted aryl or optionally substituted heteroaryl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CF3, -CN, -OH, -NO2, -O(C1-4 alkyl), -NH2, -NH(C1-4 alkyl), -N(C1-4 alkyl)(C1-4 alkyl), - O(CH2)2-4N3, or -O(CH2)1-4CCH; or a pharmaceutically acceptable salt, solvate or polymorph thereof; and pharmaceutical compositions comprising said compound and uses thereof.

Description

[0001] Hydroxy Cinnamic Acid Derivatives

[0002] Field of the invention

[0003] The invention relates to novel hydroxy cinnamic acid derivatives and their uses.

[0004] Background of the invention

[0005] Bee glue, also called propolis, is a resin-like substance used by honeybees to seal, disinfect and strengthen the structure of the hive. One of its main active components is Caffeic Acid Phenethyl Ester (CAPE), a cinnamic acid ester bearing two hydroxyls at positions 3 and 4 of the phenyl ring and a phenethyl moiety. CAPE has been shown to have anti-inflammatory, immunomodulatory, and antioxidant properties and acts as a potent inhibitor of Nf-KB. Additionally, CAPE can exert anti-proliferative and pro-apoptotic activity on cancer cells by interfering with pro-oncogenic pathways [Liangl ] and inducing oxidative stress [Marin], A number of CAPE analogs have been described, being useful e.g. as lipoxygenase and cyclooxygenase inhibitors or as inhibitors of vesicular monoamine2 -oxidase.

[0006] Some disorders where cell growth regulation is disturbed or not properly regulated are based on or associated with disturbances in tubulin dynamics and / or mitotic spindle formation. Such disorders include some forms of cancer.

[0007] Some naturally occurring compounds bind to tubulin, interfering with tubulin dynamics and mitotic spindle formation. Substances that act in this manner are collectively defined herein as Microtubules Targeting Agents (MTA). Disorders where interference with tubulin dynamics and mitotic spindle formation may provide a benefit for the patient are collectively defined herein as MTA-influenceable disorders.

[0008] Strategies to treat MTA-influenceable disorders include the use of MTAs. Some MTAs known in the art are Taxanes. Taxanes are diterpenes originally identified from yew (genus Taxus) which comprise a taxadiene core. Taxanes include Paclitaxel (Taxol), docetaxel (Taxotere), and Cabazitaxel. Taxanes are difficult in formulation as medicines because they are poorly soluble in water. Furthermore, Taxanes comprise a complex multiring structure. They can be isolated from natural sources, and some have also been semi-synthesized, but synthesis of the entire molecule remains difficult due to its complex structure.

[0009] Some of these MTAs are used successfully in the treatment of cancer. For instance, therapeutics like taxanes and vinca alkaloids are among the most successful and widely used cancer drugs. Taxanes have turned out to be successful in solid cancers including breast, lung, bladder and prostate cancer. Specifically, taxanes have been used in prostate cancer, ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer.

[0010] Further MTAs include vinca alkaloids like Vincristine. Vincristine is used clinically in the treatment of non-Hodgkin's lymphoma, Hodgkin's lymphoma, nephroblastoma, Ewing's Sarcoma and hematological malignancies including acute lymphoblastic leukemia (ALL) and childhood leukemia [Jordan],

[0011] Vincristine is also used in disorders where suppression of the immune system is desirable, such as thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP).

[0012] Another vinca alkaloid is vinblastine. Vinblastine is used as monotherapy in relapsed ALK+ patients, [Brugieres] underlining the therapeutic relevance of using MTAs as a single agent.

[0013] Another MTA is Monomethyl auristatin E (MMAE). Because of its high toxicity, MMAE is targeted to tumor cells by coupling to an antibody. MMAE is used clinically coupled to an anti- CD30 antibody (Brentuximab-Vedotin) [Horwitz, Bai],

[0014] Anaplastic lymphoma kinase (ALK) is an enzyme that in humans is encoded by the ALK gene. It is also known as ALK tyrosine kinase receptor or CD246. ALK plays an important role in cellular communication and in the normal development and function of the nervous system. ALK is a tyrosine kinase that activities PI3K / AKT / mT0R, Ras-activated ERKs, Janus kinase- activated STAT proteins, and other cell signaling pathways. Mutations in the ALK gene, in particular mutations that increase its expression or function, can lead to dysregulated cell growth and cancer. Therefore, ALK inhibitors are used in the therapy of cancers where ALK overexpression or mutation plays a decisive role. These cancers include anaplastic large cell lymphoma (ALCL) and lung cancer, in particular non-small cell lung cancer (NSCLC). ALK inhibitors known in the art include Crizotinib (Pfizer), Ceritinib (Novartis), Alectinib (Roche), Brigatinib (Ahad, Takeda), and Lorlatinib (Pfizer).

[0015] A common problem in the application inhibitors like MTAs or ALK inhibitors is the development of resistance [Hare], For instance, the therapy of ALCL or lung cancer with ALK inhibitors frequently faces the problem of inhibitor resistance or development of inhibitor resistance [Pan], Most tumors eventually develop resistance through various mechanisms, namely compound-mutations (two or three mutations simultaneously) or activation of alternative pathways, such as the c-MET pathway. Some inhibitors are able to overcome certain resistance mutations (e.g. Brigatinib is active against the common Alectinib-resistance mutation G1202R). However, many cancers will develop resistance within a year of treatment, even if they are not resistant initially [Cooper],

[0016] Similarly, the clinical use of MTAs like Taxanes and Vincristine faces resistance and / or development of resistance [Maloney],

[0017] Thus, there is a need in the art to provide compounds that are able to overcome existing resistance.

[0018] It is an object of the present invention to provide novel compounds useful as CAPE analogs. It is another object of the present invention to provide compounds useful as ALK inhibitors. Yet another object of the present invention is to provide compounds useful as MTAs.

[0019] A further object of the present invention is to provide compounds useful in overcoming resistance to ALK inhibitors and / or MTAs. As such, the compounds of the present invention are useful by themselves, but also as combination with known compounds. One such combination includes a compound of the invention and an MTA. A preferred MTA is a taxane. A preferred taxane is Docetaxel. Another preferred taxane is Paclitaxel (Taxol). Yet another preferred taxane is Cabazitaxel. Another preferred combination includes a compound of the invention and a vinca alkaloid. A preferred vinca alkaloid is Vincristine. Yet another preferred combination includes a compound of the invention and an ALK inhibitor. A preferred ALK inhibitor is Alectinib.

[0020] Some CAPE analogs have been described in the literature. Selka et al [Selka] discloses CAPE analogs useful as inhibitors 5-lipoxygenase (5-LO). WO 2020 / 210920 discloses CAPE analogs useful in blood cancer treatment. WO2019075549 discloses ester analogs of CAPE useful as lipoxygenase and cyclooxygenase inhibitors. EP3423429 discloses CAPE analogs useful as modulators of lipoxgenase and cyclooxygenase. WO 2017147718 discloses CAPE analogs useful as modulators of lipoxgenase and cyclooxygenase. US11 ,999,676 discloses CAPE analogs useful as vesicular monoamine transporter-2 ligands to be used in the treatment of psychostimulant abuse.

[0021] US 4,733,002 A, US 4,959,503 A, and US 4,810,716 A disclose lipoxygenase inhibitors. JP 2006 / 273839 A discloses an adiponectin production promotor.

[0022] Brief description of the Figures

[0023] The invention is also described by the following illustrative figures:

[0024] Fig. 1 : Structure and activity of CM14. See Example 2.

[0025] Fig. 2: CM14 induces apoptosis of ALCL cells and overcomes drug resistance. See Example 3. Fig. 3: RNA-Seq and Propidium Iodide staining reveal G2 / M arrest induced by CM14. See Example 4.

[0026] Fig. 4: Testing of click chemistry derivatives of CM 14. See Example 5.

[0027] Fig. 5: TUBGCP2 as a target of CM39AL. See Example 6.

[0028] Figure 6: Effect of CM14 on viability, PARP cleavage, N-Acetyl-Cysteine Rescue, and cell cycle distribution. See Example 3.

[0029] Figure 7: Identification of cellular binding sites of CM39AL, see example 6.

[0030] Figure 8: Vincristine vs CM14 synergy analysis, CM39AL binding, see example 6.

[0031] Figure 9: CM 14 overcomes Doctaxel resistance in prostate cancer, see example 7.

[0032] Figure 10: Chemical structure of CAPE and synthetic strategy used for derivatives generation. See Example 1 .

[0033] Figure 11 : Structures of azide derivative CM38AZ and alkyne derivative CM39AL shown together with the analogs CM14 and MT114. See Example 1 .

[0034] Summary of the invention

[0035] The invention provides a compound of formula (I) wherein:

[0036] A is -CHCH-, -CH2CH2- or -CH2-;

[0037] B is -CO-, -0- or -NH-;

[0038] C is C3-9 alkylene, C3-9 alkenylene, or C3-9 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from -C1-4 alkyl, -CF3, -CN, -OH, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl), and further wherein one or more -CH2- selected from the second to last -CH2 unit comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-4alkyl)-, -CO-, -CO-NH-, -NH-CO-, -S-, -SO-, or -SO2-; D is optionally substituted aryl or optionally substituted heteroaryl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from Ci-4alkyl, halogen, -CF3, -CN, -OH, -NO2, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), -N(CI-4alkyl)(Ci-4alkyl), -O(CH2)2-4N3, or -O(CH2)I-4CCH;

[0039] R1, R4are independently -OH, -OCH3, -CH2OH, halo, -NH2and R2, R3are H, or

[0040] R2, R3are independently -OH, -OCH3, -CH2OH, halo, -NH2and R1, R4are H, or

[0041] R1, R2are independently -OH, -OCH3, -CH2OH, halo, -NH2and R3, R4are H; provided that when R2and R3are OH, A is CH2CH2, B is CO, C is C4alkylene with an optional

[0042] OH substituent at position 2 or an optional double bond between positions 1 ,2, D is not 3,4 OH- phenyl, provided that when R2and R3are OH, A is CH2CH2and B is CO, and C is C4alkylene, D is not 4-OH phenyl, provided that when R2and R3are OH, A is CHCH, B is CO, and C is C4alkylene with -CO- at position 2, and a double bond between positions 3 and 4, D is not 4 OH-phenyl, provided that when R2and R3are OH, A is CHCH, B is CO, and C is C4alkylene, D is not unsubstituted phenyl or 2-OH-phenyl, provided that when R2and R3are OH, A is CHCH and B is CO, C is C3alkylene, D is not unsubstituted phenyl, provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C9 alkylene with C7 replaced by -NH-, D is not unsubstituted phenyl, provided that provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C3alkylene with Ci substituted with -CH3, D is not 4-OH-phenyl, provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C3alkylene with C2substituted with -CH3, D is not 3-OH-phenyl. or a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0043] Definitions

[0044] Within the meaning of the present application the following definitions apply:

[0045] “Microtubules Targeting Agents (MTA)” refers to Substances that bind to tubulin, interfering with tubulin dynamics and mitotic spindle formation.

[0046] “MTA-influenceable disorder” refers to a disorder where interference with tubulin dynamics and mitotic spindle formation, generally exerted by a microtubule targeting agent (MTA), may provide a benefit for the patient. "Alkyl" refers to a saturated straight organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have 1 to 9 carbon atoms, preferably 1 to 4 carbon atoms, and include methyl, ethyl, propyl, isopropyl, n-butyl. Unless otherwise specified, alkyls include branched alkyls, such as isopropyl, t-butyl.

[0047] "Carbocyclyl" refers to a cyclic organic moiety consisting of carbon and hydrogen atoms. Examples of suitable carbocyclyl groups have 3 ot 10 carbon atoms, preferably 3, 4, 5 or 6 carbon atoms. The carbocyclyl group can be unsaturated or saturated. The term "carbocyclyl" also covers an aromatic cyclic organic moiety (aryl group) consisting of carbon and hydrogen atoms. Examples of the carbocyclyl group include cyclopentyl, cyclohexyl and phenyl.

[0048] "Heterocyclyl" refers to a carbocyclyl group as defined above in which at least one of the carbon atoms has been replaced by a heteroatom which is, e.g., selected from N, 0 or S, or heteroatom (e.g., N, 0 and / or S)-containing moiety. The heterocyclyl group can be unsaturated or saturated. It covers both heteroalkyl groups and heteroaryl groups. The heterocyclyl can also be annelated, connected in a bridged manner or connected in a spiro manner such as 6- membered bicyclic rings, 7-membered bicyclic rings, 8-membered bicyclic rings, 6-membered spirocyclic rings, 7-membered spirocyclic rings or 8-membered spirocyclic rings. Examples include azetidine, pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene, imidazolidine, pyrazolidine, imidazole, pyrazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazolidine, isothiazolidine, thiazole, isothiazole, dioxolane, dithiolane, triazole, furazan, oxadiazoles, thiadiazole, dithiazole, tetrazole, piperidine, oxane, thiane, pyridine, pyran, thiopyran, piperazine, diazine (including pyrazine and pyrimidine), morpholine, oxazine, thiomorpholine, thiazine, dioxane, dioxine, dithiane, dithiine, triazine, trioxane, tetrazine, azepane, azepine, oxepane, oxepine, thiepane, thiepine, 3-azabicyclo [3.1.O]hexane, azaspiro[3.3]heptane, diazaspiro[3.3]heptane, azabicyclo[3.2. 1 ]octane and diazabicyclo[3.2. 1 ]octane.

[0049] Examples of preferred heterocyclyl groups include azetidine, morpholine, piperazine, pyrrolidine, tetrahydrofuran, piperidine, Azaspiro[3.3]heptane, etc. Examples of possible heteroaryl groups include pyridine, pyrazole, etc.

[0050] "Alkenyl" refers to an organic moiety consisting of carbon and hydrogen atoms which includes at least one double bond. Examples of suitable alkenyl groups have 2 to 6 carbon atoms, 20 preferably 2 to 4 carbon atoms, and include propenyl and butenyl.

[0051] "Alkynyl" refers to an organic moiety consisting of carbon and hydrogen atoms which includes at least one triple bond. Examples of suitable alkynyl groups have 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and include propinyl and butinyl. "Aryl" refers to homocyclic aromatic organic moieties containing 1 or 2 or more rings, preferably 1 to 2 rings, more preferably 1 ring, consisting of carbon and hydrogen atoms which preferably have 6 to 12 carbon atoms, more preferably 5 or 6 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthryl, pyrenyl.

[0052] "Heteroaryl" refers to an aryl group in which at least one of the carbon atoms has been replaced by a heteroatom which is, e.g., selected from N, 0 or S, or heteroatom (e.g., N, Oand / or S)-containing moiety. Examples of heteroaryl groups include pyridine, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, furazanyl.

[0053] "Hal" or "halo" or "halogen" refers to F, Cl, Br, and I. With respect to pharmaceutical applications, Cl or F is preferred.

[0054] "Carbocyclylalkyl" refers to a group carbocyclyl-alkyl-.

[0055] "Heterocyclylalkyl" refers to a group heterocyclyl-alkyl-.

[0056] The term "leaving group" (LG) as employed herein is any leaving group and means an atom or group of atoms that can be replaced by another atom or group of atoms. Examples are given e.g. in Synthesis (1982), p. 85-125, table 2, Carey and Sundberg, Organische Synthese, (1995), page 279-281 , table 5.8; or Netscher, Recent Res. Dev. Org. Chem., 2003, 7, 71 -83, scheme 1 , 2, 10 and 15 and others). (Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), PET- Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp.15-50, explicitly: scheme 4 pp. 25, scheme 5 pp 28, table 4 pp 30, Figure 7 pp 33). Preferably, the "leaving group" (LG) is selected from nitro, halogen, trimethylammonium, C1 -4 alkyl sulfonate and C6-10 aryl sulfonate.

