Anticancer compounds

Abstract

Provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof: (I), the substituents of which are as defined herein. Also provided are conjugates of formula (XI), or a pharmaceutically acceptable salt or solvate thereof: (XI), the substituents of which are as defined herein. Also provided are pharmaceutical compositions comprising the compounds or conjugates, as well as use of the compounds or conjugates as a medicament. Also provided are compounds, conjugates or compositions for use in the treatment of cancer. Also provided is the use of the compounds, conjugates or compositions as cytostatic agents.

Description

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. First isolated in 1973, these two compounds were found to have high systemic toxicity in mice, i.e. intravenous LD50values of 1 mg / kg for poriolide and 1.6 mg / kg in the case of isoporiolide (Ogiso et al., Chem. Pharm. Bull., 1974, 22, 1, 135-143). Further, while poriolide and isoporiolide were shown to have antimicrobial activities against phytopathogenic bacterium and fungus, the two compounds were almost inactive against other bacteria and fungi (Sakata et al., J. Pesticide Sci., 1977, 2, 453-456). Thus, poriolide and isoporiolide are unsuitable for antibiotic use.

[0004] Novel treatments for cancer remain highly desirable worldwide. 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. For example, 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). However, the toxicity of these compounds can lead to undesirable side effects.

[0005] Accordingly, there remains a need in the art to identify alternative cancer treatments having novel mechanisms of action relative to existing cancer therapies, with a view to providing an improved means of cancer treatment. There is also a need in the art to identify cancer treatments effective against a broad range of cancers. BRIEF SUMMARY OF THE DISCLOSURE

[0006] The invention provides compounds of formula (I), as well as pharmaceutically acceptable salts or solvates thereof. The compounds may be useful as anticancer agents.

[0007] Without wishing to be bound by theory, the inventors have found that compounds of formula (I) are highly active against a broad range of cancer cell lines. In particular, 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. Thus, the compounds of the invention achieve an anticancer activity comparable to or greater than known cytostatic agents (e.g. the clinically used cytostatic agent cisplatin), but with lower toxicity.

[0008] In a first aspect of the present invention, there is provided a compound of formula (I):pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are 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)-C3-8-halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl; R3is 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, -C(O)NHRa, -C(O)NRa-C2-6alkylene-NHRaand -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -C(O)NRa-C0-6alkylene-Z-C(O)Ra, -C(O)NRa-C0-6alkylene-Z-Ra, -C(O)-Z-C0-6alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6alkylene-NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle; R4is 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; each of R5, R6and R7are 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, wherein, when present, any of the aforementioned alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl groups is optionally substituted where chemically possible with one or more groups selected from: =O; =NRa, =NORa, C1-C4-alkyl, halo, nitro, cyano, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NRaRb, S(O)2Ra, S(O)Ra, S(O)(NRa)Ra, S(O)2NRaRa, CO2Ra, C(O)Ra, CONRaRb, ORaand SRa; wherein Rais independently selected from H and C1-C4-alkyl; and Rbis independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0009] In an embodiment of the first aspect, each of R3and R4are 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.

[0010] In a second aspect of the present invention, there is provided a conjugate comprising at least one targeting moiety attached to at least one compound as defined in the first aspect.

[0011] In a third aspect of the present invention, there is provided a conjugate of formula (XI) or formula (XIa):pharmaceutically acceptable salt or solvate thereof, wherein R1’ and R2’ 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)-C3-8-halocycloalkyl, -OC(O)-heterocycloalkyl, -OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B; R3’ 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, -C(O)NHRa, -C(O)NRa-C2-6alkylene- NHRa, -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -L-B, -C(O)-L-B, -C(O)NRa-C2-6alkylene-NRaC(O)-L- B, -C(O)NRa-C0-6alkylene-Z-C(O)-L-B and -C(O)-Z-C0-6alkylene-NRaC(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle; R4’ 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, -C(O)-L-B; each of R5’, R6’ and R7’ 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; L is a linker; and B is a targeting moiety; wherein at least one of R1’, R2’, R3’, R4’, R5’, R6’ and R7’ comprises a B; and wherein, when present, any of the aforementioned alkyl, aryl, cycloalkyl, haloalkyl, halocycloalkyl, heterocycloalkyl and heteroaryl groups is optionally substituted where chemically possible with one or more groups selected from: =O; =NRa, =NORa, C1-C4-alkyl, halo, nitro, cyano, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NRaRb, S(O)2Ra, S(O)Ra, S(O)(NRa)Ra, S(O)2NRaRa, CO2Ra, C(O)Ra, CONRaRb, ORaand SRa; wherein Rais independently selected from H and C1-C4-alkyl; and Rbis independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0012] In an embodiment of the third aspect, each of R3’ and R4’ 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.

[0013] In an embodiment of the third aspect, R3’ is selected from the group comprising: -L-B, - C(O)-L-B, -C(O)NRa-C2-6 alkylene-NRaC(O)-L-B, -C(O)NRa-C0-6 alkylene-Z-C(O)-L-B and -C(O)- Z-C0-6 alkylene-NRaC(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. In an embodiment of the third aspect, R3’ is selected from the group comprising: -L-B, -C(O)-L-B and -C(O)NRa-C2-6 alkylene-NRaC(O)-L-B.

[0014] In a fourth aspect of the present invention, there is provided 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.

[0015] In a fifth aspect of the present invention, there is provided a compound, conjugate or composition of the invention for use as a medicament.

[0016] In a sixth aspect of the present invention, there is provided a compound for use in the treatment of cancer, the compound being a compound of formula (I):pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are 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)-C3-8-halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl; R3is 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, -C(O)NHRa, -C(O)NRa-C2-6 alkylene- NHRa, -C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -C(O)NRa-C0-6 alkylene-Z-C(O)Ra, -C(O)NRa-C0-6 alkylene-Z-Ra, -C(O)-Z-C0-6 alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6 alkylene-NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle; R4is 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; each of R5, R6and R7are 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,wherein, when present, any of the above alkyl, aryl, cycloalkyl, haloalkyl, halocycloalkyl, heterocycloalkyl and heteroaryl groups is optionally substituted where chemically possible with one or more groups selected from: =O; =NRa, =NORa, C1-C4-alkyl, halo, nitro, cyano, C1-C4- haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NRaRb, S(O)2Ra, S(O)Ra, S(O)(NRa)Ra, S(O)2NRaRa, CO2Ra, C(O)Ra, CONRaRb, ORaand SRa; wherein Rais independently selected from H and C1- C4-alkyl; and Rbis independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1- C4-alkyl.

[0017] In an embodiment of the sixth aspect, each of R3and R4are 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.

[0018] In a seventh aspect of the present invention, there is provided 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] In an eighth aspect of the present invention, there is provided a use of 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which: Figure 1 shows an exemplary dose response curve indicating the IC50, GI50and LD50of a compound. A) Full efficacy, i.e.100% inhibition. B) Partial efficacy, i.e.50% inhibition. 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 shows1H and13C NMR spectra obtained for poriolide that was isolated according to the examples described herein. Figure 3 shows1H and13C 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. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0022] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0023] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0024] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. DEFINITIONS

[0025] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure.

[0026] The invention concerns amongst other things the treatment of a disease. The term “treatment”, and the therapies encompassed by this invention, include the following and combinations thereof: (1) hindering, e.g. delaying initiation and / or progression of, 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 conditiondeveloping in an animal (e.g. human) that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; and / or (3) relieving and / or curing an event, state, disorder or condition (e.g., causing regression of the event, state, disorder or condition or at least one of its clinical or subclinical symptoms, curing a patient or putting a patient into remission). The benefit to a patient to be treated may be either statistically significant or at least perceptible to the patient or to the physician. It will be understood that 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.

[0027] 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. The outcome of the prophylaxis may be, for example, preservation of health or delaying the initiation and / or progression of an event, state, disorder or condition. It will be recalled that, in any individual patient or even in a particular patient population, a treatment may fail, and this paragraph is to be understood accordingly.

[0028] The term “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. The term includes reference to, for example, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl and the like. In particular, alkyl may be a “C1-C8alkyl”, i.e. an alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; “C1-C6alkyl”, i.e. an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; “C1-C4alkyl”, i.e. an 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. The term “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, ORaor NHRa.

[0029] The term “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, ORaor NHRa.

[0030] The term “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. Forexample, “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, ORaor NHRa.

[0031] The term “cycloalkyl” refers to a saturated hydrocarbon ring system containing, for example, 3, 4, 5 or 6 carbon atoms. For example, “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, ORaor NHRa.

[0032] The term “aryl” may refer to any aromatic carbocyclic ring system (i.e. a ring system containing 2(2n + 1)π 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.

[0033] The term “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. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2- CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O- CH3, -Si(CH3)3, -CH2-CH=N-OCH3, –CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, and –CN. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and –CH2-O- Si(CH3)3. Similarly, the term “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-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula –C(O)2R’- represents both -C(O)2R’- and –R’C(O)2-. As described above, heteroalkyl groups, as used herein, 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’. Where “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 arerecited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR’R’’ or the like.

[0034] The term "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. For example, 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. This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl and the like.

[0035] The term “heteroaryl” as used herein may refer to any aromatic (i.e. a ring system containing 2(2n + 1)π 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). Thus, 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. Specifically, 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.

[0036] The term “heterocycle” may refer to either a heterocycloalkyl or a heteroaryl, as defined above.

[0037] 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, NRaRa, NRaS(O)2Ra, NRaC(O)Ra, NRaCONRaRa, NRaCO2Ra, ORa, SRa, S(O)Ra, S(O)2ORa, S(O)2Ra, S(O)2NRaRa, CO2RaC(O)Ra, CONRaRa, CRbRbNRaRa, CRbRbORa, C1-C4-alkyl, C2-C4- alkenyl, C2-C4-alkynyl and C1-C4-haloalkyl; wherein Raand Rbare as described above for formula I.

[0038] The terms “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. Additionally, terms such as “haloalkyl,” are meant to includemonohaloalkyl and polyhaloalkyl. For example, the term “haloalkyl” refers to an alkyl group where one or more hydrogen atoms are substituted by a corresponding number of halogens. For example, the term “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.

