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WO2025221148A1 - Composés anticancéreux - Google Patents

Composés anticancéreux

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Publication number
WO2025221148A1
WO2025221148A1 PCT/NL2025/050186 NL2025050186W WO2025221148A1 WO 2025221148 A1 WO2025221148 A1 WO 2025221148A1 NL 2025050186 W NL2025050186 W NL 2025050186W WO 2025221148 A1 WO2025221148 A1 WO 2025221148A1
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WIPO (PCT)
Prior art keywords
alkyl
cancer
compound
group
aryl
Prior art date
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Pending
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PCT/NL2025/050186
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English (en)
Inventor
Nathaniel Isaac MARTIN
Meiling GAO
Livia Maria Anna PIETROW
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Universiteit Leiden
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Universiteit Leiden
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Publication of WO2025221148A1 publication Critical patent/WO2025221148A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Anticancer Compounds [0001] This invention relates to compounds for use in the treatment of cancer.
  • the invention also relates to conjugates of said compounds and compositions comprising said compounds.
  • the invention also relates to uses of the compounds, conjugates and compositions.
  • BACKGROUND [0002] Plants have the potential to produce a range of bioactive compounds. Aside from screening libraries of synthetic small molecules, it remains important to include natural products in screenings, due to the large structural diversity and high target specificity of these compounds. [0003] Plant-derived compounds have been previously identified as possible antibacterial agents (Chassagne et al., Front. Pharmacol, 2021, 11). Two such compounds are poriolide and isoporiolide.
  • a number of known natural products are generally toxic to rapidly dividing cells, and as such exhibit cytostatic activity towards both bacteria and cancer cells.
  • natural products like bleomycin, actinomycin, and doxorubicin exhibit such activity and are clinically used as chemotherapeutics (Gao et al., J. Cancer, 2020, 11, 17, 5135– 5149; Cragg et al., Advances in Phytomedicine, Ch. 1, 2002, 1, pp 23–37).
  • the toxicity of these compounds can lead to undesirable side effects.
  • the invention provides compounds of formula (I), as well as pharmaceutically acceptable salts or solvates thereof.
  • the compounds may be useful as anticancer agents.
  • the inventors have found that compounds of formula (I) are highly active against a broad range of cancer cell lines.
  • the inventors have identified poriolide, isoporiolide and structural derivatives thereof as highly potent cytostatic agents with IC50 values of less than 100 nm against various cancer cell lines, as well as high LD50 values.
  • a compound of formula (I) pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are each independently selected from the group comprising: -H, -OH, -halo, -OC 1-20 - alkyl, -OC(O)-C 1-20 -alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 - cycloalkyl, -OC(O)-C 3-8 -halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl; R 3 is selected
  • each of R 3 and R 4 are independently selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)-C3-8-cycloalkyl, - C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • a conjugate comprising at least one targeting moiety attached to at least one compound as defined in the first aspect.
  • R 1 ’ and R 2 ’ are each independently selected from the group comprising: -H, -OH, -halo, -OC1-20- alkyl, -OC(O)-C1-20-alkyl, -OC1-20-haloalkyl, -OC(O)-C1-20-haloalkyl, -OC(O)-aryl, -OC(O)-C3-8- cycloalkyl, -OC(O)-C 3-8 -halocycloalkyl, -OC(O)-heterocycloalkyl, -OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B;
  • R 3 ’ is selected from the group comprising: -H, -C 1-20 -alkyl, -
  • each of R 3 ’ and R 4 ’ are independently selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)-C3-8-cycloalkyl, - C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B, and -C(O)-L-B.
  • R 3 ’ is selected from the group comprising: -L-B, - C(O)-L-B, -C(O)NR a -C2-6 alkylene-NR a C(O)-L-B, -C(O)NR a -C0-6 alkylene-Z-C(O)-L-B and -C(O)- Z-C0-6 alkylene-NR a C(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle.
  • R 3 ’ is selected from the group comprising: -L-B, -C(O)-L-B and -C(O)NR a -C2-6 alkylene-NR a C(O)-L-B.
  • a pharmaceutical composition comprising a compound of the first aspect or a conjugate of the second aspect or third aspect; optionally further comprising a pharmaceutically acceptable excipient.
  • a compound, conjugate or composition of the invention for use as a medicament.
  • a compound for use in the treatment of cancer the compound being a compound of formula (I): pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are each independently selected from the group comprising: -H, -OH, -halo, -OC 1-20 - alkyl, -OC(O)-C 1-20 -alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 - cycloalkyl, -OC(O)-C 3-8 -halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl; R 3 is selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -al
  • each of R 3 and R 4 are independently selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, -C(O)-C 3-8 -cycloalkyl, - C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • a conjugate of the invention for use in the treatment of cancer; optionally wherein the cancer is selected from: lung cancer, breast cancer, skin cancer, bladder cancer, testicular cancer, thyroid cancer, endometrial cancer, ovarian cancer, cervical cancer, brain cancer, prostate cancer, kidney cancer, colon cancer, bone cancer, leukaemia, lymphoma, soft tissue cancer, head and neck cancer, bowel cancer, stomach/oesophageal cancer and pancreatic cancer [0019]
  • a compound, conjugate or pharmaceutical composition as a cytostatic agent, wherein the compound is as defined in the first aspect aspect, the conjugate is as defined in the second or third aspects, or the pharmaceutical composition is as defined in the fourth aspect.
  • Figure 1 shows an exemplary dose response curve indicating the IC 50 , GI 50 and LD 50 of a compound.
  • the IC50, GI50 and LD50 values in the examples of the invention were determined by extrapolating the dose response curve generated for each cancer cell line treated with the compound of the invention as demonstrated in Figure 1.
  • Figure 2 shows 1 H and 13 C NMR spectra obtained for poriolide that was isolated according to the examples described herein.
  • Figure 3 shows 1 H and 13 C NMR spectra obtained for isoporiolide that was isolated according to the examples described herein.
  • Figure 4 provides a reaction scheme for formation of poriolide prodrugs.
  • Figure 5 provides a reaction scheme for synthesis of exemplary conjugate precursors of the disclosure. Such conjugate precursors may be attached to a targeting moiety using techniques known in the art.
  • DETAILED DESCRIPTION [0021] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires.
  • an event, state, disorder or condition for example arresting, reducing or delaying the development of the event, state, disorder or condition, or a relapse thereof in case of maintenance treatment or secondary prophylaxis, or of at least one clinical or subclinical symptom thereof; (2) preventing or delaying the appearance of clinical symptoms of an event, state, disorder or condition developing in an animal (e.g.
  • the benefit to a patient to be treated may be either statistically significant or at least perceptible to the patient or to the physician.
  • a medicament will not necessarily produce a clinical effect in each patient to whom it is administered; thus, in any individual patient or even in a particular patient population, a treatment may fail or be successful only in part, and the meanings of the terms “treatment” and “prophylaxis” and of cognate terms are to be understood accordingly.
  • the compositions and methods described herein are of use for therapy and/or prophylaxis of the mentioned conditions.
  • the term “prophylaxis” includes reference to treatment therapies for the purpose of preserving health or inhibiting or delaying the initiation and/or progression of an event, state, disorder or condition, for example for the purpose of reducing the chance of an event, state, disorder or condition occurring.
  • alkyl as used herein includes reference to a straight or branched chain alkyl moiety having up to 20 (e.g.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms.
  • alkyl may be a “C 1 -C 8 alkyl”, i.e. an alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; “C 1 -C 6 alkyl”, i.e. an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; “C 1 -C 4 alkyl”, i.e.
  • alkyl having 1, 2, 3 or 4 carbon atoms; or a “C1-C3 alkyl”, i.e. an alkyl having 1, 2 or 3 carbon atoms.
  • lower alkyl includes reference to alkyl groups having 1, 2, 3 or 4 carbon atoms. Specific substituents for any saturated carbon atom in each alkyl group independently may be fluorine, OR a or NHR a .
  • alkenyl refers to a branched or linear hydrocarbon group containing at least one double bond. The double bond(s) may be present as the E or Z isomer.
  • the double bond may be at any possible position of the hydrocarbon chain; for example, “C2-C6-alkenyl” may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • the alkenyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkenyl group independently may be fluorine, OR a or NHR a .
  • alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond.
  • the triple bond may be at any possible position of the hydrocarbon chain.
  • C2-C6-alkynyl may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • the alkynyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkynyl group independently may be fluorine, OR a or NHR a .
  • cycloalkyl refers to a saturated hydrocarbon ring system containing, for example, 3, 4, 5 or 6 carbon atoms.
  • C3-C6-cycloalkyl may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the cycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each cycloalkyl group independently may be fluorine, OR a or NHR a .
  • aryl may refer to any aromatic carbocyclic ring system (i.e. a ring system containing 2(2n + 1) ⁇ electrons).
  • Aryl groups may have from 6 to 12 carbon atoms in the ring system. Aryl groups will typically be phenyl groups.
  • Aryl groups may be naphthyl groups or biphenyl groups.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, sulfur and phosphorus atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P, S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S- CH2-CH2- and –CH2-S-CH2-CH2-NH-CH2-.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R’, -C(O)NR’, -NR’R’’, - OR’, -SR’, and/or -SO2R’.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR’R’’ or the like, it will be understood that the terms heteroalkyl and -NR’R’’ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR’R’’ or the like.
