Therapeutic bifunctional agents

Abstract

The present invention relates to compounds of Formula I that inhibit LMO2 activity: Formula I wherein R1, R2, R3, R4, Q, X1, X2, X3, L and E3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which LMO2 activity is implicated. The present invention also relates to chimaeric proteins.

Description

THERAPEUTIC BIFUNCTIONAL AGENTSINTRODUCTION

[0001] The present invention relates to certain pharmacologically active bifunctional agents that modulate activity of the T cell leukaemia chromosomal translocation protein, LIM domain only protein 2 (LMO2) and chimeric proteins. The agents of the present invention may be used to treat diseases or conditions mediated, at least in part, by inappropriate and / or elevated LMO2 activity, for example hyperproliferative diseases, including cancer. The invention furthermore relates to processes for the preparation of these agents, their use as pharmaceuticals, and pharmaceutical compositions comprising them.BACKGROUND OF THE INVENTION

[0002] Tumour-associated aberrant chromosomes that activate oncogenic proteins by gene activation or gene fusion are known to be caused by chromosomal translocations, wherein an unusual rearrangement of chromosomes occurs. Recurring chromosomal translocations are abundant in leukaemias / lymphomas, in sarcomas and in carcinomas (Rabbitts, 2009) and represent a class of tumour-specific proteins that could be targets for therapy. Generally, the products of chromosomal translocations are intracellular proteins and do not have enzyme active sites perse but rather are proteins that function in various cellular processes, such as transcription where protein-protein interactions (PPIs) are critical. PPIs have relatively large interaction surfaces involving several binding hotspots but also usually lack a well-defined binding site (or pocket) (Scott et al., 2016). PPIs, however, can be inhibited by macromolecules such as intracellular antibody fragments (e.g. single chain Fragment variable (scFv) (Cochet et al., 1998; Tanaka and Rabbitts, 2003; Visintin et al., 1999) or intracellular domains antibodies (iDAbs) (Tanaka and Rabbitts, 2010; Tanaka et al., 2011; Tanaka et al., 2007)) and other intracellular antibody-like formats (Bery et al., 2019; Spencer-Smith et al., 2017). The advantages of intracellular antibody-based reagents are that the natural properties of antibodies such as their high affinity and specificity can be exploited. Furthermore, their relatively quick selection processes with methods such as intracellular antibody capture (Visintin et al., 1999) allow their use to investigate their effects on a target disease in relevant preclinical models (target validation) (Tanaka and Rabbitts, 2010; Tanaka et al., 2011; Tanaka et al., 2007).

[0003] While the aim of using intracellular antibodies as drugs in their own right (termed macrodrugs (Tanaka and Rabbitts, 2008)) is still being developed, the small size of the iDAb interaction surface with target antigens has been explored as a template for small molecule surrogates in a method called Abd technology (Antibody-derived compound technology)(Quevedo et al., 2018). As reported by Quevedo et al., initial Abd selection was carried out as a biochemical assay in which a competitive surface plasmon resonance (cSPR) method was used where the location of interaction of compounds from a fragment library with HRASG12V was assessed by competition with HRAS-intracellular antibody dimer. Such an in vitro selection method yielded RAS-binding fragment hits that were developed by medicinal chemistry to nM interacting compounds. The in vitro Abd depends on favourable binding properties of the intracellular antibody with its target (very high affinity, high on-rate constant (Kon) and low off-rate constant (Koff)) and on the selected compounds having advantageous properties in cellular uptake.

[0004] One intracellular protein produced from a chromosomal translocation is LIM domain only protein 2 (LMO2) which is activated by chromosomal translocations t(11;14)(p13;q11) and t(7; 11)(q35;p13) in T cell acute lymphoblastic leukaemia (T-ALL) (Chambers and Rabbitts, 2015). LMO2 is overexpressed in more than 50% T-ALL (Fernando and Look, 2003) and notably is not expressed in normal T cells (McCormack et al., 2003). Previously an intracellular VH, VH576, binding to LMO2 (hereafter named iDAb LMO2) has been employed to show that T cell tumours do not grow when LMO2 is blocked (Tanaka et al., 2011) and showed the iDAb binds to LMO2 causing a stable structure that precludes the PPI with its natural partners (Sewell et al., 2014). In spite of this, there remains a need for agent / compounds that bind to the same interface of the LMO2 as the iDAb LMO2 in order to interfere with LMO2 PPI in cells and modulate the activity of the T cell leukaemia chromosal translocation protein, LMO2.

[0005] In view of the relevance of the LMO2 protein for various physiological processes outlined above, inhibitors of the LMO2 protein can be used in the treatment of various disease states in which LMO2 activity plays a role or which are associated with inappropriate LMO2 activity, or in which inhibition, regulation or modulation of signal transduction by the LMO2 protein is desired. Taken together these studies suggest selective inhibition of the LMO2 protein to be a promising therapeutic approach, particularly for the treatment of hyperproliferative diseases, such as cancer.

[0006] International PCT Patent Publication No. WQ2022 / 038356 discloses a series of compounds that inhibit LMO2 activity. However, there remains a need for additional therapeutic strategies for inhibiting LMO2 activity.

[0007] The present invention has been devised with the foregoing in mind.SUMMARY OF THE INVENTION

[0008] According to a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0009] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, ora pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0010] According to a further aspect of the present invention, there is provided a method of inhibiting LMO2 activity, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.

[0011] According to a further aspect of the present invention, there is provided a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0012] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which LMO2 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0013] According to a further aspect of the present invention, there is provided a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0014] According to a further aspect of the present invention, there is provided a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0015] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0016] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or apharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.

[0017] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer.

[0018] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of LMO2 activity.

[0019] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which LMO2 activity is implicated.

[0020] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[0021] Suitably, the proliferative disorder I condition is cancer, suitably a human cancer. Particular examples of suitable cancers are any cancers in which LMO2 activity is implicated and include, but are not limited to, haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), which includes T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)) and multiple myeloma

[0022] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0023] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of LMO2 activity.

[0024] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which LMO2 activity is implicated.

[0025] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0026] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.

[0027] According to a further aspect of the present invention, there are provided novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.

[0028] According to a further aspect of the present invention, there is provided a chimaeric protein comprising a ubiquitin ligase domain and an LMO2-specific endogenous targeting portion, wherein the ubiquitin ligase domain is a IIBOX domain of CHIP, or a fragment or variant thereof having ubiquitin ligase activity and wherein the protein shares at least 85% identity with the amino acid sequence of SEQ ID NO: 1 or 2.

[0029] According to a further aspect of the present invention, there is provided a nucleic acid molecule comprising a nucleic acid sequence encoding a chimaeric protein in accordance with the present invention.

[0030] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a chimaeric protein of the invention and / or a nucleic acid molecule of the invention, and a pharmaceutically acceptable carrier.

[0031] According to a further aspect of the present invention, there is provided a method of preventing or treating a condition associated with expression of LMO2, the method comprising providing a therapeutically effective amount of a chimaeric protein according to the invention to a subject in need thereof. The condition associated with expression of LMO2 may be selected from the group consisting of: T-cell acute lymphoblastic leukaemia (T-ALL); LMO2+ breast cancer; LMO2+ prostate cancer; LMO2+ acute myeloid leukaemia (AML) and LMO2+ diffuse large B cell lymphoma. The chimaeric protein may be provided by administration of the protein itself, or by administration of a nucleic acid molecule encoding the protein. Either a protein or nucleic acid molecule may be provided by administration of an appropriate pharmaceutical composition of the invention.

[0032] According to a further aspect of the present invention, there is provided the medical uses of the chimaeric proteins of the invention, of nucleic acid molecules of the invention encoding such chimaeric proteins, or of pharmaceutical compositions of the invention comprising such chimaeric proteins or nucleic acids. The medical use may be for preventing or treating a condition associated with expression of LMO2. The condition associated with LMO2 may be selected from the group consisting of: T-ALL; LMO2+ breast cancer; LMO2+ prostate cancer; and LMO2+ diffuse large B cell lymphoma. Suitably the medical use is for preventing or treating T-ALL.

[0033] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0034] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0035] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a 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, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0036] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0037] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For example, “(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and t butyl. The term “alkyl” also includes deuterated forms of said alkyl. For example, “(1-6C)alkyl” includes deuterated (1-6C)alkyl.

[0038] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0039] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), ethylene (-CH2CH2-),propylene (-CH2CH2CH2-), 2-methylpropylene (-CH2CH(CH3)CH2-), pentylene (-CH2CH2CH2CH2CH2-), and the like.

[0040] The term “alkyenyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group. Examples of alkenyl groups include ethenyl, propenyl and but-2, 3-enyl and includes all possible geometric (E / Z) isomers.

[0041] The term “alkynyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0042] “(3-10C)cycloalkyl” means a hydrocarbon ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.

[0043] The term “alkoxy” refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and t-butoxy.

[0044] The term “haloalkyl” is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms. Examples of haloalkyl groups include -CH2F, -CHF2 and -CF3.

[0045] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.

[0046] The term “carbocyclyl”, “carbocyclic” or “carbocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s). Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms. Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.

[0047] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogeninclude, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1, 3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro oxathiolyl, tetrahydro oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro oxathiazolyl, hexahydrotriazinyl, tetrahydro oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1 -dioxide and thiomorpholinyl 1,1 -dioxide. Heterocycles may comprise 1 or 2 oxo (=0) or thioxo (=S) substituents. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2 oxopyrrolidinyl, 2 thioxopyrrolidinyl, 2 oxoimidazolidinyl, 2 thioxoimidazolidinyl, 2 oxopiperidinyl, 2,5 dioxopyrrolidinyl, 2,5 dioxoimidazolidinyl or 2,6 dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0048] By “bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

[0049] By “spiro bi-cyclic ring systems” we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6-azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0050] The term “heteroaryl” or “heteroaromatic” means an aromatic mono, bi, or polycyclic ring incorporating one or more (for example 1 4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species anddivalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0051] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5 triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3 b]furanyl, 2H furo[3,2 b] pyranyl, 5H pyrido[2,3 d] o oxazinyl, 1H pyrazolo[4,3 d] oxazolyl, 4H imidazo[4,5 d]thiazolyl, pyrazino[2,3 d]pyridazinyl, imidazo[2,1 b]thiazolyl, imidazo[1,2 b][1,2,4]triazinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2, 3, 4 tetrahydro 1,8 naphthyridinyl, 1,2, 3, 4 tetrahydropyrido[2,3 b]pyrazinyl and 3,4 dihydro 2H pyrido[3,2 b][1,4]oxazinyl.

[0052] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0053] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0054] A bicyclic heteroaryl group may be, for example, a group selected from:a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; anda cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

[0055] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0056] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0057] The term “aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.

[0058] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example (3-6C)cycloalkyl(m-nC)alkyl comprises (m-nC)alkyl substituted by (3-6C)cycloalkyl.

[0059] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term “wherein a / any CH, CH2, CH3 group or heteroatom (i.e. NH) within a R1 group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R1 group is substituted by a relevant stipulated group.

[0060] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0061] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.Compounds of the invention