[0039] The term “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. For example, “C3-C6-halocycloalkyl” may refer to, for example, fluoro-cyclopropyl, chloro-cyclobutyl, fluoro-cyclopentyl, bromo-cyclohexyl, etc.. The halocycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each halocycloalkyl group independently may be ORaor NHRa.

[0040] The term “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. This term includes reference to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. The term “lower alkoxy” includes reference to alkoxy groups having 1, 2, 3 or 4 carbon atoms.

[0041] The term “haloalkoxy” as used herein refers to an alkoxy group where one or more hydrogen atoms are substituted by a corresponding number of halogens.

[0042] Each of the above terms (e.g., “alkyl,” “cycloalkyl,” “heteroalkyl,” and “alkoxyl”), unless otherwise noted, are meant to include both substituted and unsubstituted forms of the indicated radical. Where a substituent is 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). Certain examples of substituents for each type of radical are provided below.

[0043] The term “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. Unless otherwise specified, exemplary substituents include –OH, -CN, -NH2, - NH(C1-C6 alkyl), -N(C1-C4 alkyl)2, =O, -halo, -C1-C6 alkyl, -C2-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkoxy and -C2-C6 haloalkenyl, -C1-C6 alkylcarboxylic acid (e.g. –CH3COOH or -COOH). Where the substituent is a -C1-C6 alkyl or -C1-C6 haloalkyl, the C1-C6 chain is optionally interrupted by an ether linkage (-O-) or an ester linkage (-C(O)O-). Exemplary substituents for a substituted alkyl may include –OH, -CN, -NH2, =O, -halo, -CO2H, -C1-C6 haloalkyl, -C1-C6 haloalkoxy and -C2-C6haloalkenyl, -C1-C6 alkylcarboxylic acid (e.g. –CH3COOH or -COOH). For example, exemplary substituents for an alkyl may include –OH, -CN, -NH2, =O, -halo.

[0044] It will, of course, be understood that 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. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds. Additionally, it will of course be understood that the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled person.

[0045] Where steric issues determine placement of substituents on a group, the isomer having the lowest conformational energy may be preferred.

[0046] Where a compound, moiety, process or product is described as “optionally” having a feature, 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. Thus, when a moiety is described as “optionally substituted”, the disclosure comprises the unsubstituted moiety and the substituted moiety.

[0047] Where 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. The identity of each moiety is therefore independent of the identities of the one or more other moieties.

[0048] The term “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.

[0049] The term “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. When compounds of the present invention contain relatively acidic functionalities, 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. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, 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, orphosphorous 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. Also included are 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.

[0050] 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.

[0051] 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.

[0053] 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. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). In addition, the compounds may be labeled with stable isotopes that have a relatively low natural abundance, such as deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). Similarly, isotopic variants of O (e.g. O17or O18) may be utilised. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0054] Conventional techniques for the preparation / isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane,containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g.0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

[0055] Alternatively, 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. 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.

[0056] When any racemate crystallises, 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.

[0057] While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. 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).

[0058] Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in “Advanced Organic Chemistry”, 7th edition J. March, John Wiley and Sons, New York, 2013).

[0059] Compounds of the Formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N- oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. 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.

[0060] 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. Unless the context indicates otherwise, all references to a “composition” herein are references to a pharmaceutical formulation.

[0061] The term “conjugate” refers to a chemical compound formed by the covalent binding of two or more chemical compounds together. In the present invention, 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.

[0062] The term “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.

[0063] Where the or each targeting moiety is an antibody or fragment thereof, the conjugate may be referred to as an “antibody-drug conjugate” (ADC). ADCs synergistically target and kill cancer cells. In particular, 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) are subsequently released inside the cancer cell, resulting in cell apoptosis or death via targeting DNA or microtubules. ADC technologies are well known in the art (Fu et al., Signal Transduction and Targeted Therapy, 2022, 7, 93; Sheyi et al., Pharmaceutics, 2022, 14, 396; Su et al., Acta Pharmaceutica Sinica B, 2021, 11(12) 3889; Hamblett et al., Clinical Cancer Research, 2004, 10, 7063; and Doronina et al, Nature Biotechnology, 2003, 21(7) 778).

[0064] The term “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.

[0065] The term “chemically cleavable linker” may refer to pH-sensitive linkers (e.g. acid-labile hydrazone linkers) or reducible linkers (e.g. disulfide linkers).

[0066] 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. β-glucuronidase-cleavable linkers, β-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.

[0067] 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 maydepend 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)).

[0068] The term “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.

[0069] 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. Examples of 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. For a review of certain antibody fragments, see Holliger and Hudson, Nature Biotechnology 23:1126-1136 (2005).

[0070] In an ADC, 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. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, 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. For example, 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] In one aspect, the invention provides compounds of formula (I) as previously described, or a pharmaceutically acceptable salt or solvate thereof.

[0072] In embodiments, each of R3and R4are 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.

[0073] In embodiments, the compound of formula (I) is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:wherein R1, R2, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0074] In embodiments, the compound of formula (I) is a compound of formula (IIa), (IIb) or (IIc), or a pharmaceutically acceptable salt or solvate thereof:wherein R1, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0075] In embodiments, the compound of formula (I) is a compound of formula (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof:wherein R1, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0076] In embodiments, the compound of formula (I) is a compound of formula (IVa), (IVb) or (IVc), or a pharmaceutically acceptable salt or solvate thereof:wherein R2, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0077] In embodiments, the compound of formula (I) is a compound of formula (Va), (Vb) or (Vc), or a pharmaceutically acceptable salt or solvate thereof:wherein R2, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0078] In embodiments, the compound of formula (I) is a compound of formula (VIa) or (VIb), or a pharmaceutically acceptable salt or solvate thereof:

[0079] In embodiments, the compound of formula (I) is a compound of formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof:wherein R3and R4are as defined herein in relation to compounds of the invention.

[0080] In embodiments, the compound of formula (I) is a compound of formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt or solvate thereof:wherein R1, R2, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0081] In embodiments, the compound of formula (I) is a compound of formula (IXa) or (IXb), or a pharmaceutically acceptable salt or solvate thereof:wherein R5, R6and R7are as defined herein in relation to compounds of the invention.

[0082] In embodiments, the compound of formula (I) is a compound of formula (X) or (Xa), or a pharmaceutically acceptable salt or solvate thereof:wherein R1and R2are as defined herein in relation to compounds of the invention.

[0083] In embodiments, the compound is not

[0085] In embodiments, one or more of R1, R2, R3, R4, R5, R6, R7, and n are as described in the following paragraphs:

[0086] R1is 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. R1may be selected from the group comprising -H, -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl. For example, R1may 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.

[0087] R1may 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. R1may be selected from the group comprising: -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl. For example, R1may 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.

[0088] R1may be selected from -H and -OH. R1may be -H. R1may be -OH.

[0089] R2is 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. R2may be selected from the group comprising -H, -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl. For example, R2may 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.

[0090] R2may 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. R2may be selected from the group comprising: -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl. For example, R2may 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.

[0091] R2may be selected from -H and -OH. R2may be -H. R2may be -OH.

[0092] One of R1and R2may be H.

[0093] It may be that R1is H and R2is 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. It may be that R1is H and R2is OH.

[0094] It may be that R2is H and R1is 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. It may be that R2is H and R1is OH.

[0095] R3may 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, -C(O)-heteroaryl, -C(O)NHRa, -C(O)NRa-C2-6 alkylene-NHRa, -C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -C(O)NRa-C0-6 alkylene-Z-C(O)Ra, - C(O)NRa-C0-6 alkylene-Z-Ra, -C(O)-Z-C0-6 alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6 alkylene- NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. For example, Z may be a nitrogen-containing 5- or 6-membered heterocycloalkyl, e.g. pyrrolidine or piperidine.

[0096] Where R3includes a Z group, it may be that R3is selected from:each m is independently selected from 1 and 2.

[0097] R3may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-heteroaryl, -C(O)NRa-C2-6 alkylene-NHRaand -C(O)NRa-C2-6 alkylene-NRaC(O)Ra. For example, R3may 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.

[0098] R3may 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. R3may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R3may 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.

[0099] R3may 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)NHRa, -C(O)NRa-C2-6alkylene-NHRa, -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -C(O)NRa-C0-6alkylene-Z-C(O)Ra, - C(O)NRa-C0-6alkylene-Z-Ra, -C(O)-Z-C0-6alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6alkylene- NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. R3may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)-heteroaryl, - C(O)NRa-C2-6alkylene-NHRaand -C(O)NRa-C2-6alkylene-NRaC(O)Ra. For example, R3may 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(CH3)(CH2)2-NHCH3and - 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.

[0100] R3may 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. R3may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R3may 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.

[0101] It may be that R3is selected from: -H, -C(O)NRa-C2-6 alkylene-NHRa, -C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -C(O)NRa-C0-6 alkylene-Z-C(O)Ra, -C(O)NRa-C0-6 alkylene-Z-Ra, -C(O)-Z- C0-6 alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6 alkylene-NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. It may be that R3is selected from: -C(O)NRa-C2-6 alkylene-NHRa, - C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -C(O)NRa-C0-6 alkylene-Z-C(O)Ra, -C(O)NRa-C0-6 alkylene- Z-Ra, -C(O)-Z-C0-6 alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6 alkylene-NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle.

[0102] It may be that R3is 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 R3is selected from -C(O)N(CH3)(CH2)2- NHCH3 and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3.

[0103] R4is 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. R4may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R4may 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.

[0104] R4may 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. R4may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R4may 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.

[0105] It may be that both of R3and R4are 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[(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.

[0106] It may be that at least one of R3and R4is -H.

[0107] It may be that R3is H and R4is 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.

[0108] It may be that R4is H and R3is 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. It may be that R4is H and R3is 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 R4is H and R3is selected from the group comprising: -C(O)N(CH3)(CH2)2-NHCH3 and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3.

[0109] It may be that R4is H and R3is 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.

[0110] It may be that R3is H and R4is H.

[0111] R5is 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. R5may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R5may 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.