  • heterocycloalkyl as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur.
  • a heterocycloalkyl may comprise 3, 4, or 5 ring carbon atoms and 1 or 2 ring heteroatoms selected from nitrogen and oxygen.
  • the group may be a polycyclic ring system but more often is monocyclic.
  • heteroaryl as used herein may refer to any aromatic (i.e.
  • a ring system containing 2(2n + 1) ⁇ electrons) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N).
  • any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 14 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from O, S and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms.
  • heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzothiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.
  • heterocycle may refer to either a heterocycloalkyl or a heteroaryl, as defined above.
  • It may be that, in any group which is an aryl or heteroaryl group, that aryl or heteroaryl group is unsubstituted or is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently selected at each occurrence from: halo, nitro, cyano, NR a R a , NR a S(O)2R a , NR a C(O)R a , NR a CONR a R a , NR a CO2R a , OR a , SR a , S(O)R a , S(O)2OR a , S(O)2R a , S(O)2NR a R a , CO2R a C(O)R a , CONR a R a , CR , CR
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom; for example a halo may be a fluorine, chlorine or bromine.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • haloalkyl refers to an alkyl group where one or more hydrogen atoms are substituted by a corresponding number of halogens.
  • halo(C1-C4)alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • halocycloalkyl refers to a saturated hydrocarbon ring system containing, for example, 3, 4, 5 or 6 carbon atoms and substituted with one or more halogen atoms.
  • C3-C6-halocycloalkyl may refer to, for example, fluoro-cyclopropyl, chloro-cyclobutyl, fluoro-cyclopentyl, bromo-cyclohexyl, etc..
  • halocycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each halocycloalkyl group independently may be OR a or NHR a .
  • alkoxy as used herein include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. In one class of embodiments, alkoxy has 1, 2, 3 or 4 carbon atoms, e.g.1, 2 or 3 carbon atoms.
  • haloalkoxy refers to an alkoxy group where one or more hydrogen atoms are substituted by a corresponding number of halogens.
  • substituents are R-substituted (e.g. an Rx-substituted alkyl, where “x” is an integer)
  • the substituent may be substituted with one or more R groups as allowed by chemical valency rules where each R group is optionally different (e.g. an Rx-substituted alkyl may include multiple Rx groups wherein each Rx group is optionally different).
  • substituents for each type of radical are provided below.
  • substituted as used herein in reference to a moiety means that one or more, especially 1 to 5, more especially 1, 2 or 3, (e.g.1 or 2) of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents.
  • substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible.
  • amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds.
  • substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled person.
  • the isomer having the lowest conformational energy may be preferred.
  • the disclosure includes such a compound, moiety, process or product having that feature and also such a compound, moiety, process or product not having that feature.
  • the disclosure comprises the unsubstituted moiety and the substituted moiety.
  • two or more moieties are described as being “independently” or “each independently” selected from a list of atoms or groups, this means that the moieties may be the same or different.
  • each moiety is therefore independent of the identities of the one or more other moieties.
  • pharmaceutically acceptable as used herein includes reference to 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 or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. This term includes acceptability for both human and veterinary purposes.
  • pharmaceutically acceptable salts is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. [0052] Certain compounds of the present invention possess asymmetric carbon atoms (optical centres) or double bonds; the racemates, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention do not include those which are known in the art to be too unstable to synthesize and/or isolate.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • the compounds may be labeled with stable isotopes that have a relatively low natural abundance, such as deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N).
  • isotopic variants of O e.g.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallisation and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • crystals of two different types are possible.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • racemic mixtures may be separated by conventional techniques known to those skilled in the art – see for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid); this is described in general textbooks such as Advanced Organic Chemistry, by J. March referred to above.
  • N-oxides can be made in a variety of ways which are known to the skilled person; for example, by reacting the amine compound with m-chloroperoxybenzoic acid (mCPBA) in a solvent such as dichloromethane.
  • mCPBA m-chloroperoxybenzoic acid
  • the term “pharmaceutical composition” as used herein includes reference to a composition comprising at least one active compound and optionally one or more additional pharmaceutically acceptable ingredients, for example a pharmaceutically acceptable carrier.
  • conjugate refers to a chemical compound formed by the covalent binding of two or more chemical compounds together.
  • the conjugate of the invention comprises a compound of formula (I) that is covalently bound to a targeting moiety B (e.g. via a covalent linker) where chemically possible.
  • targeting moiety refers to a chemical moiety having a high specificity and/or strong binding affinity towards a therapeutic target in vitro and/or in vivo, thereby allowing for precise and effective treatment.
  • Exemplary targeting moieties include: antibodies or fragments thereof, lectins, targeting peptides, aptamers, and the like.
  • the conjugate may be referred to as an “antibody-drug conjugate” (ADC).
  • ADCs synergistically target and kill cancer cells.
  • the antibody moiety binds to a target antigen specifically expressed on a cancer cell and is endocytosed/internalised by the cancer cells.
  • the cytotoxic payload i.e. drug
  • linker refers to a chemical spacer group employed to attach a compound of the invention to a targeting moiety. Typically, the linker has a chain length that is sufficiently long such that the targeting moiety cannot interact with the same binding site as the compound of the invention.
  • the linker may be cleavable (e.g. chemically cleavable or enzymatically cleavable) or non-cleavable.
  • the linker may be introduced via any suitable techniques, for example, in accordance with any of the techniques disclosed in Sheyi et al., Pharmaceutics 2022, 14, 396. Examples of suitable linkers are disclosed in Su et al., Acta Pharmaceutica Sinica B, 2021, 11(12) 3889; and and Doronina et al, Nature Biotechnology, 2003, 21(7) 778.
  • the term “chemically cleavable linker” may refer to pH-sensitive linkers (e.g.
  • the term “enzymatically cleavable linker” may refer to peptide-based linkers (e.g. dipeptide linkers such as valine-citrulline, phenylalanine-lysine, and valine-alanine), glycosidase-sensitive linkers (e.g. ⁇ -glucuronidase-cleavable linkers, ⁇ -galactosidase-cleavable linkers) or phosphatase-cleavable linkers.
  • the dipeptide bond of a peptide-based linker is cleaved by the action of an intracellular protease.
  • the glycosidic bond of a glycosidase- sensitive linker is cleaved by the action of a glycosidase in vivo.
  • the pyrophosphate or terminal monophosphate group of a phosphatase-cleavable linker is cleaved by the action of pyrophosphatase or acid phosphatase enzymes in vivo.
  • the term “non-cleavable linker” may refer to stable bonds that prevent or resist cleavage (e.g. proteolytic cleavage) in vivo.
  • Conjugates comprising a non-cleavable linker may depend on the complete lysosomal enzymatic degradation of the targeting moiety to release the active compound in vivo, resulting in simultaneous detachment of the linker.
  • exemplary non- cleavable linkers include thioethers and maleimido-caproyls (e.g. N-succinimidyl-4- (maleimidomethyl) cyclohexane-1-carboxylate (SMCC)).
  • antibody is used herein in the broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, monospecific antibodies (e.g., antibodies consisting of a single heavy chain sequence and a single light chain sequence, including multimers of such pairings), multispecific antibodies (e.g., bispecific antibodies) and antibody fragments so long as they exhibit the desired antigen- binding activity.
  • monospecific antibodies e.g., antibodies consisting of a single heavy chain sequence and a single light chain sequence, including multimers of such pairings
  • multispecific antibodies e.g., bispecific antibodies
  • antibody fragments so long as they exhibit the desired antigen- binding activity.
  • an “antibody fragment,” “antigen-binding portion” of an antibody (or simply “antibody portion”) or “antigen-binding fragment” of an antibody, as used herein, refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • antibody fragments include, but are not limited to, Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, and scFab); single domain antibodies (dAbs); and multispecific antibodies formed from antibody fragments.
  • the antibody may preferably be a monoclonal antibody or fragment thereof.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies in accordance with the presently disclosed subject matter can be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
  • COMPOUNDS [0071]
  • the invention provides compounds of formula (I) as previously described, or a pharmaceutically acceptable salt or solvate thereof.
  • each of R 3 and R 4 are independently selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)-C3-8-cycloalkyl, -C(O)- heterocycloalkyl, and -C(O)-heteroaryl.
  • the compound of formula (I) is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (IIa), (IIb) or (IIc), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (IVa), (IVb) or (IVc), or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of formula (I) is a compound of formula (Va), (Vb) or (Vc), or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of formula (I) is a compound of formula (VIa) or (VIb), or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of formula (I) is a compound of formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 3 and R 4 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 , R 2 , R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (IXa) or (IXb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (X) or (Xa), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 and R 2 are as defined herein in relation to compounds of the invention.
  • the compound is not [0085]
  • one or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as described in the following paragraphs: [0086]
  • R 1 is selected from the group comprising -H, -OH, -halo, -OC 1-20 -alkyl, -OC(O)-C 1-20 - alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 -cycloalkyl, -OC(O)-C 3- 8-halocycloalky
  • R 1 may be selected from the group comprising -H, -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl.