[0057] If a group is defined as being "optionally substituted" (unless defined otherwise), as chemically appropriate, it can have one or more substituents selected from -Hal, -CN, -OH,-(O- CH2CH2)n-R, -(CHCH2-O)n-R*, -(CH2CH2-O)n-(CH2CH2)-R (with R=H or Hal and R*=H, (CH2CH2)nHal, CHal3or CH3), -Ci-6alkyl, - Ci-6alkoxy, -SO2-alkyl, -NH2, -NH(CI-6alkyl) or - N(CI-6alkyl)2, preferably -Hal, -CN, -OH, -(O-CH2CH2)n-R, -(CH2CH-O)n-R*, or -(CH2CH2-O)n- (CH2CH2)-R, more preferably -Hal or -OH. In addition, typical substituents of the aryl groups include one or more alkyl groups, e.g. 1 or 2 alkyl groups, particularly 1 or 2 methyl groups. In these definitions n is 1 to 6. position”, unless otherwise indicated generally refers to the position in an alkyl numbered from left to right. For the residue C in formula I, position 1 would be therefore the one nearest to residues B and farthest from residue D. Compounds described herein having one or more optically active carbons can exist as racemates and racemic mixtures, stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are included. Compounds described herein containing olefinic double bonds include E and Z geometric isomers. Also included are all salt forms, polymorphs, hydrates and solvates.

[0058] The term "polymorphs" refers to the various crystalline structures of the compounds described herein. This may include, but is not limited to, crystal morphologies (and amorphous materials) and all crystal lattice forms. Salts can be crystalline and may exist as more than one polymorph. Solvates, hydrates as well as anhydrous forms of the salt are also encompassed. The solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and C1-4 alcohols (such as methanol or ethanol).

[0059] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non- toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 1 8 ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference. "Pharmaceutically acceptable" is defined as those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0060] "antibody derivative" refers to any immunoglobulin-based or immunoglobulin-inspired binding molecule capable of specifically recognizing an antigen. The term includes, without limitation:

[0061] (a) Full-length antibodies, including naturally occurring or recombinant antibodies from any species, such as human, humanized, mouse, rat, rabbit, goat, camelid, primate, or other vertebrate sources; and immunoglobulin classes including IgG, IgM, IgA, IgE, IgD and subclasses thereof.

[0062] (b) Humanized antibodies, wherein at least one non-human complementarity determining region (CDR) is grafted onto a human framework region; or wherein additional framework or constant-region substitutions are introduced to reduce immunogenicity.

[0063] (c) Fully human antibodies, including those obtained by transgenic animals expressing human immunoglobulin loci, B-cell cloning approaches, human antibody libraries, and in vitro selection systems.

[0064] (d) Engineered antibodies, including but not limited to:

[0065] • antibodies with engineered cysteine residues,

[0066] • antibodies with altered glycosylation,

[0067] • Fc-engineered antibodies,

[0068] • affinity-matured antibodies,

[0069] • bispecific or multispecific antibodies (e.g., tandem Fabs, IgG-scFv fusions, dual-variable- domain antibodies),

[0070] • antibodies with modified isoelectric points or stability-enhancing substitutions.

[0071] (e) Antigen-binding fragments, including but not limited to:

[0072] • Fab, Fab', F(ab')2,

[0073] • Fv,

[0074] • single-chain variable fragments (scFv),

[0075] • single-domain antibodies (e.g., VH, VL, VHH or “nanobodies”),

[0076] • diabodies, triabodies, tetrabodies, minibodies, and other multivalent fragment constructs.

[0077] (f) Phage-display-derived binding molecules, including antibody fragments, synthetic antibodies, or non-naturally occurring variable-domain constructs selected from phage display libraries, ribosome display, yeast display, mRNA display, or other combinatorial display systems.

[0078] (g) Immunoglobulin-inspired or mimetic scaffolds, including designer binding proteins exhibiting antigen specificity through engineered variable regions, consensus repeats, or synthetic CDR loops.

[0079] (h) Any functional variant of any of the foregoing, including molecules having amino-acid substitutions, deletions, insertions, or post-translational modifications that preserve specific antigen binding.

[0080] The patients or subjects in the present invention are typically animals, particularly mammals, more particularly humans.

[0081] The preferred definitions given in the "Definition"-section apply to all of the embodiments described below unless stated otherwise.

[0082] Detailed description

[0083] The compounds will be described in the following. It is to be understood that all possible combinations of the following definitions are also envisaged.

[0084] The invention provides a compound of formula (I) wherein:

[0085] A is -CHCH-, -CH2CH2- or -CH2-;

[0086] B is -CO-, -0- or -NH-;

[0087] C is C3-9 alkylene, C3-9 alkenylene, or C3-9 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from -C1-4 alkyl, -CF3, -CN, -OH, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl), and further wherein one or more -CH2- selected from the second to last -CH2 unit comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-4 alkyl)-, -CO-, -CO-NH-, -NH-CO-, -S-, -SO-, or -SO2-;

[0088] D is optionally substituted aryl or optionally substituted heteroaryl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CF3, -CN, -OH, -NO2, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), -N(CI-4alkyl)(Ci-4alkyl), - O(CH2)2-4N3, or -O(CH2)I-4CCH;

[0089] R1, R4are independently -OH, -OCH3, -CH2OH, halo, -NH2 and R2, R3are H, or

[0090] R2, R3are independently -OH, -OCH3, -CH2OH, halo, -NH2 and R1, R4are H, or

[0091] R1, R2are independently -OH, -OCH3, -CH2OH, halo, -NH2 and R3, R4are H; provided that when R2and R3are OH, A is CH2CH2, B is CO, C is C4 alkylene with an optional

[0092] OH substituent at position 2 or an optional double bond between positions 1 ,2, D is not 3,4 OH- phenyl, provided that when R2and R3are OH, A is CH2CH2 and B is CO, and C is C4 alkylene, D is not 4-OH phenyl, provided that when R2and R3are OH, A is CHCH, B is CO, and C is C4 alkylene with -CO- at position 2, and a double bond between positions 3 and 4, D is not 4 OH-phenyl, provided that when R2and R3are OH, A is CHCH, B is CO, and C is C4 alkylene, D is not unsubstituted phenyl or 2-OH-phenyl, provided that when R2and R3are OH, A is CHCH and B is CO, C is C3alkylene, D is not unsubstituted phenyl, provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C9 alkylene with C7 replaced by -NH-, D is not unsubstituted phenyl, provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C3alkylene with Ci substituted with -CH3, D is not 4-OH-phenyl, provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C3alkylene with C2 substituted with -CH3, D is not 3-OH-phenyl, or a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0093] In a preferred embodiment, the invention provides compounds of formula I wherein D is selected from phenyl, naphthyl, anthracenyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, or furazanyl, optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CF3, -CN, -OH, NO2, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl). In a further preferred embodiment, the invention provides compounds of formula I wherein D is selected from phenyl, naphthyl, anthracenyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrim idinyl, pyridazinyl, optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CF3, -CN, -OH, NO2, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl).

[0094] Also preferred are such compounds wherein D is selected from phenyl, naphthyl, or anthracenyl, optionally substituted with one or more groups independently selected from Ci-4alkyl, halogen, -CF3, -CN, -OH, NO2, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl).

[0095] More preferred are such compounds wherein D is selected from phenyl, naphthyl, or anthracenyl. Still more preferred are such compounds wherein D is phenyl.

[0096] The invention provides such compounds, including any preferred embodiments thereof, wherein C is C3-9 alkylene, optionally substituted with one or more groups independently selected from -Ci-4alkyl, -CF3, -CN, -OH, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl).

[0097] In a preferred embodiment, C is C3-9 alkylene, preferably unbranched. In any of the aforementioned embodiments, R1, R2, R3, R4is preferably OH or H.

[0098] In a further preferred embodiment, B is -CO-. In any of the aforementioned embodiments, A is preferably -CHCH-.

[0099] Also preferred are compounds wherein R1, R4are independently OH, OCH3, halo and R2, R3are H.

[0100] More preferred are compounds wherein R1, R4are OH.

[0101] Preferably, B is CO. Also preferably, A is CHCH.

[0102] Also preferably, C is C3alkyl or C4alkyl.

[0103] In another preferred embodiment, D is phenyl.

[0104] Also preferred are compounds where D is phenyl, C is C3 alkyl or C4 alkyl. Among these compounds, A is preferably CHCH. Among these compounds, B is preferably CO.

[0105] In a preferred embodiment, R1, R4are independently -OH, -OCH3, -CH2OH, halo, -NH2 and R2, R3are H. Preferred within that embodiment are compounds wherein R1, R4are independently -OH, -OCH3, -CH2OH, more preferred -OH, -OCH3, most preferred -OH. Preferred compounds in that embodiment include compounds wherein D is selected from phenyl, naphthyl, anthracenyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrim idinyl, pyridazinyl, optionally substituted with one or more groups independently selected from Ci-4alkyl, halogen, -CF3, -CN, -OH, NO2, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl). More preferred compounds in that embodiment include compounds wherein D is selected from phenyl, naphthyl, or anthracenyl, optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CF3, -CN, -OH, NO2, -0(0-4 alkyl), -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl)(Ci-4 alkyl). Even more preferred compounds in that embodiment include compounds wherein D is selected from phenyl, naphthyl, or anthracenyl. More preferably in that embodiment, D is phenyl. Also more preferred compounds in that embodiment include compounds wherein C is C3-9 alkylene, optionally substituted with one or more groups independently selected from -C1-4 alkyl, -CF3, -CN, -OH, -O(Ci-4 alkyl), -NH2, -NH(C1-4 alkyl), or -N(CI-4 alkyl)(Ci-4 alkyl). In a preferred embodiment thereof, C is C3-9 alkylene. In another preferred embodiment, R1, R2, R3, R4is OH or H. In yet another preferred embodiment thereof, B is -CO-. In another preferred embodiment thereof, A is -CHCH-.

[0106] Also preferred are compounds wherein R1, R4are independently OH, OCH3, halo and R2, R3are H. More preferred are compounds wherein R1, R4are OH. Within these compounds, B is preferably CO, A is -CHCH-. Also preferably within these compounds, C is C3 alkyl or C4 alkyl. More preferably, D is phenyl. Most preferably, R1, R4are OH, A is -CHCH-, B is -CO, D is phenyl, C is C4 alkylene. Most preferred is CM 14.

[0107] The invention also provides a compound of formula (II) wherein

[0108] A is a bond or optionally substituted C1-C7 alkylene, C1-7 alkenylene, or C1-7 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from -C1-4 alkyl, -CF3, -CN, -OH, -O(Ci-4 alkyl), -NH2, - NH(CI-4 alkyl), or -N(CI-4 alky l)(Ci -4 alkyl), and further wherein one or more -CH2- selected from the second to last -CH2 unit comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-4 alkyl)-, - CO-, -CO-NH-, -NH-CO-, -S-, -SO-, or -SO2-, and R1is -CCH or -CH2CH2N3. The last CH2unit generally refers to the CH2 unit drawn on the right hand side, which in this case is the one closest to the phenyl residue. Preferably, A is an optionally substituted C1-C7 alkylene. More preferably, A is an optionally substituted C1-C2 alkylene. Also preferably, A is a bond.

[0109] The alkylene, alkenylene, or alkynylene is preferably substituted with one or more groups independently selected from -C1-4 alkyl, -CF3, -CN, -OH, -O(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), or -N(Ci-4 alkyl)(Ci-4 alkyl). Preferred substituents are -C1-4 alkyl, -OH, -O(Ci-4 alkyl), -NH2, -NH(Ci- 4 alkyl). More preferred substituents are -OH, -NH2. More preferably, A is unsubstituted. Most preferably, A is unsubstituted C1-2 alkylene.

[0110] The invention further provides the use of a compound of formula II as an intermediate in the synthesis of a compound of formula I.

[0111] The invention further provides a compound of formula I or any preferred embodiment thereof, wherein the compound is capable of reducing viability of tumor cells. The invention further provides a method of treating a patient wherein reducing the viability of tumor cells provides therapeutic benefit for the patient, using a compound of formula I or any preferred embodiment thereof.

[0112] Preferred tumor cells are Mac-1 , Mac-2a, K299, FEPD, and SUPM2 cell lines. Preferably, the viability is reduced to less than 25%, more preferably 15% or less. Also preferably, the compound is capable of reducing the viability of tumor cells at least twice, more preferably three times, most preferably four times, as effective as CAPE.

[0113] In a preferred embodiment, the compound of formula I or a compound of one of the preferred embodiments is an MTA. Preferably, the compound is capable of binding to gammatubulin, more preferably to TUBGCP2. Also preferably, the compound is capable of reducing the viability of tumor cells resistant to an MTA and / or an ALK inhibitor.

[0114] Preferred MTAs include Taxanes and vinca alkaloids. Preferred Taxanes include Docetaxel, Paclitaxel (Taxol), docetaxel (Taxotere), and Cabazitaxel. More preferred is Docetaxel. Preferred vinca alkaloids include Vincristine and Vinblastine. More preferred is Vincristine. Another preferred MTA is Monomethyl auristatin E (MMAE). In a preferred embodiment, the MTA, such as MMAE, is coupled to an antibody. The antibody preferably serves the targeting of the MTA. A preferred antibody is an anti-CD30 antibody. A preferred MMAE-antibody conjugate is Brentuximab-Vedotin.

[0115] In a preferred embodiment, the tumor cells are taxane resistant. The taxane-resistant cells are preferably Docetaxel-resistant DU145 or docetaxel-resistant PC3 cells.

[0116] Preferably, the compound of formula I or of any preferred embodiment thereof is useful in the treatment of an MTA-influenceable disorder or an ALK-inhibitor-influenceable disorder. Preferred MTA-influenceable disorders include including breast, lung, bladder and prostate cancer. Preferred cancers are prostate cancer, ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, pancreatic cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, nephroblastoma, Ewing's Sarcoma and hematological malignancies including acute lymphoblastic leukemia (ALL) and childhood leukemia. More preferred cancers include ALCL and lung cancer. Lung cancer is preferably NSCLC.

[0117] In another preferred embodiment, MTA-influenceable disorders are selected from disorders where suppression of the immune system is desirable, such as thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP).

[0118] Preferred ALK-inhibitor influenceable disorders include ALCL. More preferred ALK- inhibitor-influenceable disorders include disorders in ALK+ patients, preferably relapsed ALK+ patients.

[0119] The invention further provides A method of treating a patient having cancer selected from blood cancer, solid cancer, using a compound of formula I or any preferred embodiment thereof.

[0120] The invention further provides a pharmaceutical composition for the treatment of an MTA-influenceable disorder or an ALK-inhibitor influenceable disorder. The invention further provides the use of a compound of formula I in the manufacturing of a drug for the treatment of an MTA-influencable disorder or of an ALK-inhibitor influenceable disorder. The disorder is preferably cancer. The cancer is preferably resistant to an ALK-inhibitor or to an MTA. The cancer is selected preferably from blood cancer, solid cancer. The cancer is preferably selected from leukemia, breast cancer, prostate cancer, lung cancer, head and neck cancer, ovarian cancer, esophageal cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer.

[0121] Labeling

[0122] The compounds described herein can be detectably labeled. The type of the label is not specifically limited and will depend on the detection method chosen. Examples of possible labels include isotopes such as radionuclides, positron emitters, gamma emitters, as well as fluorescent, luminescent and chromogenic labels. With respect to the detectably labeled compounds which include a radioisotope, a positron emitter, or a gamma emitter, it is to be understood that the radioisotope, positron emitter, or gamma emitter is to be present in an amount which is not identical to the natural amount of the respective radioisotope, positron emitter, or gamma emitter. Furthermore, the employed amount should allow detection thereof by the chosen detection method. Examples of suitable labels include fluorescent, luminescent and chromogenic labels. Preferred are fluorescent labels.

[0123] A label may be attached to a compound of the invention by one of a number of well known procedures. An example of such a procedure is the use of click chemistry.

[0124] Copper(l)-catalyzed azide-alkyne cycloaddition (CuAAC), also called “click chemistry” is a versatile tool to link marker molecules to drug candidates [Parker], In brief, an azide reacts with an alkyne side group forming a triazole ring that covalently binds the drug candidate to the desired probe.

[0125] In a first step, a compound of formula S2 (see Example 1 ) and 1 -azido-3-chloropropane or propargyl bromide are used to synthesize the corresponding ketone (see Example 1 for details). Reaction with the propargyl bromide will produce an alkyne derivate, while reaction with the 1 -azido-3-chloropropane will produce an azido derivate. Preferably, the azido derivate is used.