[0062] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula I, shown below:Formula Iwherein:R1 is selected from:(i) (1-6C)alkylene which is optionally substituted by one or more Ra;(ii) a group of the formula:whereindenotes the point of attachment;n is 0 or 1;Riaand R are selected from hydrogen or methyl;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N; or(iii) a group of the formula:whereindenotes the point of attachment;n, Riaand R are as defined above;Ring B is a saturated or partially unsaturated ring;one X?, Xs and Xg is a group C-LRI- and the others are selected from C- H, C-Raor N if a bond connecting them to an adjacent atom is an unsaturated double bond, or C-H2, C-HRa, C-(Ra)2, N-H, N-Rb, S orO if the bonds attaching them to adjacent atoms are single bonds; wherein each Rais independently selected from (1-4C)alkyl (including deuterated (1-4C)alkyl), halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, nitro, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, (CH2)qiNRabRac, (CH2)qiORab, (CH2)qiC(O)Rab, (CH2)qiC(O)ORab, (CH2)qiOC(O)Rab, (CH2)qiC(O)N(Rac)Rab, (CH2)qiN(Rac)C(O)Rab, (CH2)qiS(O)pRab(where p is 0, 1 or 2), (CH2)qiSO2N(Rac)Riab, or (CH2)qiN(Rac)SO2Rab, and wherein:q1 is 0, 1, 2 or 3;Rabis selected from hydrogen, (1-4C)alkyl (including deuterated (1-4C)alkyl), (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl,and wherein Rabis optionally further substituted by one or more substituentgroups independently selected from oxo, (1 -4C)alkyl (including deuterated (1- 4C)alkyl), halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1- 4C)hydroxyalkyl, cyano, nitro, NRadRae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)pRad (where p is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad, or (CH2)q2NRadRae (where q2 is 1, 2 or 3); wherein Rad and Raeare each independently selected from hydrogen or (1 -6C)alkyl;and Racis selected from hydrogen or (1-2C)alkyl (including deuterated (1- 2C)alkyl);or where Rab and Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for Rab above;wherein Rb is independently selected from (1-4C)alkyl (including deuterated (1- 4C)alkyl), (1-4C)haloalkyl or -C(O)Rba, wherein Rba is selected from (1 -4C)alkyl, (3- 6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl, and wherein Rba is optionally further substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl (including deuterated (1-4C)alkyl), halo, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, nitro, NRbdRbe, ORbd, C(O)Rbd, C(O)ORbd, OC(O)Rbd, C(O)N(Rbe)Rbd, N(Rbe)C(O)Rbd, S(O)pRbd (where p is 0, 1 or 2), SO2N(Rbe)Rbd, N(Rbe)SO2Rbd, or (CH2)q3NRbdRbe (where q3 is 1, 2 or 3); wherein Rbd and Rbe are each independently selected from hydrogen or (1-6C)alkyl (including deuterated (1-6C)alkyl);LRI is a bond or a linking group that connects Ri to L which is optionally selected from (1-4C)alkylene, (3-6C)cycloalkylene, (3-6C)cycloalkyl(1-2C)alkylene, (CH2)qi-NRi_Ri-, - (CH2)q1-O-, -(CH2)q1-C(O)-, -(CH2)q1-C(O)O-, -(CH2)q1-OC(O)-, -(CH2)q1-C(O)NRLR1-, - (CH2)qiN(RLRi)C(O)-, -(CH2)qi-S(O)p- (where p is 0, 1 or 2), -(CH2)qi-SO2NRLRi-, - (CH2)qi-N(R LRI)SO2-, or -(CH2)qi-[triazole]-;and wherein:q1 is as defined above;RLRI is selected from hydrogen or (1 -4C)alkyl;Xi, X2and X3 are selected from N, N-R5, O, S and CRe, wherein R5 is hydrogen or methyl and Re is hydrogen, methyl or halo, with the proviso that at least one of Xi, X2and X3 is selected from N, N-R5, O and S;Q is a group of the formula:or -X12-CH2-CH2-NR7- or -Xi3-C(O)-NR8-;wherein:X and Xu are selected from N or CH;X12 and X13 are selected from NRg, CH2, CHRg or C(Rg)2; andR7, Rs and Rg are selected from hydrogen or (1-2C)alkyl (including deuterated (1-2C)alkyl);R2 and R3 are selected from hydrogen (including deuterium) or (1-2C)alkyl (including deuterated (1 -2C)alkyl);R4 is a phenyl, heteroaryl, or heterocyclyl ring optionally substituted by (1-4C)alkyl (including deuterated (1-4C)alkyl), halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, nitro, NR4aR4b, OR4a, C(O)R4a, C(O)OR4a, OC(O)R4a, C(O)N(R4b)R4a, N(R4b)C(O)R4a, S(O)pR4a (where p is 0, 1 or 2), SO2N(R4b)R4a, N(R4b)SO2R4a,or (CH2)q4NR4aR4b (where q4 is 1, 2 or 3); wherein R4ais selected from hydrogen, (1-4C)alkyl (including deuterated (1-4C)alkyl), (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl, and wherein:R4ais optionally further substituted by (1-4C)alkyl (including deuterated (1-4C)alkyl), halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, nitro, NR4aaR4ab, OR4aa, C(O)R4aa, C(O)OR4aa, OC(O)R4aa, C(O)N(R4ab)R4aa, N(R4ab)C(O)R4aa, S(O)pR4aa (where p is 0, 1 or 2), SO2N(R4ab)R4aa, N(R4ab)SO2R4aa, or (CH2)q5NR4aaR4ab (where q5 is 1, 2 or 3) and R4aaand R4abare hydrogen or (1-2C)alkyl (including deuterated (1-2C)alkyl);R4b is selected from hydrogen or (1 -2C)alkyl (including deuterated (1 -2C)alkyl); or, when R4aand R4b are linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for R4above;L is a bivalent linker group covalently linking Ri to E3; andE3 is an E3 ubiquitin ligase-binding moiety.Compounds of Formula I

[0063] Particular compounds of the formula I include, for example, compounds of the Formula I, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise stated, each of Ri, Xi, X2, X3, Q, R2, R3, and R4 and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (22), including (10a), hereinafter:(1) R1 is selected from:(i) (1-4C)alkylene which is optionally substituted by one or more Ra;(ii) a group of the formula:whereindenotes the point of attachment;n is 0 or 1;Ria and R are selected from hydrogen or methyl;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N;(iii) a group of the formula:whereindenotes the point of attachment;n, Ria and R are as defined above;Ring B is a saturated or partially unsaturated ring;one X7, Xs and Xg is a group C-LRI- and the others are selected from C-H or C- Raif a bond connecting them to an adjacent atom is an unsaturated double bond, or C-H2, C-HRa, or C-(Ra)2 if the bonds attaching them to adjacent atoms are single bonds;wherein each Rais independently selected from (1 -2C)alkyl, halo, (1 -2C)haloalkyl, (1-2C)haloalkoxy, cyano, nitro, (5-6C)cycloalkyl, (5-6C)cycloalkyl(1-2C)alkyl, phenyl, (CH2)qlNRabRac, (CH2)qlORab, (CH2)ql C(O) Rab, (CH2)qlC(O)ORab, (CH2)qlOC(O)Rab, (CH2)qiC(O)N(Rac)Rab, (CH2)qiN(Rac)C(O)Rab, (CH2)qiS(O)pRab (where p is 0, 1 or 2), (CH2)qlSO2N(Rac)Rlab, or (CH2)qlN(Rac)SO2Rab,and wherein:q1 is 0, 1 or 2;Rab is selected from hydrogen, (1-4C)alkyl, (5-6C)cycloalkyl, (5- 6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl,and wherein Rabis optionally further substituted by one or more substituent groups independently selected from oxo, (1 -2C)alkyl, halo, (1 -2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl, cyano, nitro, NRadRae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)pRad (where p is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad, or (CH2)q2NRadRae (where q2 is 1, 2 or 3); wherein Rad and Raeare each independently selected from hydrogen or (1 -4C)alkyl;and Racis selected from hydrogen or methyl;or where Raband Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for Rababove;LRI is a bond or a linking group that connects R1 to L which is optionally selected from (1-2C)alkylene, -(CH2)qi-NRLRi-, -(CH2)qi-O-, -(CH2)qi-C(O)-, -(CH2)qi-C(O)O-, -(CH2)qi-OC(O)-, -(CH2)qi-C(O)NRLRi-, -(CH2)qiN(RLRi)C(O)-, -(CH2)qi-S(O)P- (where p is 0, 1 or 2), -(CH2)qi-SO2NR Ri-, -(CH2)qi-N(R LRi)SO2- or -(CH2)qi-[triazole]-; and wherein:q1 is as defined above;RLRI is selected from hydrogen or (1 -2C)alkyl;(2) Ri is selected from:(i) (1-4C)alkylene which is optionally substituted by one or more Ra;(ii) a group of the formula:whereindenotes the point of attachment;n is 0 or 1;Ria and R are selected from hydrogen or methyl;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N;(iii) a group of the formula:whereindenotes the point of attachment;n, Ria and R are as defined above;Ring B is a saturated or partially unsaturated ring;one X7, Xs and Xg is a group C-LRI- and the others are selected from C- H or C-Raif a bond connecting them to an adjacent atom is an unsaturated double bond, or C-H2, C-HRa, or C-(Ra)2 if the bonds attaching them to adjacent atoms are single bonds;wherein each Rais independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, cyano, nitro, (5-6C)cycloalkyl(1-2C)alkyl, phenyl, (CH2)qiNRabRac, (CH2)qiORab, (CH2)qi C(O) Rab, (CH2)qiC(O)ORab, (CH2)qiOC(O)Rab, or (CH2)qlN(Rac)SO2Rab, and wherein:q1 is 0, or 1;Rab is selected from hydrogen, (1-4C)alkyl, (5-6C)cycloalkyl, (5- 6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl and heterocyclyl(1- 2C)alkyl,and wherein Rab is optionally further substituted by one or more substituent groups independently selected from oxo, methyl, halo, cyano, nitro, NRad ae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)SO2Rad, Or (CH2)q2N RadRae (where q2 is 1 or 2); wherein Rad and Raeare each independently selected from hydrogen or (1 -2C)alkyl;and Racis selected from hydrogen or methyl;or where Rab and Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for Rab above;LRI is a bond or a linking group that connects Ri to L which is optionally selected from (1-2C)alkylene, -(CH2)qi-NRLRi-, -(CH2)qi-O-, -(CH2)qi-C(O)-, -(CH2)qi-C(O)O-, - (CH2)qi-OC(O)-, -(CH2)qi-C(O)NRLRi-, -(CH2)qiN(RLRi)C(O)-, -(CH2)qi-S(O)P- (where p is 0, 1 or 2), -(CH2)qi-SO2NR Ri-, -(CH2)qi-N(R Ri)SO2-or-(CH2)qi-[triazole]-; and wherein:q1 is as defined above;RLRI is selected from hydrogen or (1 -2C)alkyl;(3) Ri is selected from:(i) (1-4C)alkylene which is optionally substituted by one or more Ra;(ii) a group of the formula:whereindenotes the point of attachment;n is 0 or 1;Ria and R are hydrogen;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N;(iii) a group of the formula:whereindenotes the point of attachment;n, Ria and R are as defined above;Ring B is a saturated ring;one X7, Xs and Xg is a group C-LRI- and the others are C-H;wherein each Rais independently selected from methyl, halo, cyano, phenyl, (CH2)q1 N RabRac, (CH2)qlORab, (CH2)q1 C(O) Rab Or (CH2)qlC(O)ORab,and wherein:q1 is 0;Rab is selected from hydrogen, (1-4C)alkyl, aryl, aryl(1-2C)alkyl,and wherein Rab is optionally further substituted by one or more substituent groups independently selected from oxo, methyl, halo, or cyano;and Racis selected from hydrogen;or where Rab and Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for Rab above;LRI is a bond or a linking group that connects R1 to L which is optionally selected from (1-2C)alkylene, -NRLRI-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NRLRI-, -N(RLRI)C(O)-, - S(O)P- (where p is 0, 1 or 2), -SO2NRLRI-, or -N(R LRI)SO2-;and wherein RLRI is selected from hydrogen or (1 -2C)alkyl;(4) Ri is selected from:(i) (1-4C)alkylene which is optionally substituted by one or more Ra;(ii) a group of the formula:whereindenotes the point of attachment;n is 0 or 1;Ria and R are hydrogen;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N;(iii) a group of the formula:whereindenotes the point of attachment;n, Ria and R are as defined above;Ring B is a saturated ring;one X7, Xs and Xg is a group C-LRI- and the others are C-H; wherein each Rais independently selected from methyl, halo, (CH2)qiNRabRac, (CH2)qlORab, (CH2)q1 C(O) Rab Or (CH2)qlC(O)ORab,and wherein:q1 is 0;Rab is selected from hydrogen, (1-4C)alkyl, aryl, aryl(1-2C)alkyl, and wherein Rab is optionally further substituted by one or moresubstituent groups independently selected from, halo;and Racis hydrogen;or where Rab and Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 membered heteroaryl ring or a 5 or 6 membered heterocyclic ring, each of which is optionally substituted as for Rab above;LRI is a bond that connects Ri to L;(5) Ri is selected from a group of the formula:whereindenotes the point of attachment;n is 0 or 1;Riaand R are hydrogen;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N;wherein each Rais independently selected from methyl, halo, (CH2)qiNRabRac, (CH2)qiORab, (CH2)qiC(O)Rabor (CH2)qiC(O)ORab,and wherein:q1 is 0;Rab is selected from hydrogen, (1-2C)alkyl, phenyl, benzyl,and wherein Rab is optionally further substituted by one or more substituent groups independently selected from, halo;and Racis hydrogen;or where Rab and Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 membered heteroaryl ring or a 5 or 6 membered heterocyclic ring, each of which is optionally substituted as for Rab above;LRI is a bond that connects Ri to L;(6) Ri is:whereindenotes the point of attachment to the NH group of Formula I; andwhereindenotes the point of attachment to the NH group of Formula I; anddenotes the point of attachment to L;(8) Xi, X2 and X3 are selected from N, O, S and CRe, wherein Re is hydrogen, methyl or halo, with the proviso that at least one of Xi, X2 and X3 is selected from N, O and S; (9) Xi, X2 and X3 are selected from N, O, S and CRe, wherein Re is hydrogen, with the proviso that at least one of Xi, X2 and X3 is selected from N, O and S;(10) Xi is N; X2 is O or S; and X3 is CRe, wherein Re is hydrogen;(10a) Xi is O or S; X2 is N; and X3 is CRe, wherein Re is hydrogen;(11) Q is a group of the formula:or -X12-CH2-CH2-NR7- or -Xi3-C(O)-NR8-; wherein:X and Xu are selected from N or CH;X12 and X13 are selected from NRg and CH2; and R7, R8and Rg are selected from hydrogen or methyl;and whereindenotes the point of attachment;(12) Q is a group of the formula:or -X12-CH2-CH2-NR7- or -Xi3-C(O)-NR8-; wherein:X and Xu are selected from N;X12 and X13 are selected from NRg; andR7, Rs and Rg are selected from hydrogen;and wherein denotes the point of attachment;(13) Q is a group of the formula:wherein:X and Xu are selected from N;and whereindenotes the point of attachment;(14) Q is selected fromwhereindenotes the point of attachment;(15) R2 and R3 are selected from hydrogen or methyl;(16) R2 and R3 are hydrogen;(17) R4 is a phenyl, heteroaryl, or heterocyclyl ring optionally substituted by (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl, cyano, nitro, NR4aR4b, OR4a, C(O)R4a, C(O)OR4a, OC(O)R4a, C(O)N(R4b)R4a, N(R4b)C(O)R4a, S(O)pR4a (where p is 0, 1 or 2), SO2N(R4b)R4a, N(R4b)SO2R4a, or (CH2)q4NR4aR4b (where q4 is 1, 2 or 3); wherein R4a is selected from hydrogen, (1 -2C)alkyl, (5-6C)cycloalkyl, (5-6C)cycloalkyl(1-2C)alkyl, phenyl, phenyl(1-2C)alkyl, heteroaryl, heteroaryl(1- 2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl, and wherein:R4a is optionally further substituted by (1-2C)alkyl, halo, (1-2C)haloalkyl, (1- 2C)haloalkoxy, cyano, nitro, NR4 aaR4ab, OR4aa, C(O)R4aa, C(O)OR4aa, OC(O)R4aa, C(O)N(R4ab)R4aa, N(R4ab)C(O)R4aa, S(O)pR4aa (where p is 0, 1 or 2), SO2N(R4ab)R4aa, N(R4ab)SO2R4aa, or (CH2)q5NR4aaR4ab (where q5 is 1, 2 or 3) and R4aaand R4ab are hydrogen or (1-2C)alkyl;R4bis selected from hydrogen or (1 -2C)alkyl;or R4a and R4b are linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for R4 above;(18) R4 is a phenyl, heteroaryl, or heterocyclyl ring optionally substituted by (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl, cyano, nitro, NR4aR4b, 0R4a, C(0)R4a, C(0)0R4a, 0C(0)R4a, C(O)N(R4b)R4a, N(R4b)C(O)R4a, S(O)pR4a (where p is 0, 1 or 2), SO2N(R4b)R4a, N(R4b)SO2R4a, or (CH2)q4NR4aR4b (where q4 is 1, 2 or 3); wherein R4a is selected from hydrogen, (1-2C)alkyl, phenyl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl, and wherein:R4a is optionally further substituted by (1-2C)alkyl, halo, (1-2C)haloalkyl, (1- 2C)haloalkoxy, cyano, nitro;R4bis selected from hydrogen or (1 -2C)alkyl;or R4a and R4b are linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for R4 above;(19) R4 is a phenyl, heteroaryl, or heterocyclyl ring optionally substituted by (1-2C)alkyl, halo, cyano, nitro, NR4aR4b, OR4a, C(O)R4a, N(R4b)C(O)R4a; whereinR4a is selected from hydrogen, (1-2C)alkyl, (1-2C)haloalkyl, phenyl(1-2C)alkyl; R4bis selected from hydrogen or methyl;or R4a and R4b are linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for R4 above;(20) R4 is a phenyl or heteroaryl ring optionally substituted by (1 -2C)alkyl, halo, cyano, nitro, NR4aR4b, OR4a, C(O)R4a, N(R4b)C(O)R4a; whereinR4a is selected from hydrogen, (1-2C)alkyl, (1-2C)haloalkyl, phenyl(1-2C)alkyl; andR4bis selected from hydrogen;(21) R4 is selected fromwhereindenotes the point of attachment;(22) R4 is selected from:whereindenotes the point of attachment.