[0112] R5may 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. R5may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R5may 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.

[0113] R6is 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. R6may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R6may 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.

[0114] R6may 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. R6may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R6may 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.

[0115] R7is 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. R7may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R7may 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.

[0116] R7may 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. R7may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R7may 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.

[0117] It may be that one or more of R5, R6and R7are 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[(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.

[0118] It may be that at least one of R5, R6and R7is -H. For example, it may be that R5is H and R6and R7are 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[(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. Alternatively, it may be that R6is H and R5and R7are 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[(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. Alternatively, it may be that R7is H and R5and R6are 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[(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.

[0119] It may be that two of R5, R6and R7are -H, and the other one of R5, R6and R7is 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. For example, it may be that R5and R6are -H and R7is 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. Alternatively, it may be that R5and R7are -H and R6is 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. Alternatively, it may be that R6and R7are -H and R5is 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.

[0120] It may be that each of R5, R6and R7is -H.

[0121] It may be that one or more of R3, R4, R5, R6and R7is -H. It may be that two of R3, R4, R5, R6and R7are -H. It may be that three of R3, R4, R5, R6and R7are -H. It may be that four of R3, R4, R5, R6and R7are -H. It may be that each of R3, R4, R5, R6and R7is -H.

[0122] When each of R3, R4, R5, R6and R7is -H, it may be that R1and R2are 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)-C3-8- halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl, with the proviso that R1may not be -H when R2is -OH, and that R2may not be -OH when R1is -H.

[0123] 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

[0124] In another aspect, there is provided a conjugate comprising at least one targeting moiety attached to at least one compound of the invention. For example, the conjugate may comprise one targeting moiety and one compound of the invention. In another example, the conjugate may comprise one targeting moiety and 1, 2, or more compounds of the invention. In a further example, the conjugate may comprise 1 or 2 targeting moieties and at least one compound of the invention.

[0125] The at least one targeting moiety may be attached to the at least one compound via a covalent linker.

[0126] The covalent linker may be a chemically cleavable linker or an enzymatically cleavable linker.

[0127] In another aspect, there is provided a conjugate of formula (XI) or formula (XIa), as previously described.

[0128] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XIIa), (XIIb) or (XIIc), or a pharmaceutically acceptable salt or solvate thereof:wherein R1’, R3’, R4’, R5’, R6’ and R7’ are as defined herein in relation to conjugates of the invention.

[0129] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XIIIa), (XIIIb) or (XIIIc), or a pharmaceutically acceptable salt or solvate thereof:wherein R1’, R3’, R4’, R5’, R6’ and R7’ are as defined herein in relation to conjugates of the invention.

[0130] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XIVa), (XIVb) or (XIVc), or a pharmaceutically acceptable salt or solvate thereof:wherein R2’, R3’, R4’, R5’, R6’ and R7’ are as defined herein in relation to conjugates of the invention.

[0131] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XVa), (XVb) or (XVc), or a pharmaceutically acceptable salt or solvate thereof:wherein R2’, R3’, R4’, R5’, R6’ and R7’ are as defined herein in relation to conjugates of the invention.

[0132] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XVIa) or (XVIb), or a pharmaceutically acceptable salt or solvate thereof:wherein R1’, R2’, R3’ and R4’ are as defined herein in relation to conjugates of the invention.

[0133] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XVIIa) or (XVIIb), or a pharmaceutically acceptable salt or solvate thereof:(XVIIb) wherein R3’ and R4’ are as defined herein in relation to conjugates of the invention.

[0134] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XVIIIa) or (XVIIIb), or a pharmaceutically acceptable salt or solvate thereof:wherein R1’, R2’, R5’, R6’ and R7’ are as defined herein in relation to conjugates of the invention.

[0135] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XIXa) or (XIXb), or a pharmaceutically acceptable salt or solvate thereof:wherein R5’, R6’ and R7’ are as defined herein in relation to conjugates of the invention.

[0136] In embodiments, the conjugate of formula (XI) or formula (XIa) is a conjugateformula (XX) or (XXa), or a pharmaceutically acceptable salt or solvate thereof:wherein R1’ and R2’ are as defined herein in relation to conjugates of the invention.

[0137] In embodiments, the conjugate of formula (XI) is a conjugate of formula (XXIa) or (XXIb), or a pharmaceutically acceptable salt or solvate thereof:wherein R3’ is as defined herein in relation to conjugates of the invention.

[0138] In embodiments, 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.

[0139] In embodiments, the conjugate of formula (XI) or formula (XIa) includes one or more of R1’, R2’, R3’, R4’, R5’, R6’, R7’, L, B, and n as described in the following paragraphs:

[0140] R1’ 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, -OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B. R1’ may be selected from the group comprising -H, -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, - OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B. For example, R1’ 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.

[0141] R1’ 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. R1’ 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. For example, R1’ 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, -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.

[0142] R1’ may be selected from -H, -OH, -O-L-B and -OC(O)-L-B. R1’ may be selected from - H and -OH. R1’ may be selected from -O-L-B and -OC(O)-L-B. R1’ may be -H. R1’ may be -OH. R1’ may be -O-L-B. R1’ may be -OC(O)-L-B.

[0143] R2’ 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, -OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B. R2’ may be selected from the group comprising -H, -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, - OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B. For example, R2’ 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.

[0144] R2’ 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. R2’ 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. For example, R2’ 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, -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.

[0145] R2’ may be selected from -H, -OH, -O-L-B and -OC(O)-L-B. R2’ may be selected from - H and -OH. R2’ may be selected from -O-L-B and -OC(O)-L-B. R2’ may be -H. R2’ may be -OH. R2’ may be -O-L-B. R2’ may be -OC(O)-L-B.

[0146] One of R1’ and R2’ may be H.

[0147] It may be that R1’ is H and R2’ 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. It may be that R1’ is -H and R2’ is -OH, -O-L-B or -OC(O)-L-B. It may be that R1’ is -H and R2’ is -OH.

[0148] It may be that R2’ is H and R1’ 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. It may be that R2’ is -H and R1’ is -OH, -O-L-B or -OC(O)-L-B. It may be that R2’ is -H and R1’ is -OH.

[0149] R3’ 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, -C(O)-heteroaryl, -C(O)NHRa, - C(O)NRa-C2-6 alkylene-NHRa, -C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -L-B, -C(O)-L-B, -C(O)NRa- C2-6 alkylene-NRaC(O)-L-B, -C(O)NRa-C0-6 alkylene-Z-C(O)-L-B, and -C(O)-Z-C0-6 alkylene- NRaC(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. For example, Z may be a nitrogen-containing 5- or 6-membered heterocycloalkyl, e.g. pyrrolidine or piperidine.

[0150] Where R3’includes a Z group, it may be that R3’is selected from:, wherein each m is independently selected from 1 and 2.

[0151] For example, R3’ 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, 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, and p is an integer independently selected at each occurrence from 0, 1 and 2.

[0152] R3’ may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, - C(O)-aryl, -C(O)-heteroaryl, -C(O)NRa-C2-6 alkylene-NHRa, -C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -L-B, -C(O)-L-B, and -C(O)NRa-C2-6 alkylene-NRaC(O)-L-B. For example, R3’ 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, and -C(O)N(CH3)(CH2)2-N(CH3)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.

[0153] R3’ 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, -C(O)-heteroaryl, -L-B and -C(O)-L-B. R3’ 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. For example, R3’ 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.

[0154] R3’ 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)NHRa, -C(O)NRa-C2-6 alkylene-NHRa, -C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -L-B, -C(O)-L-B, -C(O)NRa-C2-6 alkylene- NRaC(O)-L-B, -C(O)NRa-C0-6 alkylene-Z-C(O)-L-B, and -C(O)-Z-C0-6 alkylene-NRaC(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. R3’ may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)NRa-C2-6 alkylene-NHRa, -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -L-B, -C(O)-L-B, and -C(O)NRa-C2-6alkylene-NRaC(O)-L-B. For example, R3’ 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(CH3)(CH2)2-NHCH3, -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3, -L-B, -C(O)-L-B, and -C(O)N(CH3)(CH2)2-N(CH3)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.

[0155] R3’ may be selected from the group comprising: -C(O)C(CH3)3, -C(O)(CH2)nCH3, - C(O)CH[(CH2)nCH3]2, -C(O)C[(CH2)nCH3]3, -L-B, -C(O)-L-B, and -C(O)NRa-C2-6alkylene- NRaC(O)-L-B, -C(O)NRa-C0-6alkylene-Z-C(O)-L-B, and -C(O)-Z-C0-6alkylene-NRaC(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. R3’ may be selected from the group comprising: -L-B, -C(O)-L-B, -C(O)NRa-C2-6alkylene-NRaC(O)-L-B, - C(O)NRa-C0-6alkylene-Z-C(O)-L-B, and -C(O)-Z-C0-6alkylene-NRaC(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. For example, R3’ may be selected from the group comprising -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, wherein p is independently selected at each occurrence from 0, 1 and 2.

[0156] R3’ 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. R3’ 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. For example, R3’ 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.

[0157] R4’ 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. R4’ 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. For example, R4’ 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.

[0158] R4’ 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. R4’ 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. For example, R4’ 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.

[0159] It may be that both of R3’ and R4’ 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[(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.

[0160] It may be that at least one of R3’ and R4’ is -H.

[0161] It may be that R3’ is H and R4’ 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.

[0162] It may be that R4’ is H and R3’ 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, -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)NRa-C0-6alkylene-Z-C(O)-L-B, and -C(O)-Z-C0-6alkylene-NRaC(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle, and wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.

[0163] It may be that R4’ is H and R3’ 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.

[0164] It may be that R3’ is H and R4’ is -L-B or -C(O)-L-B.

[0165] It may be that R4’ is H and R3’ 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. It may be that R4’ is H and R3’ 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.

[0166] It may be that R4’ is H and R3’ is -L-B or -C(O)-L-B.

[0167] It may be that R3’ is H and R4’ is H.

[0168] R5’ 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. R5’ 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. For example, R5’ 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.

[0169] R5’ 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. R5’ 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. For example, R5’ 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.