[0126] This compound is then used as an intermediate in the aldol condensation procedure, [Murugesan, Sanderson, Touaibia2] with 2,5-dihydroxybenzaldehyde (compare also Fig. 11 , see Example 1 for details). The resulting compound of the invention has the alkyne or azido group attached to moiety D. This group can then be used to attach a label.

[0127] Preferably, the compound is tested for activity. For instance, the binding to TUBGCP2 can be tested. Alternatively, or in addition, the ability of the compound to reduce the viability of tumor cells can be tested. Preferably, the tumor cells are ALCL cells. Details may be found in Examples 2, 5 and 6. Preferably, compounds with good activity in these tests are selected for further activity.

[0128] Preferably, a fluorescent label is used, more preferably, a green fluorescent label. Most preferred is the fluorophore Azide Flour-488 (Alexa Fluor 488 dye, Thermofisher [Thermofisher]).

[0129] The label / fluorophore may be coupled in situ, after the compound of the invention has been already in contact with the biological sample to be tested / investigated. Thus, the natural interaction between the compound of the invention and the target e.g. TUBGCP2 protein, can be studied without interference by the label. Examples 5 / 6 describe the procedure and the binding and coupling steps in more details.

[0130] The label-coupled compound of the invention can now be investigated further by microscope imaging using fluorescence microscopy, or further analytic steps, such as extraction of proteins from the sample and further analysis of the extract, by various methods, such as SDS PAGE, western blotting, staining with various reagents including antibodies, and more. Examples 5 and 6 provide additional details.

[0131] The skilled person will readily appreciate that various compounds of the invention, various labels, extraction methods, microscopy methods, and analytical methods can all be used, without deviating from the range of the invention.

[0132] The compounds described herein are useful as therapeutic compounds, in vitro analytical references, in vitro screening tools, or in vitro / in vivo research or diagnostic tools.

[0133] Research or diagnostic use

[0134] A compound of the invention may also be used in the diagnosis of a disorder or abnormality associated with abnormal aggregation or expression or intracellular location of the y-tubulin ring complex (y-TuRC) or its component TUBGCP2 or the conformation thereof. Examples of such disorders include neurodevelopmental diseases and brain malformations, such as Lissencephaly, lissencephaly, polymicrogyria, microlissencephaly, and simplified gyration.

[0135] A research use or diagnostic use of a compound of the invention may be achieved by detecting the specific binding of a compound described herein to the TUBGCP2 protein in a sample or in situ, which includes:

[0136] (a) bringing the sample or a specific body part or body area suspected of abnormal aggregation or expression or intracellular location of the y-tubulin ring complex (y-TuRC) or its component TUBGCP2 or the conformation thereof into contact with a compound described herein which binds TUBGCP2,

[0137] (b) allowing the compound described herein to bind to the TUBGCP2 to form a compound / (TUBGCP2) complex (hereinafter "compound / (TUBGCP2) complex" will be abbreviated a s "compound / protein aggregate complex"),

[0138] (c) detecting the formation of the compound / protein aggregate complex,

[0139] (d) optionally locating the compound / protein e.g. by microscopy, correlating the presence or absence and / or location of the compound / protein aggregate complex with the presence or absence of the neurodevelopmental disorder in the sample or specific body part or area, and

[0140] (e) optionally comparing the amount or location of the compound / protein aggregate complex to a normal control value, wherein a change in the amount of the compound / protein aggregate complex or altered location compared to a normal control value may indicate that the patient is suffering from or is at risk of developing a disorder or abnormality associated with neurodevelopmental disorder. The compound described herein can be brought into contact with the sample or the specific body part or body area suspected to contain abnormal aggregation or expression or intracellular location of the y-tubulin ring complex (y-TuRC) or its component TUBGCP2 or the conformation thereof by a suitable method. In in vitro methods, the compound described herein and a liquid sample can be simply mixed. In in vivo tests the compound described herein is typically administered to the patient by any suitable means. These routes of administration include, but are not limited to, one or more of: oral (e. g. as a tablet, capsule, or as an ingestible solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual. In some instances, parenteral administration can be preferred.

[0141] After the sample or a specific body part or body area has been brought into contact with the compound described herein, the compound is allowed to bind to the TUBGCP2. The amount of time required for binding will depend on the type of test (e.g., in vitro or in vivo) and can be determined by a person skilled in the field by routine experiments.

[0142] The compound which has bound to the TUBGCP2, can be subsequently detected by any appropriate method. The specific method chosen will depend on the detectable label which has been chosen. Examples of possible methods include, but are not limited to, a fluorescence imaging technique or a nuclear imaging technique such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI). The fluorescence imaging technique and / or nuclear imaging technique can be employed for monitoring and / or visualizing the distribution of the detectably labeled compound within the sample or a specific body part or body area. An example of visualizing the presence and location of TUBCGP2 is described in Example 6 hereinbelow.

[0143] The presence or absence of the compound / protein aggregate complex is then optionally correlated with the amount and / or intracellular location of TUBGCP2 in the sample or specific body part or area. Finally, the amount and / or location of the compound / protein aggregate complex can be compared to a normal control value which has been determined in a sample or a specific body part or body area of a healthy subject, wherein an increase in the amount and / or location of the compound / protein aggregate complex compared to a normal control value may indicate that the patient is suffering from or is at risk of developing a disorder or abnormality associated with neurodevelopmental disorder.

[0144] A compound described herein can also be incorporated into a test kit for detecting TUBGCP2 and / or y-Tubulin Ring Complex (y-TuRC) protein aggregates. The test kit typically comprises a container holding one or more compounds described herein and instructions for using the compound for the purpose of binding to TUBGCP2 to form a compound / protein aggregate complex and detecting the formation of the compound / protein aggregate complex such that presence or absence and / or location of the compound / protein aggregate complex correlates with the presence or absence of normal tubulin development and aggregation, and optionally, with disorders associated therewith, including neurodevelopmental disorder.

[0145] Conjugates

[0146] The compounds described herein can be conjugated to compounds that have specific biological activities (biologically effective molecule (BM)). For instance, an antibody or Fab fragment may be used as a BM in a conjugate to direct the compound of the invention to target cells, to complement its effect, to enhance the desired effect on the 'target cells, and / or to reduce possibly undesired effects.

[0147] Generally, the coupon of a compound of the invention is coupled to the BM directly or indirectly. The point of attachment on the compound of the invention is preferably moiety D, more preferably where D is aryl, more preferably phenyl. The point of attachment at the preferably functionalized, preferably with an -OH, -NH2, -COOH group, which may be attached directly to the ring structure or coupled to it via a linker preferably consisting of a substituted or unsubstituted C1 -C10 chain where optionally, one or more C atom may be replaced by -0- or - Nh-. Preferably, a directly coupled functional group is used. Where that group is coupled to the ring structure by a linker, the linker is preferably C2-C6 and aliphatic, not branched. The benzoyl ring may include substituents such as: azidomethyl, propargyl, maleimide-bearing substituent, aminoalkyl substituent, or haloacetyl substituent.

[0148] Linkers

[0149] Linkers attached to the moiety D of the compound of the invention are selected from, inter alia, Triazole linkers formed via CuAAC (as described e.g. in US 9,884,122), peptide linkers for cathepsin-mediated cleavage (as described in e.g., US 8,586,049), disulfide linkers for reductive cleavage (described in e.g., US 9,884,122), maleimide-thiol linkers (described for e.g., anti-CD74 (US8986699B2) and anti-CD70 (US20230099074) antibody- drug conjugates), and non-cleavable cysteine-engineered linkers (e.g., STRO-001 , see e.g. Abrahams et al. Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001. Oncotarget. 2018;9(102):37700-37714).

[0150] Linkers may be selected to control circulation stability, intracellular release kinetics, solubility, and conjugation efficiency. Amino acid-based linkers, PEGylated linkers, triazole- bearing linkers, and disulfide-containing linkers are described in the prior art.

[0151] In certain embodiments, linker systems comprise a PEG or polyether segment that improves aqueous solubility and reduces aggregation. For lipid-based antibody attachment, PEG spacers terminate in reactive anchors such as maleimide-DSPE, enabling insertion into liposome membranes followed by reaction with antibody thiol groups to create surface- displayed Fab' or full antibody constructs (see e.g. US8586049).

[0152] Peptide-based linkers incorporate dipeptides or tetrapeptides that undergo enzymatic cleavage within lysosomes. These linkers are used extensively in ADCs delivering SN-38, doxorubicin, and auristatins and can be optimized by including self-immolative motifs that accelerate payload release following proteolysis. Such linkers are described in anti-CD74 conjugates including milatuzumab-SN-38 and milatuzumab-doxorubicin conjugates, where linker cleavage determines drug release efficiency within malignant B-cell or solid-tumor environments (see e.g. Govindan et al., Mol Cancer Ther; 12(6) June 2013, doi: 10.1158 / 1535- 7163.MCT-12-1170).

[0153] Disulfide-containing linkers enable reductive cleavage in response to intracellular glutathione concentrations. Disulfide linkers combined with CAIX-targeting sulfonamidothiadiazole binding moieties and drug payloads produce small-molecule conjugates that demonstrate tumor-selective drug release in vivo, as disclosed in US9884122.

[0154] Triazole-containing linkers, produced by click chemistry, are chemically robust and non- cleavable. In certain embodiments, acetazolam ide-derived CAIX binders are ligated to dipeptide-linked drug moieties by a CuAAC-derived triazole group, improving conjugate stability and synthetic modularity. Such triazole-bearing linkers are specifically illustrated in the CAIX- targeting therapeutic platform described in US 9884122.

[0155] Non-cleavable linkers such as those used in STRO-001 include engineered cysteine residues and defined thiol-reactive maleimide linkers that remain intact following internalization, resulting in intracellular degradation of the antibody and release of the active maytansinoid derivative (see e.g. Molina et al., Hem. One. Vol. 35, No S2, pp 255-256, doi:10.1002 / hon.2438_121 ). Biologically effective molecules

[0156] The biologically effective molecule (BM) is preferably a binder capable of binding to target structures within the body with high affinity. Preferred BMs are antibodies or antibody derivatives such as Fab fragments. Preferred antibodies include antibodies of the lgG1 , lgG2, lgG3, or lgG4 class. Also preferably, the antibody is humanized or fully human. Further preferably, the antibody derivative is a Fab, Fab', F(ab')2, scFv, fragment or a peptide comprising the VH / VL domains. Also preferred are antibody derivatives / equivalents that are cysteine-engineered antibodies providing controlled drug-to-antibody ratio (DAR). Further preferred are bispecific or multispecific antibodies (e.g., ApoL1 -binding multispecifics).

[0157] Preferable BMs used in conjugates are antibodies and antibody derivatives.

[0158] A wide range of antibodies and antigen-binding fragments may be used as targeting moieties in conjugates, including clinically relevant monoclonal antibodies, engineered fragments, and multispecific constructs. A preferred antibody is an anti-CD74 antibody which may be used to targeting targeting hematologic malignancies. Examples of linking small molecules (analogous to the such as the molecules of the invention) are found in constructs like Milatuzumab (hLL1 ), which has been used to deliver SN-38 and doxorubicin to CD74- expressing cancers (see doi: 10.1158 / 1535-7163. MCT-12-1170). This is also used in nextgeneration constructs such as STRO-001 which features site-specific cysteine engineering and a non-cleavable maytansinoid payload (see doi: 10.1002 / hon.2438_121 ). Also preferably are Anti-Trop-2 antibodies which have been used in SN-38-based ADCs, including constructs analogous to sacituzumab govitecan (see e.g. doi: 10.1158 / 1535-7163.MCT-12-1170). Further preferable are anti-CEACAM6 antibodies which have similarly been used as targeting moieties for SN-38-conjugated ADCs (see e.g. doi: 10.1158 / 1535-7163. MCT-12-1170). Also preferably the antibody is an anti-5T4 antibody which appears in ADC formats featuring auristatin payloads and cleavable linkers, as disclosed in US8586049, providing targeted delivery to 5T4- expressing tumors. Any of these described antibody-small molecule coupling processes may be used with the said antibody, but also with another antibody, coupling that said antibody to a compound of the invention in an analogous fashion.

[0159] Also preferably are Anti-CD70 antibodies are presented as candidates for cytotoxic drug conjugation to treat CD70-positive lymphomas and immune disorders. These antibodies undergo conjugation to auristatins and other cytotoxic warheads using cleavable and non- cleavable linkers as shown in US8535678. Further preferably are claudin18.2-targeting antibodies described in EP4450521A1 include ADC embodiments directed towards gastrointestinal tumors, where the antibody is coupled to a cytotoxic payload through conventional linker technologies.

[0160] In another class of constructs, multivalent and multispecific antibodies are used for cargo recruitment or cellular targeting. For example, antibodies bispecific for ApoL1 and cell-surface antigens are employed to traffic ApoL1 -containing complexes into target cells to induce cell death, as disclosed in W02024 / 050524.

[0161] Antibody fragments, including Fab and Fab' fragments, can also serve as targeting domains of the BM. Such fragments have been conjugated to lipid anchors such as maleimide- PEG-DSPE to create particle-bound targeting systems, enabling high-density, oriented presentation on liposomal surfaces.

[0162] The present invention therefore also relates to a compound according to the present invention, wherein the compound is covalently coupled to a biologically effective molecule, wherein said biologically effective molecule is preferably selected from an antibody or Fab fragment, a binder capable of binding to target structures within the body with high affinity, such as antibodies, especially antibodies of the lgG1 , lgG2, lgG3, or lgG4 class, preferably humanized or fully human antibodies; or antibody derivatives such as Fab, Fab', F(ab')2, scFv, fragment or a peptide comprising the VHA / L domains; wherein the specificity of the biologically effective molecule is preferably selected from the group of anti-CD74 binding molecules, especially anti-CD74 antibody, such as Milatuzumab; anti-Trop-2 binding molecules, especially anti-Trop-2 antibodies; anti-CEACAM6 binding molecules, especially anti-CEACAM6 antibodies anti-5T4 binding molecules, especially anti-5T4 antibody anti-CD70 binding molecules, especially anti-CD70 antibodies; claudin18.2-targeting binding molecules, especially anti- claudin18.2 antibodies; bonding molecules bispecific for ApoL1 and cell-surface antigens, especially bispecific anti-ApoL1 -anti-cell-surface antigen antibodies.

[0163] Target structures

[0164] Target structures include CD74 (known e.g. from milatuzumab, STRO-001 , trop-2 (described e.g. in SN-38 ADCs (e.g. 10.1158 / 1535-7163.MCT-12-1170)), CEACAM6 (also described for SN-38 ADCs ), 5T4 (described for auristatin ADCs, see e.g. US8586049), Claudin18.2 (described in e.g. EP4450521 ), CD 30 (described e.g. in US 10,808,039). The target structures preferably reside on cancer cells or on tissue within solid cancers or on nearby tissue. The are preferably specifically enhanced within the cancerous tissue, on the cancer cells, or on directly surrounding tissue. A preferred target is CD 30, CD74 and / or CD79. A preferred BM is an anti-CD30 antibody.

[0165] Preferred target antigens include those that may be found on cancer cells, in particular cancer cells resistant to docetacel. Preferably, the target molecule is ABCB1 (P- glycoprotein / MDR1 / CD243). This molecule is overexpressed by docetaxel-resistant lines such as C4-2B, DU145 and LNCaP frequently overexpress ABCB1 , which drives taxane efflux and resistance.

[0166] A further preferred target is CXCR4. CXCR4 inhibition can re-sensitize cells against docetaxel. The compound if the invention is therefore particularly effective in cells overexpressing CXCR4.

[0167] Further, CD44 and CD147 (EMMPRIN) are co-overexpressed in docetaxel resistant cells. Both CD44 and CD147 are preferred targets. In a preferred embodiment, a multispecific construct (e.g. a bispecific / multispecific antibody / antibody derivative) is used. Preferably such a constructs target both CD44 and CD147 (EMMPRIN).

[0168] Other preferred targets include SSEA-4 and CD95 (Fas), particular where cells with EMT-like features are targeted. IN these cases, either antigen may be targeted. In a preferred embodiment, both targets are targeted, using a bispecific or multispecific antibody / construct / antibody derivative.