[0064] Suitably, R1 is as defined in any one of paragraphs (4) to (7) above. More suitably, R1 is as defined in paragraph (6) above. Most suitably, R1 is as defined in paragraph (7) above.

[0065] Suitably, Xi is as defined in any one of paragraphs (8) to (10a) above. More suitably, Xi is as defined in paragraph (10a) above. Most suitably, Xi is as defined in paragraph (10) above.

[0066] Suitably, X2 is as defined in any one of paragraphs (8) to (10a) above. More suitably, X2 is as defined in paragraph (10a) above. Most suitably, X2 is as defined in paragraph (10) above.

[0067] Suitably, X3 is as defined in any one of paragraphs (8) to (10a) above. More suitably, X3 is as defined in paragraph (10a) above. Most suitably, X3 is as defined in paragraph (10)above.

[0068] Suitably, Xi, X2 and X3 are as defined in any one of paragraphs (8) to (10a) above. More suitably, Xi, X2 and X3 are as defined in paragraph (10a) above. Most suitably, Xi, X2 and X3 are as defined in paragraph (10) above.

[0069] Suitably, Q is as defined in any one of paragraphs (11) to (14) above. Most suitably, Q is as defined in paragraph (14) above.

[0070] Suitably, R2 is as defined in paragraph (15) or (16) above. Most suitably, R2 is as defined in paragraph (16) above.

[0071] Suitably, R3 is as defined in paragraph (15) or (16) above. Most suitably, R3 is as defined in paragraph (16) above.

[0072] Suitably R2 and R3 are as defined in paragraph (15) or (16) above. Most suitably, R2 and R3 is as defined in paragraph (16) above.

[0073] Suitably, R4 is as defined in any one of paragraphs (19) to (22) above. More suitably, R4 is as defined in paragraph (21) above. Most suitably, R4 is as defined in paragraph (22) above.

[0074] In an embodiment, X5 is C-LRI-. In an embodiment, Xs is C-LRI-.

[0075] In some embodiments, the compounds of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, may include moieties derived from any of the following compounds:2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(4-phenoxyphenyl)oxazole-4-carboxamide (Abd-L6); A / -(4-(1H-pyrrol-1-yl)phenyl)-2-(3-(3-chlorobenzyl)-2-oxoimidazolidin-1-yl)oxazole-4-carboxamide (Abd-L7);2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-N-(3,4-dimethoxyphenyl)oxazole-5-carboxamide (Abd-L8); / V-(4-(benzyloxy)phenyl)-2-(3-(3-methoxybenzyl)-2-oxoimidazolidin-1-yl)oxazole-4-carboxamide (Abd-L9);A / -(4-(1H-pyrrol-1-yl)phenyl)-2-(3-(3-cyanobenzyl)-2-oxoimidazolidin-1-yl)oxazole-4-carboxamide (Abd-L10);2-(3-(2-chlorobenzyl)-2-oxoimidazolidin-1-yl)-N-(4-phenoxyphenyl)oxazole-4-carboxamide (Abd-L12);2-(3-benzyl-2-oxoimidazolidin-1-yl)- / V-(4-phenoxybenzyl)oxazole-4-carboxamide (Abd-L13); 2-(3-(2-chlorobenzyl)-2-oxoimidazolidin-1-yl)-A / -(4-phenoxybenzyl)oxazole-4-carboxamide(Abd-L14);A / -(4-(1H-pyrrol-1-yl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamide (Abd-L15);A / -(4-(benzyloxy)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamide (Abd-Li 6);A / -(4-(benzyloxy)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide (Abd-Li 7);A / -(4-(1H-pyrrol-1-yl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide (Abd-L18);A / -(4-(1H-pyrrol-1-yl)phenyl)-2-(4-(4-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamide (Abd-L19);A / -(4-(1H-pyrrol-1-yl)phenyl)-2-(4-(2-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide (Abd-L20);2-(4-(3-methoxybenzyl)piperazin-1-yl)-N-(4-(trifluoromethoxy)phenyl)thiazole-4-carboxamide (Abd-L21);2-(4-(3-methoxybenzyl)piperazin-1-yl)- / V-(6-methoxypyridin-3-yl)thiazole-4-carboxamide (Abd-L22);2-(4-(3-methoxybenzyl)piperazin-1-yl)- / V-(2-methoxypyrimidin-5-yl)thiazole-4-carboxamide (Abd-L23);A / -(4-(benzyloxy)phenyl)-2-(4-(4-nitrobenzyl)piperazin-1-yl)oxazole-4-carboxamide (Abd-L27);ethyl 4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzoate;ethyl 3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzoate;ethyl 4-(2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamido)benzoate; ethyl 4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-5-carboxamido)benzoate;ethyl 4-(2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-5-carboxamido)benzoate; andethyl 4-(2-(4-(3-cyanobenzyl)piperazin-1-yl)thiazole-5-carboxamido)benzoate.

[0076] Suitably, the moiety derived from any one of the aforementioned compounds may be connected to L via the Ri group I position on said moiety. For illustrative purposes, the compounds of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof,may include a moiety derived from 2-(4-(3-methoxybenzyl)piperazin-1-yl)-N-(4-(trifluoromethoxy)phenyl)thiazole-4-carboxamide (Abd-L21). The structure of Abd-L21, as well as the structure of the Abd-L21 moiety connected to L via the R1 group I position, are shown below:

[0077] Therefore, it will be understood that any of the aforementioned compounds, when bound to E3 via L at the Ri group I position, may form a compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0078] The various functional groups and substituents making up the compounds of the Formula I are typically chosen such that the molecular weight of the compound of the formula I does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.The linker group L

[0079] The linker L is a group that serves to link Ri to E3. Suitable linkers are well known in the PROTAC field for this purpose. Accordingly, any suitable linker known in the PROTAC field could be used in the compounds of the present invention.

[0080] In one embodiment, the linker is a carbon chain that optionally comprises one, two, three, or more heteroatoms selected from N, O, and S. In one embodiment, the carbon chaincomprises only saturated chain carbon atoms. In another embodiment, the carbon chain optionally comprises two or more unsaturated chain carbon atoms. In one embodiment, one or more chain carbon atoms in the carbon chain are optionally substituted with one or more substituents, including but not limited to oxo, (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-3C) alkoxy, OH, halogen, deuterium, N(1-3C)alkyl, N[(1-3C)alkyl)]2, ON, (3-8C)cycloalkyl, heterocyclyl, phenyl, and heteroaryl.

[0081] In one embodiment, the Linker comprises at least 5 chain atoms, selected from to C, O, N, and S atoms. In one embodiment, the Linker comprises less than 40 chain atoms, selected from C, O, N, and S atoms. In one embodiment, the Linker comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 chain atoms, selected from C, O, N, and S atoms. In one embodiment, the Linker comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24 or 25 chain atoms, selected from C, O, N, and S atoms. In one embodiment, the Linker comprises 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 chain atoms, selected from C, O, N, and S atoms. In one embodiment, the Linker comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 1920, 21, 22, 23, 24 or 25 chain atoms, selected from C, O, N, and S atoms.

[0082] It will be appreciated that the term “chain atom” will be understood to mean the atoms which space apart Ri and E3 (i.e., bridging atoms between Ri and E3). It will be understood that the number of bond lengths in the “chain atom” moiety will be n+1, wherein n is the number of “chain atoms”. It will be appreciated that L can be defined in terms of “bond lengths” and “chain atoms”.

[0083] In further embodiments, the linker group is a straight chain alkylene group of 3 to 40, 5 to 30, 10 to 25 or 13 to 23 carbon atoms wherein one or more carbon atoms are optionally

[0084] In further embodiments, the linker group is a straight chain alkylene group of 3 to 40, 5 to 30, 10 to 25 or 13 to 23 carbon atoms wherein one or more carbon atoms are optionallyreplaced by one or more groups independently selected from: -O-, -NH-, -N(CHs)-, CO,carbocyclyl, heterocyclyl

[0085] In further embodiments, linker group is a straight chain alkylene group of 3 to 40, 5 to 30, 10 to 25 or 13 to 23 carbon atoms wherein one or more carbon atoms are optionally replaced by one or more groups independently selected from: -O-, -NH-, CO,