[0170] R6’ 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. R6’ 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. For example, R6’ 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.

[0171] R6’ 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. R6’ 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. For example, R6’ 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.

[0172] R7’ 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. R7’ 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. For example, R7’ 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.

[0173] R7’ 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. R7’ 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. For example, R7’ 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.

[0174] It may be that one or more of R5’, R6’ and R7’ 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[(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.

[0175] It may be that at least one of R5’, R6’ and R7’ is -H. For example, it may be that R5’ is H and R6’ and R7’ 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[(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. Alternatively, it may be that R6’ is H and R5’ and R7’ 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[(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. Alternatively, it may be that R7’ is H and R5’ and R6’ 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[(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.

[0176] It may be that two of R5’, R6’ and R7’ are -H, and the other one of R5’, R6’ and R7’ 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. For example, it may be that R5’ and R6’ are -H and R7’ 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. Alternatively, it may be that R5’ and R7’ are -H and R6’ 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. Alternatively, it may be that R6’ and R7’ are -H and R5’ 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.

[0177] It may be that each of R5’, R6’ and R7’ is -H.

[0178] It may be that at least one of R5’, R6’ and R7’ is -L-B or -C(O)-L-B. For example, it may be that R5’ is -L-B or -C(O)-L-B, and R6’ and R7’ 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[(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. Alternatively, it may be that R6’ is -L-B or -C(O)-L-B, and R5’ and R7’ 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[(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. Alternatively, it may be that R7’ is -L-B or -C(O)-L-B, and R5’ and R6’ 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[(CH2)nCH3]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.

[0179] It may be that R5’ is --L-B or -C(O)-L-B, and each of R6’ and R7’ are -H.

[0180] It may be that R6’ is -L-B or -C(O)-L-B, and each of R5’ and R7’ are -H.

[0181] It may be that R7’ is -L-B or -C(O)-L-B, and each of R5’ and R6’ are -H.

[0182] It may be that one or more of R3’, R4’, R5’, R6’ and R7’ is -H. It may be that two of R3’, R4’, R5’, R6’ and R7’ are -H. It may be that three of R3’, R4’, R5’, R6’ and R7’ are -H. It may be that four of R3’, R4’, R5’, R6’ and R7’ are -H. It may be that each of R3’, R4’, R5’, R6’ and R7’ is -H.

[0183] It may be that one, two, three, four, five or six of R1’, R2’, R3’, R4’, R5’, R6’ and R7’ are defined as follows: R1’ is R1, as defined herein; R2’ is R2, as defined herein; R3’ is R3, as defined herein; R4’ is R4, as defined herein; R5’ is R5, as defined herein; R6’ is R6, as defined herein; and R7’ is R7, as defined herein.

[0184] It may be that at least one of R1’ and R2’ is -O-L-B or -OC(O)-L-B; and / or at least one of R3’, R4’, R5’, R6’ and R7’ is -L-B or -C(O)-L-B.

[0185] It may be that the conjugate includes no more than one targeting moiety. For example, it may be that no more than one of R1’, R2’, R3’, R4’, R5’, R6’ and R7’ comprises a B. For example, it may be that one of R1’ and R2’ is -O-L-B or -OC(O)-L-B, or it may be that one of R3’, R4’, R5’, R6’ and R7’ is -L-B or -C(O)-L-B.

[0186] 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.

[0187] L may be a cleavable linker.

[0188] 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.

[0189] It may be that L is -L1-L2-L3-L4, wherein L1is a bond or a spacer moiety, L2is a cleavable moiety, L3is a bond or a spacer moiety, and L4is a ligated moiety.

[0190] L1may be a bond. Alternatively, L1may be a spacer moiety.

[0191] L3may be a bond. Alternatively, L3may be a spacer moiety.

[0192] It may be that one of L1and L3is a bond and the other of L1and L3is a spacer moiety. It may be that both L1and L3are spacer moieties.

[0193] Where L1or L3is a spacer moiety, each of L1or L3may be independently selected from or comprise: -NH-C(O)O-CRaRa-aryl-NH-, -CRaRa-aryl-NH-, -CRaRa-heteroaryl-NH-, -C2-24-alkyl (e.g. -C4-24-alkyl or -C6-24-alkyl), -O-CRaRa-aryl-NH-, -O-CRaRa-heteroaryl-NH-, -O-C2-24-alkyl (e.g. -O-C4-24-alkyl or -O-C6-24-alkyl), and C2-24-alkyl (e.g. C4-24-alkyl or C6-24-alkyl), optionally wherein said -O-C2-24-alkyl or C2-24-alkyl may be interrupted by one, two, or three of: -NC(O)-, - NH-, -O-, -C(O)-, and -C(O)O-. Each of L1or L3may be independently selected from or comprise: -CRaRa-aryl-NH-, -O-CRaRa-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-. For example, each of L1or L3may be independently selected from: -O- CRaRa-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)-.

[0194] In embodiments, L1may be a bond, -O-CH2-phenyl-NH-, or -CH2-phenyl-NH-.

[0195] In embodiments, L3may be a bond, -O-CH2-phenyl-NH-, -C(O)-C4-12-alkyl or -NHC(O)- C4-12-alkyl.

[0196] It may be that L2is 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. β-glucuronidase-cleavable linkers, β-galactosidase-cleavable linkers), aphosphatase-cleavable moiety (e.g. pyrophosphate), and a sulfatase-cleavable moiety (e.g. arylsulfate).

[0197] L2may be selected from: a polyethylene glycol (e.g. –(CH2CH2O)4–) and a dipeptide (e.g. -Val-Cit-).

[0198] For the avoidance of doubt, L4may be any species onto which a targeting moiety has been ligated. For example, L4may be a heterocycloalkyl (e.g. succinimide). In these embodiments, the succinimide of L4may be formed from the ligation reaction between a maleimide and a cysteine residue of the targeting moiety.

[0199] L may be selected from:

[0200] 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.

[0201] The or each targeting moiety B may comprise an antibody or fragment thereof. The antibody may be a monoclonal antibody or fragment thereof.

[0202] The antibody or fragment thereof may be an immunoglobulin G (IgG) or fragment thereof. For example, the antibody or fragment thereof may be an IgG1, an IgG2, or an IgG4.

[0203] 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.

[0204] It may be that 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.

[0205] It may be that the conjugate is:COMPOSITIONS AND ADMINISTRATION

[0206] According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention or a conjugate of the invention.

[0207] The composition may further comprise a pharmaceutically acceptable excipient. The composition may provide the compound or conjugate in admixture with at least one pharmaceutically acceptable adjuvant, carrier, or diluent.

[0208] 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. Preferably, 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. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.

[0209] 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 theinvention could be started at a dose of about 5 μmol per kg (e.g. by injection) and dosage could be gradually increased until the desired effect is achieved.

[0210] 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. Examples of 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. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0211] These 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. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (for example, aluminium monostearate and gelatine) which delay absorption.

[0212] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, 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 kaolin and bentonite clay and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, 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.

[0213] Oral formulations may contain a dissolution aid. Examples of 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 alkylethers, 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. chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and salts thereof, and glycine or taurine conjugate thereof); 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.

[0214] 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.

[0215] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds or conjugates, 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. Besides inert diluents, 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.

[0216] 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.

[0217] Dosage forms for topical administration of a compound or conjugate of this invention include powders, sprays, creams, foams, gels, ointments and inhalants. The active compoundor conjugate is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

[0218] The 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, 13thEd., Brunton et al., Eds. McGraw-Hill Education (2017), and Remington’s Pharmaceutical Sciences, 17thEd., Mack Publishing Co., Easton, Pa. (1990), both of which are incorporated by reference herein in their entirety.

[0219] The compositions may be used in combination with an additional pharmaceutical dosage form to enhance their effectiveness in treating any of the disorders described herein. In this regard, 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

[0220] The compounds and conjugates of the invention are anticancer agents.

[0221] 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).

[0222] In another aspect, 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.

[0223] In embodiments, the compound of formula (I) is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:wherein R1, R2, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0224] In embodiments, the compound of formula (I) is a compound of formula (IIa), (IIb) or (IIc), or a pharmaceutically acceptable salt or solvate thereof:wherein R1, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0225] In embodiments, the compound of formula (I) is a compound of formula (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt or solvate thereof:invention.

[0226] In embodiments, the compound of formula (I) is a compound of formula (IVa), (IVb) or (IVc), or a pharmaceutically acceptable salt or solvate thereof:wherein R2, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0227] In embodiments, the compound of formula (I) is a compound of formula (Va), (Vb) or (Vc), or a pharmaceutically acceptable salt or solvate thereof:wherein R2, R3, R4, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0228] In embodiments, the compound of formula (I) is a compound of formula (VIa) or (VIb), or a pharmaceutically acceptable salt or solvate thereof:

[0229] In embodiments, the compound of formula (I) is a compound of formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof:wherein R3and R4are as defined herein in relation to compounds of the invention.

[0230] In embodiments, the compound of formula (I) is a compound of formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt or solvate thereof:wherein R1, R2, R5, R6and R7are as defined herein in relation to compounds of the invention.

[0231] In embodiments, the compound of formula (I) is a compound of formula (IXa) or (IXb), or a pharmaceutically acceptable salt or solvate thereof:wherein R5, R6and R7are as defined herein in relation to compounds of the invention.

[0232] In embodiments, the compound of formula (I) is a compound of formula (X) or (Xa), or a pharmaceutically acceptable salt or solvate thereof:wherein R1and R2are as defined herein in relation to compounds of the invention.

[0233] In embodiments, one or more of R1, R2, R3, R4, R5, R6, R7and n are as described in the following paragraphs.

[0234] R1is 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. R1may be selected from the group comprising -H, -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl. For example, R1may 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.

[0235] R1may 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. R1may be selected from the group comprising: -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl. For example, R1may 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.

[0236] R1may be selected from -H and -OH. R1may be -H. R1may be -OH.

[0237] R2is 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. R2may be selected from the group comprising -H, -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl. For example, R2may 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.

[0238] R2may 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. R2may be selected from thegroup comprising: -OH, -OC1-20-alkyl, -OC(O)-C1-20-alkyl, -OC(O)-aryl, and -OC(O)-heteroaryl. For example, R2may 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.