[0169] Another preferred target is TACSTD2 (EpCAM), which is particularly relevant in castration-resistant tumors and may be used independently of docetaxel resistance.

[0170] Conjugation strategies

[0171] Suitable chemistries include for the conjugation include triazole-linked conjugates, were a benzoyl-ring substituent containing an azide reacts with an alkyne on the linker to generate a triazole. The antibody is functionalized separately with the corresponding complementary reactive group. This provides a stable, non-cleavable spacer / linker structure. Also preferably, maleimide-thiol coupling is used, where an engineered cysteine on the antibody reacts with a maleimide group installed on the benzoyl ring. The thioether bond provides good serum stability. Further preferably, disulfide linkers are used, where a thiol-functionalized benzoyl ring (moiety D of the compound of the invention) can be connected to a pyridyl-activated disulfide moiety on the linker, allowing intracellular reductive cleavage. In a further embodiment, peptide linkers are used, where a cleavable dipeptide (e.g., Val-Cit) is inserted between the benzoyl substituent and an antibody-reactive moiety. Cleavage occurs in endolysosomal compartments. Cleavable linkers have the advantage that they can release the active compound of the invention specifically at the target site, while during transport when the compound is still attached, it is sterically hindered from binding to its target and less effective, thereby reducing potential unwanted effects on non-target cells and / or tissues.

[0172] In certain embodiments, an antibody, antibody fragment, or other targeting protein is covalently coupled to a compound of the invention directly or via a functionalized linker through chemistries that provide controlled stoichiometry, stability during circulation, and predictable intracellular release. Suitable conjugation procedures include thiol-reactive coupling, azidealkyne cycloaddition, disulfide exchange, lysine acylation, or combinations thereof. These approaches are exemplified throughout the prior art describing ADCs and small-molecule drug conjugates.

[0173] Maleimide-thiol addition represents a preferred approach for coupling cysteine residues within an antibody (native or engineered) to a maleimide-functionalized linker or small molecule. Maleimide-PEG-DSPE reagents have been used to attach Fab' fragments or whole IgG molecules to liposomal phospholipids or lipid-anchored linkers, forming particle-bound targeting complexes; such strategies are disclosed for attaching cetuximab Fab' fragments and other targeting proteins to PEGylated phospholipids for multivalent liposomal constructs. In representative embodiments, a partially reduced antibody yields solvent-accessible thiols which undergo Michael addition with the maleimide moiety to generate a stable thioether bond. The reaction proceeds efficiently near neutral pH, providing site-defined conjugation.

[0174] Bioorthogonal azide-alkyne cycloaddition reactions constitute an alternative conjugation strategy suitable for construction of antibody conjugates or small-molecule drug conjugates. In some embodiments, an azide-functionalized linker is reacted with an alkyne-modified antibody surface or vice versa to form a stable triazole linkage by Cu( I) -catalyzed azide-alkyne cycloaddition (CuAAC). Triazole-containing linkers are explicitly disclosed for CAIX-targeting small-molecule drug conjugates, where the binding moiety, linker, and payload are joined through CuAAC-derived triazole groups that provide metabolic stability and modular assembly.

[0175] Cleavable peptide linkers may be incorporated between the antibody and drug to enable controlled intracellular release. Suitable linkers include dipeptide sequences sensitive to lysosomal cathepsins, such as Val-Cit or Phe-Lys, which have been widely used in conjugates of SN-38, doxorubicin, and auristatins. Cleavable peptide linkers are incorporated into anti- CD70, anti-5T4, and other conjugates disclosed in the ADC literature, where the peptide segment undergoes proteolysis following endocytosis to liberate the active cytotoxic agent within tumor cells. In additional embodiments, disulfide-containing linkers enable release by reductive cleavage in intracellular environments. Small-molecule drug conjugates designed for CAIX- expressing tumors utilize disulfide bonds within the linker framework, providing controlled drug liberation under intracellular reductive conditions while maintaining adequate stability in plasma.

[0176] Non-cleavable linker systems may also be employed. For example, STRO-001 incorporates a non-cleavable maytansinoid linker-payload attached via engineered cysteine residues introduced during cell-free antibody synthesis, yielding a defined drug-antibody ratio of 2 and high stability in vitro and in vivo.

[0177] Lysine acylation using activated esters (e.g., NHS-esters) constitutes another viable approach for conjugating small molecules to antibodies. In such embodiments, exposed lysine residues on the antibody surface react with activated carboxyl groups on a linker-payload construct to produce stable amide bonds. This method is described in traditional ADC constructs such as the anti-5T4 antibody conjugates and the SN-38 ADCs directed against Trop-2 and CEACAM6 antigens.

[0178] In one embodiment, an anti-CD74 antibody is linked through a Val-Cit-PABC peptide linker to a compound of formula I, wherein the D moiety is modified at the para-position with a with a thiol-reactive maleimide group. In this embodiment, D is preferably Phenyl. Also preferably, D is unsubstituted except for the modification at the para position. In another embodiment, a Claudin18.2 antibody is joined to a compound of formula I through a triazole linker, wherein an azidomethyl substituent on the D moiety participates in CuAAC. In this embodiment, the D moiety is preferably phenyl, is further preferably unsubstituted except for the azidomethyl substituent, and is more preferably substituted in para-position with the azidomethyl substituent. In another embodiment, a bispecific antibody recognizing ApoL1 and a tumor antigen is coupled to a compound of formula I via a disulfide linker configured for reductive cleavage upon internalization. In a further embodiment, a non-cleavable linker is attached through engineered cysteine residues (DAR 2) to the antibody or antibody derivative, analogous to STRO-001 strategies, with the payload being a compound of formula I. The compound of formula I preferably has a D moiety which is phenyl, the linker is preferably attached in para position. In another embodiment, an Fab' fragment bearing an available thiol couples to a pyridyl-disulfide-activated compound of formula I, where the moiety D is preferably phenyl and the pyridyl-disulfide groups is attached in para position. The disulfide confers intracellular reductive release. In these embodiments, R1 , R4 are preferably OH, A is preferably -CHCH-, B is preferably -CO-, C is preferably -(CH2)3-, D is preferably phenyl, preferably unsubstituted phenyl except for the modification that is used to attach the linker, which is preferably in para-position. More preferably, R1 , R4 are OH, A is -CHCH-, B is -CO-, C is - (CH2)3-, D is phenyl, preferably unsubstituted phenyl except for the modification that is used to attach the linker, which is in para-position.

[0179] In one embodiment, the invention provides a conjugate between a compound of formula I and an antibody or antibody derivative, comprising:

[0180] (a) an antibody, andtibody deerivative or antigen-binding fragment thereof;

[0181] (b) a compou d of formula I; and

[0182] (c) a linker connecting the antibody to the compound of formula I through a substituent on the D moiety ring, wherein the catechol ring of the coimpound of formula I is free of substituents and is not a point of attachment to the antibody.

[0183] More preferably, R1 and R4 are -OH. Further preferably, D is a phenyl ring. More preferably, D is unsubstituted except for the functionalized group that serves as attachmewnt point to the linker or to the antibody or antibody derivative. Also preferably, A is -CHCH-. Also preferably, B is -CO-. Also preferably, C is -(CH2)3-. More preferably, the compound of formula I is a CM 14 derivative, where the phenyl ring is functionalized to allow attachment of the linker.

[0184] The invention further provides the conjugate wherein the linker comprises a cathepsin- cleavable peptide linker comprising valine— citrulline (Val-Cit). Preferably, the linker further comprises a para-aminobenzylcarbamate (PABC) self-immolative spacer. The linker preferably further comprises a maleimide functional group configured to form a thioether bond with a cysteine residue of the antibody or antibody derivative. The antibody derivative is preferably an antibody or an antigen-binding fragment thereof. The antibody or antibody derivative preferably binds a target structure that resides on cancer cells or on tissue within solid cancers or on nearby tissue. More preferably, the target is upregulated or enhanced in resistant cancer tissue, preferably in cancers resistant to an MTA, preferably docetaxel.

[0185] The target is preferably CD74, trop-2, CEACAM6, 5T4, Claudin18.2, CD 30, CD 30, CD74 and / or CD79, ABCB1 , CXCR4, CD44, CD147, SSEA-4, CD95 and / or TACSTD2. In a preferred embodiment, the antibody derivative is multispecific or bispecific and binds specifically to at least two targets. In a preferred embodiment, the target is CD 30, CD79, including CD79a, CD79b, or a heterodimer thereof. The antinbody derivative is preferably an antibody or antibody fragment. The antibody is preferably human, humanized, or chimeric IgG 1 , or a target-binding antibody fragment of any of these antibodies. The antibody or antibody fragment preferably comprises engineered cysteine residues providing a controlled drug-to- antibody ratio (DAR). The compound of formula I is preferably attached at the moiety D. The moiety D is preferably phenyl. The position of the attachment is preferably para. The attachment is preferably conferred through a CH2-linked carbonate or carbamate to spacer. The spacer is preferably a PABC spacer. The linker preferably comprises a Val-Cit-PABC-(spacer)- maleimide architecture. The average drug-to-antibody ratio (DAR) is preferably between 2 and 4. The antibody is preferably an anti-CD79 lgG1 and the payload is released intracellularly following cathepsin-mediated cleavage of the Val-Cit linker and self-immolation of the PABC spacer. In a further embodiment, a pharmaceutical composition is provided comprising the antibody-drug conjugate of any of the above embodiments and a pharmaceutically acceptable carrier.

[0186] Pharmaceutical compositions

[0187] The compounds described herein can be employed in treating, preventing or alleviating a disorder or abnormality selected from an MTA-influenceable disorder and an ALK-inhibitor- influenceable disorder.

[0188] Due to their design and to the binding characteristics, the compounds described herein are suitable for treating, preventing or alleviating a disorder selected from an MTA-influenceable disorder and an ALK-inhibitor-influenceable disorder.

[0189] The MTA is preferably selected from a taxane, a vinca alkaloid or a synthetic MTA.

[0190] The taxane is preferably Docetaxel, Paclitaxel (Taxol), Docetaxel (Taxotere), or Cabazitaxel. More preferred is Docetaxel.

[0191] The vinca alkaloid id preferably Vincristine or Vinblastine. More preferred is Vincristine.

[0192] The synthetic MTA is preferably Monomethyl auristatin E (MMAE). The MMAE is preferably coupled to an antibody. The antibody is preferably an anti-CD30 antibody. A preferred MMAE-antibody conjugate is Brentuximab-Vedotin.

[0193] The ALK inhibitor is preferably Crizotinib (Pfizer), Ceritinib (Novartis), Alectinib (Roche), Brigatinib (Ahad, Takeda), Lorlatinib (Pfizer). Preferred is Alectinib.

[0194] The ALK-inhibitor influenceable disorder is preferably associated with abnormal expression and / or function of the ALK protein. The abnormal expression and / or function is preferably augmented expression and / or function. A preferred ALK-influenceable disorder is a disorder in a patient who is ALK+, preferably a relapsed ALK+ patient.

[0195] ALK-influenceable disorders include cancer, more preferably leukemia, more preferably

[0196] ALCL. Other disorders influenceable by MTA and / or ALK inhibitors include cancers involving abnormal expression of the ALK gene, cancers involving abnormal expression, conformation, or location of the TUBGCP2 protein. The cancer is preferably selected from cancer is selected preferably from blood cancer, solid cancer. The cancer is preferably selected from leukemia, breast cancer, prostate cancer, lung cancer, head and neck cancer, ovarian cancer, esophageal cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer.

[0197] In pharmaceutical applications, the compound described herein is preferably administered in a pharmaceutical composition comprising the compound described herein. A "pharmaceutical composition" is defined herein as a composition comprising one or more compounds described herein in a form suitable for administration to a patient, e.g., a mammal such as a human, and which is suitable for treating, alleviating or preventing the specific disorder or abnormality at issue. Preferably a pharmaceutical composition further comprises a physiologically acceptable carrier, diluent, adjuvant or excipient. The dose of the compound described herein will vary depending on the exact compound to be administered, the weight of the patient, and other variables as would be apparent to a physician skilled in the art.

[0198] While it is possible for the compounds described herein to be administered alone, it is preferable to formulate them into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, provided is also a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I) in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0199] Pharmaceutically acceptable excipients are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publishing Co., New Jersey (1975). The pharmaceutical excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof.

[0200] Pharmaceutically useful excipients that may be used in the formulation of the pharmaceutical composition may comprise, for example, carriers, vehicles, diluents, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil cottonseed oil, oily esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickening agents, stabilizers, disintegrants, glidants, lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl - [3-cyclodextrin, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

[0201] The routes for administration (delivery) of the compounds described herein include, but are not limited to, one or more of: oral (e. g. as a tablet, capsule, or as an ingestible solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual. Generally,, where a conjugate with a larger molecule (such as an antibody) is used, the route of administration is preferably parenteral, intramuscular, or intravenously, more preferably intravenously.

[0202] For example, the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

[0203] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably com, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0204] If the compounds described herein are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compounds; and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0205] As indicated, the compounds described herein can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetrafluoroethane (HFA134AT) or 1 ,1 ,1 , 2, 3,3,3- heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e. g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e. g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0206] Alternatively, the compounds described herein can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds described herein may also be dermally or transdermally administered, for example, by using a skin patch.

[0207] They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH was adjusted, sterile saline, or, preferably, as solutions in isotonic, pH was adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0208] For application topically to the skin, the compounds described herein can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0209] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.

[0210] A proposed dose of the compounds described herein for administration to a human (of approximately 70 kg body weight) is 0.1 mg to 1 g, preferably 1 mg to 500 mg of the active ingredient per unit dose. The unit dose may be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0211] The compounds described herein may also be used in combination with one or more therapeutic agents. When a compound described herein is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone.

[0212] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound described herein or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

[0213] The pharmaceutical compositions described herein can be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publishing Co., New Jersey (1975).

[0214] A pharmaceutical composition suitable for administering a conjugate, preferably and antibody-drug conjugate (ADC) comprises a therapeutically effective amount of the conjugate and at least one pharmaceutically acceptable excipient, wherein the composition maintains the structural integrity, biological activity, and in vivo stability of the ADC under storage and administration conditions. The pharmaceutical composition preferably includes a Buffer system. A preferable, physiologically acceptable buffer is capable of maintaining the ADC in a stable pH range, typically between pH 4.5 and 7.5. The buffer preferably includes histidine, citrate, acetate, phosphate, and / or succinate to stabilize pH. Also preferably, the pharmaceutical composition comprises stabilizers that preserve conformational stability and prevent aggregation of the antibody portion of the ADC. Preferably, the stabilizers include sugars such as sucrose, trehalose, lactose, or mannitol, amino acids such as glycine, arginine, serine, or histidine, and / or polyols such as glycerol or sorbitol. The pharmaceutical composition preferably also comprises one or more surfactants which are preferably non-ionic surfactants to reduce surface-induced aggregation and maintain solubility. Preferred surfactants include but are not limited to polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), poloxamers (e.g., Pluronic F- 68). The pharmaceutical composition further preferably comprises one or more tonicity agents to achieve isotonicity preferably for parenteral administration. These include, but are not limited to sodium chloride, dextrose, and / or mannitol. The pharmaceutical composition further preferably includes antioxidants and chelators, which are optional agents that inhibit oxidative degradation of the linker or payload. Preferred antioxidants and chelators include, but are not limited to, methionine, ascorbate, and / or EDTA, DTPA, or related chelating agents. Also preferably, the pharmaceutical composition includes one or more preservatives, including, but not limited to benzyl alcohol, phenol, m-cresol. Preferably, preservatives are omitted in singleuse vials.

[0215] The pharmaceutical composition is preferably formulated as: a sterile aqueous solution for intravenous or subcutaneous injection, a lyophilized (freeze-dried) powder reconstituted prior to use, a ready-to-use, prefilled syringe or vial, or a polymer-stabilized formulation for slow release. The pharmaceutical composition is sterilized prior to use, preferably by filtration through a 0.2 pm sterile filter or equivalent.