[0086] The linker group L of formula I is either as defined hereinbefore or has one of the definitions set out in paragraphs (23) to (37) below:(23) L is a linker comprising 2 to 40 chain atoms (or 3 to 41 bond lengths).(24) L is a linker comprising 3 to 30 chain atoms (or 4 to 31 bond lengths).(25) L is a linker comprising 3 to 25 chain atoms (or 4 to 26 bond lengths).(26) L is a linker comprising 3 to 20 chain atoms (or 4 to 21 bond lengths).(27) L is a linker comprising 3 to 15 chain atoms (or 4 to 16 bond lengths).(28) L is a linker comprising 3 to 12 chain atoms (or 4 to 13 bond lengths).(29) L is a linker comprising 4 to 12 chain atoms (or 5 to 13 bond lengths).(30) L is a linker comprising 4 to 10 chain atoms (or 5 to 11 bond lengths).(31) L is a linker of the formula:*-XL1 - AL1 - RL1 -X|_2- AL2-X|_3- RL2-AL3-X|_4-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3;XLI is absent or -O-, NRXLI, -C(O)-, -C(O)NRXLI-, -NRXLIC(O)- or (2-4C)alkynyl; wherein Rxn is hydrogen or methyl;ALI is absent or (1-15C)alkylene, (2-8C)alkenylene, (2-8C)alkynylene, -(CH2)ai- [O-CH2CH2]a2- or -[O-CH2CH2]a2-(CH2)ai-;RLI is absent, a 5- or 6-membered heteroaryl, phenyl, carbocyclyl, heterocyclyl or:wherein YLI and YL2 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo;XL2 is either absent or, when YL2 is N, XL2 may be selected from -C(O)- or - C(O)NRXL2-; or when YL2 is CH, XL2 may be selected from -O-, NRXL2, -C(O)-, - C(O)NRXL2 or -NRXL2C(O)-; wherein RXL2 is hydrogen or methyl;AL2 is absent or (1-15C)alkylene, -(CH2)a3-[O-CH2CH2]a4- or -[O-CH2CH2]a4- (CH2)a3- XLS is absent or -O-, NRXLS, -C(O)-, -C(O)NRXL3- or -NRXL3C(O)- or (2- 4C)alkynyl; wherein RXLS is hydrogen or methyl;RL2 is absent, a 5- or 6-membered heteroaryl, phenyl, carbocyclyl, heterocyclyl or:wherein YLS and YL4 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo;ALS is absent or (1-15C)alkylene, -(CH2)a5-[O-CH2CH2]a6- or -[O-CH2CH2]a6- (CH2)a5- XL4 is absent or -O-, -C(O)-, -C(O)NRXL4- or -NRXL4C(O)- or (2-4C)alkynyl; wherein RXL4 is hydrogen or methyl;integers a1, a3 and a5 are each independently 1 to 4; andintegers a2, a4 and a6 are each independently 1 to 7;(32) L is a linker of the formula:-XL1 - AL1 - RLI -XL2- AL2-XL3- RL2-AL3-XL4-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3;XLI is absent or -O-, NRXLI, -C(O)-, -C(O)NRXLI-, -NRXLIC(O)- or (2-4C)alkynyl; wherein Rxn is hydrogen or methyl;ALI is absent or (1-8C)alkylene, -(CH2)ai-[O-CH2CH2]a2- or -[O-CH2CH2]a2- (CH2)ai-;RLI is absent, a 5- or 6-membered heteroaryl, phenyl, 4- to 8-membered carbocyclyl, 4- to 12- membered heterocyclyl or:wherein YLI and YL2 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo; XL2 is either absent or, when YL2 is N, XL2 may be selected from -C(O)- or - C(O)NRXL2-; or when YL2 is CH, XL2 may be selected from -O-, NRXL2, -C(O)-, - C(O)NRXL2 or -NRXL2C(O)-; wherein RXL2 is hydrogen or methyl;AL2 is absent or (1-8C)alkylene, -(CH2)a3-[O-CH2CH2]a4- or -[O-CH2CH2]a4- (CH2)a3- XLS is absent or -O-, NRXLS, -C(O)-, -C(O)NRXL3- or -NRXL3C(O)-; wherein RXLS is hydrogen or methyl;RL2 is absent, a 5- or 6-membered heteroaryl, phenyl, 4- to 8-membered carbocyclyl, 4- to 12- membered heterocyclyl or:wherein YLS and YL4 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo; ALS is absent or (1-8C)alkylene, -(CH2)a5-[O-CH2CH2]a6- or -[O-CH2CH2]a6-(CH2)a5- XL4 is absent or -O-, -C(O)-, -C(O)NRXL4- or -NRXL4C(O)- or (2-4C)alkynyl; wherein RXL4 is hydrogen or methyl;integers a1, a3 and a5 are each independently 1 to 3; andintegers a2, a4 and a6 are each independently 1 to 4;(33) L is a linker of the formula:*-XL1 - AL1 - RL1 -X|_2- AL2-X|_3- RL2-AL3-X|_4-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3;XLI is absent or -O-, NRXLI, -C(O)-, -C(O)NRXLI-, -NRXLIC(O)- or (2-4C)alkynyl; wherein Rxn is hydrogen or methyl;ALI is absent or (1-4C)alkylene, -(CH2)ai-[O-CH2CH2]a2- or -[O-CH2CH2]a2- (CH2)ai-;RLI is absent, a 5- or 6-membered heteroaryl, phenyl, a nitrogen containing 4- to 12- membered heterocyclyl or:wherein YLI and YL2 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo;XL2 is either absent or, when YL2 is N, XL2 may be selected from -C(O)- or - C(O)NRXL2-; or when YL2 is CH, XL2 may be selected from -O-, NRXL2, -C(O)-, - C(O)NRXL2 or -NRXL2C(O)-; wherein RXL2 is hydrogen or methyl; AL2 is absent or (1-4C)alkylene, -(CH2)a3-[O-CH2CH2]a4- or -[O-CH2CH2]a4- (CH2)a3- XLS is absent or -O-, NRXLS, -C(O)-, -C(O)NRXL3- or -NRXL3C(O)-; wherein RXLS is hydrogen or methyl;RL2 is absent, a 5- or 6-membered heteroaryl, phenyl, a nitrogen-containing 4- to 12- membered heterocyclyl or:wherein YLS and YL4 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo;ALS is absent or (1-4C)alkylene, -(CH2)a5-[O-CH2CH2]a6- or -[O-CH2CH2]a6- (CH2)a5- XL4 is absent or -O-, -C(O)-, -C(O)NRXL4- or -NRXL4C(O)- or (2-4C)alkynyl; wherein RXL4 is hydrogen or methyl;integers a1, a3 and a5 are each independently 1 to 3; andintegers a2, a4 and a6 are each independently 1 to 4;(34) L is a linker of the formula:*-XL1 - AL1 - L1 -X|_2- AL2-X|_3- L2-AL3-X|_4-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3;XLI is absent or -O-, NRxn, -C(O)-, -C(O)NRXLI-; wherein Rxn is hydrogen or methyl;ALI is absent or (1-4C)alkylene, or -(CH2)ai-[O-CH2CH2]a2-;RLI is absent, a 5- or 6-membered heteroaryl, phenyl, a nitrogen-containing 4- to 12- membered heterocyclyl or:wherein YLI and YL2 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo;XL2 is absent;AI_2 is absent or (1-4C)alkylene, or -(CH2)a3-[O-CH2CH2]a4-;XLS is absent or-0-, NRXLS, -C(0)- or-C(O)NRxL3-; wherein RXLS is hydrogen or methyl;RL2 is absent, a 5- or 6-membered heteroaryl, phenyl, a nitrogen-containing 4- to 12- membered heterocyclyl or:wherein YLS and YL4 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo;ALS is absent or (1-4C)alkylene, -(CH2)a5-[O-CH2CH2]a6- or -[O-CH2CH2]a6- (CH2)a5- XL4 is absent or -O-, -C(O)-, -C(O)NRXL4-, or (2-4C)alkynyl; wherein RXL4 is hydrogen or methyl;integers a1, a3 and a5 are each independently 1 to 3; andintegers a2, a4 and a6 are each independently 1 to 4;(35) L is selected from:*-XLI-[CH2]2-IO-0-***-XLI-[CH2]2-IO-NH-***-XLI-[CH2CH2O]2-8-O-***-XLI-[CH2CH2O]2-8-NH-***-XLI-[CH2]2-IO-0-***-XLI-[CH2]2-IO-NH-***-XLi-[CH2CH2O]2-8-O-(3-4C)alkynyl-***-XLi-[CH2CH2O]2-8-NH-(3-4C)alkynyl-***-XLi-[CH2]i-8-(2-4C)alkynyl-***-XLI-HET-[CH2]O-6-NH-***-XLI-[CH2]O-6-HET-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3;XLI is absent or -O-, NRxn, -C(O)-, -C(O)NRXLI-; wherein Rxn is hydrogen or methyl; andHET is a nitrogen-containing 4- to 12-memebered heterocyclyl;(36) L is a linker of the formula:*-XLI-CH2-CH2-O-***-XLI-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-***-XLI-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH-***-XLI-CH2-CH2-O-CH2-CH2-O-**-XLI-CH2-CH2-O-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-***-XLI-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH-***-XLi-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-(2-4C)alkynyl-***-XLi-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH-(2-4C)alkynyl-***-XLi-CH2-CH2-CH2-(2-4C)alkynyl-***-XLi-CH2-CH2-CH2-CH2-(2-4C)alkynyl-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3; andXLI is absent or -0-, NRxn, -C(0)-, -C(O)NRXLI-; wherein Rxn is hydrogen ormethyl; or(37) L is a linker of the formula:*-XLI-CH2-CH2-O-***-XLI-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-***-XLI-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH-***-XLI-CH2-CH2-O-CH2-CH2-O-***-XLI-CH2-CH2-O-CH2-CH2-NH-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-O-***-XLI-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-NH-***-XLI-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-** *-XLI-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH-** *-XLi-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-(2-4C)alkynyl-** *-XLi-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH-(2-4C)alkynyl-** *-XLi-CH2-CH2-CH2-(2C)alkynyl-***-XLi-CH2-CH2-CH2-CH2-(2C)alkynyl-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3; andXLI is -O-, NRXLI, -C(O)-, or -C(O)NRXLI-; wherein Rxn is hydrogen or methyl.

[0087] Suitably, L is as defined in any one of numbered paragraphs (23) to (37) above. More suitably, L is as defined in numbered paragraph (31) above. More suitably, L is as defined in numbered paragraph (32) above. More suitably, L is as defined in numbered paragraph (33) above. More suitably, L is as defined in numbered paragraph (34) above. More suitably, L is as defined in numbered paragraph (35) above. More suitably, L is as defined in numbered paragraph (36) above. More suitably, L is as defined in numbered paragraph (37) above.The E3 ubiquitin ligase-binding moiety E3

[0088] The E3 ubiquitin ligase-binding moiety E3 may be any suitable E3 ubiquitin ligase-binding moiety known in the art.

[0089] E3 may be a small molecule or peptide E3 ubiquitin ligase-binding moiety. In a particular embodiment, E3 is a small molecule E3 ubiquitin ligase-binding moiety.

[0090] The E3 group of formula I is either as defined hereinbefore or has one of the definitions set out in paragraphs (38) to (46) below:(38) E3 is a small molecule or peptide E3 ubiquitin ligase-binding moiety;(39) E3 is a small molecule E3 ubiquitin ligase-binding moiety.(40) E3 is an E3 ubiquitin ligase-binding moiety capable of binding an E3 ubiquitin ligase selected from the group consisting of: von Hippel-Lindau (VHL); cereblon, XIAP, E3A; MDM2; Anaphase-promoting complex; EIBR5 (EDDI); SOCS / BC-box / eloBC / CLIL5 / RING; LNXp80; CBX4; CBLL1; HACE1; HECTD1; HECTD2; HECTD3; HECW1; HECW2; HERC1; HERC2; HERC3; HERC4; HUWE1; ITCH; NEDD4; NEDD4L; PPIL2; PRPF19; PIAS1; PIAS2; PIAS3; PIAS4; RANBP2; RNF4; RBX1; SMURF 1; SMURF2; STUB1; TOPORS; TRIP 12; UBE3A; UBE3B; UBE3C; UBE4A; UBE4B; UBOXS; UBR5; VWVP1; VWVP2; Parkin; A20 / TNFAIP3; AMFR / gp78; ARA54; beta- TrCPI / BTRC; BRCA1; CBL; CHIP / STUB 1; E6; E6AP / UBE3A; F-box protein 15 / FBX015; FBXW7 / Cdc4; GR AIL / RNF 128; HOIP / RNF31; clAP-l / HIAP-2; clAP- 2 / HIAP-l; clAP (pan); ITCH / AIP4; KAP1; MARCH8, Mind Bomb 1 / MIB1; Mind Bomb 2 / MIB2; MuRF 1 / TRIM63; NDFIP1; NEDD4; NleL; Parkin; RNF2; RNF4; RNF8; RNF168; RNF43; SART1; Skp2; SMURF2; TRAF-I; TRAF-2; TRAF-3; TRAF-4; TRAF- 5; TRAF-6; TRIMS; TRIM21; TRIM32; UBR5; ZNRF3, DCAF15, DCAF16, KEAP, AhR, FEM1B, or Cullin ring.(41) E3 is an E3 ubiquitin ligase-binding moiety capable of binding an E3 ubiquitin ligase selected from the group consisting of: von Hippel-Lindau (VHL) or cereblon.(42) E3 is an E3 ubiquitin ligase-binding moiety capable of binding the E3 ubiquitin ligase cereblon.(43) E3 is selected from thalidomide, pomalidomide, lenalidomide, VHL ligand, methyl- bestatin or nutlin, or a derivative thereof.(44) E3 is selected from thalidomide, pomalidomide, lenalidomide or VHL ligand.(45) E3 is selected from:wherein:denotes the point of attachment to L;Rqis hydrogen or fluoro;RVHL is cyclopropyl optionally substituted by fluoro; X2 is selected from -CH2- or -C(O)-;R100 is fluoro or CF3; andR i is hydrogen or methyl.(46) E3 is selected from:wherein:denotes the point of attachment to L;Rqis hydrogen or fluoro;RVHL is cyclopropyl optionally substituted by fluoro;X2 is selected from -CH2- or -C(O)-.

[0091] Suitably, E3 is as defined in any one of numbered paragraphs (38) to (46) above. More suitably, E3 is as defined in paragraph (41) above. More suitably, E3 is as defined in paragraph (42) above. More suitable, E3 is as defined in numbered paragraph (43) above. More suitably, E3 is as defined in numbered paragraph (44) above. More suitably, E3 is as defined in numbered paragraph (45) above. More suitably, E3 is as defined in numbered paragraph (46) above.Particular embodiments of formula I

[0092] Further compounds of the invention are those in which A is a compound of formula I as defined herein and L and E3 are as defined herein. Such compounds have the formula Ila shown below:Formula Ilawherein Xi, X2, X3, R1, R2, R3, R4, Q, L and E3 are each as defined herein before.

[0093] In a particular group of compounds of Formula Ila, R2 and R3 are hydrogen and Q is, denotes the points of attachment. These compounds have the structural formula lib, a sub-definition of Formula I and Ila, shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:Formula libwherein Xi, X2, X3, R1, R4, L and E3 are each as defined herein before.

[0094] In an embodiment of the compounds of Formula lib:R1 is as defined in any one of paragraphs (1) to (7) above;Xi, X2, and X3 are as defined in any one of paragraphs (8) to (10a) above;R4 is as defined in any one of paragraphs (17) to (22) above; andL and E3 each have any one of the definitions set out herein.

[0095] In another embodiment of the compounds of Formula lib:R1 is as defined in paragraph (4) above;Xi, X2, and X3 are as defined in paragraph (8) above; andR4 is as defined in paragraph (18) above; andL and E3 each have any one of the definitions set out herein.

[0096] In another embodiment of the compounds of Formula lib:R1 is as defined in paragraph (5) above;Xi, X2, and X3 are as defined in paragraph (9) above; andR4 is as defined in paragraph (19) above; andL and E3 each have any one of the definitions set out herein.

[0097] In another embodiment of the compounds of Formula lib:Ri is as defined in paragraph (6) or paragraph (7) above;Xi, X2, and X3 are as defined in paragraph (10) above; and R4 is as defined in paragraph (21) or paragraph (22) above; and L and E3 each have any one of the definitions set out herein.

[0098] In another embodiment of the compounds of Formula lib:R1 is as defined in paragraph (6) or paragraph (7) above;Xi, X2, and X3 are as defined in paragraph (10a) above; and R4 is as defined in paragraph (21) or paragraph (22) above; and L and E3 each have any one of the definitions set out herein.

[0099] In another embodiment of the compounds of Formula lib:R1 is as defined in paragraph (6) above;Xi, X2, and X3 are as defined in paragraph (10) above; and R4 is as defined in paragraph (21) above; andL and E3 each have any one of the definitions set out herein.

[0100] In another embodiment of the compounds of Formula lib:R1 is as defined in paragraph (6) above;Xi, X2, and X3 are as defined in paragraph (10a) above; and R4 is as defined in paragraph (21) above; andL and E3 each have any one of the definitions set out herein.