[0239] R2may be selected from -H and -OH. R2may be -H. R2may be -OH.

[0240] One of R1and R2may be H.

[0241] It may be that R1is H and R2is 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. It may be that R1is H and R2is OH.

[0242] It may be that R2is H and R1is 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. It may be that R2is H and R1is OH.

[0243] R3may 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, -C(O)-heteroaryl, -C(O)NHRa, -C(O)NRa-C2-6alkylene-NHRa, -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -C(O)NRa-C0-6alkylene-Z-C(O)Ra, - C(O)NRa-C0-6alkylene-Z-Ra, -C(O)-Z-C0-6alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6alkylene- NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. For example, Z may be a nitrogen-containing 5- or 6-membered heterocycloalkyl, e.g. pyrrolidine or piperidine.

[0244] Where R3includes a Z group, it may be that R3is selected from:each m is independently selected from 1 and 2.

[0245] R3may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)- aryl, -C(O)-heteroaryl, -C(O)NRa-C2-6alkylene-NHRaand -C(O)NRa-C2-6alkylene-NRaC(O)Ra. For example, R3may 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-NHCH3and -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.

[0246] R3may 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. R3may be selectedfrom the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R3may 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.

[0247] R3may 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)NHRa, -C(O)NRa-C2-6 alkylene-NHRa, -C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -C(O)NRa-C0-6 alkylene-Z-C(O)Ra, - C(O)NRa-C0-6 alkylene-Z-Ra, -C(O)-Z-C0-6 alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6 alkylene- NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. R3may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, -C(O)-heteroaryl, - C(O)NRa-C2-6 alkylene-NHRaand -C(O)NRa-C2-6 alkylene-NRaC(O)Ra. For example, R3may 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(CH3)(CH2)2-NHCH3and - 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.

[0248] R3may 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. R3may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R3may 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.

[0249] It may be that R3is selected from: -H, -C(O)NRa-C2-6alkylene-NHRa, -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -C(O)NRa-C0-6alkylene-Z-C(O)Ra, -C(O)NRa-C0-6alkylene-Z-Ra, -C(O)-Z- C0-6alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6alkylene-NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle. It may be that R3is selected from: -C(O)NRa-C2-6alkylene-NHRa, - C(O)NRa-C2-6 alkylene-NRaC(O)Ra, -C(O)NRa-C0-6 alkylene-Z-C(O)Ra, -C(O)NRa-C0-6 alkylene- Z-Ra, -C(O)-Z-C0-6 alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6 alkylene-NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle.

[0250] It may be that R3is 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 R3is selected from -C(O)N(CH3)(CH2)2- NHCH3 and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3.

[0251] R4is 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. R4may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R4may 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.

[0252] R4may 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. R4may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R4may 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.

[0253] It may be that both of R3and R4are 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[(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.

[0254] It may be that at least one of R3and R4is -H.

[0255] It may be that R3is H and R4is 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.

[0256] It may be that R4is H and R3is 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-NHCH3and -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. It may be that R4is H and R3is selected from the group comprising: -H, -C(O)N(CH3)(CH2)2-NHCH3and - C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3. It may be that R4is H and R3is selected from the group comprising: -C(O)N(CH3)(CH2)2-NHCH3and -C(O)N(CH3)(CH2)2-N(CH3)C(O)CH3.

[0257] It may be that R4is H and R3is 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.

[0258] It may be that R3is H and R4is H.

[0259] R5is 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. R5may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R5may 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.

[0260] R5may 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. R5may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R5may 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.

[0261] R6is 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. R6may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R6may 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.

[0262] R6may 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. R6may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R6may 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.

[0263] R7is 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. R7may be selected from the group comprising: -H, -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R7may 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.

[0264] R7may 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. R7may be selected from the group comprising: -C1-20-alkyl, -C(O)-C1-20-alkyl, -C(O)-aryl, and -C(O)-heteroaryl. For example, R7may 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.

[0265] It may be that one or more of R5, R6and R7are 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.

[0266] It may be that at least one of R5, R6and R7is -H. For example, it may be that R5is H and R6and R7are 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. Alternatively, it may be that R6is H and R5and R7are 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. Alternatively, it may be that R7is H and R5and R6are 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.

[0267] It may be that two of R5, R6and R7are -H, and the other one of R5, R6and R7is 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. For example, it may be that R5and R6are -H and R7is 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. Alternatively, it may be that R5and R7are -H and R6is 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. Alternatively, it may be that R6and R7are -H and R5is 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.

[0268] It may be that each of R5, R6and R7is -H.

[0269] It may be that one or more of R3, R4, R5, R6and R7is -H. It may be that two of R3, R4, R5, R6and R7are -H. It may be that three of R3, R4, R5, R6and R7are -H. It may be that four of R3, R4, R5, R6and R7are -H. It may be that each of R3, R4, R5, R6and R7is -H.

[0270] 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.

[0271] The compound may be selected from:acceptable salt thereof.

[0272] The compound may be selected from:acceptable salt thereof.

[0273] The compound may be selected from:

[0274] 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.

[0275] 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).

[0276] 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.

[0277] 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).

[0278] The use may be in vitro and / or ex vivo.

[0279] 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). Thecomposition may comprise a compound of any of formulae (I) to (X) or a conjugate of any of formulae (XI) to (XXIIa).

[0280] 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. EXAMPLES

[0281] The inventors have identified the compounds poriolide, isoporiolide and structural derivatives thereof as an anticancer agents. Materials and Methods Characterisation

[0282] Reagents and solvents were purchased from Acros (Geel, Belgium), Alfa Aesar (Kandel, Germany), Sigma-Aldrich (Zwijndrecht, Netherlands), TCI (Tokyo, Japan), Merck (Amsterdam, Netherlands), Fluka (Landsmeer, Netherlands) and Enamine (Kyiv, Ukraine), they were of American Chemical Society (ACS) grade or finer and were used without further purification, unless stated otherwise. Column chromatography was performed using Siliflash P60 silica gel (particle size 40-63 μm) (SiliCycle Inc., Quebec, Canada).

[0283] Thin Layer Chromatography (TLC) analyses were performed with F254 glass silica plates (SiliCycle Inc., Quebec, Canada) using UV visualization (254 nm) and / or staining typically with potassium permanganate (10% aq. NaOH 1.25 mL, K2CO310 g, water 200 mL, KMnO41.5 g).

[0284] 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 μm) at 30 °C and equipped with a UV detector monitoring at 214 and 254 nm. The following solvent system, at a flow rate of 0.5 mL / min, was used, unless stated otherwise: solvent A, 0.1 % formic acid in water; solvent B, acetonitrile. 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. This system was connected to a Shimadzu 8040 triple quadrupole mass spectrometer (ESI ionization).

[0285] HPLC analyses were performed on a Shimadzu Prominence-i LC-2030 system with a Dr. Maisch ReproSil Gold 120 C18 column (4.6 × 250 mm, 5 or 10 μm) at 30 °C and equipped with a UV detector monitoring at 214 and 254 nm. The following solvent system, at a flow rate of 1 mL / min, was used: solvent A, 0.1 % TFA in H2O:Acetonitrile (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.

[0286] Preparative HPLC was performed on a BESTA-Technik system with a Dr. Maisch Reprosil Gold 120 C18 column (25 × 250 mm, 10 μm) 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.

[0287] 1H and13C NMR spectra were recorded on Bruker AV 400 MHz (at 400.2 (1H) and 100.6 (13C) MHz), AV 600 MHz (at 600.1 (1H) and 150.9 (13C) MHz). The temperature of the NMR experiments was 296 K unless stated otherwise. Chemical shifts are reported in ppm (δ) and were calibrated using residual deuterated solvent as an internal reference. (δ1H NMR: in acetone 2.05; δ13C NMR: acetone 29.84, 206.26.). The NMR data are processed as; chemical shift, multiplicity (s = singlet, d = doublet, dd = double doublet, t = triplet, dt = double triplet, q = quartet, m = multiplet), integration, coupling constants (Hz) and number of nuclei. NMR spectra were analysed and processed using Mestrenova version 14.2.0.

[0288] HRMS analyses were performed on a Shimadzu Nexera X2 UHPLC system with a Waters Acquity HSS C18 column (2.1 × 100 mm, 1.8 μm) at 30 °C and equipped with a diode array detector. The following solvent system, at a flow rate of 0.5 mL / min, was used: 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

[0289] 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. For the extraction of each sample, 50 g of frozen plant material was ground into a powder, of which 40 g (v / w=200 mL), was extracted with 96.5% ethanol, after which it was sonicated for 15 minutes and shaken overnight. 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 μL. The products were purified by chromatography and their identities confirmed by NMR. The1H and13C NMR spectraobtained 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 1Cell preparation

[0290] 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. Compound preparation Solid powders of reference compounds were stored as indicated by supplier. Compounds were weighed on a calibrated balance and dissolved in 100 % DMSO. DMSO samples were stored at room temperature. At the day of the experiment, the compound stock was diluted in 3.16 fold steps in 100 % DMSO to obtain a 9-point dilution series. This was further diluted 31.6 times in 20mM sterile Hepes buffer pH 7.4. A volume of 5 L was transferred to the cells to generate the test concentration range in duplicate. The final DMSO concentration during incubation was 0.4 % in all wells. If a compound showed very potent activity, the testing range was expanded to ensure a full dose-response curve could be measured in duplicate. If a compound could only be dissolved in an aqueous solution, the recommended buffer was used instead of 100 % DMSO. Assays Cell proliferation assay

[0291] 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. At t=end, 24 L of ATPlite 1Step™ (PerkinElmer) solution was added to each well, and subsequently shaken for 2 minutes. After 10 minutes of incubation in the dark, the luminescence was recorded on an Envision multimode reader (PerkinElmer). Controlst = 0 signal

[0292] On a parallel plate, 45 L cells were dispensed and incubated in a humidified atmosphere of 5 % CO2 at 37 ºC. After 24 hours, 5 µL DMSO-containing Hepes buffer and 24 µL ATPlite 1Step™ solution were mixed, and luminescence measured after 5 minutes incubation (= luminescence t=0). Reference compound

[0293] 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. Cell growth control

[0294] The cellular doubling times of all cell lines are calculated from the t = 0 hours and t = end growth signals of the untreated cells. If the doubling time is out of specification (0.5 – 2.0 times deviating from historic average) the assay is invalidated. Maximum signals

[0295] For each cell line, the maximum luminescence was recorded after incubation until t= end without compound in the presence of 0.4% DMSO (= luminescenceuntreated, t=end). Data Analysis

[0296] IC50data was calculated by non-linear regression using IDBS XLfit 5. The percentage growth after incubation until t = end (% growth) was calculated as follows: 100% x (luminescencet=end / luminescenceuntreated, t=end). This was fitted to the10log compound concentration (conc) by a 4 parameter logistics curve: %-growth = bottom + (top – bottom) / (1 + 10(logIC50 – conc) x hill), where hill is the Hill-coefficient, and bottom and top are the asymptotic minimum and maximum cell growth that the compound allows in that assay.