[0216] The pharmaceutical composition comprising the conjugate is preferably suitable for intravenous infusion, intravenous bolus, or subcutaneous injection. The ingredients and conditions (like pH) are chosen in such a way that preferable, the maleimide-thiol thioether linkage (or other ADC linker) remains stable, the antibody retains antigen-binding activity, the small-molecule payload does not prematurely release, and / or aggregation, fragmentation, and deamidation of the antibody are minimized.

[0217] Accordingly, the present invention also relates to a compound of the present invention for use in the treatment of a cancer selected from blood cancer and solid cancer, especially for the treatment of ALCL and non-Hodgkin lymphoma. Moreover, the present invention also relates to a method for treating a cancer patient, wherein an effective amount of a compound of the present invention is administered to said patient and wherein said cancer is selected from blood cancer and solid cancer, especially for the treatment of ALCL and non-Hodgkin lymphoma.

[0218] Moreover, the present invention also relates to the use of a compound of the present invention for the manufacture of a medicament for the treatment of a cancer selected from blood cancer and solid cancer, especially for the treatment of ALCL and non-Hodgkin lymphoma.

[0219] Mixtures with other compounds

[0220] The compounds described herein can also be provided in the form of a mixture with at least one compound selected from a therapeutic agent different from the compound described herein, a pharmaceutically acceptable carrier, a diluent and an excipient. The compound and / or the therapeutic agent different from the compound described herein are preferably present in a therapeutically effective amount.

[0221] The nature of the therapeutic agent different from the compound described herein will depend on the intended use of the mixture. The therapeutic agent different from the compound described herein may exert its biological effect by the same or a similar mechanism as the compound described herein or by an unrelated mechanism of action or by a multiplicity of related and / or unrelated mechanisms of action.

[0222] Generally, the therapeutic agent different from the compound described herein may include an MTA or an ALK inhibitor or a compound used in a clinical regimen with an ALK inhibitor or MTA, or an antibody, including any functionally equivalent antibody or functional parts thereof.

[0223] MTAs include Taxanes, vinca alkaloids, and synthetic MTAs.

[0224] Taxanes include Docetaxel, Paclitaxel (Taxol), docetaxel (Taxotere), and Cabazitaxel. A preferred Taxane is Docetaxel.

[0225] Vinca alkaloids include Vincristine and Vinblastine. A preferred vinca alkaloid is Vincristine.

[0226] Synthetic MTAs include Monomethyl auristatin E (MMAE). MMAE is preferably coupled to an antibody. A preferred antibody is an anti-CD30 antibody. A preferred MMAE-antibody conjugate is Brentuximab-Vedotin. Clinical regimens include the treatment of ALCL and non-Hodgkin lymphoma, such as the CHOP or R-CHOP regimen, or the combination therapy for treatment of ALCL. Accordingly, compounds that may be used in a mixture with a compound of the invention include DNA alkylating agents, DNA intercalating agents, Tubulin binding agents, Steroids.

[0227] A preferred DNA alkylating agent is Cyclophosphamide.

[0228] A preferred DNA intercalating agent is doxorubicin.

[0229] A preferred tubulin binding agent is Vincristine.

[0230] A preferred Steroid is a corticosteroid. Preferred corticosteroids are Prednisone and Prednisolone.

[0231] ALK inhibitors include Crizotinib (Pfizer), Ceritinib (Novartis), Alectinib (Roche), Brigatinib (Ahad, Takeda), Lorlatinib (Pfizer). Preferred is Crizotinib and Alectinib. More preferred is Alectinib.

[0232] A preferred antibody is an anti-CD30 antibody.

[0233] The compound of the invention may be used not only in a mixture with the above mentioned therapeutic agent different from the compound of the invention, but also in combination therapy or treatment regimen together with the said therapeutic agent different from the compound of the invention. The therapeutic agent different from the compound of the invention is preferably selected from MTA, ALK inhibitor, or a compound used in a clinical regimen with an ALK inhibitor or MTA.

[0234] MTAs include Taxanes, vinca alkaloids, and synthetic MTAs.

[0235] Taxanes include Docetaxel, Paclitaxel (Taxol), docetaxel (Taxotere), and Cabazitaxel. A preferred Taxane is Docetaxel.

[0236] Vinca alkaloids include Vincristine and Vinblastine. A preferred vinca alkaloid is Vincristine.

[0237] Synthetic MTAs include Monomethyl auristatin E (MMAE). MMAE is preferably coupled to an antibody. A preferred antibody is an anti-CD30 antibody. A preferred MMAE-antibody conjugate is Brentuximab-Vedotin.

[0238] Clinical regimens include the treatment of ALCL and non-Hodgkin lymphoma, such as the CHOP or R-CHOP regimen, or the combination therapy for treatment of ALCL. Accordingly, compounds that may be used in a mixture with a compound of the invention include DNA alkylating agents, DNA intercalating agents, Tubulin binding agents, Steroids.

[0239] A preferred DNA alkylating agent is Cyclophosphamide.

[0240] A preferred DNA intercalating agent is doxorubicin.

[0241] A preferred tubulin binding agent is Vincristine. A preferred steroid is a corticosteroid. Preferred corticosteroids are Prednisone and Prednisolone.

[0242] ALK inhibitors include Crizotinib (Pfizer), Ceritinib (Novartis), Alectinib (Roche), Brigatinib (Ahad, Takeda), Lorlatinib (Pfizer). Preferred is Crizotinib and Alectinib. More preferred is Alectinib.

[0243] A preferred antibody is an anti-CD30 antibody.

[0244] The mixtures generally comprise the therapeutic agent different from the compound of the invention, together with a compound described herein and, optionally, a pharmaceutically acceptable carrier and / or a diluent and / or an excipient.

[0245] Preferred compounds are illustrated in the examples.

[0246] The compounds described herein can be synthesized by one of the general methods shown in the following schemes (see Example 1 ). These methods are only given for illustrative purposes and should not be construed as limiting.

[0247] The invention is illustrated by the following examples which, however, should not be construed as limiting.

[0248] Examples

[0249] Example 1 : Synthesis of compounds

[0250] This example details the general synthetic procedures used in the preparation of the compounds of the invention.

[0251] Compounds of Formula S1

[0252] CM3: X = CH2, n = 3

[0253] CM14: X = CH2, n = 2 Compounds of Formula S2

[0254] General synthetic experimental procedures

[0255] All reactions were carried out under an argon atmosphere in oven-dried glassware. All reagents and chemicals were purchased from commercial suppliers and used without further purification unless otherwise noted. All purification procedures were carried out with reagentgrade solvents in air. Thin layer chromatography (TLC) analysis was conducted using silica gel- coated aluminum sheets (SiliaPlate TLC, Silicycle®) with detection by UV light (254 nm, UVS- 11 , Mineralight® shortwave UV lamp). Purification was carried out by flash chromatography (Isco, Inc. CombiFlash™ Sg100c).1H and13C nuclear magnetic resonance (NMR) spectra were recorded at room temperature using BrukerAV-lll-400 spectrometer. Chemical shifts (5 values) were reported in parts per million and were referenced to the deuterated residual solvent peak. NMR data were reported as 5 value (where s = singlet, d = doublet, t = triplet, q = quartet, and quin = quintuplet, integration, J value (Hz)). High-resolution mass spectrometry (HRMS) measurements were performed on an Agilent 6200 high-resolution time-of-flight mass spectrometer equipped with a Dual ESI ion source. Analytical high-performance liquid chromatography (HPLC) was performed on an Agilent Technologies system (AgilentHOO Series) with an ACE C18 column (150 mm x 4.6 mm, 5p) using miliQ water (A) and HPLC grade methanol (B) as mobile phase in a gradient mode (gradient steps: 75:25 (A:B; 1 min), 15:85 (A:B; 7 min) and 75:25 (A:B; 7 min); flow rate of 1.0 ml / min, detection at 320 nm). The purity of >98% has been established for all tested compounds.

[0256] Ester analogs were synthesized either by a one-step esterification of hydroxycinnamic acids or via the Witting coupling using the appropriate aldehyde and stabilized phosphonium ylide [Murugesan, Selka, Sanderson], Ketone analogs were synthesized through an aldol condensation with the appropriate benzaldehyde and ketone [Selka, Touaibia2], Ketone (K1) and (K2) required for the synthesis of CM3 and CM14 are described in schemes 1 and 2. Ketone (k1) required for the synthesis of CM3 was synthesized as described in the literature (Scheme 1 ) [Ferreira, Mankee] with some changes, notably in the hydrogenation step.

[0257] Scheme 1. Reagents and conditions: (i) Acetone, reflux; (ii) Pd / c (5%), H2, 2.75 MPa, 30 min.

[0258] Synthesis of (3E,5E)-6-phenylhexa-3,5-dien-2-one (KO)

[0259] To a stirred solution of cinnamaldehyde (1) (7.9 g, 60 mmol, 1 eq) and acetone (13.2 mL, 178 mmol, 3 eq) in water was added NaOH (1 .2 g, 30 mmol, 0.5 eq). The solution was heated at 70°C for 8 h. The white solid obtained after coolness of the solution was dissolved in EtOAC (250 mL) was added followed by extractions with EtOAc (3 x 25 mL). The combined organic fractions were then combined and stirred with sodium bisulfite (NaHSC ) solution (100 mL, 2M) for 30 min to remove any traces of the starting aldehyde. After separation, the combined organic fractions were washed with brine (3 x 50 mL), dried over MgSCU, filtered, and concentrated under vacuum. The obtained yellow solid (yield = 92 %, m.p. 57-59°C) was analyzed by NMR after evaporation of the solvent and used in the next step without any further purification.1H NMR (400 MHz, CDCI3) 5 7.50 (d, J = 6.7 Hz, 2H, Har), 7.43 - 7.30 (m, 4H, 3Har, CH=), 7.02 - 6.85 (m, 2H, CH=), 6.29 (d, J = 15.5 Hz, 1 H, CH=), 2.34 (s, 3H, CH3).13C NMR (101 MHz, CDCI3) 6 198.44, 143.45, 141.29, 135.98, 130.51 , 129.24, 128.87, 127.26, 126.67, 27.39. Synthesis of 6-phenylhexan-2-one (K1) In high-pressure autoclave [Touaibial ] equipped with a glass liner containing a stirring bar, were introduced (3E,5E)-6-phenylhexa-3,5-dien-2-one (2) (2 g, 11.6 mmol, 1 eq), Pd / C (5 wt %, 10Omg, 0.047 mmol, 0.004 eq of Pd) and EtOAc (15 mL). The autoclave was pressurized at 2.75 MPa at room temperature and the mixture is stirred for 1 h. At the end of hydrogen consumption, the mixture was filtered under a flow of nitrogen through a Celite pad. The obtained colorless liquid (yield = 98 %) was analyzed by NMR after evaporation of the solvent and used in the next step without any further purification.

[0260] 1H NMR (400 MHz, CDCI3) 6 7.33 - 7.26 (m, 2H, Har), 7.22 - 7.18 (m, 3H, Har), 2.66 (d, J = 6.7 Hz, 2H, ArCH2), 2.50 - 2.43 (m, 2H, COCH2), 2.14 (s, 3H, CH3), 1.68 - 1.61 (m, 4H, ArCH2CH2CH2CH?CO).13C NMR (101 MHz, CDCI3) 6 209.00, 142.19, 128.38, 128.32, 125.77, 43.58, 35.73, 30.95, 29.89, 23.47.

[0261] General procedure 1 : Synthesis of CM3 and CM14

[0262] To a stirred solution of the appropriate hydroxybenzaldehyde (1 eq) and the appropriate ketone (1.1 eq) in tetrahydrofuran (THF) was added successively a catalytic amount of acetic acid (4 drops) and 100 pL of pyrrolidine. The solution was refluxed under argon atmosphere for 12h. After the removal of under vacuum, water (50 mL) was added followed by extractions with EtOAc (3 x 25 mL). The combined organic fractions were then combined and stirred with sodium bisulfite (NaHSOs) solution (100 mL, 2M) for 30 min to remove any traces of starting aldehyde. After separation, the combined organic fractions were washed with brine (3 x 50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The resulting crud product was purified by flash chromatography.

[0263] Compound CM3

[0264] Following general procedure 2 with trans 2,5-dihydroxybenzaldehyde (250 mg, 1.8 mmol, 1 eq), 6-phenylhexan-2-one (K1) (350 mg, 2 mmol, 1.1 eq) and 10 mL of THF, compound CM3 was obtained as a green solid after flash chromatography (EtOAc / Hexane (1 / 9) to EtOAc / Hexane (1 / 1 ), yield = 66 %, m.p.: 115-117°C.1H NMR (400 MHz, DMSO) 5 9.50 (s, 1 H, OH), 8.89 (s, 1 H, OH), 7.74 (d, J = 16.3 Hz, 1 H, ArCH=), 7.29 - 7.26 (m, 2H, Har), 7.24 - 7.12 (m, 3H, Har), 6.94 (d, J = 2.7 Hz, 1 H, Har), 6.78 - 6.67 (m, 3H, 2Har, COCH=), 2.67 (t, J = 6.7 Hz, 2H, COCH2), 2.60 (t, J = 6.9 Hz, 2H, ArCH2), 1 .65 - 1 .50 (m, 4H, OCH2CH2).13C NMR (101 MHz, DMSO) 5 200.39, 150.40, 150.39, 142.55, 137.78, 128.74, 128.70, 126.11 , 125.77, 121.63, 119.85, 117.48, 113.54, 40.30, 35.44, 31.01 , 24.00. HRMS m / z calc, for C19H20O3 + (H+): 297.1485; found: 297.1480.

[0265] Synthesis of 5-phenylpentan-2-one (K2)

[0266] Ketone (K2) was synthesized via high-pressure hydrogenation (scheme 2) instead of hydrogenation at balloon pressure as described in the literature [Hattori].

[0267] Scheme 2. Reagents and conditions: (i) Pd / C (10%), MeOH, H2, 2.75 MPa, 24h.

[0268] Following the procedure described above for the synthesis of (K1 ) with 1 -phenylpentane- 1 , 4-dione (1 g, 5.67 mmol, 1 eq), Pd / C (10%) (300 mg, 0.28 mmol, 0.05 eq of Pd), and 10 mL of methanol (MeOH), 5-phenylpentan-2-one (K2) was obtained after filtration over a Celite pad and evaporation of the methanol. The yellow liquid (yield = 93 %) was analyzed by NMR and used in the next step without any further purification.

[0269] 1H NMR (400 MHz, CDCI3) 6 7.33 - 7.29 (m, 2H, Har), 7.24 - 7.19 (m, 3H, Har), 2.65 (t, J = 7.5 Hz, 2H, ArCH2), 2.46 (t, J = 7.4 Hz, 2H, COCH2), 2.14 (s, 3H, CH3), 1.94 (p, J = 7.5 Hz, 2H, ArCH2CH2CH2CO).13C NMR (101 MHz, CDCI3) 6 208.79, 141.58, 128.47, 128.40, 125.97, 42.85, 35.03, 29.96, 25.21.

[0270] Compound CM14 Following general procedure 1 with 2,5-dihydroxybenzaldehyde (314 mg, 2.57 mmol, 1 eq), 5-phenylpentan-2-one (K2) (405 mg, 2.49 mmol, 1.1 eq) and 10 mL of THF, compound CM14 was obtained as a green solid after flash chromatography (EtOAc / Hexane (1 / 9) to EtOAc / Hexane (1 / 1 ), yield = 48 %, m.p.: 82-85°C.1H NMR (400 MHz, DMSO) 5 9.51 (s, 1 H, OH), 8.90 (s, 1 H, OH), 7.73 (d, J = 16.3 Hz, 1 H, ArCH=), 7.34 - 7.14 (m, 5H, Har), 6.94 (s, 1 H, Har), 6.79 - 6.67 (m, 3H, 2Har, COCH=), 2.66 (t, J = 6.9 Hz, 2H, COCH2), 2.59 (d, J = 7.4 Hz, 2H, ArCH2), 1.86 (p, J = 7.5 Hz, 2H, COCH^FhCH^.13C NMR (101 MHz, DMSO) 5 200.17, 150.40, 142.28, 137.81 , 128.77, 126.25, 125.70, 121.61 , 119.88, 117.48, 113.53, 35.00, 26.16. HRMS m / z calc, for CisH Os + (H+): 283.1329; found: 283.1337.