  • R 1 may be selected from -H, -OH, -OC(O)CH3, -OC(O)CH(CH3)2, -OC(O)C(CH3)3, -OC(O)(CH2)nCH3 , -OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, and -OC(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 1 may be selected from the group comprising -OH, -halo, -OC1-20-alkyl, -OC(O)-C1-20- alkyl, -OC1-20-haloalkyl, -OC(O)-C1-20-haloalkyl, -OC(O)-aryl, -OC(O)-C3-8-cycloalkyl, -OC(O)-C3- 8-halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl.
  • R 1 may be selected from the group comprising: -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl.
  • R 1 may be selected from -OH, -OC(O)CH3, -OC(O)CH(CH3)2, -OC(O)C(CH3)3, - OC(O)(CH2)nCH3 , -OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, and -OC(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 1 may be selected from -H and -OH.
  • R 1 may be -H.
  • R 1 may be -OH.
  • R 2 is selected from the group comprising -H, -OH, -halo, -OC1-20-alkyl, -OC(O)-C1-20- alkyl, -OC1-20-haloalkyl, -OC(O)-C1-20-haloalkyl, -OC(O)-aryl, -OC(O)-C3-8-cycloalkyl, -OC(O)-C3- 8-halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl.
  • R 2 may be selected from the group comprising -H, -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl.
  • R 2 may be selected from -H, -OH, -OC(O)CH3, -OC(O)CH(CH3)2, -OC(O)C(CH3)3, -OC(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -OC(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 2 may be selected from the group comprising -OH, -halo, -OC1-20-alkyl, -OC(O)-C1-20- alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 -cycloalkyl, -OC(O)-C 3- 8 -halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl.
  • R 2 may be selected from the group comprising: -OH, -OC 1-20 -alkyl, -OC(O)-C 1-20 -alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl.
  • R 2 may be selected from -OH, -OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , - OC(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -OC(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. [0091] R 2 may be selected from -H and -OH. R 2 may be -H. R 2 may be -OH.
  • R 1 and R 2 may be H.
  • R 1 is H and R 2 is selected from: -OH, -OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , - OC(O)C(CH 3 ) 3 , -OC(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -OC(O)- phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 1 is H and R 2 is OH.
  • R 2 is H and R 1 is selected from: -OH, -OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , - OC(O)C(CH 3 ) 3 , -OC(O)(CH 2 ) n CH 3, -OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -OC(O)- phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. It may be that R 2 is H and R 1 is OH.
  • R 3 may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -C(O)NHR a , -C(O)NR a -C2-6 alkylene-NHR a , -C(O)NR a -C2-6 alkylene-NR a C(O)R a , -C(O)NR a -C0-6 alkylene-Z-C(O)R a , - C(O)NR a -C0-6 alkylene-Z-C(O)R a , - C(O)NR a -C0-6 alkylene-Z-R a , - C(O)
  • Z may be a nitrogen-containing 5- or 6-membered heterocycloalkyl, e.g. pyrrolidine or piperidine.
  • R 3 includes a Z group, it may be that R 3 is selected from: each m is independently selected from 1 and 2.
  • R 3 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-heteroaryl, -C(O)NR a -C2-6 alkylene-NHR a and -C(O)NR a -C2-6 alkylene-NR a C(O)R a .
  • R 3 may be selected from the group comprising -H, -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, -C(O)-phenyl, - C(O)N(CH3)(CH2)2-NHCH3 and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 3 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 3 may be selected from the group comprising -H, -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -C(O)NHR a , -C(O)NR a -C 2-6 alkylene-NHR a , -C(O)NR a -C 2-6 alkylene-NR a C(O)R a , -C(O)NR a -C 0-6 alkylene-Z-C(O)R a , - C(O)NR a -C 0-6 alkylene-Z-C(O)R a , - C(O)NR a -C 0-6 alkylene-Z-R a , - C(O)
  • R 3 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, -C(O)-heteroaryl, - C(O)NR a -C 2-6 alkylene-NHR a and -C(O)NR a -C 2-6 alkylene-NR a C(O)R a .
  • R 3 may be selected from the group comprising: -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, -C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 and - C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 , wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 3 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 3 may be selected from the group comprising -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 is selected from: -H, -C(O)NR a -C2-6 alkylene-NHR a , -C(O)NR a -C2-6 alkylene-NR a C(O)R a , -C(O)NR a -C0-6 alkylene-Z-C(O)R a , -C(O)NR a -C0-6 alkylene-Z-R a , -C(O)-Z- C0-6 alkylene-NR a C(O)R a , and -C(O)-Z-C0-6 alkylene-NHR a , wherein Z is a nitrogen-containing 5- or 6-membered heterocycle.
  • R 3 is selected from: -C(O)NR a -C2-6 alkylene-NHR a , - C(O)NR a -C2-6 alkylene-NR a C(O)R a , -C(O)NR a -C0-6 alkylene-Z-C(O)R a , -C(O)NR a -C0-6 alkylene- Z-R a , -C(O)-Z-C0-6 alkylene-NR a C(O)R a , and -C(O)-Z-C0-6 alkylene-NHR a , wherein Z is a nitrogen-containing 5- or 6-membered heterocycle.
  • R 3 is selected from -H, -C(O)N(CH3)(CH2)2-NHCH3 and - C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 . It may be that R 3 is selected from -C(O)N(CH 3 )(CH 2 ) 2 - NHCH3 and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3.
  • R 4 is selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, - C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 4 may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 4 may be selected from the group comprising -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 4 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 4 may be selected from the group comprising -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 and R 4 are independently selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , - C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 and R 4 are -H.
  • R 3 is H and R 4 is selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 is H and R 3 is selected from the group comprising: -H, -C(O)CH3, - C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, - C(O)-phenyl, -C(O)N(CH3)(CH2)2-NHCH3 and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 is H and R 3 is selected from the group comprising: -H, -C(O)N(CH3)(CH2)2-NHCH3 and - C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3. It may be that R 4 is H and R 3 is selected from the group comprising: -C(O)N(CH3)(CH2)2-NHCH3 and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3.
  • R 4 is H and R 3 is selected from the group comprising: -H, -C(O)CH3, - C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. [00110] It may be that R 3 is H and R 4 is H.
  • R 5 is selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, - C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 5 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 5 may be selected from the group comprising -H, -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 5 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 5 may be selected from the group comprising -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 is selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, - C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 6 may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 6 may be selected from the group comprising -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 6 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 6 may be selected from the group comprising -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 is selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, - C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 7 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 7 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 7 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 7 may be selected from the group comprising -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 , R 6 and R 7 are independently selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, - C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. [00118] It may be that at least one of R 5 , R 6 and R 7 is -H.
  • R 5 is H and R 6 and R 7 are independently selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 is H and R 5 and R 7 are independently selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 is H and R 5 and R 6 are independently selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , - C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 , R 6 and R 7 are -H
  • the other one of R 5 , R 6 and R 7 is selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, - C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 and R 6 are -H and R 7 is selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, - C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 and R 7 are -H and R 6 is selected from the group comprising: - H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 and R 7 are -H and R 5 is selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. [00120] It may be that each of R 5 , R 6 and R 7 is -H.
  • R 3 , R 4 , R 5 , R 6 and R 7 is -H. It may be that two of R 3 , R 4 , R 5 , R 6 and R 7 are -H. It may be that three of R 3 , R 4 , R 5 , R 6 and R 7 are -H. It may be that four of R 3 , R 4 , R 5 , R 6 and R 7 are -H. It may be that each of R 3 , R 4 , R 5 , R 6 and R 7 is -H.
  • R 1 and R 2 are independently selected from the group comprising -H, -OH, -halo, -OC 1-20 -alkyl, -OC(O)-C 1-20 -alkyl, -OC 1-20 - haloalkyl, -OC(O)-C1-20-haloalkyl, -OC(O)-aryl, -OC(O)-C3-8-cycloalkyl, -OC(O)-C3-8- halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl, with the proviso that R 1 may not be -H when R 2 is -OH, and that R 2 may not be -OH when R 1 is -H.
  • n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5 and 6.
  • CONJUGATES [00124]
  • the conjugate may comprise one targeting moiety and one compound of the invention.
  • the conjugate may comprise one targeting moiety and 1, 2, or more compounds of the invention.
  • the conjugate may comprise 1 or 2 targeting moieties and at least one compound of the invention.
  • the at least one targeting moiety may be attached to the at least one compound via a covalent linker.
  • the covalent linker may be a chemically cleavable linker or an enzymatically cleavable linker.
  • the conjugate of formula (XI) is a conjugate of formula (XIIa), (XIIb) or (XIIc), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 ’, R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ are as defined herein in relation to conjugates of the invention.
  • the conjugate of formula (XI) is a conjugate of formula (XIIIa), (XIIIb) or (XIIIc), or a pharmaceutically acceptable salt or solvate thereof:
  • the conjugate of formula (XI) is a conjugate of formula (XIVa), (XIVb) or (XIVc), or a pharmaceutically acceptable salt or solvate thereof:
  • the conjugate of formula (XI) is a conjugate of formula (XVa), (XVb) or (XVc), or a pharmaceutically acceptable salt or solvate thereof:
  • the conjugate of formula (XI) is a conjugate of formula (XVIa) or (XVIb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 ’, R 2 ’, R 3 ’ and R 4 ’ are as defined herein in relation to conjugates of the invention.