[0297] The LD50, the concentration at which 50% of cells die, is the concentration where luminescence t=end = ½ x luminescence t = 0.

[0298] The GI50, the concentration of 50% growth inhibition, is the concentration where cell growth is half maximum. This is the concentration associated with the signal: ((luminescence untreated, t=end – luminescence t = 0) / 2) + luminescence t = 0.

[0299] 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. Curves were invalidated when the F-test value for fitting quality was >1.5 or when the compound was inactive (<20% maximal effect), in which cases curves were removed from the graphs. When a curve had a biphasic character, it was fitted on the most potent IC50. Incidentally, when technical failures were likely, concentration points were knocked out.

[0300] The maximal effect (Max effect) was calculated as 100% (signal of untreated cells) minus the curve bottom when the dose-response curve was completely determined for more than 85%. A dose-response curve is considered 100% complete when the data points at the highest concentrations reach the curve bottom. If the completeness was smaller than 85%, Max effect was calculated as 100% minus the average of the lowest signal. In cases where the bottom of the curve was locked on 0%, the maximal effect was always calculated as 100% minus the growth inhibition at the highest concentration. Example 1: Anticancer activity of poriolide

[0301] Poriolide was isolated according to the methods disclosed herein.

[0302] 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 IC50, max effect, GI50and LD50values were determined (as described above). The results of this assay are provided in Table 2 below.

[0303] As shown in Table 2, poriolide was shown to be highly active, achieving an IC50value of <100 nM against 71 out of 102 of the tested cell lines. Further, an LD50value of 10,000 nM was achieved for 94 out of 102 of the tested cell lines, thereby demonstrating low toxicity poriolide. Table 2Example 2: Anticancer activity of poriolide and isoporiolide

[0304] Poriolide and isoporiolide were isolated according to the methods disclosed herein and were subsequently tested in a MTT assay against a panel of 7 well-characterized cancer cell lines (U2OS, 786-O, HSC-3, A549, MCC13, A375 and T24) over a 72 hour period). The activity of both poriolide and isoporiolide in this assay was compared to the clinically used chemotherapeutic drug cisplatin. Both poriolide and isoporiolide demonstrated cytostatic activity against the 7 cancer cell lines. Examples 3-5: General procedures for synthesis and analyses for Examples 3-5

[0305] 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 µm) at 30 °C and equipped with a diode array detector. The following conditions and solvent system were used: i) flow rate of 0.5 mL / min; ii) with solvent A = 0.1% formic acid in water, and 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 ionization) calibrated internally with Agilent’s API-TOF reference masssolution 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.

[0306] 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 μm) at 30 °C and equipped with a UV detector monitoring at 214 and 254 nm. The following solvent system, at a flow rate of 0.5 mL / min, was used: solvent A, 0.1 % formic acid in water; solvent B, acetonitrile. 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. This system was connected to a Shimadzu 8040 triple quadrupole mass spectrometer (ESI ionization.

[0307] Compounds were purified via preparative high performance liquid chromatography (HPLC) using a BESTA-Technik system with a Dr. Maisch Reprosil Gold 120 C18 column (25 × 250 mm, 10 µm) and equipped with a ECOM Flash UV detector monitoring at 214 nm. Purity of the conjugates was assessed by integration and confirmed to be >95% unless stated otherwise, using a Shimadzu Prominence-i LC-2030 system with a Dr. Maisch ReproSil Gold 120 C18 column (4.6 × 250 mm, 5 µm) at 30 °C and equipped with a UV detector monitoring at 214 nm. At a flow rate of 1 mL / min, a solvent system with solvent A, 0.1 % TFA in water / acetonitrile 95:5, and solvent B, 0.1 % TFA in water / acetonitrile 5:95, was used. 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.

[0308] 1H and13C NMR spectra were recorded on Bruker AV 400 MHz (at 400.2 (1H) and 100.6 (13C) MHz), AV 600 MHz (at 600.1 (1H) and 150.9 (13C) MHz), AV 850 MHz (at 850.2 (1H) and 214.6 (13C) MHz),. The temperature of the NMR experiments was 296 K unless stated otherwise. Chemical shifts are reported in ppm (δ) and were calibrated using residual deuterated solvent as an internal reference. (δ 1H NMR: in CDCl37.26; CD3OD 3.31; DMSO 2.50, δ 13C NMR: CDCl377.16; CD3OD 49.00; DMSO 39.52). The NMR data are processed as; chemical shift, multiplicity (s = singlet, d = doublet, dd = double doublet, t = triplet, dt = double triplet, q = quartet, m = multiplet), integration, coupling constants (Hz) and number of nuclei. NMR spectra were analysed and processed using MestreNova version 14.2.0. Example 3: Synthesis of Poriolide Prodrugs

[0309] 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.

[0310] 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 ℃. A solution of Boc2O (0.70 g, 3.00 mmol, 1 eq) in dry THF(10 mL) was added dropwise at 0 ℃. 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. The organic layer was dried with Na2SO4and concentrated, affording as colorless liquid (459 mg, 2.44 mmol, 81 %), which was used without further purification.1H NMR (400 MHz, CDCl3) δ 3.31 (d, J = 7.3 Hz, 2H), 2.84 (s, 3H), 2.69 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H), 1.42 (s, 9H).13CNMR (101 MHz, CDCl3) δ 125.58, 49.73, 48.48, 36.36, 34.65, 28.52. LC-MS: Rt= 6.47 min, m / z 189.00 (observed), 189.16 (calculated for C9H20N2O2[M+H]+).

[0311] N-methyl-N-(2-(methylamino)ethyl)acetamide (Intermediate 2)To a solution of Intermediate 1 (50 mg, 0.25 mmol, 1 eq) in DCM (2.5 mL), Ac2O (50 μL, 0.53 mmol, 2 eq) and pyridine (107 μL, 1.33 mmol, 5 eq) were added at room temperature. After stirring for 4 hours, the reaction mixture was diluted with EtOAc (25 mL) and washed with a 1 M aq. KHSO4 solution (2 x 5 mL). The organic phase was dried and concentrated, affording 120 mg of amide. The crude was added to DCM / TFA(1:1) for 1h at room temperature. Then the solvent was removed by reduced pressure rotary evaporator, affording intermediate 2 (a amine TFA salt) (15 mg, 43%) with good purity for subsequent synthetic steps. LC-MS: Rt= 1.80 min, m / z 131.00(observed), 131.11 (calculated for C6H14N2O [M+H]+).

[0312] (32R,52S,53R,54S,55S,56R)-14,35,53,54,55-pentahydroxy-36-methyl-34,8-dioxo- 53,54,55,56-tetrahydro-52H-4,7-dioxa-3(2,7)-chromana-5(2,6)-pyrana-1,2(1,3)- dibenzenacyclooctaphane-26-yl methyl(2-(methylamino)ethyl)carbamate (Compound 1)Poriolide (31 mg, 0.06 mmol, 1 eq) was dissolved in dry DMF (0.6 mL) under nitrogen atmosphere at 0 ℃. Then DIPEA (23 μL, 0.13 mmol, 2.4 eq) and 4-nitrophenyl chloroformate (13 mg, 0.07 mmol, 1.2 eq) were added at 0 ℃. The reaction was left to stirred for 1h at room temperature. Then intermediate 1 (31 mg, 0.17 mmol, 3 eq) was added and the mixture was leftto stirred for overnight. The mixture was purified by prep-HPLC. The product treat with 1 mL DCM / TFA(1:1) for 1h at room temperature. Then the solvent was removed by reduced pressure rotary evaporator, affording Compound 1 as the TFA salt (14 mg, 0.02 mmol, 36 %) as a white powder.1H NMR (850 MHz, DMSO, 333K) δ 12.02 (s, 1H), 10.52 (s, 1H), 7.70 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.66 – 7.63 (m, 1H), 7.31 (ddd, J = 8.5, 2.3, 1.0 Hz, 1H), 7.26 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.52 (s, 1H), 5.97 (dq, J = 6.2, 1.2 Hz, 1H), 5.33 (d, J = 7.8 Hz, 1H), 5.05 (dd, J = 11.8, 2.1 Hz, 1H), 4.03 (td, J = 10.0, 2.2 Hz, 1H), 3.89 (dd, J = 11.8, 10.3 Hz, 2H), 3.63 (dd, J = 17.6, 6.1 Hz, 2H), 3.44 (d, J = 9.0 Hz, 1H), 3.41 (dd, J = 17.6, 1.6 Hz, 3H), 3.35 – 3.34 (m, 1H), 3.16 (t, J = 9.3 Hz, 2H), 3.04 (s, 2H), 2.87 (s, 3H), 2.53 (s, 3H), 1.89 (s, 3H).13C NMR (214 MHz, DMSO, 333K) δ 195.60, 168.20, 162.95, 159.91, 159.74, 158.50, 153.97, 147.44, 136.13, 135.53, 132.76, 130.19, 128.46, 127.84, 125.51, 117.09, 116.54, 115.63, 113.15, 105.21, 103.59, 97.70, 92.44, 75.77, 75.34, 73.64, 72.60, 70.81, 65.82, 45.88, 45.22, 38.11, 34.65, 32.79, 6.83. HRMS (ESI+): m / z 681.2302 (observed), 681.2297 (calculated for C34H36N2O13[M+H]+).