[0271] Ketones (K3) and (K4), bearing the azido or the alkenyl moiety, required for the synthesis of CM38AZ and CM39AI analogs were synthetized as outlined in scheme 3:

[0272] Scheme 3. Reagents and conditions : i) 1 -azido-3-chloropropane6[Verdoes], K2CO3, DMF, 80°C, 12 h; ii) : propargyl bromide, K2CO3, DMF, 80°C, 12 h.

[0273] Synthesis of 4-(4-(3-Azidopropoxy)phenyl)butan-2-one (K3)

[0274] To a stirred solution of 4-(4-hydroxyphenyl)butan-2-one (1 g, 6.1 mmol, 1 eq) and 1 - azido-3-chloropropane [Verdoes] (1.1 g, 9.1 mmol, 1.1 eq) in dimethylformamide (DMF) (10 mL) was added K2CO3(1 .26 g, 9.1 mmol, 1.5 eq). The solution was heated at 80°C under argon atmosphere for 12 h. Water (50 mL) was added followed by extractions with EtOAc (3 x 25 mL). The combined organic fractions were then combined were washed with brine (3 x 50 mL), dried over MgSCU, filtered, and concentrated under vacuum. The resulting crud product was purified by flash chromatography. 4-(4-(3-Azidopropoxy)phenyl)butan-2-one (K3) was obtained as a colourless oil after flash chromatography (Hexane (1 / 9) to EtOAc / Hexane (1 / 9), yield = 68 %.1H NMR (400 MHz, CDCI3) 6 7.12 (d, J = 8.6 Hz, 2H, Har), 6.84 (d, J = 8.7 Hz, 2H, Har), 4.04 (t, J = 5.9 Hz, 2H, OCH2), 3.53 (t, J = 6.7 Hz, 2H, ArCH2), 2.90 - 2.82 (m, 2H, COCH2CH2), 2.78 - 2.71 (m, 2H, OCH2CH2), 2.15 (s, 3H, COCH3), 2.11 - 2.01 (m, 2H, N3CH2).13C NMR (101 MHz, CDCI3) 6 208.11 , 157.06, 133.35, 129.29, 114.53, 64.53, 48.29, 45.43, 30.12, 28.90, 28.84. HRMS m / z calc, for C13H17N3O2 + (H+): 220.1332; found: 220.1319.

[0275] Synthesis of 4-(4-(prop-2-ynyloxy)phenyl)butan-2-one (K4)

[0276] K4

[0277] Following the above procedure for the synthesis of (K3) with 4-(4- hydroxyphenyl)butan-2-one (1 g, 6.1 mmol, 1 eq), propargyl bromide (1.1 g, 9.1 mmol, 1.1 eq), and K2CO3 (1.26 g, 9.1 mmol, 1.5 eq) in DMF (10 mL), 4-(4-(prop-2- ynyloxy)phenyl)butan-2-one (K4) was obtained as a yellow oil after flash chromatography (Hexane (1 / 9) to EtOAc / Hexane (1 / 9), yield = 81 %.1H NMR (400 MHz, CDCI3) 5 7.13 (d, J = 8.6 Hz, 2H, Har), 6.92 (d, J = 8.7 Hz, 2H, Har), 4.68 (d, J = 2.4 Hz, 2H, OCH2), 2.92 - 2.81 (m, 2H, ArCH2), 2.81 - 2.68 (m, 2H, COCH2), 2.53 (t, J = 2.4 Hz, 1 H, CH), 2.15 (s, 3H, CH3).13C NMR (101 MHz, CDCI3) 6 208.04, 155.96, 134.05, 129.27, 114.96, 78.70, 75.42, 55.87, 45.35, 30.11 , 28.88. HRMS m / z calc, for C13H14O2 + (H+): 203.1067; found: 203.1051.

[0278] Compound CM38AZ CM38AZ

[0279] Following general procedure 1 with trans 2,5-dihydroxybenzaldehyde (225 mg, 1.63 mmol, 1 eq), 4-(4-(3-azidopropoxy)phenyl)butan-2-one (K3) (444 mg, 1.79 mmol, 1.1 eq) and 10 mL of THF, compound CM38AZ was obtained as a brown oil after flash chromatography (EtOAc / Hexane (1 / 9) to EtOAc / Hexane (1 / 1 ), yield = 42 %.1H NMR (400 MHz, CDCI3) 6 7.86 (d, J = 16.3 Hz, 1 H, ArCH=), 7.14 (d, J = 8.7 Hz, 2H, Har), 6.96 (s, 1 H, Har), 6.87 - 6.68 (m, 5H, 4Har, COCH=), 4.02 (t, J = 6.0 Hz, 2H, OCH2), 3.57 - 3.47 (m, 2H, COCH2), 3.04 - 2.88 (m, 4H, ArCH2, CH2N3), 2.05 (p, 2H J = 6.3 Hz, CH2CH2CH2N3).13C NMR (101 MHz, CDCI3) 6 157.05, 149.63, 149.54, 138.74, 133.44, 129.41 , 126.51 , 122.18, 119.52, 117.56, 114.59, 114.29, 64.57, 48.29, 42.21 , 29.51 , 28.78. HRMS m / z calc, for C20H21N3O4 + (H+): 368.1605; found: 368.1591.

[0280] Compound CM39AL

[0281] CM39AL

[0282] Following general procedure 1 with trans 2,5-dihydroxybenzaldehyde (250 mg, 1.81 mmol, 1 eq), 4-(4-(prop-2-ynyloxy)phenyl)butan-2-one (K4) (403 mg, 2 mmol, 1.1 eq) and 10 mL of THF, compound CM39AL was obtained as a green solid after flash chromatography (EtOAc / Hexane (1 / 9) to EtOAc / Hexane (1 / 1 ), yield = 58 %. mp: 99-101 °C.1H NMR (400 MHz, DMSO) 5 9.50 (s, 1 H, OH), 8.90 (s, 1 H, OH), 7.75 (d, J = 16.3 Hz, 1 H, ArCH=), 7.18 (d, J = 8.6 Hz, 2H, Har), 6.94 (d, J = 2.7 Hz, 1 H, Har), 6.90 (d, J = 8.7 Hz, 2H, Har), 6.77 (d, J = 16.3 Hz, 1 H, COCH=), 6.74 - 6.68 (m, 2H, Har), 4.75 (d, J = 2.4 Hz, 2H, OCH2), 3.53 (t, J = 2.4 Hz, 1 H, CH), 2.95 (t, J = 7.7 Hz, 2H, CHCHa), 2.82 (t, J = 7.4 Hz, 2H, ArCH2).13C NMR (101 MHz, DMSO) 5 199.55, 155.90, 150.43, 150.40, 137.93, 134.49, 129.71 , 125.63, 121.62, 119.91 , 117.50, 115.15, 113.53, 79.91 , 78.51 , 55.81 , 42.39, 29.18. HRMS m / z calc, for C20H18O4 + (H+): 323.1278; found: 323.1266.

[0283] Example 2: Efficacy of CM14 in reducing viability of ALCL cell lines Relative viability / metabolic activity compared to untreated control was measured via resazurin assay as a surrogate marker for viability (see Example 8). For the test, the ALCL cell line Mac-2a was incubated with 5 pM of respective compound for 72h.

[0284] Esters

[0285] Ester analogs were synthesized either by the one-step esterification of hydroxycinnamic acids or via the Witting coupling using the appropriate aldehyde and stabilized phosphonium ylide [Sanderson, Murugesan, Selka, Touaibia2] (Fig.1 , Fig. 10, see Example 1 for further details). To investigate the position of the hydroxyls, structures with 2,5-, 2,4-, 2,3-, and 3,5- dihydroxyl and 2-, 3- and 4- monohydroxyl substitution were synthesized (Fig. 10, Fig. 1 ). With the appropriate reagents analogs were synthesized having a linker between the carbonyl and the second phenyl of the molecule with two and three methylenes (Fig. 10, Fig. 1 ).

[0286] Results are shown in Fig. 1 , where the position of OH groups (R) and number of methylenes (n) are indicated; non-specified R groups are H atoms. Compounds in the bar diagram which showed higher activity than CAPE are colored blue (see Fig. 1 ).

[0287] Esters CM1 and CM6 were the most active molecules in reducing ALCL cell viability (Fig. 1A). The change of the positions of the hydroxyls to positions 2 and 5 (CM1 ) of the phenyl ring as well as to positions 2 and 3 (CM6) resulted in enhanced viability reduction as compared to CAPE. In contrast, the 3,5-dihydroxyl and 2,4-dihydroxyl substitutions, as in compounds CM5 and CM10, resulted in complete loss of activity (Fig. 1A). Surprisingly, the addition of a single methylene to the linker between the phenyl ring and the ester moiety (CM2) resulted in reduced activity. Derivates with a single hydroxyl, whether at position 2 (CM11 ), at position 3 (CM 12), or at position 4 (CM13) had no effect on viability (Fig. 1A).

[0288] Ketones

[0289] In addition, ketones were synthesized through an aldol condensation with the appropriate benzaldehyde and acetone (Fig.1 , Fig. 10, see Example 1 for further details). [Selka, Touaibia2],

[0290] Ketones CM4, CM15, CM18, CM19, CM20 and CM21 of the second subseries showed low or no activity (Fig. 1 B). In contrast, CM3 was substantially more active than its ester analog CM1. CM16 performed worse than its ester analog CM6 (Fig.1 B). Thus, the 2,5-hydroxyl substitution is a preferred embodiment for a ketone derivative.

[0291] Various linker lengths The linker length between the carbonyl and unsubstituted phenyl was investigated by compounds CM14 and MT114 which were synthesized with the same strategy (see Fig. 1 , Fig. 10, see Example 1 for further details).

[0292] CM 14 (3 methylenes) showed higher activity than MT114 (2 methylenes) or CM3 (4 methylenes), suggesting an optimal linker length of 3 methylenes. (Fig. 1 C).

[0293] Example 3: CM14 induces cell death by apoptosis and overcomes drug resistance

[0294] CM14 was tested in a panel of ALK- (Mac-1 , Mac-2a, FEPD) and ALK+ (K299, SUPM2) ALCL cell lines. Cells were treated with CM14 and CAPE for 72h. Relative viability compared to control was measured via resazurin assay (see Example 8). 72h IC50 values for CM 14 and CAPE are shown in pM ± SD (Fig. 2A).

[0295] CM14 was able to reduce ALCL viability in all cell lines tested and had a 2.1 - to 4.8-fold lower IC50 than CAPE regardless of the ALK status (Fig. 2A, Fig. 6A).

[0296] Two ALK+ ALCL cell lines were generated, resistant to the 2ndgeneration ALK inhibitor alectinib, by long term incubation with increasing concentrations of the drug. The parental ALK+ ALCL cell lines DEL and SUDHL1 and the corresponding alectinib-resistant cell lines were treated with various concentrations of alectinib and CM 14 for 72h. Viability was measured with resazurin assay (see Example 8). As shown in Fig. 2B, both parental cell lines are sensitive to alectinib as expected with an IC50 of 28.7 nM for SUHDL1 and 73.5 nM for DEL, while the desensitized cell lines had an IC50 of 429 nM for SUDHL1 and 1081 nM for DEL. Surprisingly, when treated with CM14, the alectinib-resistant SUDHL1 cells were equally sensitive than the parental cell line (IC50= 3.2±0.29 pM vs 4.2±0.56 pM, p= 0.066). Even more surprisingly, the alectinib-resistant DEL cells had even higher CM14 susceptibility than the parental cells (IC50= 1 ,76± 0.2 pM vs 1 .15 ±0.05 pM, p= 0.007), suggesting activity of CM14 in ALK inhibitor resistant ALCL (Fig. 2B).

[0297] CM14 was also tested in cell lines from cutaneous Peripheral T-cell Lymphoma (cPTCL), T-cell Acute Lymphoblastic Leukemia (T-ALL) and Acute Myeloid Leukemia (AML) patients, which showed IC50 values between 1.9 and 6.3 pM, indicating potential wider clinical applicability of cm 14 (Fig. 6B, Dose-response curves of cPTCL, T-ALL and AML cell lines treated with CM 14 for 72h).

[0298] In order to elucidate how CM14 reduces ALCL cell viability, Annexin V and 7-AAD staining was performed and analyzed by flow cytometry.

[0299] Mac-1 and K299 ALCL cell lines were stained with Alexa Fluor-488 Annexin-V and 7- AAD after treatment with CM 14 and CAPE for 24h at indicated concentrations. Density plots show one representative replicate and bar graphs show means ± SD of biological triplicates. A marked induction of apoptosis as shown by positivity for Annexin V staining following 24h exposure to 2.5 pM CM14 was seen in all 4 ALCL cell lines tested, whereas no or only minor effects were observed for CAPE (Fig. 2B, Fig. 2C, Fig. 6C).).

[0300] Fig 6C shows viability of Mac-2a and FEPD ALCL cell lines after treatment with CM 14 and CAPE for 24h. Cell lines were stained with Alexa Fluor-488-Annexin-V and 7-AAD after treatment. Quantification of the four populations are shown in the bar graph (Fig. 6C).

[0301] Fig 2C shows AnnexinV / 7-AAD staining. Following VM14 treatment, 68% AnnexinV / 7- AAD positive cells were observed versus 7.4% following CAPE treatment.

[0302] PARP cleavage

[0303] Western blot analysis of PARP was performed after 24h treatment with CM 14 and CAPE (Mac-1 2.5 pM, FEPD and K299 5 pM). PARP cleavage was apparent in CM14-treated cell lines consistent with apoptosis (Mac1 , K299, FEPD). In contrast, CAPE-treated cell lines showed no (K299, FEPD) or minor (Mac-1 ) PARP cleavage (total (t) and cleaved (c) PARP, Fig. 6D.

[0304] Example 4: CM14 represses DNA replication genes and affects cell cycle distribution

[0305] The ALK- ALCL cell line Mac-2a was treated with 2.5 pM of CM14 or DMSO for 12h. RNA-Seq was performed with the Illumina NextSeq 500 platform. Differentially expressed genes with adj. p-value <0.05 were selected for Ingenuity Pathway Analysis (Qiagen).

[0306] A strong deregulation of oxidative stress response genes was found. The top 10 significant pathways (p-value <0.05) with a z-score >1 (blue) and <-1 (red) are shown: “Cell Cycle Control of Chromosomal Replication”; “NRF2-mediated Oxidative Stress Response”; “Xenobiotic Metabolism General Signaling Pathway”; “ILK Signaling”; “Death Receptor Signaling”; “IL-8 Signaling”; “EIF2 Signaling”; “Unfolded protein response”; “Purine Nucleotides De Novo Biosynthesis II”; “IL-22 Signaling" (See Fig. 3 A)

[0307] N-acetylcysteine (NAC) rescue

[0308] It was investigated whether addition of N-acetylcysteine, a strong antioxidant and glutathione-replenishing molecule, could rescue viability of CM14-treated cells.

[0309] ALCL cell lines were pretreated with N-acetylcysteine at 1 mM for 30 min before addition of CM14 at 5 pM. Cells were incubated for 72h and viability was measured via resazurin assay (see Example 8). Viability was normalized on untreated Ctrl for CM14-treated samples and on NAC-treated Ctrl for the CM14+NAC-treated samples.

[0310] Surprisingly, supplementation of N -acetylcysteine only partially rescued cell viability, suggesting that other mechanisms apart from redox unbalance contribute to CM 14 activity (Fig. 6E). Indeed, at the 12 hours timepoint, down-regulation of genes involved in replication initiation and mitosis was observed (e.g. CDK1, CDK2, CDT1, LIG1, MCM2, MDM3, MCM4, MCM5, MCM7, PCNA) (Fig. 3A).

[0311] Further, cell cycle progression in CM14 treated ALCL cells was investigated. DNA content was measured via intracellular propidium Iodide staining. Histograms from representative replicates with the corresponding percentage of cells in G1 , S and G2 / M phase were selected.