  • the conjugate of formula (XI) is a conjugate of formula (XVIIa) or (XVIIb), or a pharmaceutically acceptable salt or solvate thereof: (XVIIb) wherein R 3 ’ and R 4 ’ are as defined herein in relation to conjugates of the invention.
  • the conjugate of formula (XI) is a conjugate of formula (XVIIIa) or (XVIIIb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 ’, R 2 ’, R 5 ’, R 6 ’ and R 7 ’ are as defined herein in relation to conjugates of the invention.
  • the conjugate of formula (XI) is a conjugate of formula (XIXa) or (XIXb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 5 ’, R 6 ’ and R 7 ’ are as defined herein in relation to conjugates of the invention.
  • the conjugate of formula (XI) or formula (XIa) is a conjugate formula (XX) or (XXa), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 ’ and R 2 ’ are as defined herein in relation to conjugates of the invention.
  • the conjugate of formula (XI) is a conjugate of formula (XXIa) or (XXIb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 3 ’ is as defined herein in relation to conjugates of the invention.
  • the conjugate of formula (XI) or formula (XIa) is a conjugate of formula (XXIIa) or (XXIIb), or a pharmaceutically acceptable salt or solvate thereof: Wherein L and B are as defined herein in relation to conjugates of the invention.
  • the conjugate of formula (XI) or formula (XIa) includes one or more of R 1 ’, R 2 ’, R 3 ’, R 4 ’, R 5 ’, R 6 ’, R 7 ’, L, B, and n as described in the following paragraphs: [00140]
  • R 1 ’ is selected from the group comprising -H, -OH, -halo, -OC 1-20 -alkyl, -OC(O)-C 1-20 - alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 -cycloalkyl, -OC(O)-C 3- 8 -halocycloalkyl, -OC(O)-heterocycloalkyl, -OC(O)-heteroaryl, -O-L-B, and -OC(
  • R 1 ’ may be selected from the group comprising -H, -OH, -OC 1-20 -alkyl, -OC(O)-C 1-20 -alkyl, -OC(O)-aryl, - OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B.
  • R 1 ’ may be selected from -H, -OH, - OC(O)CH3, -OC(O)CH(CH3)2, -OC(O)C(CH3)3, -OC(O)(CH2)nCH3 , -OC(O)CH[(CH2)nCH3]2, - OC(O)C[(CH2)nCH3]3, -OC(O)-phenyl, -O-L-B, and -OC(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 1 ’ may be selected from the group comprising -OH, -halo, -OC1-20-alkyl, -OC(O)-C1-20- alkyl, -OC1-20-haloalkyl, -OC(O)-C1-20-haloalkyl, -OC(O)-aryl, -OC(O)-C3-8-cycloalkyl, -OC(O)-C3- 8-halocycloalkyl, -OC(O)-heterocycloalkyl, -OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B.
  • R 1 ’ may be selected from the group comprising -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, - OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B.
  • R 1 ’ may be selected from -OH, - OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , -OC(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , - OC(O)C[(CH2)nCH3]3, -OC(O)-phenyl, -O-L-B, and -OC(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 1 ’ may be selected from -H, -OH, -O-L-B and -OC(O)-L-B.
  • R 1 ’ may be selected from - H and -OH.
  • R 1 ’ may be selected from -O-L-B and -OC(O)-L-B.
  • R 1 ’ may be -H.
  • R 1 ’ may be -OH.
  • R 1 ’ may be -O-L-B.
  • R 1 ’ may be -OC(O)-L-B.
  • R 2 ’ is selected from the group comprising -H, -OH, -halo, -OC 1-20 -alkyl, -OC(O)-C 1-20 - alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 -cycloalkyl, -OC(O)-C 3- 8 -halocycloalkyl, -OC(O)-heterocycloalkyl, -OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B.
  • R 2 ’ may be selected from the group comprising -H, -OH, -OC 1-20 -alkyl, -OC(O)-C 1-20 -alkyl, -OC(O)-aryl, - OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B.
  • R 2 ’ may be selected from -H, -OH, - OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , -OC(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , - OC(O)C[(CH 2 ) n CH 3 ] 3 , -OC(O)-phenyl, -O-L-B, and -OC(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 2 ’ may be selected from the group comprising -OH, -halo, -OC 1-20 -alkyl, -OC(O)-C 1-20 - alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 -cycloalkyl, -OC(O)-C 3- 8 -halocycloalkyl, -OC(O)-heterocycloalkyl, -OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B.
  • R 2 ’ may be selected from the group comprising -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, - OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B.
  • R 2 ’ may be selected from -OH, - OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , -OC(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , - OC(O)C[(CH2)nCH3]3, -OC(O)-phenyl, -O-L-B, and -OC(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 2 ’ may be selected from -H, -OH, -O-L-B and -OC(O)-L-B.
  • R 2 ’ may be selected from - H and -OH.
  • R 2 ’ may be selected from -O-L-B and -OC(O)-L-B.
  • R 2 ’ may be -H.
  • R 2 ’ may be -OH.
  • R 2 ’ may be -O-L-B.
  • R 2 ’ may be -OC(O)-L-B.
  • One of R 1 ’ and R 2 ’ may be H.
  • R 1 ’ is H and R 2 ’ is selected from: -OH, -OC(O)CH3, -OC(O)CH(CH3)2, - OC(O)C(CH3)3, -OC(O)(CH2)nCH3 , -OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, -OC(O)- phenyl, -O-L-B, and -OC(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 1 ’ is -H and R 2 ’ is -OH, -O-L-B or -OC(O)-L-B. It may be that R 1 ’ is -H and R 2 ’ is -OH. [00148] It may be that R 2 ’ is H and R 1 ’ is selected from: -OH, -OC(O)CH3, -OC(O)CH(CH3)2, - OC(O)C(CH3)3, -OC(O)(CH2)nCH3, -OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, -OC(O)- phenyl, -O-L-B, and -OC(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 2 ’ is -H and R 1 ’ is -OH, -O-L-B or -OC(O)-L-B. It may be that R 2 ’ is -H and R 1 ’ is -OH.
  • R 3 ’ may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, - C(O)-aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -C(O)NHR a , - C(O)NR a -C2-6 alkylene-NHR a , -C(O)NR a -C2-6 alkylene-NR a C(O)R a , -L-B, -C(O)-L-B, -C(O)NR a -C(
  • Z may be a nitrogen-containing 5- or 6-membered heterocycloalkyl, e.g. pyrrolidine or piperidine.
  • R 3’ includes a Z group, it may be that R 3’ is selected from: , wherein each m is independently selected from 1 and 2.
  • R 3 ’ may be selected from the group comprising -H, -C(O)CH3, - C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, - C(O)-phenyl, -C(O)N(CH3)(CH2)2-NHCH3, -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3, -L-B, -C(O)-L-B, -C(O)N(CH3)(CH2)2-N(CH3)C(O)-L-B, -C(O)-pyrrolidyl-(CH2)p-N(CH3)C(O)-L-B and - C(O)N(CH3)(CH2)p-pyrrolidyl-C(O)-L-B
  • R 3 ’ may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, - C(O)-aryl, -C(O)-heteroaryl, -C(O)NR a -C2-6 alkylene-NHR a , -C(O)NR a -C2-6 alkylene-NR a C(O)R a , -L-B, -C(O)-L-B, and -C(O)NR a -C2-6 alkylene-NR a C(O)-L-B.
  • R 3 ’ may be selected from the group comprising -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, - C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, -C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 , - C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 , -L-B, -C(O)-L-B, and -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 ’ may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, - C(O)-aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 3 ’ may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, - C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 3 ’ may be selected from the group comprising -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , - C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 ’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -C(O)NHR a , -C(O)NR a -C2-6 alkylene-NHR a , -C(O)NR a -C2-6 alkylene-NR a C(O)R a , -L-B, -C(O)-L-B, -C(O)NR a -C2-6 alkylene- NR a C(O)-L-B, -C(O)NR a -C2-6 alkylene- NR a C(O)-L-B, -C(O)NR a -C0-6 alky
  • R 3 ’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)NR a -C2-6 alkylene-NHR a , -C(O)NR a -C 2-6 alkylene-NR a C(O)R a , -L-B, -C(O)-L-B, and -C(O)NR a -C 2-6 alkylene-NR a C(O)-L-B.
  • R 3 ’ may be selected from the group comprising -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, - C(O)-phenyl, -C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 , -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 , -L-B, -C(O)-L-B, and -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 ’ may be selected from the group comprising: -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , - C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , -L-B, -C(O)-L-B, and -C(O)NR a -C 2-6 alkylene- NR a C(O)-L-B, -C(O)NR a -C 0-6 alkylene-Z-C(O)-L-B, and -C(O)-Z-C 0-6 alkylene-NR a C(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle, and wherein n is an integer selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 ’ may be selected from the group comprising: -L-B, -C(O)-L-B, -C(O)NR a -C 2-6 alkylene-NR a C(O)-L-B, - C(O)NR a -C 0-6 alkylene-Z-C(O)-L-B, and -C(O)-Z-C 0-6 alkylene-NR a C(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle.