[0101] In another embodiment of the compounds of Formula lib:R1 is as defined in paragraph (7) above;Xi, X2, and X3 are as defined in paragraph (10) above; and R4 is as defined in paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0102] In another embodiment of the compounds of Formula lib:R1 is as defined in paragraph (7) above;Xi, X2, and X3 are as defined in paragraph (10a) above; andR4 is as defined in paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0103] In a particular group of compounds of Formula Ila, the compounds have structural formula lie shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:Formula Hewherein each of Ri, Xi, X2, X3, R4, L and E3 are as defined hereinabove.

[0104] In an embodiment of the compounds of Formula He:R1 is as defined in any one of paragraphs (1) to (7) above;Xi, X2, and X3 are as defined in any one of paragraphs (8) to (10a) above;R4 is as defined in any one of paragraphs (17) to (22) above andL and E3 each have any one of the definitions set out herein.

[0105] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (4) above;Xi, X2, and X3 are as defined in paragraph (8) above;R4 is as defined in paragraph (18) above; andL and E3 each have any one of the definitions set out herein.

[0106] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (5) above;Xi, X2, and X3 are as defined in paragraph (9) above;R4 is as defined in paragraph (19) above; andL and E3 each have any one of the definitions set out herein.

[0107] In another embodiment of the compounds of Formula He: Ri is as defined in paragraph (6) or paragraph (7) above;Xi, X2, and X3 are as defined in paragraph (10) above;R4 is as defined in paragraph (21) or paragraph (22) above; and L and E3 each have any one of the definitions set out herein.

[0108] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (6) or paragraph (7) above;Xi, X2, and X3 are as defined in paragraph (10a) above;R4 is as defined in paragraph (21) or paragraph (22) above; and L and E3 each have any one of the definitions set out herein.

[0109] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (6) above;Xi, X2, and X3 are as defined in paragraph (10) above;R4 is as defined in paragraph (21) above; andL and E3 each have any one of the definitions set out herein.

[0110] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (6) above;Xi, X2, and X3 are as defined in paragraph (10a) above;R4 is as defined in paragraph (21) above; andL and E3 each have any one of the definitions set out herein.

[0111] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (7) above;Xi, X2, and X3 are as defined in paragraph (10) above;R4 is as defined in paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0112] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (7) above;Xi, X2, and X3 are as defined in paragraph (10a) above;R4 is as defined in paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0113] In a particular group of compounds of Formula I, the compounds have structural formula lid shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:Formula lidwherein each of Ri, Q, R2, R3, R4, L and E3 are as defined hereinabove.

[0114] In an embodiment of the compounds of Formula lid:R1 is as defined in any one of paragraphs (1) to (7) above;Q is as defined in any one of paragraphs (11) to (14) above;R2 and R3 are as defined in paragraphs (15) and (16) above;R4 is as defined in any one of paragraphs (17) to (22) above; andL and E3 each have any one of the definitions set out herein.

[0115] In another embodiment of the compounds of Formula lid:R1 is as defined in paragraph (4) above;Q is as defined in paragraph (12) above;R2 and R3 are as defined in paragraph (15) above;R4 is as defined in paragraph (18) above; andL and E3 each have any one of the definitions set out herein.

[0116] In another embodiment of the compounds of Formula lid:R1 is as defined in paragraph (5) above;Q is as defined in paragraph (12) above;R2 and R3 are as defined in paragraph (15) above;R4 is as defined in paragraph (19) above; andL and E3 each have any one of the definitions set out herein.

[0117] In another embodiment of the compounds of Formula lid:Ri is as defined in paragraphs (6) or paragraph (7) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (21) or paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0118] In another embodiment of the compounds of Formula lid:R1 is as defined in paragraph (6) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (21) above; andL and E3 each have any one of the definitions set out herein.

[0119] In another embodiment of the compounds of Formula lid:R1 is as defined in paragraph (7) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0120] In a particular group of compounds of Formula Ila, the compounds have structural formula He shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:Formula Hewherein each of Ri, Q, R2, R3, R4, L and E3 are as defined hereinabove.

[0121] In an embodiment of the compounds of Formula He:R1 is as defined in any one of paragraphs (1) to (7) above;Q is as defined in any one of paragraphs (11) to (14) above;R2 and R3 are as defined in paragraphs (15) and (16) above;R4 is as defined in any one of paragraphs (17) to (22) above; and L and E3 each have any one of the definitions set out herein.

[0122] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (4) above;Q is as defined in paragraph (12) above;R2 and R3 are as defined in paragraph (15) above;R4 is as defined in paragraph (18) above; andL and E3 each have any one of the definitions set out herein.

[0123] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (5) above;Q is as defined in paragraph (12) above;R2 and R3 are as defined in paragraph (15) above;R4 is as defined in paragraph (19) above; andL and E3 each have any one of the definitions set out herein.

[0124] In another embodiment of the compounds of Formula He:R1 is as defined in paragraphs (6) or paragraph (7) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (21) or paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0125] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (6) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (21) above; andL and E3 each have any one of the definitions set out herein.

[0126] In another embodiment of the compounds of Formula He:R1 is as defined in paragraph (7) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0127] In a particular group of compounds of Formula Ila, the compounds have structural formula Ilf shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:Formula Ilfwherein each of R1, Q, R2, R3, R4, L and E3 are as defined hereinabove.

[0128] In an embodiment of the compounds of Formula Ilf:R1 is as defined in any one of paragraphs (1) to (7) above;Q is as defined in any one of paragraphs (11) to (14) above;R2 and R3 are as defined in paragraphs (15) and (16) above;R4 is as defined in any one of paragraphs (17) to (22) above; andL and E3 each have any one of the definitions set out herein.

[0129] In another embodiment of the compounds of Formula Ilf:R1 is as defined in paragraph (4) above;Q is as defined in paragraph (12) above;R2 and R3 are as defined in paragraph (15) above;R4 is as defined in paragraph (18) above; andL and E3 each have any one of the definitions set out herein.

[0130] In another embodiment of the compounds of Formula Ilf:R1 is as defined in paragraph (5) above;Q is as defined in paragraph (12) above;R2 and R3 are as defined in paragraph (15) above;R4 is as defined in paragraph (19) above; andL and E3 each have any one of the definitions set out herein.

[0131] In another embodiment of the compounds of Formula Ilf:R1 is as defined in paragraphs (6) or paragraph (7) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (21) or paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0132] In another embodiment of the compounds of Formula Ilf:R1 is as defined in paragraph (6) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (21) above; andL and E3 each have any one of the definitions set out herein.

[0133] In another embodiment of the compounds of Formula Ilf:R1 is as defined in paragraph (7) above;Q is as defined in paragraph (14) above;R2 and R3 are as defined in paragraph (16) above;R4 is as defined in paragraph (22) above; andL and E3 each have any one of the definitions set out herein.

[0134] In all the aforementioned embodiments of formulae lib, lie, lid, lie or Ilf, L isoptionally as defined in paragraph (23) and E3 is optionally as defined on paragraph (38) above.

[0135] In all the aforementioned embodiments of formulae lib, lie, lid, lie or Ilf, L is optionally as defined in paragraph (26) and E3 is optionally as defined on paragraph (40) above.

[0136] In all the aforementioned embodiments of formulae lib, lie, lid, lie or Ilf, L is optionally as defined in paragraph (29) and E3 is optionally as defined on paragraph (42) above.

[0137] In all the aforementioned embodiments of formulae lib, lie, lid, lie or Ilf, L is optionally as defined in paragraph (32) and E3 is optionally as defined on paragraph (44) above.

[0138] In all the aforementioned embodiments of formulae lib, lie, lid, lie or Ilf, L is optionally as defined in paragraph (36) and E3 is optionally as defined on paragraph (46) above.

[0139] Particular compounds of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, include any of the following:A / -(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamide;A / -(4-((2-(2-(2-(((R)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl) carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(3-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide; / V-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide; / V-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)carbamoyl)phenyl)- 2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)carbamoyl)phenyl)- 2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamoyl)phenyl)- 2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole- 4-carboxamide;A / -(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-5-carboxamide;2-(4-(3-cyanobenzyl)piperazin-1-yl)- / V-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)thiazole-5-carboxamide;A / -(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)phenyl)-2- (4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)azetidine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)azetidine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide; A / -(4-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide; A / -(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide; orA / -(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide.Salts, isomers and prodrugs

[0140] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0141] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0142] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual ( )- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or byresolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers).

[0143] It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.

[0144] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and18O; and the like.

[0145] It is also to be understood that certain compounds of the Formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.

[0146] It is also to be understood that certain compounds of the Formula I may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.

[0147] Compounds of the Formula I may exist in a number of different tautomeric forms and references to compounds of the Formula I include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0148] 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), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly,N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0149] The compounds of Formula I may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I.

[0150] Accordingly, the present invention includes those compounds of the Formula I as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically-produced compound or a metabolically-produced compound.

[0151] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0152] Various forms of pro-drug have been described, for example in the following documents:-a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);c) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A. C. S. Symposium Series, Volume 14; andh) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0153] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and terf-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1 -cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0154] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N, N-(1-6C)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N, N-dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(1-4C)alkylpiperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0155] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I, that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1-4C)alkylamine such as methylamine, a [(1-4C)alkyl]2amine such as dimethylamine, N-ethyl-N-methylamine ordiethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0156] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N, N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(1-4C)alkyl)piperazin-1-ylmethyl.

[0157] The in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I. As stated hereinbefore, the in vivo effects of a compound of the Formula I may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0158] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0159] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.Synthesis

[0160] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. Particular processes for the preparation of compounds of formula I defined herein with different R2, R3, R4, Q, Xi, X2, X3 and R1 groups are described in International PCT Patent Publication No. WO2022 / 038356.

[0161] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0162] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0163] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0164] For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0165] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0166] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a terf-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0167] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0168] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0169] Resins may also be used as a protecting group.

[0170] Once a compound of Formula I has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:(i) removing any protecting groups present;(ii) converting the compound Formula I into another compound of Formula I;(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0171] An example of (ii) above is when a compound of Formula I is synthesised and then one or more of the groups may be further reacted to change the nature of the group and provide an alternative compound of Formula I.

[0172] The resultant compounds of Formula I can be isolated and purified using techniques well known in the art.

[0173] The compounds of Formula I may be synthesised by the general synthetic routes shown in the Examples section below, specific examples of which are described in more detail in the Examples.Biological Activity

[0174] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.

[0175] Although the pharmacological properties of the compounds of Formula I vary with structural change, as expected, the compounds of the invention were found to be active in the assays described in the Examples section.Pharmaceutical Compositions

[0176] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0177] According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0178] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0179] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0180] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0181] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0182] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the ageand sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0183] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.Therapeutic Uses and Applications

[0184] The present invention provides compounds that function as inhibitors of LMO2 activity. Accordingly, the compounds of the present invention are suitable for treating diseases and conditions, such as cancers, in which LMO2 activity is implicated.

[0185] The present invention therefore provides a method of inhibiting LMO2 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0186] The present invention also provides a method of treating a disease or disorder in which LMO2 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0187] The present invention provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0188] The present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0189] The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0190] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0191] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.

[0192] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer.

[0193] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the inhibition of LMO2 activity.

[0194] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which LMO2 activity is implicated.

[0195] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[0196] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0197] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of LMO2 activity.

[0198] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which LMO2 activity is implicated.

[0199] The term "proliferative disorder" and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignantneoplasms and tumours, cancers (including breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary), lymphomas (including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), which includes T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)), multiple myeloma lymphomas (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lymphatic, blood, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.

[0200] Particular proliferative disorders of interest are haematological cancers, such as, for example, lymphomas (including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), which includes T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)) and multiple myeloma. Diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), angioimmunoblastic T-cell lymphoma (AITL), T-cell acute lymphoblastic leukaemia (T-ALL), and acute myeloid leukaemia (AML) are of particular interest. In a further embodiment, the cancer is selected from: T-ALL; LMO2+ breast cancer; LMO2+ prostate cancer; LMO2+ acute myeloid leukaemia (AML) and LMO2+ diffuse large B cell lymphoma.

[0201] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).

[0202] The compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, being an inhibitor of LMO2, has potential therapeutic uses in a variety of LMO2-mediated disease states.

[0203] According to a further aspect of the specification there is provided a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore for use in the treatment of cancer.

[0204] According to a further feature of this aspect of the specification there is provided a method for treating cancer in a warm-blooded animal, such as man, that is in need of suchtreatment, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore.

[0205] According to a further feature of this aspect of the specification there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancer.

[0206] LMO2 is also known to play a role in angiogenesis (vascular remodelling). Accordingly, the compounds of the present invention can be used as anti-angiogenic agents to interfere with the angiogenesis by inhibiting LMO2 activity. Particular conditions associated with angiogenesis in which LMO2 inhibition is beneficial may include: tumour metastasis; diabetic retinopathy; corneal neovascularisation; age-related macular degeneration; and pathological angiogenesis arising in, for example, autoimmune diseases, rheumatoid arthritis, atherosclerosis, cerebral ischemia, cardiovascular diseases and delayed wound healing.

[0207] Thus, in another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore for use in the treatment of angiogenesis or for use as an anti-angiogenic agent.

[0208] In another aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore in the manufacture of medicament for use in the treatment of angiogenesis or for use as an anti-angiogenic agent.

[0209] In another aspect, the present invention provides a method of treating angiogenesis in a warm-blooded animal, such as man, that is in need of such treatment, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore.

[0210] In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore for use in the treatment of angiogenesis associated with one or more of the following: tumour metastasis, diabetic retinopathy; corneal neovascularisation; age-related macular degeneration; and pathological angiogenesis arising in, for example, autoimmune diseases, rheumatoid arthritis, atherosclerosis, cerebral ischemia, cardiovascular diseases and delayed wound healing.

[0211] In another aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore in the manufacture of medicament for use in the treatment of angiogenesisassociated with one or more of the following: tumour metastasis, diabetic retinopathy; corneal neovascularisation; age-related macular degeneration; and pathological angiogenesis arising in, for example, autoimmune diseases, rheumatoid arthritis, atherosclerosis, cerebral ischemia, cardiovascular diseases and delayed wound healing.