[0312] Following 12h of CM14 (1.25 pM in Mac-1 and Mac-2a, 2.5 pM in K299) or CAPE (2.5 pM in Mac-1 and Mac-2a, 5 pM In K299) exposure, ALCL cells treated with CM 14 showed a marked accumulation of cells at the G2 / M phase and reduction of cells in the S-phase as shown by intracellular PI (propidium iodide) staining in all 3 ALCL cell lines analyzed (Fig. 3B, 6F). At the tested concentration, CAPE had only minor effects on cell cycle distribution, further indicating that CM14 has a different mechanism of action than its parental compound (Fig. 3B, Fig. 6F). The observed G2 / M arrest corresponds to the downregulation of replication and mitosis associated genes observed in the RNA-seq analysis and may be indicative of ‘mitotic stress’ leading to apoptosis. This is reminiscent of a phenomenon termed “mitotic catastrophe” which promotes apoptosis as a protective to misguided chromosome separation or DNA damage [Vitale],

[0313] Example 5: Identification of site of action

[0314] Copper(l)-catalyzed azide-alkyne cycloaddition (CuAAC), also called “click chemistry” is a versatile tool to link marker molecules to drug candidates [Parker], In brief, an azide reacts with an alkyne side group forming a triazole ring that covalently binds the drug candidate to the desired probe. Analog MT114, a mimic of CM14, was synthesized by a simple and efficient synthesis strategy using the commercially available 4-(4-hydroxyphenyl)butan-2-one. The azide or the terminal alkyne moieties were attached to the unsubstituted phenyl ring by a covalent ether bond. To this end, ketones K3 and K4 were synthesized from 4-(4- hydroxyphenyl)butan-2-one and 1-azido-3-chloropropane or propargyl bromide (see Example 1 for details). Using an optimized aldol condensation procedure [Murugesan, Sanderson, Touaibia2] with 2,5-dihydroxybenzaldehyde and ketone K3 or K4, new analogs CM38AZ or CM39AL bearing an azide or a terminal alkyne moiety were obtained (Fig. 11 ) (see Example 1 for details). The two analogs CM38AZ and CM39AL have two methylenes in the linker like MT114 but preserve the position and number of hydroxyl groups of CM14 on the substituted phenyl ring, which are the main determinants of the activity of CM 14. This makes it very plausible that CM39AL and CM38AZ preserve the mechanism of action and molecular targets of CM14.

[0315] CM38AZ and CM39AL were tested for their potential to reduce viability of ALCL cells. The effect of CM38AZ and CM39AL on the viability of Mac-2a cells was tested after 72h incubation at 5 pM. Relative viability to DMSO control was measured via resazurin assay as described in Example 8. Means ± SD of biological triplicates were calculated. The addition of an azide (CM38AZ) strongly reduced activity, whereas addition of a terminal alkyne (CM39AL) retained the activity of the parental compound MT114 (Fig. 4A). Therefore, analog CM39AL was selected for further experiments.

[0316] To shed light on the mechanism of action of CM14 and CM39AL, the subcellular localization of CM39AL was investigated. Fig. 4 B shows a schematic of the experimental strategy: Mac-2a cells were treated for 2 h with 40 pM of CM39AL or DMSO. Cells were fixated on a glass slide and then the fluorophore Azide Flour-488 (AzF488) was linked in situ to CM39AL in a CuAAC click chemistry reaction mix. DAPI was used to stain nuclei. Photos were acquired using a spinning disk confocal microscope. (Fig. 4B-C). White arrows indicate cytoplasmic spots where green fluorescence signal accumulates (Fig. 4C). As a control, cells treated with DMSO alone were used that underwent the same procedure.

[0317] The fluorescence signal was observed in the cytosol but also in the nucleus. However, closer inspection revealed exactly one region of high fluorophore signal per cell that was located in direct vicinity to the nucleus (Fig. 4C). It was assumed that the highly fluorescent structure could be identified as the centrosome, which in interphase cells can be seen as one spot per cell close to the nucleus. The centrosome is a crucial component of cell division machinery since it orchestrates mitotic spindle assembly and chromosome segregation. Looking for actively dividing cells, it was found that the fluorophore accumulated in two spots in the center of the condensed chromosomes (Fig. 7A), again supporting the idea that CM39AL accumulates at centrosomes. In contrast to a and [3-tubulin, which form the microtubular structures of the mitotic spindle, y-tubulin is involved in microtubule nucleation at the centrosome and is therefore used broadly as a marker for the centrosome [OToole],

[0318] After click chemistry, ALCL cells were stained with anti-y-tubulin antibody and immunofluorescence imaging was performed using a spinning disk confocal microscope. The staining showed one spot per cell close to the nucleus. Overlay of y-tubulin (red) with the CM39AL-AzF488 conjugate (green) resulted in co-localization (yellow) (see white arrows, Fig. 4D), suggesting that CM39AL indeed interacts with the centrosome.

[0319] Example 6: protein interaction partners

[0320] To further exploit the possibilities of a click chemistry amenable version of CM14, the compound CM39AL was coupled to PEG-biotin-azide (AzBiotin) in order to pull down proteins that directly interact with CM39AL using Streptavidin-coated beads. Fig. 5A shows a schematic of the experimental strategy: Mac-2a cells were incubated with CM39AL or DMSO. After incubation of the cells in 4 biological replicates, cell lysis was performed via sonication. CuAAC with AzBiotin was performed in the cell extracts with (+) or without (-) CM39AL. Bound proteins were enriched using Streptavidin Agarose resin and analyzed via SDS-PAGE / Western blotting or analyzed via LC / MS-MS.

[0321] Western blotting of an aliquot of the reacted proteins revealed a marked signal of biotinylated proteins in CM39AL-treated cells but not in untreated cells using Streptavidin-HRP (Fig. 7B).

[0322] The reaction mix containing biotinylated proteins was then incubated with streptavidin- conjugated agarose resin. After extensive washing, enriched proteins were digested on-bead and peptides were analyzed via Liquid Chromatography-tandem Mass Spectrometry (LC- MS / MS).

[0323] Proteins enriched in CM39AL-treated cells were compared to DMSO treated cells using 4 biological replicates. 463 significantly enriched proteins were identified (adjusted p-value < 0.05, enriched > 2 fold, Fig. 5B).

[0324] Several enriched proteins were found to be involved in mitotic spindle and centrosome assembly (CEP43, OPTN, CLIP1 , RCC2, PCM1 , TUBGCP2) regulation of cell cycle progression and checkpoints (CDK2, CDK6, CDK9, CHK1 ) (Fig. 7C). By far, the strongest enriched protein was TUBGCP2, which was accumulated more than 20-fold in CM39AL-treated cells compared to untreated controls. TUBGCP2 is a major component of the y-Tubulin Ring Complex (y-TuRC), where together with other members of the same family it participates in the assembly of the scaffold structure required for a- and [3-tubul in nucleation [Zhu], To gain a molecular level insight into the mechanism through which CM14 acts on TUBGCP2, a combined molecular dynamics and molecular docking study was performed, using a publicly available TUBGCP2 structure (Protein data bank code 6V6B, see https: / / www.rcsb.org / structure / 6V6S ). For the docking, CM16 was also included as molecule with intermediate activity and CM18 as non-active ketone analog.

[0325] The structures obtained from this procedure revealed an identical binding site on TUBGCP2 for all tested molecules. Figure 5C shows a schematic representation of the y-TuRC and overlaid orientations of CM14 (red), CM16 (yellow), and CM18 (green) within TUBGCP2, obtained from molecular docking. Fig. 8A shows the location of the binding site of CM 14 (red) within the TUBGCP2-TUBGCP3 complex (TUBGCP2: light grey; TUBGCP3: dark grey). The structure was generated by overlaying the CM14-TUBGCP2 complex on the TUBGCP2- TUBGCP3 structure, published under the PDB code 6V6B.

[0326] It can be seen that while CM 18 and CM 16 showed interaction with the aqueous environment at the level of the substituted phenyl ring, CM14 was fully surrounded by aminoacidic residues, with no interaction with the solvent. Notably, the identified binding site is adjacent to the very domain of the protein that is responsible for the association with TUBGCP3 (Fig. 8A).

[0327] To further validate the close interaction of CM14 / CM39AL with TUBGCP2, ALCL cells were incubated with CM39AL, extracted proteins were coupled to AzBiotin using CuAAC, underwent streptavidin pulldown and were finally immunoblotted with a TUBGCP2 -specific antibody. A band at around 100 kDa (reported size 102 kDa) in the CM39AL-treated but not in the untreated cells lysate confirmed TUBGCP2 as an interaction partner of CM39AL (Fig. 5D, left hand side).

[0328] To assess the localization of compound CM39AL and the protein TUBGCP2 in relation to the centrosome in intact cells, cells underwent on slide in situ CuAAC labeling of CM39AL with AzF488. Cells were then stained with anti-y-tubulin and anti-TUBGCP2 antibodies. Photos were acquired via spinning disk confocal microscopy.

[0329] As expected, the CM39AL and the TUBGCP2 signals were found to accumulate at the centrosome, as demonstrated by a white cytoplasmic spots (White arrows indicate overlapping signals from CM39AL (green), TUBGCP2 (red) and y-tubulin (magenta), see Fig. 5E, Fig. 8B). Both CM39AL and TUBGCP2 were also visible in the nucleus in keeping with reports showing partially nuclear localization of TUBGCP2 [Thul, Draberova],

[0330] Altogether, these results show that CM39AL and very plausibly also its close analog CM 14 bind to a group of proteins involved in regulation of mitosis. By far the strongest interaction was observed with the TUBGCP2 protein, a member of the y-TuRC complex that is essential for spindle nucleation at the start of mitosis. Synergism of vincristine and CM14

[0331] Vincristine, part of the polychemotherapy regimen used for ALCL treatment, [Mussolin] causes microtubule destabilization. The ability of CM14 to interact with TUBGCP2, which is crucial for microtubule nucleation, suggests that vincristine and CM 14 target the same process, possibly at different sites.

[0332] Combinatorial treatment of FEPD cells with vincristine and CM14 were tested at the indicated concentrations. Cell viability was measured via resazurin assay (see Example 8) after 72h. Viability inhibition was calculated as % of the untreated control. Bliss Synergy analysis was performed with Synergy Finder 3.0. The results show that surprisingly, the combination of vincristine and CM 14 showed addictive effects using the Bliss synergy model, resulting in a higher reduction of viability than single treatments (Fig. 8C).

[0333] Example 7: cm14 overcomes Docetaxel resistance in prostate cancer

[0334] Docetaxel is a clinically successful therapeutic, used among others against prostate cancer. It acts by interfering with tubulin dynamics and mitotic spindle formation, thereby arresting cell cycle progression.

[0335] Since both Docetaxel and CM 14 are MTAs (they interfere with tubulin dynamics and mitotic spindle formation), it is expected that CM 14 may affect Docetaxel-sensitive cancer cells but will not affect Docetaxel-resistant cells.

[0336] In order to test the effect of CM14 on Docetaxel-resistance cancer cells, two lines of prostate cancer cells were used. PC-3 is a human prostate cancer cell line with a high metastatic potential. They are available from ATCC as CRL-1435 [ATCC1 ]. DU145 are a human prostate cancer cell line with moderate metastatic potential, available from ATCC as (htb-81 ) [ATCC2], Docetaxel-resistant variants of PC3 and DU145 are known in the art, as described e.g. by O’Neill et al [ONeill] and Wiltshire et al. [Wiltshire],

[0337] To a culture of either Docetaxel-resistant or -sensitive PC3 or Dll-145 cells, Docetaxel (6.25 to 200 nM, two-fold dilutions) or CM14 (0.625 to 20 pM, two fold dilutions) was added at concentrations varying between 0 and 200 pM. After 72 h incubation, cell viability was tested using the resazurin assay (see Example 8).

[0338] Fig. 9A shows the decrease in cell viability caused by increasing concentrations of Docetaxel in Docetaxel-sensitive, but not resistant cell lines.

[0339] Surprisingly, CM14 was able to decrease cell viability independently of Docetaxelsensitivity (Fig. 9B). These results demonstrate that CM 14 is useful in situations where the interfering with tubulin dynamics and mitotic spindle formation, and preferably the binding to and modulation of TUBGCP2, by CM14 is desirable to achieve a favorable clinical outcome not possible with prior art compounds.

[0340] Example 8: resazurin assay

[0341] Resazurin (7-Hydroxy-3H-phenoxazin-3-one 10-oxide) is a phenoxazine dye. It is reduced to resorufin by aerobic respiration of metabolically active cells. This effect can be used to test cell viability. It can be used to detect the presence of viable cells in mammalian cell cultures [see e.g. Anoopkumar] The test is well known to the skilled artisan; it is also commercially available (e.g., Vybrant (Molecular Probes), UptiBlue (Interchim)). Generally, the effect of a compound was measured after 72h incubation of the specified cell line, using the specified concentration of the compound to be tested, in 3 replicates (mean ± SD). Unpaired two-sided Student's t-test was performed for statistical evaluation.

[0342] Example 9: antibody conjugate

[0343] A caffeic-acid phenylester derivative is attached to an anti-CD30 lgG1 antibody via a cathepsin-cleavable Val-Cit-PABC linker terminating in a maleimide group for thiol coupling. The comppubnd of formula I used herein is The attachment point is located on the benzoyl (phenylester) ring, i.e., moiety D of formula I. The compound of foormula I used is one where R1, R4are OH, A is -CHCH-, B is -CO, D is phenyl, C is C4 alkylene.

[0344] The conjugate can be represented schematically as follows (of the compound of the invention, only moiety D is repesented to illustrate more clearly the point of attachment): anti-CD30-(Cys)-S-(CH2)2-CO-(maleimide)-Linker-Val-Cit-PABC-O-CO-CH=CH- D where “PABC-O-CO-CH=CH-D is the self-immolative spacer attached to the D moiety of the compound of the invention. The moiety D which is phenyl is functionalized para to the ester bond to connect to PABC.

[0345] The payload core is the specific compound of formula I as defined abive. The phenyl ring of the compound of the invention is derivatized at the para position with a linker-attachment handle, while the catechol ring (3,4-dihydroxy) is left chemically untouched.

[0346] The payload region can be written as:

[0347] Ph(1 ,4-OH)-CH=CH-CO-O-(CH2)3-Ph-(para-CH2-O-CO-O-PABC-Val-Cit-Linker- maleimide) where: Ph(1 ,4-OH)-CH=CH-CO-O-(CH2)3-Ph- is the compound of the ivnetion, the para- CH2- substituent on the benzoyl ring is the exclusive point of attachment to PABC.

[0348] Val-Cit-PABC linker segment

[0349] Immediately distal to the phenyl ring is a para-aminobenzylcarbamate (PABC) spacer. PABC connects to the benzoyl ring via a carbonate or carbamate bond and in turn is joined to the N-terminus of a valine— citrulline (Val-Cit) dipeptide.

[0350] The sequence from benzoyl ring to linker is: phenyl(para-CH2-0-C0-0-PABC-NH-Val-Cit-C0-(Linker-maleimide))

[0351] Upon internalization into CD30-positive cells and exposure to cathepsin B (or related proteases), the Val-Cit peptide is cleaved between Cit and the PABC unit. This triggers a 1 ,6- elimination within the PABC spacer, releasing the inventive compound.

[0352] Maleimide attachment group and spacer

[0353] The C-terminal end of the Cit residue is coupled to a linker segment bearing a maleimide functionality. This linker containa a short aliphatic or PEG spacer to provide flexibility and distance between the antibody surface and the Val-Cit-PABC-caffeic module. Preferably, a PEG spacer is used. Preferably, n is 2-5, more preferably 4. A preferred structure is: Val-Cit- CO-NH-(CH2)2-CO-NH-(PEG)n-(CH2)2-CO-maleimide. This terminates in a maleimide ring capable of forming a stable thioether with an antibody cysteine thiol.

[0354] Anti-CD30 antibody module

[0355] The targeting component is an anti-CD30 monoclonal antibody, for instance a humanized or fully human lgG1 specific for the CD30 antigen expressed on Hodgkin and certain non-Hodgkin lymphoma cells.

[0356] To enable controlled drug loading, the antibody is engineered to contain reactive thiols at defined positions, for example by: introducing engineered cysteine mutations at selected sites in the heavy and / or light chains, or partially reducing interchain disulfide bonds to generate a controlled number of free thiols. Thus, a reproducible drug-to-antibody ratio (DAR) is obtained, e.g. an average DAR of about 2-4.