  • R 3 ’ may be selected from the group comprising -L-B, -C(O)-L-B, -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)-L-B, -C(O)-pyrrolidyl-(CH 2 ) p - N(CH 3 )C(O)-L-B and -C(O)N(CH 3 )(CH 2 ) p -pyrrolidyl-C(O)-L-B, wherein p is independently selected at each occurrence from 0, 1 and 2.
  • R 3 ’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 3 ’ may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, -C(O)- heteroaryl, -L-B and -C(O)-L-B.
  • R 3 ’ may be selected from the group comprising - C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH2)nCH3]3, -C(O)-phenyl, - L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 ’ is selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, - C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 4 ’ may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)- heteroaryl, - L-B and -C(O)-L-B.
  • R 4 ’ may be selected from the group comprising - H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH2)nCH3]3, -C(O)-phenyl, - L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 ’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 4 ’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)- heteroaryl, -L-B and -C(O)-L-B.
  • R 4 ’ may be selected from the group comprising - C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 ’ and R 4 ’ are independently selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, - C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 ’ and R 4 ’ are -H.
  • R 3 ’ is H and R 4 ’ is selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , - C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 ’ is H and R 3 ’ is selected from the group comprising -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , - C(O)-phenyl, -C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 , -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 , -L-B, -C(O)-L-B, -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)-L-B, -C(O)N(CH
  • R 4 ’ is H and R 3 ’ is selected from the group comprising: -H, -C(O)CH3, - C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, - C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 ’ is H and R 4 ’ is -L-B or -C(O)-L-B.
  • R 4 ’ is H and R 3 ’ is -L-B, -C(O)-L-B, -C(O)N(CH3)(CH2)2-N(CH3)C(O)-L-B, -C(O)-pyrrolidyl-(CH2)p-N(CH3)C(O)-L-B or -C(O)N(CH3)(CH2)p-pyrrolidyl-C(O)-L-B, wherein p is independently selected at each occurrence from 0, 1 and 2.
  • R 4 ’ is H and R 3 ’ is - C(O)N(CH3)(CH2)2-N(CH3)C(O)-L-B, -C(O)-pyrrolidyl-(CH2)p-N(CH3)C(O)-L-B or - C(O)N(CH3)(CH2)p-pyrrolidyl-C(O)-L-B, wherein p is independently selected at each occurrence from 0, 1 and 2. [00166] It may be that R 4 ’ is H and R 3 ’ is -L-B or -C(O)-L-B. [00167] It may be that R 3 ’ is H and R 4 ’ is H.
  • R 5 ’ is selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, - C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 5 ’ may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)- heteroaryl, -L-B and -C(O)-L-B.
  • R 5 ’ may be selected from the group comprising - H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 ’ may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 5 ’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)- heteroaryl, -L-B and -C(O)-L-B.
  • R 5 ’ may be selected from the group comprising - C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , - C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 ’ is selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, - C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 6 ’ may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, -C(O)- heteroaryl, -L-B and -C(O)-L-B.
  • R 6 ’ may be selected from the group comprising - H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , - C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 ’ may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 6 ’ may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, -C(O)- heteroaryl, -L-B and -C(O)-L-B.
  • R 6 ’ may be selected from the group comprising - C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 ’ is selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, - C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 7 ’ may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)- heteroaryl, -L-B and -C(O)-L-B.
  • R 7 ’ may be selected from the group comprising - H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 ’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -L-B and -C(O)-L-B.
  • R 7 ’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)- heteroaryl, -L-B and -C(O)-L-B.
  • R 7 ’ may be selected from the group comprising - C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 ’, R 6 ’ and R 7 ’ are independently selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , - C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 ’, R 6 ’ and R 7 ’ are -H.
  • R 5 ’ is H and R 6 ’ and R 7 ’ are independently selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , - C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 ’ is H and R 5 ’ and R 7 ’ are independently selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , - C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 ’ is H and R 5 ’ and R 6 ’ are independently selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , - C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 ’, R 6 ’ and R 7 ’ are -H
  • the other one of R 5 ’, R 6 ’ and R 7 ’ is selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, - C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 ’ and R 6 ’ are -H and R 7 ’ is selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, - C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 ’ and R 7 ’ are -H and R 6 ’ is selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, - C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 ’ and R 7 ’ are -H and R 5 ’ is selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, - C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, -C(O)-phenyl, -L-B and -C(O)-L-B, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • each of R 5 ’, R 6 ’ and R 7 ’ is -H. It may be that at least one of R 5 ’, R 6 ’ and R 7 ’ is -L-B or -C(O)-L-B.
  • R 5 ’ is -L-B or -C(O)-L-B
  • R 6 ’ and R 7 ’ are independently selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , - C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 ’ is -L-B or -C(O)-L-B
  • R 5 ’ and R 7 ’ are independently selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , - C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 ’ is -L-B or -C(O)-L-B
  • R 5 ’ and R 6 ’ are independently selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 ’ is --L-B or -C(O)-L-B, and each of R 6 ’ and R 7 ’ are -H.
  • R 6 ’ is -L-B or -C(O)-L-B, and each of R 5 ’ and R 7 ’ are -H.
  • R 7 ’ is -L-B or -C(O)-L-B, and each of R 5 ’ and R 6 ’ are -H.
  • one or more of R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ is -H.
  • R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ are -H. It may be that three of R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ are -H. It may be that four of R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ are -H. It may be that each of R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ is -H.
  • R 1 ’ is R 1 , as defined herein;
  • R 2 ’ is R 2 , as defined herein;
  • R 3 ’ is R 3 , as defined herein;
  • R 4 ’ is R 4 , as defined herein;
  • R 5 ’ is R 5 , as defined herein;
  • R 6 ’ is R 6 , as defined herein;
  • R 7 ’ is R 7 , as defined herein.
  • R 1 ’ and R 2 ’ is -O-L-B or -OC(O)-L-B; and/or at least one of R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ is -L-B or -C(O)-L-B.
  • the conjugate includes no more than one targeting moiety. For example, it may be that no more than one of R 1 ’, R 2 ’, R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ comprises a B.
  • R 1 ’ and R 2 ’ are -O-L-B or -OC(O)-L-B, or it may be that one of R 3 ’, R 4 ’, R 5 ’, R 6 ’ and R 7 ’ is -L-B or -C(O)-L-B.
  • n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
  • n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5 and 6.
  • L may be a cleavable linker.
  • L may be independently selected at each occurrence from a chemically cleavable linker, an enzymatically cleavable linker or a non-cleavable linker. L may be independently selected at each occurrence from a chemically cleavable linker or an enzymatically cleavable linker. [00189] It may be that L is -L 1 -L 2 -L 3 -L 4 , wherein L 1 is a bond or a spacer moiety, L 2 is a cleavable moiety, L 3 is a bond or a spacer moiety, and L 4 is a ligated moiety. [00190] L 1 may be a bond.
  • L 1 may be a spacer moiety.
  • L 3 may be a bond.
  • L 3 may be a spacer moiety. It may be that one of L 1 and L 3 is a bond and the other of L 1 and L 3 is a spacer moiety. It may be that both L 1 and L 3 are spacer moieties.
  • each of L 1 or L 3 may be independently selected from or comprise: -NH-C(O)O-CR a R a -aryl-NH-, -CR a R a -aryl-NH-, -CR a R a -heteroaryl-NH-, -C 2-24 -alkyl (e.g. -C 4-24 -alkyl or -C 6-24 -alkyl), -O-CR a R a -aryl-NH-, -O-CR a R a -heteroaryl-NH-, -O-C 2-24 -alkyl (e.g.
  • -O-C 4-24 -alkyl or -O-C 6-24 -alkyl and C 2-24 -alkyl (e.g. C 4-24 -alkyl or C 6-24 -alkyl), optionally wherein said -O-C 2-24 -alkyl or C 2-24 -alkyl may be interrupted by one, two, or three of: -NC(O)-, - NH-, -O-, -C(O)-, and -C(O)O-.
  • Each of L 1 or L 3 may be independently selected from or comprise: -CR a R a -aryl-NH-, -O-CR a R a -aryl-NH-, and C2-24-alkyl (e.g. C4-24-alkyl or C6-24-alkyl), optionally wherein said C2-24-alkyl may be interrupted by one, two, or three of: -NC(O)-, -NH-, - O-, -C(O)-, and -C(O)O-.
  • each of L 1 or L 3 may be independently selected from: -O- CR a R a -phenyl-NH-, and C4-12-alkyl, optionally wherein said C4-12-alkyl may be interrupted by one, two, or three of: -NC(O)-, -NH-, -O-, and -C(O)-.
  • L 1 may be a bond, -O-CH2-phenyl-NH-, or -CH2-phenyl-NH-.
  • L 3 may be a bond, -O-CH2-phenyl-NH-, -C(O)-C4-12-alkyl or -NHC(O)- C4-12-alkyl.