[0212] In another aspect, the present invention provides a method of treating angiogenesis in a warm-blooded animal, such as man, that is in need of such treatment, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore; wherein the angiogenesis is associated with one or more of the following: tumour metastasis, diabetic retinopathy; corneal neovascularisation; age-related macular degeneration; and pathological angiogenesis arising in, for example, autoimmune diseases, rheumatoid arthritis, atherosclerosis, cerebral ischemia, cardiovascular diseases or delayed wound healing.Routes of Administration

[0213] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e., at the site of desired action).

[0214] Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.Combination Therapies

[0215] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:- (i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin,cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), steroid hormones, including progestogens (for example megestrol acetate) and corticosteroids (for example dexamethasone, prednisone and prednisolone), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;(iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), A / -(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase];(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as A / -(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-A / -(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threoninekinases (for example Ras / Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00 / 47212), compounds such as those disclosed in International Patent Applications WO97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avp3 function and angiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;(ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and(x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

[0216] In a particular embodiment, the antiproliferative treatment defined hereinbeforemay involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more antitumour agents selected from cyclophosphamide, epirubicin, fluorouracil, methotrexate, mitomycin C, doxorubicin, gemcitabine, docetaxel, carbazitaxel and radium-223 dichloride.

[0217] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-hormonal agents selected from a selective estrogen receptor modulator (SERM) (e.g. tamoxifen or toremifene), an aromatase inhibitor (Al) (e.g. anastrozole, fadrozole, letrozole or exemestane), a selective estrogen receptor degrader (SERD) (e.g. fulvestrant, elacestrant or GDC-0810), a luteinising hormone (LH) blocker (e.g. goserelin), direct androgen receptor (AR) antagonist (e.g. bicalutamide, enzalutamide, apalutamide, darolutamide, cyproterone acetate or flutamide), a non-competitive AR antagonist (e.g. ralaniten acetate), an androgen steroid synthesis inhibitor (e.g. abiraterone acetate), a gonadotropin-releasing hormone (GNRH) modulator (e.g. leuprorelin, goserelin, buserelin, triptorelin, degarelix).

[0218] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or cell-cycle agents selected from a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor (e.g. palbociclib, ribociclib or abemaciclib).

[0219] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or DNA damage response agents agents selected from a poly ADP ribose polymerase (PARP) inhibitor (e.g. olaparib, veliparib, rucaparib or niraparib).

[0220] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or cell signalling agent selected from a phosphatidylinositol 3 kinase (PI3K) inhibitor, (e.g. buparlisib, apitolisib, azd8186, omipalisib, duvelisib, gedatolisib, copanlisib, pictilisib, alpelisib, idelalisib, acalisib, serabelisib, pilaralisib or taselisib), an AKT inhibitor (e.g. MK2206, AZD5363, afuresertib, AT13148, miransertib or ipatasertib); a (mTOR) signaling pathway inhibitor (e.g. everolimus, sirolimus, temsirolimus, vistusertib, sapanisertib or ridaforolimus), an Fibroblast growth factor (FGF) signalling inhibitor (e.g. AZD4547 or dovitinib).

[0221] In a particular embodiment, the antiproliferative treatment defined hereinbeforemay involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more antitumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.

[0222] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more chemotherapeutic agents selected from a BCL-2 family inhibitor (e.g. Venetoclax and / or navitoclax), a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Tirabrutinib (ONO / GS-4059), BGB-3111 or Spebrutinib (CC-292) or a TNF inhibitor (e.g. Lenalidomide).

[0223] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[0224] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.

[0225] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.

[0226] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[0227] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0228] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an antitumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.Chimaeric Protein

[0229] The chimaeric proteins of the invention, as well as nucleic acids encoding these proteins, represent effective agents for the treatment of diseases associated with LMO2.

[0230] Chimaeric proteins of the invention provide effective agents that achieve their biological activity by specifically inducing the transfer of their target, LMO2, to the proteasome. Here the target protein undergoes proteolysis, and so intracellular LMO2 levels are reduced in treated cells.

[0231] Since elevated levels of LMO2, are associated with a large number of diseases, the reduction in intracellular levels of this protein has a beneficial therapeutic effect. This may be observed in respect of a number of different disorders associated with LMO2.

[0232] It is known that LMO2 drive the progression of associated cancers (which are sometimes described as “addicted” to the proteins in question). In this case reducing the presence of the proteins prevents further cancer progression. The chimaeric proteins of the invention, and nucleic acids encoding them, represent useful agents for the treatment of LMO2-associated disorders such as T-ALL.

[0233] Indeed, the inventors have found that chimaeric proteins of the invention are able to effectively bring about tumour regression, through their induction of cancer cell apoptosis. Surprisingly they can achieve this without needing to be able to recognise specific, or indeed any, mutations in the protein that they target. The advantages of the present invention include the size of the molecule, the chimaeric proteins of the invention are smaller than those in the prior art and therefore are easier to incorporate into a particle as protein per se, or as mRNA, or in expression vectors, or in viruses for expression following infection into cells.“Chimaeric proteins” of the invention

[0234] The invention relates to chimaeric proteins comprising a ubiquitin ligase domain and an LMO2-specific endogenous targeting portion. Chimaeric proteins are made upof sequences from at least two proteins. These may be artificial proteins (such as DARPins or intracellular antibodies), or naturally occurring proteins, such as ubiquitin ligases. It will be appreciated that the chimaeric proteins are not naturally occurring themselves. Suitably the ubiquitin ligase domain and the LMO2-specific endogenous targeting portion are each derived from separate proteins.

[0235] The proteins from which the requisite domains or portions are derived may be referred to as “parent” proteins in the context of the present disclosure. Parent proteins may be used for the generation of fragments or variants that can be used in the chimaeric proteins of the invention.

[0236] In order to be suitable for incorporation in a chimaeric protein of the invention a fragment or variant of a parent protein should retain some or all of the biological activity of the parent protein (for example ubiquitin ligase activity or the ability to specifically bind to LMO2).

[0237] A fragment derived from a parent protein will share 100% identity with a corresponding portion of the parent protein, though it will not comprise 100% of the full-length parent protein’s sequence.

[0238] Suitably, a fragment of a parent protein may comprise at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 90% of the full-length sequence of the parent protein. By way of example, a variant of a parent protein that may be incorporated in a chimaeric protein of the invention may share at least at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the full-length sequence of the parent protein.

[0239] Considered in another way, a fragment may comprise 10 or more contiguous amino acid residues, for example 20 or more, 30 or more, or 40 or more contiguous amino acid residues from the parent protein sequence.

[0240] In contrast with such fragments, a variant of a parent protein incorporates one or more changes as compared to the sequence of the parent protein from which it is derived. Suitably a variant of a parent protein that may be incorporated in a chimaeric protein of the invention may share at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 90% identity with a corresponding portion of the parent protein. By way of example, a variant of a parent protein that may be incorporated in a chimaeric protein of the invention may share at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity witha corresponding portion of the parent protein.

[0241] Suitably, a variant of a parent protein that may be incorporated in a chimaeric protein of the invention may share up to 99%, up to 98%, up to 97%, up to 96%, up to 95%, up to 94%, up to 93%, up to 92%, up to 91%, or up to 90% identity with a corresponding portion of the parent protein.

[0242] A variant in the present context comprises at least one modification as compared to the parent protein sequence. “Modification” as used herein refers to any change made to an amino acid sequence such that its sequence is not the same as that of the parent protein. Suitably a variant of a parent protein may comprise at least 2, 3, 4, 5, 10, or 15 amino acid modifications as compared to the parent protein sequence. Suitable modifications may include substitution or deletion of the amino acid residue present in the parent protein, or addition of amino acid residues not present in the parent protein sequence.“Endogenous targeting portions”

[0243] A chimaeric protein of the invention comprises an endogenous targeting portion in combination with a ubiquitin ligase domain. The endogenous targeting portion, specific for LMO2, is a polypeptide component of a chimaeric protein of the invention that confers on the chimaeric protein the ability to bind specifically to its corresponding target.

[0244] An endogenous targeting portion suitable for use in a chimaeric protein of the invention may be any endogenous polypeptide sequence capable of binding specifically to the chosen target. The skilled person will be aware of many suitable assays by which the ability to bind specifically to targets (such as pan RAS, KRAS, HRAS, NRAS, or LMO2) may be assessed.

[0245] Endogenous targeting portions, for the purpose of the present invention, should be understood to be targeting portions that do not naturally arise in the intracellular environment.

[0246] By way of example, suitable endogenous targeting portions may be selected from the group consisting of: DARPins (or fragments or variants of DARPins); and intracellular antibodies (or fragments or variants of intracellular antibodies).

[0247] DARPins are suitable for use as endogenous targeting portions in accordance with the present disclosure as they are not naturally occurring molecules. Thus, in a suitable embodiment, the endogenous targeting portion is a DARPin. Affinity maturation used during the production of DARPins means that these agents are able to achieve levels of affinity for their targets that are much higher affinity than naturally occurring agents.

[0248] Intracellular antibodies are also suitable for use as endogenous targeting portions in accordance with the present disclosure as they are also not naturally occurring proteins (antibodies having to be modified in order to be suitable for intracellular use). Thus, in a suitable embodiment, the endogenous targeting portion is an intracellular antibody.

[0249] The ability of an endogenous targeting portion, such as a DARPin or intracellular antibody, to bind to its target may be determined by an appropriate binding assay. In the case of an LMO2-specific endogenous targeting portion this may be an appropriate LMO2 binding assay.

[0250] Endogenous targeting portions, and particularly antibody or DARPin endogenous targeting portions, may serve as parent proteins from which fragments or variants suitable for use in embodiments of the invention, may be generated, in keeping with the considerations set out elsewhere in the specification.

[0251] The ability of fragments or variants of endogenous targeting portions, such as DARPins or intracellular antibodies, to bind to their target may be determined by an appropriate binding assay. In the case of a fragment or variant of an LMO2-specific DARPin or intracellular antibody this may be an appropriate LMO2 binding assay.

[0252] In the context of the present disclosure, references to “an endogenous targeting portion” that do not specify the target should be taken, except for where the context requires otherwise, as being applicable to all chimaeric proteins of the invention.“A LMO2-specific endogenous targeting portion”

[0253] An LMO2-specific endogenous targeting portion is a polypeptide component of a chimaeric protein of the invention that confers on the chimaeric protein the ability to bind specifically to LMO2.

[0254] An LMO2-specific endogenous targeting portion suitable for use in a chimaeric protein of the invention may be any endogenous polypeptide sequence capable of binding specifically to LMO2. The skilled person will be aware of many suitable assays by which the ability to bind specifically to LMO2 may be assessed.

[0255] In a suitable embodiment, the LMO2-specific endogenous targeting portion is selected from the group consisting of: a LMO2-specific intracellular antibody; and an LMO2-specific DARPin.‘A ubiquitin ligase domain

[0256] The ubiquitin ligase domain is a polypeptide component of a chimaeric protein of the invention that has ubiquitin ligase activity. The presence of this domain within the chimaeric protein, along with the endogenous targeting portion enables the ubiquitin ligase activity to be directed specifically to LMO2. In turn, this increases the targeting of LMO2 to the proteasome.

[0257] There are a very large number of ubiquitin ligase domains known to the skilled person. These include the VHL E3 ligase domain described above, and the IIBOX domain of carboxyl-terminus of Hsc70 interacting protein (CHIP) E3 ligase. The ubiquitin ligase domain of a chimaeric protein of the invention may be a IIBOX domain of CHIP, or a fragment or variant thereof having ubiquitin ligase activity. The skilled person will be aware of many suitable assays by which ubiquitin ligase activity may be assessed.

[0258] In a suitable embodiment the ubiquitin ligase domain of a chimaeric protein of the invention comprises the IIBOX domain of CHIP, or a fragment or variant thereof.

[0259] As referred to above, the skilled person is well aware of methods by which the ligase activity of a ubiquitin ligase domain suitable for use in a chimaeric protein of the invention may be assessed and quantified. Merely by way of example, this may be achieved using commercially available kits, such as those sold by Abeam.

[0260] A fragment or variant of ubiquitin ligase domain, such as a IIBOX domain of CHIP, suitable for use in the proteins of the invention may possess at least 75% of the ligase activity of the parent protein as measured by a suitable ligase activity assay. For example, a suitable fragment or variant may possess at least 80%, at least 85%, at least 90%, or at least 95% of the ligase activity of the parent protein. A suitable fragment or variant may possess at least 96%, at least 97%, at least 98%, or at least 99% of the ligase activity of the parent protein. A suitable variant may even possess greater ligase activity than the parent ubiquitin ligase domain from which it is derived.Structure of the chimaeric proteins of the invention

[0261] Accordingly, it is a preferred embodiment of the invention that, when the ubiquitin ligase domain is a ligase domain, or a fragment or variant thereof, that the ubiquitin ligase domain is attached to the N-terminal region of the endogenous targeting portion within a chimaeric protein of the invention.

[0262] Without wishing to be bound by any hypothesis, the inventors believe that this orientation of constituents within the chimaeric proteins of the invention advantageously improves accessibility to free lysine, and thereby increases the biological activity of thechimaeric protein of the invention. Furthermore, this arrangement may reduce steric hindrance between the endogenous targeting portion, the ligase domain and the target protein.

[0263] The ubiquitin ligase domain and the endogenous targeting portion may be indirectly attached to one another by a linker sequence. For example, the C-terminal region of the ubiquitin ligase domain may be attached to a linker sequence, which in turn is attached to the N-terminal region of the endogenous targeting portion.

[0264] A suitable linker sequence may comprise a plurality of glycine residues. Merely by way of example, a suitable linker sequence may comprise between three and seven glycine residues, for example four glycine residues. A suitable linker sequence may comprise a combination of glycine and serine residues.