[0314] (32R,52S,53R,54S,55S,56R)-14,35,53,54,55-pentahydroxy-36-methyl-34,8-dioxo- 53,54,55,56-tetrahydro-52H-4,7-dioxa-3(2,7)-chromana-5(2,6)-pyrana-1,2(1,3)- dibenzenacyclooctaphane-26-yl methyl(2-(N-methylacetamido)ethyl)carbamate (Compound 2)Poriolide (11 mg, 0.02 mmol, 1 eq) was dissolved in dry DMF (0.2 mL) under nitrogen atmosphere at 0 ℃. Then DIPEA (8 μL, 0.05 mmol, 2.4 eq) and 4-nitrophenyl chloroformate (5 mg, 0.02 mmol, 1.2 eq) were added at 0 ℃. The reaction was left to stirred for 1h at room temperature. Then Intermediate 2 (8 mg, 0.06 mmol, 3 eq) was added and the mixture was left to stirred for overnight. The mixture was purified by prep-HPLC, affording Compound 2 (5 mg, 0.01 mmol, 33 %) as a white powder.1H NMR (850 MHz, DMSO, 333K) δ 12.02 (s, 1H), 10.51 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.32 – 7.28 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.52 (s, 1H), 5.96 (dd, J = 6.1, 1.3 Hz, 1H), 5.33 (d, J = 7.8 Hz, 1H), 5.05 (d, J = 11.7 Hz, 1H), 4.01 (t, J = 10.1 Hz, 1H), 3.90 (dd, J = 11.8, 10.3 Hz, 1H), 3.61 (dd, J = 17.6, 6.2 Hz, 1H), 3.43 (d, J = 9.0 Hz, 1H), 3.41 (d, J = 3.2 Hz, 1H), 3.35 (dd, J = 9.2, 7.8 Hz, 2H), 3.19 – 3.14 (m, 2H), 2.88 (d, J = 72.5 Hz, 6H), 1.87 (d, J = 37.2 Hz, 6H).13C NMR (214 MHz, DMSO, 333K) δ 195.31, 169.67, 168.07, 162.74, 159.71, 159.56, 158.28, 153.24, 147.42, 135.73, 135.39, 132.51, 129.88, 128.23, 127.66, 125.77, 125.34, 123.18, 116.93, 115.53, 112.83, 105.07, 103.36, 97.46, 92.19, 75.54, 75.12, 73.47, 72.38, 70.58, 65.58, 46.13, 43.89, 37.91, 34.86, 21.14, 6.65. HRMS (ESI+): m / z 723.2398 (observed), 723.2403 (calculated for C36H38N2O14[M+H]+). Example 4: Synthesis of conjugate precursors

[0315] Conjugate precursors of the invention and disclosure may be synthesized as set out in the reaction scheme of figure 5, and / or as explained below.

[0316] 1-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-N-methyl-N-(2- (methylamino)ethyl)-3,6,9,12-tetraoxapentadecan-15-amide (Intermediate 3)To a solution of Intermediate 1 (55 mg, 0.29 mmol, 1.5 eq) in DCM (1 ml), monodisperse Mal- PEG4-NHS-ester (100 mg, 0.19 mmol, 1 eq) was added at room temperature. After stirring for overnight, 10 mL TFA was added into the reaction mixture and left to stirred for 1h. The solventwas removed by reduced pressure rotary evaporator and the crude was purified by prep-HPLC yielded pure intermediate 3 (53 mg, 0.11 mmol, 56 %) as colorless liquid.1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.01 (s, 2H), 4.19 (s, 1H), 3.62 (d, J = 6.9 Hz, 2H), 3.59 – 3.57 (m, 2H), 3.53 (d, J = 6.2 Hz, 2H), 3.50 (d, J = 1.7 Hz, 12H), 3.35 (d, J = 5.8 Hz, 2H), 3.15 (t, J = 5.7 Hz, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.95 (s, 3H), 2.60 – 2.57 (m, 3H), 2.55 (s, 2H), 2.32 (t, J = 7.3 Hz, 2H).13C NMR (101 MHz, DMSO) δ 171.62, 170.80, 170.32, 169.54, 134.60, 69.81, 69.77, 69.73, 69.68, 69.57, 68.99, 66.55, 46.21, 43.22, 38.49, 35.00, 34.08, 33.96, 33.13, 32.84. LC-MS: Rt= 6.39 min, m / z 487.50 (observed), 487.27 (calculated for C22H38N4O8: [M+H]+).

[0317] 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl methyl(2-(methylamino)ethyl)carbamate (Intermediate 4)To a solution of Intermediate 1 (31 mg, 0.16 mmol, 1.2 eq) in DMF (1 ml), DIPEA (36 μL, 0.20 mmol, 1.5 eq) and monodisperse Mal-PEG4-NHS-ester (100 mg, 0.14 mmol, 1 eq) were added at room temperature. After stirring for overnight, the mixture was purified by prep-HPLC. The product treat with 1 mL DCM / TFA(1:1) for 1h at room temperature. Then the solvent was removed by reduced pressure rotary evaporator, affording intermediate 4 (a amine TFA salt)(60 mg, 0.09 mmol, 65 %) as white powder. LC-MS: Rt= min, m / z 687.25 (observed), 687.38 (calculated for C33H50N8O8[M+H

[0318] 4-((R)-2-((R)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl ((32R,52S,53R,54S,55S,56R)-14,35,53,54,55- pentahydroxy-36-methyl-34,8-dioxo-53,54,55,56-tetrahydro-52H-4,7-dioxa-3(2,7)-chromana- 5(2,6)-pyrana-1,2(1,3)-dibenzenacyclooctaphane-26-yl) ethane-1,2-diylbis(methylcarbamate) (Conjugate precursor 1)Poriolide (5 mg, 0.01 mmol, 1 eq) was dissolved in dry DMF (0.4 mL) under nitrogen atmosphere at 0 ℃. Then DIPEA (4 μL, 0.02 mmol, 2.4 eq) and 4-nitrophenyl chloroformate (2 mg, 0.01 mmol, 1.2 eq) were added at 0 ℃. The reaction was left to stirred for 1h at room temperature. Then GM217 (9 mg, 0.01 mmol, 1.4 eq) was added and the mixture was left to stirred for overnight. The mixture was purified by prep-HPLC, affording Conjugate precursor 1 (4 mg, 0.003 mmol, 31 %) as white powder.1H NMR (600 MHz, DMSO) δ 12.07 (s, 1H), 10.57 (s, 1H), 10.01 – 9.95 (m, 1H), 8.07 (t, J = 6.0 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.72 – 7.65 (m, 1H), 7.63 (dd, J = 7.9, 2.3 Hz, 1H), 7.61 – 7.56 (m, 2H), 7.55 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.27 – 7.20 (m, 2H), 7.07 (d, J = 2.2 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.99 (s, 2H), 6.54 (s, 1H), 5.96 (d, J = 6.3 Hz, 1H), 5.35 (d, J = 7.7 Hz, 1H), 5.04 – 4.99 (m, 1H), 4.99 – 4.91 (m, 2H), 4.37 (s, 1H), 4.19 (s, 1H), 4.03 – 4.01 (m, 1H), 3.87 (s, 1H), 3.67 – 3.61 (m, 1H), 3.61 (s, 1H), 3.48 – 3.41 (m, 1H), 3.39 (dd, J = 17.1, 8.1 Hz, 3H), 3.35 (d, J = 7.1 Hz, 2H), 3.32 (t, J = 8.4 Hz, 1H), 3.20 (d, J = 14.1 Hz, 1H), 3.13 (td, J = 9.3, 1.9 Hz, 1H), 3.04 – 2.98 (m, 1H), 2.97 – 2.92 (m, 1H), 2.92 – 2.66 (m, 6H), 2.14 (ddt, J = 41.1, 14.1, 7.4 Hz, 2H), 2.00 – 1.92 (m, 1H), 1.87 (s, 3H), 1.72 – 1.64 (m, 1H), 1.59 (s, 1H), 1.52 – 1.45 (m, 4H), 1.43 (d, J = 12.4 Hz, 1H), 1.35 (s, 1H), 1.18 (p, J = 7.7 Hz, 2H), 0.83 (dd, J = 18.1, 6.5 Hz, 7H).13C NMR (151 MHz, DMSO) δ 195.74, 172.18, 171.20, 170.98, 170.49, 168.08, 162.88, 159.83, 159.67, 158.81, 158.41, 155.55, 153.45, 147.45, 138.54, 135.93, 135.57, 134.36, 132.67, 131.60, 129.99, 128.46, 128.29, 127.63, 125.61, 123.49, 118.89, 118.77, 117.14, 113.03, 105.17, 103.43, 97.41, 92.38, 75.48, 75.26, 73.49, 72.45, 70.58, 66.23, 65.72, 57.47, 53.00, 46.28, 45.66, 38.52, 37.90, 36.93, 34.85, 34.51, 34.36, 30.30, 29.25, 27.68, 26.71, 25.70, 24.83, 19.17, 18.11, 6.95. HRMS (ESI+): m / z 1279.5037 (observed), 1279.5049 (calculated for C63H74N8O21[M+H]+).