  • L 2 is selected from selected from: a pH-sensitive moiety (e.g. hydrazone, carbonate, silyl ether, polyethylene glycol), a reducible moiety (e.g. disulfide, disulfide carbamate), a peptide moiety (e.g. -Val-Cit-, -Phe-Lys-, -Val-Ala-), a glycosidase-sensitive moiety (e.g.
  • L 2 may be selected from: a polyethylene glycol (e.g. –(CH2CH2O)4–) and a dipeptide (e.g. -Val-Cit-).
  • L 4 may be any species onto which a targeting moiety has been ligated.
  • L 4 may be a heterocycloalkyl (e.g.
  • the succinimide of L 4 may be formed from the ligation reaction between a maleimide and a cysteine residue of the targeting moiety.
  • L may be selected from: [00200] Other suitable L groups are provided in Sheyi et al., Pharmaceutics, 2022, 14, 396; and Su et al., Acta Pharmaceutica Sinica B, 2021, 11(12), 3889.
  • the or each targeting moiety B may comprise an antibody or fragment thereof.
  • the antibody may be a monoclonal antibody or fragment thereof.
  • the antibody or fragment thereof may be an immunoglobulin G (IgG) or fragment thereof.
  • the antibody or fragment thereof may be an IgG1, an IgG2, or an IgG4.
  • the targeting moiety may be an antibody or fragment thereof selected from: gemtuzumab, brentuximab, trastuzumab, inotuzumab, moxetumomab, polatuzumab, enfortumab, sacituzumab, belantamab, loncastuximab, tisotumab, rovalpituzumab, glembatumumab, pinatuzumab, telisotuzumab, ladiratuzumab, mirvetuximab, lorvotuzumab, coltuximab, indatuximab, anetumab, huDS6, depatuxizumab, naratuximab, AGS-16C, cetuximab and disitamab.
  • L is a chemically cleavable linker and B is an antibody or fragment thereof. It may be that L is an enzymatically cleavable linker and B is an antibody or fragment thereof. It may be that L is a non-cleavable linker and B is an antibody or fragment thereof.
  • the conjugate is: COMPOSITIONS AND ADMINISTRATION
  • a pharmaceutical composition comprising a compound of the invention or a conjugate of the invention.
  • the composition may further comprise a pharmaceutically acceptable excipient.
  • composition may provide the compound or conjugate in admixture with at least one pharmaceutically acceptable adjuvant, carrier, or diluent.
  • Compounds, conjugates or compositions of the invention may be administered orally, topically, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or via inhalation.
  • the compounds, conjugates or compositions are formulated for non-oral administration.
  • the compounds or conjugates may be administered in the form of pharmaceutical preparations comprising the compound or conjugate either as a free compound or conjugate or, for example, a pharmaceutically acceptable non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Actual dosage levels of active ingredients in the pharmaceutical formulations and pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound or conjugate, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound or conjugate at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. For example, a compound or conjugate of the invention could be started at a dose of about 5 ⁇ mol per kg (e.g. by injection) and dosage could be gradually increased until the desired effect is achieved. [00210] Pharmaceutical compositions of this invention for parenteral (e.g.
  • intravenous injection may comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and non- aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters, such as ethyl oleate.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Inhibition of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol or phenol sorbic acid. It may also be desirable to include isotonic agents, such as sugars or sodium chloride, for example.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound or conjugate is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as acetyl alcohol and glycerol monostearate; h) absorbents, such as
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.
  • Oral formulations may contain a dissolution aid.
  • dissolution aids include non-ionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g.
  • sorbitan trioleate polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkyamine oxides; bile acid and salts thereof (e.g.,
  • ionic surface active agents such as sodium laurylsulfate, fatty acid soaps, alkylsufonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes. [00215] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavouring and perfuming agents.
  • Suspensions in addition to the active compounds or conjugates, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agaragar, and traganacanth and mixtures thereof.
  • compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the compounds or conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound or conjugate.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound or conjugate.
  • Dosage forms for topical administration of a compound or conjugate of this invention include powders, sprays, creams, foams, gels, ointments and inhalants.
  • compositions according to the present subject matter may also contain inactive components. Suitable inactive components are well known in the art and are described in standard textbooks, such as Goodman and Gillman’s: The Pharmacological Bases of Therapeutics, 13 th Ed., Brunton et al., Eds. McGraw-Hill Education (2017), and Remington’s Pharmaceutical Sciences, 17 th Ed., Mack Publishing Co., Easton, Pa.
  • compositions may be used in combination with an additional pharmaceutical dosage form to enhance their effectiveness in treating any of the disorders described herein.
  • the present formulations may be administered as part of a regimen additionally including any other pharmaceutical and/or pharmaceutical dosage form known in the art as effective for the treatment of any of these disorders.
  • USES AND METHODS [00220]
  • the compounds and conjugates of the invention are anticancer agents.
  • An aspect of the invention provides a compound of the invention, a conjugate of the invention, or a pharmaceutical composition of the invention, for use as a medicament.
  • the compound may, for example, be a compound of any of formulae (I) to (X).
  • the conjugate may, for example, be a conjugate of any of formulae (XI) to (XXII).
  • the composition may comprise a compound of any of formulae (I) to (X) or a conjugate of any of formulae (XI) to (XXII).
  • the invention provides compounds for use in the treatment of cancer, the compound being a compound of formula (I) as previously described, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula (I) is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (IIa), (IIb) or (IIc), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of formula (I) is a compound of formula (IVa), (IVb) or (IVc), or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of formula (I) is a compound of formula (Va), (Vb) or (Vc), or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of formula (I) is a compound of formula (VIa) or (VIb), or a pharmaceutically acceptable salt or solvate thereof:
  • the compound of formula (I) is a compound of formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 3 and R 4 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 , R 2 , R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (IXa) or (IXb), or a pharmaceutically acceptable salt or solvate thereof: wherein R 5 , R 6 and R 7 are as defined herein in relation to compounds of the invention.
  • the compound of formula (I) is a compound of formula (X) or (Xa), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 and R 2 are as defined herein in relation to compounds of the invention.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as described in the following paragraphs.
  • R 1 is selected from the group comprising -H, -OH, -halo, -OC1-20-alkyl, -OC(O)-C1-20- alkyl, -OC1-20-haloalkyl, -OC(O)-C1-20-haloalkyl, -OC(O)-aryl, -OC(O)-C3-8-cycloalkyl, -OC(O)-C3- 8-halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl.
  • R 1 may be selected from the group comprising -H, -OH, -OC 1-20 -alkyl, -OC(O)-C 1-20 -alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl.
  • R 1 may be selected from -H, -OH, -OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , -OC(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -OC(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 1 may be selected from the group comprising -OH, -halo, -OC 1-20 -alkyl, -OC(O)-C 1-20 - alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 -cycloalkyl, -OC(O)-C 3- 8 -halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl.
  • R 1 may be selected from the group comprising: -OH, -OC 1-20 -alkyl, -OC(O)-C 1-20 -alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl.
  • R 1 may be selected from -OH, -OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , - OC(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -OC(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. [00236] R 1 may be selected from -H and -OH. R 1 may be -H. R 1 may be -OH.
  • R 2 is selected from the group comprising -H, -OH, -halo, -OC 1-20 -alkyl, -OC(O)-C 1-20 - alkyl, -OC 1-20 -haloalkyl, -OC(O)-C 1-20 -haloalkyl, -OC(O)-aryl, -OC(O)-C 3-8 -cycloalkyl, -OC(O)-C 3- 8 -halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl.
  • R 2 may be selected from the group comprising -H, -OH, -OC 1-20 -alkyl, -OC(O)-C 1-20 -alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl.
  • R 2 may be selected from -H, -OH, -OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , -OC(O)(CH2)nCH3 , -OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, and -OC(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 2 may be selected from the group comprising -OH, -halo, -OC1-20-alkyl, -OC(O)-C1-20- alkyl, -OC1-20-haloalkyl, -OC(O)-C1-20-haloalkyl, -OC(O)-aryl, -OC(O)-C3-8-cycloalkyl, -OC(O)-C3- 8-halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl.
  • R 2 may be selected from the group comprising: -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl.
  • R 2 may be selected from -OH, -OC(O)CH3, -OC(O)CH(CH3)2, -OC(O)C(CH3)3, - OC(O)(CH2)nCH3 , -OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, and -OC(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 2 may be selected from -H and -OH.
  • R 2 may be -H.
  • R 2 may be -OH.
  • One of R 1 and R 2 may be H. [00241] It may be that R 1 is H and R 2 is selected from: -OH, -OC(O)CH3, -OC(O)CH(CH3)2, - OC(O)C(CH3)3, -OC(O)(CH2)nCH3, -OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, and -OC(O)- phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 1 is H and R 2 is OH.
  • R 2 is H and R 1 is selected from: -OH, -OC(O)CH3, -OC(O)CH(CH3)2, - OC(O)C(CH 3 ) 3 , -OC(O)(CH 2 ) n CH 3, -OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -OC(O)- phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. It may be that R 2 is H and R 1 is OH.