[0357] Conjugate assembly

[0358] The inventive compound defined above is functionalized at the para-position of the phenyl ring (moiety D)so that is contains a handle (e.g. para-aminomethyl or para- hydroxymethyl) that is used in a carbonate or carbamate linkage to PABC. The para-substituted moiety D handle is coupled to the PABC unit to form a benzoyl-O-PABC carbonate / carbamate linkage, and PABC is extended N-term inally with the Val-Cit dipeptide to give a PABC-Val-Cit intermediate. The C-terminus of Cit is joined to a spacer bearing a terminal maleimide group, resulting in a complete payload-linker-maleimide construct:

[0359] D-PABC-Val-Cit-spacer-maleimide

[0360] Where D represents the moiety D of the inventive compound (which is present but only moiety D is shown here for clarity).

[0361] Separately, the anti-CD30 lgG1 is provided in a form containing a controlled number of reactive thiol groups (for example, by mild reduction or cysteine engineering). The maleimide- functionalized payload-linker construct is then reacted with the thiol-containing anti-CD30 antibody under conditions suitable for formation of a stable thioether bond, yielding:

[0362] Anti-CD30-S-(CH2)2-CO-(Linker)-Val-Cit-PABC-D with a defined average DAR.

[0363] Functional behavior

[0364] In circulation, the thioether bond, Val-Cit peptide, and PABC spacer are stable under physiological conditions; the caffeic-acid catechol ring remains unmodified and the phenyl attachment point is shielded within the linker architecture. Upon binding to CD30-expressing cells and internalization into lysosomal compartments, Cathepsin B (or a similar protease) cleaves the Val-Cit dipeptide between Cit and PABC. The PABC unit undergoes a 1 ,6- elimination, fragmenting to release the phenyl-linked caffeic-acid phenylester derivative from the linker. The active caffeic-acid phenylester derivative is liberated in the intracellular environment, where it can exert its intended biological effect, while the antibody-linker fragment remains sequestered.

[0365] Example 10

[0366] An anti-CD79-Val-Cit-PABC-caffeic-acid phenylester conjugate is prepared in which the caffeic module of formula I is attached to the antibody via a maleimide linker and a cathepsin-cleavable Val-Cit-PABC segment, with the point of attachment located exclusively on the phenyl ring (moiety D).

[0367] The compound of formula I is one wherein R1 ,R4 are OH, A is -CHCH-, B is -CO-, C is -(CH2)3-, D is a phenyl ring unsubstituted except for a single para substituent that serves as the anchoring point for the linker architecture. The payload region can be viewed as a 3,4- dihydroxyphenyl-CH=CH-CO-O-(CH2)3-Ph unit, wherein both catechol hydroxyls are left intact and free of any derivatization.

[0368] The linker-payload portion starts at this para-phenyl position and proceeds through a self-immolative para-aminobenzylcarbamate (PABC) spacer into a cathepsin-cleavable Val-Cit peptide and then into a maleim ide-terminated spacer. The sequence from the moiety D phenyl ring outward can be represented as: phenyl(para-CH2-O-CO-O-PABC-NH-Val-Cit-CO- NH-(spacer)-maleimide. In this arrangement, the para-aminobenzyl (PAB) ring carries an amino group that is linked via a carbamate or carbonate to the para-benzyl substituent, and its benzylic position is configured to undergo 1 ,6-elimination upon proteolytic cleavage of the Val- Cit bond at the PABC junction. The Val-Cit dipeptide occupies the canonical position used in many cathepsin-B-cleavable ADC linkers: the N-terminal valine is attached to PABC, and the C-terminal citrulline connects via its carboxyl to a short spacer. The short spacer is preferably succinyl-(CH2)2, more preferably or a PEGylated segment, that terminates in a maleimide ring. This maleimide is designed to react with cysteine thiols on the antibody to form a stable thioether bond.

[0369] The antibody module in this example is a preferybly humanized, more preferably fully human lgG1 specific for CD79 (for instance an antibody binding CD79a or CD79b on B cells), engineered to provide a controlled number of accessible thiol groups suitable for conjugation. Thiols can be provided by engineered cysteine residues at defined positions or by partial reduction of selected interchain disulfide bonds in a way that yields a reproducible average drug-to-antibody ratio, such as about 2 to about 4 payload-linker modules per antibody molecule. Each reactive cysteine thiol on the anti-CD79 IgG can then be coupled to a maleimide group on the linker-payload, forming a stable thioether linkage of the general type Anti-CD79- S-(CH2)2-CO-(spacer)-CO-NH-Cit-Val-PABC-O-CH2-Ph- (CH2)3-CO-CH=CH- Ar(catechol).

[0370] The sequence of assembly is as follows. First, a compound of formula I is defined in which the D moiety bears a para-CH2-OH or para-CH2-NH2 handle; the catechol ring is not altered. This para handle is reacted in a carbonate / carbamate connection to a PABC unit, giving a benzoyl-O-CO-O-PABC intermediate. The PABC amino terminus is then extended with valine and citrulline to form a PABC-Val-Cit dipeptide. The citrulline carboxyl is, joined to a short, biocompatible spacer terminating in a maleimide ring, yielding a complete small-molecule linker-payload entity that can be represented as (Formula l)-(para)-PABC-Val-Cit-spacer- maleimide. Separately, the anti-CD79 IgG is provided in a thiol-bearing form with a known number of reactive cysteines. The maleim ide-terminated linker-payload construct is then allowed to react with the antibody under conditions compatible with maleimide-thiol coupling, so that each maleimide forms a thioether with an antibody cysteine to result in an anti-CD79- formula I conjugate with the desired drug-to-antibody ratio.

[0371] In vivo, the resulting anti-CD79-Val-Cit-PABC-formula I- conjugate circulates with the payload masked behind the peptide and PABC spacer. The thioether linkage to the antibody and the Val-Cit-PABC segment are stable under extracellular physiological conditions, and the catechol ring of the payload remains unmodified. After binding to CD79 on target cells, and internalization into endolysosomal compartments, lysosomal cathepsins cleave the Val-Cit bond adjacent to the PABC unit. This proteolytic event activates the PABC self-immolative spacer, which undergoes a 1 ,6-elimination to fragment and discharge the benzoyl-linked caffeic-acid phenylester from the rest of the linker. The net result is intracellular release of the formula I payload from the anti-CD79 antibody, via the designed Val-Cit-PABC mechanism, while preserving the structural requirement that all antibody-payload connectivity is through the benzoyl ring and not through the dihydroxy catechol ring.

[0372] Example 11

[0373] In this example, the small-molecule payload is a caffeic-acid aryl-ketone derivative in which the catechol ring (3,4-dihydroxyphenyl) remains chemically unmodified, whereas the phenyl ring on the ketone portion is selectively functionalized at the para position with an azide group. This provides a handle for bioorthogonal Cu(l)-catalyzed azide-alkyne cycloaddition (CuAAC). The payload is a compound of formula I wherein R1 ,R4 are -OH, A is -CHCH-, B is - CO-, C is -(CH2)3-, D is unsubstituted phenyl (CM14) This compound is functionalized at the para position of the phenyl the para position of with an azidomethyl substituent: -CH2-N3. The linker includes a Val-Cit cathepsin-cleavable peptide, a PABC self-immolative spacer, a terminal alkyne group at the small-molecule end, and a maleimide group at the antibody end. The linker architecture is: maleimide-(spacer)-Val-Cit-PABC-CH2-C=CH. The terminal alkyne (-C=CH) is positioned such that it reacts with the azide on the phenyl ring.

[0374] The azide on the phenyl ring undergoes a Cu(l)-catalyzed 1 , 3-d ipolar cycloaddition with the alkyne on the Val-Cit-PABC linker to form a 1 ,4-disubstituted triazole, which serves as a chemically stable, non-cleavable connection between the payload and the linker. The resulting bond is: Ph(para-CH2-N3) + CH2-C=CH — Ph(para-CH2-triazole-CH2-PABC-Val-Cit- spacer-maleimide). The triazole ring is chemically inert to hydrolysis, oxidation, and typical biological conditions, preventing premature payload loss. For the attachment to the Antibody, the maleimide moiety at the distal end of the linker reacts with an engineered cysteine on an anti-CD74 antibody through standard maleimide-thiol conjugation, forming a thioether bond. This provides a complete ADC of the form: Anti-CD74-S-(linker)-Val-Cit-PABC-triazole- benzoyl-C(O)-CH=CH-Ph(3,4-diOH).

[0375] Upon binding CD74 and undergoing internalization, Cathepsin B cleaves the Val-Cit bond. The PABC spacer self-immolates, releasing the caffeic ketone payload. The triazole bond remains intact and does not interfere with payload release. The catechol ring stays unaltered throughout. Thus, click chemistry provides controlled, regioselective attachment to the phenyl ring while preserving the delicate catechol pharmacophore.

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Claims

58Claims1 . A compound of formula (I)wherein:A is -CHCH-, -CH2CH2- or -CH2-;B is -CO-, -0- or -NH-;C is C3-9 alkylene, C3-9 alkenylene, or C3-9 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from -C1-4 alkyl, -CF3, -CN, -OH, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl), and further wherein one or more -CH2- selected from the second to last -CH2 unit comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -0-, -NH-, -N(CI-4alkyl)-, -CO-, -CO-NH-, -NH-CO-, -S-, -SO-, or -SO2-;D is optionally substituted aryl or optionally substituted heteroaryl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from Ci-4alkyl, halogen, -CF3, -CN, -OH, -NO2, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), -N(CI-4alkyl)(Ci-4alkyl), - O(CH2)2-4N3, or -O(CH2)I-4CCH;R1, R4are independently -OH, -OCH3, -CH2OH, halo, -NH2 and R2, R3are H, orR2, R3are independently -OH, -OCH3, -CH2OH, halo, -NH2 and R1, R4are H, orR1, R2are independently -OH, -OCH3, -CH2OH, halo, -NH2 and R3, R4are H; provided that when R2and R3are OH, A is CH2CH2, B is CO, C is C4alkylene with an optional OH substituent at position 2 or an optional double bond between positions 1 ,2, D is not 3,4 OH- phenyl, provided that when R2and R3are OH, A is CH2CH2 and B is CO, and C is C4alkylene, D is not 4-OH phenyl,59 provided that when R2and R3are OH, A is CHCH, B is CO, and C is C4 alkylene with -CO- at position 2, and a double bond between positions 3 and 4, D is not 4 OH-phenyl, provided that when R2and R3are OH, A is CHCH, B is CO, and C is C4 alkylene, D is not unsubstituted phenyl or 2-OH-phenyl, provided that when R2and R3are OH, A is CHCH and B is CO, C is C3 alkylene, D is not unsubstituted phenyl, provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C9 alkylene with C7 replaced by -NH-, D is not unsubstituted phenyl, provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C3 alkylene with Ci substituted with -CH3, D is not 4-OH-phenyl, provided that when R2and R3are OH, A is CH2CH2, B is -NH- and C is C3 alkylene with C2 substituted with -CH3, D is not 3-OH-phenyl, or a pharmaceutically acceptable salt, solvate or polymorph thereof.

2. A compound of claim 1 wherein D is selected from phenyl, naphthyl, or anthracenyl, optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CF3, -CN, -OH, NO2, -O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), or -N(CI-4alkyl)(Ci-4alkyl).

3. A compound of claim 2 wherein D is phenyl.

4. A compound of claims 1-3 wherein C is C3-9 alkylene.

5. A compound of claims 1-4 wherein B is -CO-.

6. A compound of claims 1-5 wherein R1, R4are OH.

7. A compound of claim 1-6 wherein A is -CHCH-.

8. A compound of claims 5-7 wherein C is C3 alkyl or C4 alkyl and / or wherein D is phenyl.

9. A compound of claims 1 to 8, wherein the compound is covalently coupled to a biologically effective molecule, wherein said biologically effective molecule is preferably selected from an antibody or Fab fragment, a binder capable of binding to target structures within the body with high affinity, such as antibodies, especially antibodies of the lgG1 , lgG2, lgG3, or lgG460 class, preferably humanized or fully human antibodies; or antibody derivatives such as Fab, Fab', F(ab')2, scFv, fragment or a peptide comprising the VH / VL domains; wherein the specificity of the biologically effective molecule is preferably selected from the group of anti-CD74 binding molecules, especially anti-CD74 antibody, such as Milatuzumab; anti-Trop-2 binding molecules, especially anti-Trop-2 antibodies; anti-CEACAM6 binding molecules, especially anti- CEACAM6 antibodies anti-5T4 binding molecules, especially anti-5T4 antibody anti-CD70 binding molecules, especially anti-CD70 antibodies; claudin18.2-targeting binding molecules, especially anti- claudin18.2 antibodies; bonding molecules bispecific for ApoL1 and cell-surface antigens, especially bispecific anti-ApoL1 -anti-cell-surface antigen antibodies.

10. A compound of formula (II)whereinA is a bond or optionally substituted C1-C7 alkylene, C1-7 alkenylene, or C1-7 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from -C1-4 alkyl, -CF3, -CN, -OH, -O(Ci-4 alkyl), -NH2, - NH(CI-4 alkyl), or -N(CI-4 alky l)(Ci -4 alkyl), and further wherein one or more -CH2- selected from the second to last -CH2 unit comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from -O-, -NH-, -N(CI-4 alkyl)-, - CO-, -CO-NH-, -NH-CO-, -S-, -SO-, or -SO2-, and R1is -CCH or -CH2CH2N3.11 . Use of a compound of claim 10 as intermediate in the synthesis of a compound of formula 1 .

12. A compound of any one of claims 1 to 9, wherein the compound is capable of reducing viability of tumor cells.

13. A compound of any one of claims 1 to 9, wherein the compound is capable of binding to gamma-tubulin.6114. A compound of claims 12 or13 wherein the compound is capable of reducing the viability of tumor cells that are resistant to an MTA and / or an ALK-inhibitor.

15. Pharmaceutical composition comprising a compound of any one of claims 1 to 9, preferably for the treatment of a cancer selected from blood cancer and solid cancer, especially for the treatment of ALCL and non-Hodgkin lymphoma.

16. Pharmaceutical composition according to claim 15 further comprising a therapeutic agent different from said compound, preferably an MTA or an ALK inhibitor, wherein a preferred ALK inhibitor is Crizotinib (Pfizer), Ceritinib (Novartis), Alectinib (Roche), Brigatinib (Ahad, Takeda), Lorlatinib (Pfizer), especially Crizotinib and Alectinib; or a compound used in a clinical regimen with an ALK inhibitor or MTA, or an antibody, including any functionally equivalent antibody or functional parts thereof; wherein MTAs include taxanes, vinca alkaloids, and synthetic MTAs; wherein taxanes include Docetaxel, Paclitaxel (Taxol), docetaxel (Taxotere), and Cabazitaxel, especially Docetaxel; wherein Vinca alkaloids include Vincristine and Vinblastine, especially Vincristine; wherein synthetic MTAs include Monomethyl auristatin E (MMAE), preferably wherein MMAE is coupled to an antibody, wherein a preferred antibody is an anti-CD30 antibody; wherein a preferred MMAE-antibody conjugate is Brentuximab-Vedotin; DNA alkylating agents, wherein a preferred DNA alkylating agent is Cyclophosphamide; DNA intercalating agents, wherein a preferred DNA intercalating agent is doxorubicin; Tubulin binding agents, wherein a preferred tubulin binding agent is Vincristine; steroids, wherein a preferred steroid is a corticosteroid, wherein preferred corticosteroids are Prednisone and Prednisolone; and, optionally, a pharmaceutically acceptable carrier and / or a diluent and / or an excipient.

17. A compound of any one of claims 1 to 9 for use in the treatment of a cancer selected from blood cancer and solid cancer, especially for the treatment of ALCL and non-Hodgkin lymphoma.

18. A method for treating a cancer patient, wherein an effective amount of a compound of any one of claims 1 to 9 is administered to said patient and wherein said cancer is selected from blood cancer and solid cancer, especially for the treatment of ALCL and non-Hodgkin lymphoma.6219. Use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for the treatment of a cancer selected from blood cancer and solid cancer, especially for the treatment of ALCL and non-Hodgkin lymphoma.

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