[0265] Alternatively, the ubiquitin ligase domain and endogenous targeting portion may be directly fused to one another. For example, the C-terminal region of the ubiquitin ligase domain may be fused directly to the N-terminal region of the endogenous targeting portion.

[0266] Suitably the ubiquitin ligase domain comprises only a single domain.

[0267] Suitably the endogenous targeting portion comprises only a single domain. DARPins and intracellular antibodies both constitute examples of endogenous targeting portions with single domains that may be used in such embodiments.

[0268] Suitably both the ubiquitin ligase domain and the endogenous targeting portion each comprise only a single domain.

[0269] Chimaeric proteins in accordance with these embodiments of the invention, in which either the ubiquitin ligase domain, the endogenous targeting portion, or both of these components each comprise only a single domain offer a number of advantages. Examples of such advantages include the relative ease with which such chimaeric proteins can be expressed at relatively high levels, the high efficiency with which such chimaeric proteins can be isolated once expressed, and the beneficial solubility of the proteins. It will be appreciated that these benefits are particularly applicable to embodiments of the chimaeric proteins of the invention in which both the ubiquitin ligase domain and the endogenous targeting portion each comprise only a single domain.Exemplary chimaeric proteins of the invention

[0270] In a suitable embodiment a chimaeric protein of the invention may share at least 80% or at least 85% identity with amino acid sequences of the exemplary chimaeric proteins set out in any of SEQ I D NOs: 1 or 2. Suitably such a chimaeric protein of the inventionmay share at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequences of the exemplary chimaeric proteins set out in any of SEQ ID NOs: 1 or 2.

[0271] A chimaeric protein of the invention may comprise the amino acid sequence set out in any of SEQ ID NOs: 1 or 2.

[0272] A chimaeric protein of the invention may consist of the amino acid sequence set out in any of SEQ ID NOs: 1 or 2.A nucleic acid molecule of the invention

[0273] Another aspect of the invention provides a nucleic acid molecule comprising a nucleic acid sequence encoding a chimaeric protein of the invention. This aspect also provides a cell comprising such a nucleic acid molecule. The protein encoded may be a protein in accordance with chimaeric protein of the invention, and may be in accordance with any of the embodiments of these aspects described herein.

[0274] Suitably a nucleic acid molecule of the invention may comprise DNA.

[0275] Suitably a nucleic acid molecule of the invention may comprise RNA.

[0276] A nucleic acid molecule of the invention may be provided in the form of a vector comprising the nucleic acid molecule. Such a vector may be expressed by a cell to produce a chimaeric protein of the invention.

[0277] Merely by way of example, a vector in accordance with such an embodiment may be a lentivirus vector, as considered further in the Examples.

[0278] A cell comprising a nucleic acid in accordance with the invention may be used to produce a chimaeric protein in accordance with the invention. Accordingly, in a further aspect, the invention provides a method of producing a chimaeric protein in accordance with invention, the method comprising: providing a cell comprising a nucleic in accordance with the invention, and maintaining the cell under conditions such that it produces a chimaeric protein in accordance with the invention.

[0279] Nucleic acids in accordance with the invention represent suitable agents that may be provided to cancer cells, such as cancer cells of tumours, in order to bring about the treatment of cancer.Methods of treatment and medical uses

[0280] The chimaeric protein, nucleic acid, or pharmaceutical composition in accordance with the invention may be used for the treatment of any condition noted above for the compounds of the present invention.

[0281] The invention also provides a chimaeric protein, nucleic acid, or pharmaceutical composition in accordance with the invention, for use as a medicament in the prevention or treatment of a disorder. Suitably the disorder is a LMO2-associated cancer.

[0282] In a suitable embodiment, the LMO2-associated cancer is selected from: LMO2-associated lung cancer; LMO2-associated pancreatic cancer; LMO2-associated colorectal cancer; adrenocortical carcinoma; bladder urothelial carcinoma; breast invasive carcinoma; cervical squamous cell carcinoma or endocervical adenocarcinoma; cholangiocarcinoma; colon adenocarcinoma; lymphoid neoplasm diffuse large B-cell lymphoma; oesophageal carcinoma; glioblastoma multiforme; head and neck squamous cell carcinoma; kidney chromophobe; kidney renal clear cell carcinoma; kidney renal papillary cell carcinoma; acute myeloid leukaemia; brain lower grade glioma; liver hepatocellular carcinoma; lung adenocarcinoma; lung squamous cell carcinoma; ovarian serous cystadenocarcinoma; pancreatic adenocarcinoma; pheochromocytoma or paraganglioma; prostate adenocarcinoma; rectum adenocarcinoma; sarcoma; skin cutaneous melanoma; stomach adenocarcinoma; testicular germ cell tumours; thyroid carcinoma; thymoma; uterine corpus endometrial carcinoma; uterine carcinosarcoma; and uveal melanoma.

[0283] The invention provides a method of preventing or treating a condition associated with expression of LMO2, the method comprising providing a therapeutically effective amount of a chimaeric protein according to the invention to a subject in need thereof. The condition associated with expression of LMO2 may be selected from the group consisting of: T-ALL; LMO2+ breast cancer; LMO2+ prostate cancer; LMO2+ acute myeloid leukaemia (AML) and LMO2+ diffuse large B cell lymphoma.

[0284] The invention also provides a chimaeric protein, nucleic acid, or pharmaceutical composition in accordance with the invention, for use as a medicament in the prevention or treatment of a condition associated with expression of LMO2, such as T-ALL.“Providing” a chimaeric protein of the invention

[0285] It will be recognised that the chimaeric proteins of the invention may be “provided” as required (for example, to a subject or to cells) by administration of the protein itself, suitably incorporated in a pharmaceutical composition of the invention.

[0286] It will be appreciated that the chimaeric proteins of the invention achieve theirtherapeutic effects via intracellular actions. Accordingly, in a suitable embodiment a chimaeric protein of the invention may be adapted in order to promote entry of the chimaeric protein into cells. Suitable adaptations may include, but are not limited to, those selected from the group consisting of: addition of protein transduction domains; and addition of internalising immunoglobulin g (IgG) sequences. Suitable protein transduction domains may be selected from the group consisting of: Antennapedia peptide; and HIV TAT peptide.

[0287] However, it will also be appreciated that the chimaeric proteins of the invention may also be provided to a subject by means of administration, and subsequent expression, of a nucleic acid molecule in accordance with the invention. Such expression may be permanent expression. Alternatively, the expression may be transient expression sufficient to provide a therapeutically effective amount of a chimaeric protein of the invention.

[0288] Suitably a nucleic acid for use to provide a chimaeric protein of the invention may be mRNA. Suitably a nucleic acid for use to provide a chimaeric protein of the invention may be provided in the form of a vector or plasmid. Suitably such a vector may be a viral vector.Therapeutic agents of the invention, and therapeutically effective amounts

[0289] A “therapeutic agent” of the invention may be a chimaeric protein of the invention, a nucleic acid molecule of the invention, or a pharmaceutical composition of the invention (comprising such a chimaeric protein or nucleic acid molecule)

[0290] A “therapeutically effective amount” of a therapeutic agent of the invention is an amount sufficient to delay, inhibit, or alleviate either clinical symptoms or progression of a disorder to be treated.

[0291] A therapeutically effective amount of a therapeutic agent of the invention may be provided in a single incidence of administration. Alternatively, a therapeutically effective amount of a therapeutic agent of the invention may be provided by means of multiple incidences of administration.

[0292] A medical use or method of treatment in accordance with the aspects of the invention may be initiated after diagnosis of a subject as having a condition associated with expression of LMO2, such as T-ALL. Alternatively, a medical use or method of treatment in accordance with the aspects of the invention may be initiated in respect of a subject having symptoms consistent with having a condition associated with expression of LMO2, such as T-ALL.Further uses of the chimaeric proteins of the invention

[0293] In a still further aspect, the invention provides a method of killing cancer cells that express LMO2, the method comprising contacting the cancer cells with an effective amount of a chimaeric protein of the invention. The cancer cells that express LMO2 may be associated with T-ALL, with LMO2+ breast cancer, with LMO2+ prostate cancer, or with LMO2+ diffuse large B cell lymphoma.

[0294] The chimaeric protein of the invention may be provided by administration of the protein, or by administration of a nucleic acid molecule of the invention. Either a protein of the invention or a nucleic acid molecule of the invention may be provided by means of a pharmaceutical composition of the invention.

[0295] As noted above, LMO2 is also known to play a role in angiogenesis (vascular remodelling). Accordingly, the chimaeric proteins of the invention can be used as anti-angiogenic agents to interfere with the angiogenesis by inhibiting LMO2 activity. Particular conditions associated with angiogenesis in which LMO2 inhibition is beneficial may include: tumour metastasis; diabetic retinopathy; corneal neovascularisation; age-related macular degeneration; and pathological angiogenesis arising in, for example, autoimmune diseases, rheumatoid arthritis, atherosclerosis, cerebral ischemia, cardiovascular diseases and delayed wound healing.

[0296] Thus, in another aspect, the present invention provides a chimaeric protein of the invention as defined hereinbefore for use in the treatment of angiogenesis or for use as an anti-angiogenic agent.

[0297] In another aspect, the present invention provides the use of a chimaeric protein of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore in the manufacture of medicament for use in the treatment of angiogenesis or for use as an anti-angiogenic agent.

[0298] In another aspect, the present invention provides a method of treating angiogenesis in a warm-blooded animal, such as man, that is in need of such treatment, which comprises administering an effective amount of a chimaeric protein of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore.

[0299] In another aspect, the present invention provides a chimaeric protein of the invention as defined hereinbefore for use in the treatment of angiogenesis associated with one or more of the following: tumour metastasis, diabetic retinopathy; corneal neovascularisation; age-related macular degeneration; and pathological angiogenesis arising in, for example, autoimmune diseases, rheumatoid arthritis, atherosclerosis, cerebral ischemia,cardiovascular diseases and delayed wound healing.

[0300] In another aspect, the present invention provides the use of a chimaeric protein of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined hereinbefore in the manufacture of medicament for use in the treatment of angiogenesis associated with one or more of the following: tumour metastasis, diabetic retinopathy; corneal neovascularisation; age-related macular degeneration; and pathological angiogenesis arising in, for example, autoimmune diseases, rheumatoid arthritis, atherosclerosis, cerebral ischemia, cardiovascular diseases and delayed wound healing.

[0301] In another aspect, the present invention provides a method of treating angiogenesis in a warm-blooded animal, such as man, that is in need of such treatment, which comprises administering an effective amount of a chimaeric protein of the invention, as defined hereinbefore; and wherein the angiogenesis is associated with one or more of the following: tumour metastasis, diabetic retinopathy; corneal neovascularisation; age-related macular degeneration; and pathological angiogenesis arising in, for example, autoimmune diseases, rheumatoid arthritis, atherosclerosis, cerebral ischemia, cardiovascular diseases or delayed wound healing.“Pharmaceutical compositions of the invention”

[0302] Another aspect of the invention provides a pharmaceutical composition comprising a chimaeric protein of the invention and / or a nucleic acid encoding a chimaeric protein of the invention and a pharmaceutically acceptable carrier.

[0303] Nanoparticles represent a suitable example of a pharmaceutically acceptable carrier that may be used in the pharmaceutical compositions of the invention.

[0304] The protein may be a protein in accordance with the invention (which is to say the pharmaceutical composition may comprise a chimaeric protein comprising a ubiquitin ligase domain and an LMO2-specific endogenous targeting portion and / or a nucleic acid molecule comprising a nucleic acid sequence encoding a chimaeric protein comprising a ubiquitin ligase domain and an LMO2-specific endogenous targeting portion).

[0305] An appropriate chimaeric protein and / or nucleic acid molecule of the invention to be incorporated in a pharmaceutical composition may be determined with respect to the medical use to which the pharmaceutical composition is to be put (in keeping with the discussions of medical uses elsewhere in the specification).

[0306] A pharmaceutical composition of the invention may be formulated for use by any desired route of administration.

[0307] Suitably, the pharmaceutical composition may be formulated for injection. For instance, the pharmaceutical composition may be formulated for intravenous administration, such as intravenous infusion. Such a pharmaceutical composition may comprise pharmaceutically acceptable excipients, buffers, and the like, as is conventional in the art.

[0308] The pharmaceutical composition may be in lyophilized form.

[0309] The pharmaceutical composition of the present invention may optionally comprise a pharmaceutically acceptable additive, in addition to the chimaeric protein or nucleic acid molecule of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof and / or a carrier as described above. Examples of such an additive include an emulsifier aid (e.g., a fatty acid containing 6 to 22 carbon atoms or a pharmaceutically acceptable salt, hydrate or solvate thereof, albumin, dextran), a stabilizing agent (e.g., cholesterol, phosphatidic acid), an isotonizing agent (e.g., sodium chloride, glucose, maltose, lactose, sucrose, trehalose), and a pH adjuster (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, triethanolamine). These additives may be used either alone or in combination. The content of the additive(s) in the pharmaceutical composition of the present invention is reasonably 90% by weight or less, such as 60% by weight or less, and suitably 50% by weight or less.

[0310] The pharmaceutical composition of the present invention may be prepared by adding the compound (e.g. chimaeric protein or nucleic acid molecule) of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof to a dispersion of a carrier, followed by adequate stirring. The additive(s) may be added at any appropriate stage, either before or after adding the compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof. Any aqueous solvent may be used for adding the compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof as long as it is pharmaceutically acceptable, and examples include injectable water, injectable distilled water, electrolytic solutions (e.g., physiological saline), and sugar solutions (e.g., glucose solution, maltose solution). Moreover, in this case, conditions including pH and temperature may be selected as appropriate by those skilled in the art.