  • R 3 may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -C(O)NHR a , -C(O)NR a -C 2-6 alkylene-NHR a , -C(O)NR a -C 2-6 alkylene-NR a C(O)R a , -C(O)NR a -C 0-6 alkylene-Z-C(O)R a , - C(O)NR a -C 0-6 alkylene-Z-C(O)R a , - C(O)NR a -C 0-6 alkylene-Z-C(O)R a
  • Z may be a nitrogen-containing 5- or 6-membered heterocycloalkyl, e.g. pyrrolidine or piperidine.
  • R 3 may be that R 3 is selected from: each m is independently selected from 1 and 2.
  • R 3 may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-heteroaryl, -C(O)NR a -C 2-6 alkylene-NHR a and -C(O)NR a -C 2-6 alkylene-NR a C(O)R a .
  • R 3 may be selected from the group comprising -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, - C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 and -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 , wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 3 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 3 may be selected from the group comprising -H, -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, -C(O)-heteroaryl, -C(O)NHR a , -C(O)NR a -C2-6 alkylene-NHR a , -C(O)NR a -C2-6 alkylene-NR a C(O)R a , -C(O)NR a -C0-6 alkylene-Z-C(O)R a , - C(O)NR a -C0-6 alkylene-Z-R a , - C(O)NR a -C0-6 alkylene-Z-R a , -C(O)-Z-C0-6 alkylene-NR
  • R 3 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)-heteroaryl, - C(O)NR a -C2-6 alkylene-NHR a and -C(O)NR a -C2-6 alkylene-NR a C(O)R a .
  • R 3 may be selected from the group comprising: -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , -C(O)-phenyl, -C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 and - C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 , wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 3 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 3 may be selected from the group comprising -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 is selected from: -H, -C(O)NR a -C 2-6 alkylene-NHR a , -C(O)NR a -C 2-6 alkylene-NR a C(O)R a , -C(O)NR a -C 0-6 alkylene-Z-C(O)R a , -C(O)NR a -C 0-6 alkylene-Z-R a , -C(O)-Z- C 0-6 alkylene-NR a C(O)R a , and -C(O)-Z-C 0-6 alkylene-NHR a , wherein Z is a nitrogen-containing 5- or 6-membered heterocycle.
  • R 3 is selected from: -C(O)NR a -C 2-6 alkylene-NHR a , - C(O)NR a -C2-6 alkylene-NR a C(O)R a , -C(O)NR a -C0-6 alkylene-Z-C(O)R a , -C(O)NR a -C0-6 alkylene- Z-R a , -C(O)-Z-C0-6 alkylene-NR a C(O)R a , and -C(O)-Z-C0-6 alkylene-NHR a , wherein Z is a nitrogen-containing 5- or 6-membered heterocycle.
  • R 3 is selected from -H, -C(O)N(CH3)(CH2)2-NHCH3 and - C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3. It may be that R 3 is selected from -C(O)N(CH3)(CH2)2- NHCH3 and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3.
  • R 4 is selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, - C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 4 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 4 may be selected from the group comprising -H, -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 4 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 4 may be selected from the group comprising -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 3 and R 4 are independently selected from the group comprising: -H, -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, - C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. [00254] It may be that at least one of R 3 and R 4 is -H.
  • R 3 is H and R 4 is selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 is H and R 3 is selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , - C(O)-phenyl, -C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 and -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 , wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 4 is H and R 3 is selected from the group comprising: -H, -C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 and - C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 . It may be that R 4 is H and R 3 is selected from the group comprising: -C(O)N(CH 3 )(CH 2 ) 2 -NHCH 3 and -C(O)N(CH 3 )(CH 2 ) 2 -N(CH 3 )C(O)CH 3 .
  • R 4 is H and R 3 is selected from the group comprising: -H, -C(O)CH 3 , - C(O)CH(CH 3 ) 2 , -C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. [00258] It may be that R 3 is H and R 4 is H.
  • R 5 is selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, - C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 5 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 5 may be selected from the group comprising -H, -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 5 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 5 may be selected from the group comprising -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 is selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, - C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 6 may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 6 may be selected from the group comprising -H, -C(O)CH3, -C(O)CH(CH3)2, - C(O)C(CH3)3, -C(O)(CH2)nCH3, -C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C3-8-cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 6 may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 6 may be selected from the group comprising -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 is selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, - C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 7 may be selected from the group comprising: -H, -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 7 may be selected from the group comprising -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)- aryl, -C(O)-C 3-8 -cycloalkyl, -C(O)-heterocycloalkyl, and -C(O)-heteroaryl.
  • R 7 may be selected from the group comprising: -C 1-20 -alkyl, -C(O)-C 1-20 -alkyl, -C(O)-aryl, and -C(O)-heteroaryl.
  • R 7 may be selected from the group comprising -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - C(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -C(O)CH[(CH 2 ) n CH 3 ] 2 , -C(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 , R 6 and R 7 are independently selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , - OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 , R 6 and R 7 are -H.
  • R 5 is H and R 6 and R 7 are independently selected from the group comprising: -H, -C(O)CH3, - C(O)CH(CH3)2, -OC(O)C(CH3)3, -C(O)(CH2)nCH3, -OC(O)CH[(CH2)nCH3]2, - OC(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 is H and R 5 and R 7 are independently selected from the group comprising: -H, -C(O)CH3, - C(O)CH(CH3)2, -OC(O)C(CH3)3, -C(O)(CH2)nCH3, -OC(O)CH[(CH2)nCH3]2, - OC(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 7 is H and R 5 and R 6 are independently selected from the group comprising: -H, -C(O)CH3, - C(O)CH(CH3)2, -OC(O)C(CH3)3, -C(O)(CH2)nCH3, -OC(O)CH[(CH2)nCH3]2, - OC(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 , R 6 and R 7 are -H, and the other one of R 5 , R 6 and R 7 is selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , - C(O)(CH2)nCH3, -OC(O)CH[(CH2)nCH3]2, -OC(O)C[(CH2)nCH3]3, and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 and R 6 are -H and R 7 is selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , - OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 5 and R 7 are -H and R 6 is selected from the group comprising: - H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , -OC(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , - OC(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)-phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • R 6 and R 7 are -H and R 5 is selected from the group comprising: -H, -C(O)CH 3 , -C(O)CH(CH 3 ) 2 , - OC(O)C(CH 3 ) 3 , -C(O)(CH 2 ) n CH 3 , -OC(O)CH[(CH 2 ) n CH 3 ] 2 , -OC(O)C[(CH 2 ) n CH 3 ] 3 , and -C(O)- phenyl, wherein n is an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • each of R 5 , R 6 and R 7 is -H.
  • one or more of R 3 , R 4 , R 5 , R 6 and R 7 is -H. It may be that two of R 3 , R 4 , R 5 , R 6 and R 7 are -H. It may be that three of R 3 , R 4 , R 5 , R 6 and R 7 are -H. It may be that four of R 3 , R 4 , R 5 , R 6 and R 7 are -H. It may be that each of R 3 , R 4 , R 5 , R 6 and R 7 is -H.
  • n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. n may be an integer independently selected at each occurrence from 1, 2, 3, 4, 5 and 6. [00271] The compound may be selected from: acceptable salt thereof. [00272] The compound may be selected from: acceptable salt thereof.
  • the compound may be selected from: [00274]
  • the cancer may be selected from: lung cancer, breast cancer, skin cancer, bladder cancer, testicular cancer, thyroid cancer, endometrial cancer, ovarian cancer, cervical cancer, brain cancer, prostate cancer, kidney cancer, colon cancer, bone cancer, leukaemia, lymphoma, soft tissue cancer, head and neck cancer, bowel cancer, stomach/oesophageal cancer and pancreatic cancer.
  • Another aspect of the invention provides a conjugate of the invention, or a pharmaceutical composition of the invention, for use in the treatment of cancer.
  • the conjugate may, for example, be a conjugate of any of formulae (XI) (XXII).
  • the composition may comprise a compound of any of formulae (I) to (X) or a conjugate of any of formulae (XI) to (XXII).
  • the cancer may be selected from: lung cancer, breast cancer, skin cancer, bladder cancer, testicular cancer, thyroid cancer, endometrial cancer, ovarian cancer, cervical cancer, brain cancer, prostate cancer, kidney cancer, colon cancer, bone cancer, leukaemia, lymphoma, soft tissue cancer, head and neck cancer, bowel cancer, stomach/oesophageal cancer and pancreatic cancer.
  • Another aspect of the invention provides the use of a compound of the invention, a conjugate of the invention, or a pharmaceutical composition of the invention, as a cytostatic agent.
  • the compound may, for example, be a compound of any of formulae (I) to (X).
  • the conjugate may, for example, be a conjugate of any of formulae (XI) to (XXIIa).
  • the composition may comprise a compound of any of formulae (I) to (X), or a conjugate of any of formulae (XI) to (XXIIa).
  • the use may be in vitro and/or ex vivo.
  • Another aspect of the invention provides a method of treating cancer, the method comprising administering a pharmaceutically effective amount of a compound of the invention, a conjugated of the invention, or a pharmaceutical composition of the invention, to a patient in need thereof.
  • the compound may, for example, be a compound of any of formulae (I) to (X).
  • the conjugate may, for example, be a conjugate of any of formulae (XI) to (XXIIa).
  • the composition may comprise a compound of any of formulae (I) to (X) or a conjugate of any of formulae (XI) to (XXIIa).