[0319] (32R,52S,53R,54S,55S,56R)-14,35,53,54,55-pentahydroxy-36-methyl-34,8-dioxo- 53,54,55,56-tetrahydro-52H-4,7-dioxa-3(2,7)-chromana-5(2,6)-pyrana-1,2(1,3)- dibenzenacyclooctaphane-26-yl (22-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-methyl-4,20-dioxo-7,10,13,16-tetraoxa-3,19-diazadocosyl)(methyl)carbamate (Conjugate precursor 2)Poriolide (11 mg, 0.02 mmol, 1 eq) was dissolved in dry DMF (0.4 mL) under nitrogen atmosphere at 0 ℃. Then DIPEA (8 μL, 0.04 mmol, 2.4 eq) and 4-nitrophenyl chloroformate (4 mg, 0.02 mmol, 1.2 eq) were added at 0 ℃. The reaction was left to stirred for 1h at room temperature. Then GM214 (9 mg, 0.02 mmol, 1 eq) was added and the mixture was left to stirred for overnight. The mixture was purified by prep-HPLC, affording GM222 (3 mg, 0.003 mmol, 15 %) as white powder.1H NMR (600 MHz, DMSO) δ 12.07 (d, J = 2.4 Hz, 1H), 10.57 (t, J = 4.2 Hz, 1H), 8.00 (t, J = 5.7 Hz, 1H), 7.67 (dt, J = 8.6, 2.7 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.61 (q, J = 2.8 Hz, 1H), 7.30 (td, J = 7.8, 7.0, 2.3 Hz, 1H), 7.20 – 7.10 (m, 1H), 7.09 – 7.03 (m, 1H), 6.99 (s, 2H), 6.54 (s, 1H), 5.96 (d, J = 5.8 Hz, 1H), 5.35 (d, J = 7.8 Hz, 1H), 5.02 (ddd, J = 11.8, 4.6, 2.1 Hz, 1H), 4.02 (td, J = 8.6, 7.3, 4.8 Hz, 1H), 3.87 (t, J = 11.2 Hz, 1H), 3.65 – 3.60 (m, 1H), 3.59 (d, J = 7.2 Hz, 2H), 3.56 (d, J = 9.7 Hz, 4H), 3.49 – 3.42 (m, 20H), 3.13 (td, J = 8.3, 7.3, 5.2 Hz, 4H), 2.96 (s, 1H), 2.91 (s, 2H), 2.82 (d, J = 8.3 Hz, 2H), 2.78 (s, 1H), 2.75 (s, 1H), 2.71 (s, 1H), 2.32 (t, J = 7.3 Hz, 2H), 1.87 (s, 3H).13C NMR (151 MHz, DMSO) δ 195.75, 170.66, 170.48, 170.35, 169.90, 169.40, 168.11, 162.88, 159.83, 159.67, 158.41, 157.90, 157.69, 153.38, 147.45, 135.94, 135.67, 134.46, 132.64, 129.97, 128.34, 127.63, 125.63, 125.56, 123.51, 117.17, 113.03, 105.16, 103.43, 97.42, 92.39, 75.48, 75.25, 73.45, 72.45, 70.58, 69.67, 69.62, 69.61, 69.59, 69.56, 69.45, 69.44, 68.89, 66.74, 66.54, 65.74, 46.22, 45.09, 37.90, 35.00, 34.61, 33.97, 33.85, 6.94. HRMS (ESI+): m / z 1079.3979 (observed), 1079.3987 (calculated for C52H62N4O21[M+H]+). Example 5: Antibody-drug conjugate

[0320] 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

[0321] 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.

Claims

CLAIMS 1. A compound for use in the treatment of cancer, the compound being a compound of formula (I):pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are 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)-C3-8-halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl; R3is 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, -C(O)NHRa, -C(O)NRa-C2-6alkylene- NHRa, -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -C(O)NRa-C0-6alkylene-Z-C(O)Ra, -C(O)NRa-C0-6alkylene-Z-Ra, -C(O)-Z-C0-6alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6alkylene-NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle; R4is 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; each of R5, R6and R7are 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, wherein, when present, any of the aforementioned alkyl, aryl, cycloalkyl, haloalkyl, halocycloalkyl, heterocycloalkyl and heteroaryl groups is optionally substituted where chemically possible with one or more groups selected from: =O; =NRa, =NORa, C1-C4-alkyl, halo, nitro, cyano, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NRaRb, S(O)2Ra, S(O)Ra, S(O)(NRa)Ra, S(O)2NRaRa, CO2Ra, C(O)Ra, CONRaRb, ORaand SRa; wherein Rais independently selected from H and C1-C4-alkyl; and Rbis independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl..

2. The compound for use of claim 1, wherein each of R3and R4are 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.

3. The compound for use of claim 1 or claim 2, wherein one of R1and R2is H.

4. The compound for use of claim 1 or claim 2, wherein R1is H and R2is 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; optionally wherein R2is -OH.

5. The compound for use of any of claims 1 to 3, wherein R2is H and R1is 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; optionally wherein R1is -OH.

6. The compound for use of any preceding claim, wherein one or both of R3and R4are 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[(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.

7. The compound for use of any preceding claim, wherein one or more of R5, R6and R7are 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[(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.

8. The compound for use of any preceding claim, wherein at least one of R5, R6and R7is - H, optionally wherein each of R5, R6and R7is -H.

9. The compound for use of any preceding claim, wherein at least one of R3and R4is -H.

10. The compound for use of any preceding claim, the compound being a compound of formula (Ia):pharmaceutically acceptable salt or solvate thereof.

11. The compound for use of any preceding claim, wherein the compound ispharmaceutically acceptable salt or solvate thereof.

12. The compound for use of any preceding claim, 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.

13. A compound of formula (I):pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are 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)-C3-8-halocycloalkyl, -OC(O)-heterocycloalkyl, and -OC(O)-heteroaryl; R3is 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, -C(O)NHRa, -C(O)NRa-C2-6alkylene- NHRa, -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -C(O)NRa-C0-6alkylene-Z-C(O)Ra, -C(O)NRa-C0-6alkylene-Z-Ra, -C(O)-Z-C0-6alkylene-NRaC(O)Ra, and -C(O)-Z-C0-6alkylene-NHRa, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle; R4is 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; each of R5, R6and R7are 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, wherein, when present, any of the aforementioned alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl groups is optionally substituted where chemically possible with one or more groups selected from: =O; =NRa, =NORa, C1-C4-alkyl, halo, nitro, cyano, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NRaRb, S(O)2Ra, S(O)Ra, S(O)(NRa)Ra, S(O)2NRaRa, CO2Ra, C(O)Ra, CONRaRb, ORaand SRa; wherein Rais independently selected from H and C1-C4-alkyl; and Rbis independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl, wherein the compound is not14. The compound of claim 13, wherein each of R3and R4are 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.

15. The compound of claim 13 or claim 14, wherein one of R1and R2is H.

16. The compound of any of claims 13 to 15, wherein R1is H and R2is selected from: - 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.

17. The compound of any of claims 13 to 15, wherein R2is H and R1is selected from: - 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.

18. The compound of any of claims 13 to 17, wherein one or more of R3and R4are 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.

19. The compound of any of claims 13 to 18, wherein one or more of R5, R6and R7are 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.

20. The compound of any of claims 13 to 19, wherein at least one of R5, R6and R7is -H, optionally wherein each of R5, R6and R7is -H.

21. The compound of any of claims 13 to 20, wherein at least one of R3and R4is -H.

22. A conjugate comprising at least one targeting moiety attached to a compound as defined in any of claims 1 to 21.

23. The conjugate of claims 22, wherein the at least one targeting moiety is attached to the compound as defined in any of claims 1 to 21 via a covalent linker.

24. The conjugate of claim 23, wherein the covalent linker is a chemically cleavable linker or an enzymatically cleavable linker.

25. A conjugate of formula (XI) or formula (XIa):pharmaceutically acceptable salt or solvate thereof, wherein R1’ and R2’ 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)-C3-8-halocycloalkyl, -OC(O)-heterocycloalkyl, -OC(O)-heteroaryl, -O-L-B, and -OC(O)-L-B; R3’ 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, -C(O)NHRa, -C(O)NRa-C2-6alkylene- NHRa, -C(O)NRa-C2-6alkylene-NRaC(O)Ra, -L-B, -C(O)-L-B, -C(O)NRa-C2-6alkylene-NRaC(O)-L- B, -C(O)NRa-C0-6alkylene-Z-C(O)-L-B and -C(O)-Z-C0-6alkylene-NRaC(O)-L-B, wherein Z is a nitrogen-containing 5- or 6-membered heterocycle; R4’ 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; each of R5’, R6’ and R7’ 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; L is a linker; and B is a targeting moiety; wherein at least one of R1’, R2’, R3’, R4’, R5’, R6’ and R7’ comprises a B moiety; and wherein, when present, any of the aforementioned alkyl, aryl, cycloalkyl, haloalkyl, halocycloalkyl, heterocycloalkyl and heteroaryl groups is optionally substituted where chemically possible with one or more groups selected from: =O; =NRa, =NORa, C1-C4-alkyl, halo, nitro, cyano, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NRaRb, S(O)2Ra, S(O)Ra, S(O)(NRa)Ra, S(O)2NRaRa, CO2Ra, C(O)Ra, CONRaRb, ORaand SRa; wherein each Rais independently selected from H and C1-C4-alkyl; and each Rbis independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

26. The conjugate of claim 25, wherein one, two, three, four, five or six of R1’, R2’, R3’, R4’, R5’, R6’and R7’are defined as follows: R1’ is R1; R2’ is R2; R3’ is R3; R4’ is R4; R5’ is R5; R6’ is R6; and R7’ is R727. The conjugate of any of claims 22 to 26, comprising not more than one targeting moiety B.

28. The conjugate of any of claims 22 to 27, wherein the or each targeting moiety B comprises an antibody or fragment thereof.

29. The conjugate of claim 28, wherein the antibody or fragment thereof is an immunoglobulin G (IgG) or fragment thereof, optionally an IgG1, an IgG2 or an IgG4.

30. A pharmaceutical composition comprising a compound of any of claims 13 to 21 or a conjugate of any of claims 22 to 29; optionally further comprising a pharmaceutically acceptable excipient.

31. The compound of any of claims 13 to 21, the conjugate of any of claims 22 to 29, or the pharmaceutical composition of claim 30, for use as a medicament.

32. The conjugate of any of claims 22 to 29, or the composition of claim 30, 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.

33. Use of a compound, conjugate or pharmaceutical composition as a cytostatic agent, wherein the compound is as defined in any of claims 13 to 21, the conjugate is as defined in any of claims 22 to 29, or the pharmaceutical composition is as defined in claim 30.

34. The use of claim 33, wherein the use is in vitro and / or ex vivo.

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