  • the cancer may be selected from: lung cancer, breast cancer, skin cancer, bladder cancer, testicular cancer, thyroid cancer, endometrial cancer, ovarian cancer, cervical cancer, brain cancer, prostate cancer, kidney cancer, colon cancer, bone cancer, leukaemia, lymphoma, soft tissue cancer, head and neck cancer, bowel cancer, stomach/oesophageal cancer and pancreatic cancer.
  • LCMS analyses were performed on a Shimadzu LC-20AD system with a Shimadzu Shim-Pack GISS-HP C18 column (3.0 x 150 mm, 3 ⁇ m) at 30 °C and equipped with a UV detector monitoring at 214 and 254 nm.
  • Maisch Reprosil Gold 120 C18 column (25 ⁇ 250 mm, 10 ⁇ m) and equipped with a ECOM Flash UV detector monitoring at 214 and 254 nm.
  • the following solvent system at a flow rate of 12 mL/min, was used, unless stated otherwise: solvent A, 0.1 % TFA in H2O:ACN 95:5; solvent B, 0.1 % TFA in H2O:ACN 5:95.
  • Gradient elution was as follows: 95:5 (A:B) for 2 min, 95:5 to 0:100 (A:B) over 13 min, 0:100 (A:B) for 2 min, then reversion back to 95:5 (A:B) over 1 min, 95:5 (A:B) for 2 min.
  • NMR spectra were analysed and processed using Mestrenova version 14.2.0.
  • HRMS analyses were performed on a Shimadzu Nexera X2 UHPLC system with a Waters Acquity HSS C18 column (2.1 ⁇ 100 mm, 1.8 ⁇ m) at 30 °C and equipped with a diode array detector.
  • solvent A 0.1 % formic acid in water
  • solvent B 0.1 % formic acid in acetonitrile.
  • Gradient elution was as follows: 95:5 (A/B) for 1 min, 95:5 to 15:85 (A/B) over 6 min, 15:85 to 0:100 (A/B) over 1 min, 0:100 (A/B) for 3 min, then reversion back to 95:5 (A/B) for 3 min.
  • This system was connected to a Shimadzu 9030 QTOF mass spectrometer (ESI ionisation) calibrated internally with Agilent’s API-TOF reference mass solution kit (5.0 mM purine, 100.0 mM ammonium trifluoroacetate and 2.5 mM hexakis(1H,1H,3H-tetrafluoropropoxy)phosphazine) diluted to achieve a mass count of 10000.
  • Compound Isolation [00289] Poriolide and isoporiolide were isolated from plant materials derived from the Leucothoe species. The plant material was wrapped in aluminium foil and frozen in liquid nitrogen for 2 minutes. The material was ground into a powder and transferred into a frozen tube.
  • the tubes containing the plant material were connected to a freeze-dryer for 72 hours.
  • the mixture was centrifugated and filtered over filter paper, and the supernatant was collected in tubes, resulting in a final ethanol concentration of 89%.
  • the crude extracts were stored at -80 °C and distributed in vials of 500 ⁇ L.
  • the products were purified by chromatography and their identities confirmed by NMR.
  • the 1 H and 13 C NMR spectra obtained for the isolated poriolide and isoporiolide are shown in Figures 2 and 3.
  • the samples were analysed by LCMS and the expected masses were confirmed by high resolution mass spectrometry (see Table 1).
  • Table 1 Cell preparation [00290] All cell lines have been licensed from the American Type Culture Collection (ATCC) Manassas, Virginia (US). Master and working cell banks (MCB and WCB) were prepared by subculturing in ATCC-recommended media and freezing according to ATCC recommended protocols (www.atcc.org). Cell line stocks for the assays were prepared from the WCB. The MCB, WCBs and assay stocks were prepared within respectively 3, 6 and 10 passages of the ATCC vial.
  • Cell proliferation assay [00291] Cells were diluted in the corresponding ATCC recommended medium and dispensed in a 384-well plate, depending on the cell line used, at a density of 100 - 6400 cells per well in 45 L medium. For each cell line, the optimal cell density was used. The margins of the plate were filled with phosphate-buffered saline. Plated cells were incubated in a humidified atmosphere of 5 % CO2 at 37 oC. After 24 hours, 5 L of compound dilution was added and plates were further incubated.
  • Reference compound [00293] The IC50 of the reference compound doxorubicin was measured on a separate plate. The IC50 is trended. If the IC50 was out of specification (0.32 - 3.16 times deviating from historic average), the assay was invalidated.
  • Curves calculated automatically by the software were adjusted manually according to the following protocol: The curve bottom was fixed at 0% when the calculated curve had a bottom below zero. The hill was fixed on -6 when the software calculated a lower value.
  • Example 1 Anticancer activity of poriolide
  • Poriolide was isolated according to the methods disclosed herein.
  • the cytostatic activity of poriolide was tested against a panel of 102 human cancer cell lines. In each case, poriolide in the tested concentration ranges of 1 nM to 10,000 nM was incubated with the cell culture for 72 hours. After 72 hours, the luminescence of each sample was recorded, a dose response was generated according to the methods described above, and the IC 50 , max effect, GI 50 and LD 50 values were determined (as described above). The results of this assay are provided in Table 2 below.
  • Examples 3-5 General procedures for synthesis and analyses for Examples 3-5 [00305] Commercially available reagents used were American Chemical Society (ACS) grade or finer and used without further purification unless stated otherwise. For characterization of new compounds, high resolution mass spectrometry (HRMS) analyses were performed on a Shimadzu Nexera X2 UHPLC system with a Waters Acquity HSS C18 column (2.1 ⁇ 100 mm, 1.8 ⁇ m) at 30 °C and equipped with a diode array detector.
  • HRMS high resolution mass spectrometry
  • This system was connected to a Shimadzu 9030 QTOF mass spectrometer (ESI ionization) calibrated internally with Agilent’s API-TOF reference mass solution kit (5.0 mM purine, 100.0 mM ammonium trifluoroacetate and 2.5 mM hexakis(1H,1H,3H-tetrafluoropropoxy)phosphazine) diluted to achieve a mass count of 10000.
  • API-TOF reference mass solution kit 5.0 mM purine, 100.0 mM ammonium trifluoroacetate and 2.5 mM hexakis(1H,1H,3H-tetrafluoropropoxy)phosphazine
  • LCMS analyses were performed on a Shimadzu LC-20AD system with a Shimadzu Shim-Pack GISS-HP C18 column (3.0 x 150 mm, 3 ⁇ m) at 30 °C and equipped with a UV detector monitoring at 214 and 254 nm.
  • NMR spectra were analysed and processed using MestreNova version 14.2.0.
  • Example 3 Synthesis of Poriolide Prodrugs [00309] Poriolide prodrugs may be synthesized as set out in the reaction scheme of figure 4, and/or as explained below. This reaction scheme can be readily adapted to provide prodrugs of poriolide derivatives.
  • N-Boc-N, N'-dimethylethylenediamine (Intermediate 1) N,N'-Dimethylethylenediamine (1.00 mL, 9.29 mmol, 3.1 eq) was dissolved in dry THF (10 mL) under nitrogen atmosphere at 0 °C. A solution of Boc2O (0.70 g, 3.00 mmol, 1 eq) in dry THF(10 mL) was added dropwise at 0 °C. The mixture was left to stirred overnight at room temperature. The solvent was removed by reduced pressure rotary evaporator and the crude was dissolved in EtOAc (50 mL) and extracted with water and washed with brine.
  • Example 5 Antibody-drug conjugate
  • the conjugate precursors of Example 4 may be transformed into an antibody-drug conjugate by chemical ligation between the maleimide group of the conjugate precursor and the thiol group of a cysteine residue on an antibody (e.g. a monoclonal antibody). Suitable reagents, reaction conditions and solvents used in said ligation would be well known to the skilled person in the art.
  • Example 6 Poriolide release data [00321] Slow release of poriolide from Compound 1 was observed in an acetate buffer at pH 5.5. In particular, after 8 hours, around 70% of the sample of Compound 1 remained intact. In contrast, fast release of poriolide from Compound 1 was achieved in a phosphate buffer at 7.5, with complete degradation of Compound 1 to poriolide observed after 30 minutes.

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Abstract

L'invention concerne des composés de formule (I), ou un sel ou solvate pharmaceutiquement acceptable de ceux-ci : (I), dont les substituants sont tels que définis dans la description. L'invention concerne également des conjugués de formule (XI), ou un sel ou solvate pharmaceutiquement acceptable de ceux-ci : (XI), dont les substituants sont tels que définis dans la description. L'invention concerne également des compositions pharmaceutiques comprenant les composés ou les conjugués, ainsi que l'utilisation des composés ou des conjugués en tant que médicament. L'invention concerne également des composés, des conjugués ou des compositions destinés à être utilisés dans le traitement du cancer. L'invention concerne également l'utilisation des composés, des conjugués ou des compositions en tant qu'agents cytostatiques.
PCT/NL2025/050186 2024-04-17 2025-04-17 Composés anticancéreux Pending WO2025221148A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4852912A (fr) * 1971-11-08 1973-07-25

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JPS4852912A (fr) * 1971-11-08 1973-07-25

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