[0311] Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985. For a brief review of methods for drug delivery, see, e.g., Langer (Science 249:1527-1533, 1990). WO 2007 / 031091 provides further suitable and preferred examples of pharmaceutically acceptable diluents and carriers (hereby incorporated by reference). Suitable dosages, formulations, administration routes, compositions, dosage forms, combinations with other therapeutic agents, pro-drug formulations are also provided in W02007 / 031091.

[0312] The pharmaceutical composition of the present invention may be formulated into a solution or a lyophilized formulation thereof. Such a lyophilized formulation may be prepared in a standard manner by freeze-drying the pharmaceutical composition of the present invention in a solution form. For example, the pharmaceutical composition of the present invention in a solution form may be sterilized as appropriate (e.g. by conventional sterilization or sterile filtration techniques) and then dispensed in given amounts into vial bottles, followed by preliminary freezing under conditions of about -40°C to -20°C for about 2 hours, primary drying at about 0°C to 10°C under reduced pressure and then secondary drying at about 15°C to 25°C under reduced pressure. Moreover, in most cases, the vials may be purged with a nitrogen gas and then capped, thereby giving a lyophilized formulation of the pharmaceutical composition of the present invention.

[0313] Such a lyophilized formulation of the pharmaceutical composition of the present invention may generally be used after being reconstituted by addition of any appropriate solution (i.e., a reconstituting solution). Examples of such a reconstituting solution include injectable water, physiological saline, and other commonly used infusion solutions. The volume of such a reconstituting solution will vary, e.g., depending on the intended use and is not limited in any way, but it is reasonably 0.5- to 2-fold greater than the solution volume before freeze-drying, or 500 mL or less.

[0314] The pharmaceutical composition of the present invention may be administered in any pharmaceutically acceptable mode, which may be selected as appropriate for the intended therapeutic method. Suitable methods include intravenous administration, intraarterial administration, intramuscular administration, subcutaneous administration, oral administration, interstitial administration, percutaneous administration and so on. Moreover, the composition of the present invention may be in any dosage form, and examples include various types of injections, oral formulations, drops, inhalants, ointments, lotions, etc.SEQUENCE INFORMATION

[0315] SEQ ID NO: 1Amino acid sequence of UBOX-VH 576, an exemplary chimaeric protein of the invention MRLNFGDDIPSALRIAKKKRWNSIEERRIHQESELHSYLSRLIAAERERELEECQRNHEGDE DDSHVRAQQACIEAKHDKYMADMDELFSQVDEKRKKRDIPDYLCGKISFELMREPCITPSGI TYDRKDIEEHLQRVGHFDPVTRSPLTQEQLIPNLAMKEVIDAFISENGWVEDYLEGGGGSA AAMDYKDDDDKTSMAEVQLLESGGGLVQPGGSLRLSCAASGFSFSHSPMNWVRQAPGKGLEWVSYISYNSSSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGLTESLE LTADWFDYWGQGTLVTVSS

[0316] SEQ ID NO: 2Amino acid sequence of VH576-UBOX, an exemplary chimaeric protein of the invention MDYKDDDDRPMAEVQLLESGGGLVQPGGSLRLSCAASGFSFSHSPMNWVRQAPGKGLE WVSYISYNSSSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGLTESLELTA DWFDYWGQGTLVTVSSLEGGGGSAAARLN FGDDI PSALRI AKKKRWNSI EERRI HQESELH SYLSRLIAAERERELEECQRNHEGDEDDSHVRAQQACIEAKHDKYMADMDELFSQVDEKR KKRDIPDYLCGKISFELMREPCITPSGITYDRKDIEEHLQRVGHFDPVTRSPLTQEQLIPNLA MKEVIDAFISENGWVEDYEXAMPLES

[0317] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.AbbreviationsAbd for antibody derivedAITL for angioimmunoblastic T cell lymphomaALL for acute lymphoblastic leukaemiaAR for androgen receptorBL for Burkitt lymphomaBME for 2-MercaptoethanolBoc for tert-butyloxycarbonylBRET for bioluminescence resonance energy transferCML for chronic myeloid leukaemiacSPR for competitive surface plasmon resonanceDLBCL for diffuse large B cell lymphomaDMF for N, N-dimethylformamideDMSO for dimethylsulfoxide.EDTA for ethylenediaminetetraacetic acidESI for electrospray ionisationEtOAc for ethyl acetateFBS for fetal bovine serumFL for follicular lymphomaGFP for green fluorescent proteinGNRH for gonadotropin-releasing hormoneGS for glycine serineh for hoursHATU for N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBSS for Hank’s balanced salt solutionHPLC for high performance liquid chromatography HPLC for High Pressure Liquid Chromatography.HRMS for high resolution mass spectrometryHTS for high throughput screeningiDAbs for intracellular domain antibodiesIPTG for isopropyl 1-thio-beta-D-galactopyranosidLB for lysogeny brothLC-MS for liquid chromatography mass spectrometryLH for leutenising hormoneLMO2 for LIM domain only proteinLRMS for low resolution mass spectrometrymCPBA for meta-chloroperoxybenzoic acidMl for Molecular IonMin for minutesNMR for Nuclear Magnetic Resonance.NSCLC for non-small cell lung cancerPAL for photoaffinity labellingPAMPA for parallel artificial membrane permeability assay Papp for apparent permeabilityPARP for poly ADP ribose polymerasePBS for phosphate buffer salinePCR for polymerase chain reactionPEG for polyethylene glycolPPI for protein protein interactionsppm for parts per millionPS for penicillin / streptomycinPVDF for polyvinylidene difluorideRT for Room temperatureRll for response unitsSAR for structure activity relationshipSCC for squamous cell carcinomaSDS-PAGE for sodium dodecyl sulfate polyacrylamide gel electrophoresisSERM for selective estrogen receptor degraderSPR for surface plasmon resonanceTFA for trifluoroacetic acidTHF for tetrahydrofuranTLC for thin layer chromatographyPART AFiguresFigure 1. LMO2 protein degradation in HEK293T cells after transfection with biodegrader constructs

[0318] HEK293T cells were co-transfected with 1 pg pEF-BOS-LMO2 and plasmids expressing different iDAb LMO2-E3 ligase fusions for 24 hours. The amount of the iDAb LMO2-E3 ligase plasmids was titrated from 0 to 1.0 pg. pEF-BOS (vector plasmid) was used to equalise the amount of plasmid transfection to 2 ug. Western blotting analysis showing the expression of LMO2 in cells transfected with CRBN-iDAb LMO2 (panel A), iDAb LMO2-CRBN (panel B), anti-RAS iDab-CRBN (panel C), UBOX-iDAb LMO2 (panel D), iDAb LMO2-UBOX (panel E), UBOX-anti-RAS DARPin (panel F), VHL-iDAb LMO2 (panel G), iDAb LMO2-VHL (panel H), and VHL-anti-RAS DARPin) (panel I). The antibodies used for protein detection are shown to the right of each panel. The anti-FLAG and anti-myc 9E10 antibodies detect the FLAG and myc tag on each iDAb-E3 ligase, the anti-CRBN antibody detects the transfected iDAb-CRBN in panels A-C and anti-VHL detects the transfected iDAb-VHL in panels G-l. Loading control proteins were detected with either anti-cyclophilin B or anti- -actin.Figure 2. Lentiviral infection of T cells for biodegrader expression

[0319] The T cell lines Jurkat (LMO2-), KOPT-K1 (LMO2+) and P12-lchikawa (LMO2+) cells were infected with lentivirus packaging plasmids and transfer vector (TLCV2-VH576-L10-CRBN) for 16 hours followed by 2 pg / ml doxycycline induction for 9, 24, and 48 hours. The lentivirus packaging plasmids and starting vector (TLCV2-Cas9) were infected in Jurkat, and KOPT-K1 cells for 16 hours, followed by 2 pg / ml doxycycline induction for 9 and 24 hours. The infection efficiency was determined as a percentage of GFP expressing cells using FACS analysis (panel A). Cell viabilities were determined using CellTiter-Glo assays (panel B) and caspase 3 / 7 activity determined after lentivirus infection using a Caspase-Gio 3 / 7 assay (panel C). Data represent mean + SEM (n=3). Western blotting analysis was used to show LMO2 levels in Jurkat and KOPT-K1 cells after infected with the TLCV2-Cas9 vector following 2 pg / ml doxycycline induction for 24 hours, a-tubulin was used as an internal loading control for Western blotting analysis (panel D). The levels of LMO2 (panel E), endogenous CRBN and VH576-L10-CRBN (panel F) were determined after Jurkat, KOPT-K1 or P12-Ichikawa cells were infected with TLCV2-VH576-L10-CRBN followed by 2 pg / ml doxycycline induction for 9, 24, and 48 hours and a-tubulin was used as an internal loading control (panel G).Figure 3. Chemical structures of Abd degrader PROTAC compounds

[0320] Structure-activity observations of LMO2-binding compounds derived using iDAb VH576 in competitive, cell-based BRET (designated Abd compounds)

[0017] contributed to a general structure of the LMO2-binding compounds (panel A). Based on broad tolerance to chemical modification at position R’, two PROTACs were synthesised, one bearing the VHL ligand (Abd-VHL, panel B) and the other bearing thalidomide (the CRBN ligand) (Abd-CRBN, panel C). Each PROTAC thus comprises the LMO2-binding ligand, a linker and an E3 ligase ligand.Figure 4. LMO2 protein in KOPT-K1 and Jurkat cells after treatment with Abd compounds

[0321] KOPT-K1 and Jurkat cells were treated with different concentration of Abd-degraders at 0, 5, 10, and 20 pM for 2, 6, and 24 hours, protein extracts prepared and fractioned by SDS-PAGE followed by Western blotting with the antibodies indicated by each panels A-F. Abd-CRBN was used on cells in panels A-C and Abd-VHL in panels D-F. Cell treated with 1% DMSO was used as a control and p-actin was used as an internal loading control for the Western blotting analysis. On the right-hand side of each panel, quantification densitometry is shown for LMO2 levels in the treated KOPT-K1 cells, presented as mean relative densitometry units, with standard deviation. The viability of KOPT-K1 cells were treated with 15 pM Abd-CRBN (panel G) or 15 pM Abd-VHL (panel H) for 0, 2, 4, 6, and 24 hours viability determined using CellTiter-Glo assay. Data are presented as a relative to luminescence at 0 hours, normalized to 100%. Determination of DC50 values of Abd-CRBN and Abd-VHL after 24 hours treatment in KOPT-K1 was determined using CellTiter-Glocalculated by GraphPad Prism 9.0 software (panels I and J, respectively). All the values were presented as the average values relative to cell viability values in control (DMSO treated cells) normalized to 100%. Data represent mean + SEM (n=3).Figure 5. LMO2 levels and viability of KOPT-K1 cells treated with Abd degrader compounds and E3 ligase inhibitors

[0322] The involvement of proteasome machinery was investigated in KOPT-K1 cells with either proteosome inhibitors or by competing the potential of the Abd degraders with free E3 ligase ligand. Western blot data show LMO2 expression in KOPT-K1 cells after the treatment with or without inhibitors followed by Abd-compounds (panels A, C, E). Inhibitors used were the proteasome inhibitor epoxomicin (0.8 pM), or CRBN inhibitors (10 pM thalidomide, and 10 pM lenalidomide) (panels A, C) orfree VHL ligand (panel E). These were added to cell cultures for 2 hours prior the treatment of 20 pM Abd-CRBN or Abd-VHL and further cultured for 24 hours. Cells treated with 1% DMSO was used as a control, p-actin was used as an internal loading control for Western blotting analysis. Densitometry analysis of LMO2 expression in KOPT-K1 was presented as mean relative densitometry units, with standard deviation (panels B, D, F). After the treatment, cell viability was measured by counting live cells after staining with trypan blue (panels G, H and I). Data represent mean + SEM (n=3). KOPT-K1 cells were also treated with or without protein NEDDYIation inhibitor (10 pM MLN4941) for 2 hours prior the treatment of Abd-CRBN (J) or Abd-VHL (panel K) for 24 hours. CellTiter-Glo assays (panels L and M) was used to measure viability and presented as a relative to luminescence in in DMSO treated cells and normalized to 100%. Data represent mean + SEM (n=3).Figure 6. LMO2 protein in T cells after treatment with Abd compounds

[0323] LMO2 expressing T-cells were treated with 20 pM Abd-CRBN or Abd-VHL for 24 and 48 hours and protein extracts were prepared for Western blot to detect LMO2 protein, RAS protein as negative control and p-actin was used as an internal loading control. Western blotting analysis data show LMO2 expression in KOPT-K1 (panel A), PF382 (B), P12-lchikawa (C), CCRF-CEM (D), MOLT-16 (E), and LOUCY (F) that was affected by treatment with the LMO2 PROTAC compounds. Comparative cell numbers were determined from increase in viability determined using the CellTiter-Glo assay. Data represent mean + SEM (n=3). LMO2 expressing cell lines tested were KOPT-K1 ((G) t(11; 14)(p13;q11)), PF382 (H), P12-lchikawa (I, t(11;14)(p13;q11)), CCRF-CEM (J), MOLT-16 (K), and LOUCY (L). LMO2 non-expressing T-cells were also treated with 20 pM Abd-CRBN or Abd-VHL for 24 and 48 hours after which relative luminescence was determined using the CellTiter-Glo assay. Cells tested were Jurkat (M), DND-41 (N), ALL-SIL (O), SUPT-1 (P), and RPMI8402 (Q). Data represent mean + SEM(n=3).Figure 7. Caspase and PARP cleavage in K0PT-K1 and Jurkat cells after treatment with Abd degraders

[0324] KOPT-K1 and Jurkat cells were treated with Abd-CRBN or Abd-VHL and effects on viability and programmed cell death were analysed at different times. Panel A. Time course of progressive expression of caspases after the treatment with compounds was assayed for caspase 3 / 7 levels using Caspase-Gio® 3 / 7. Treatment was with 20 pM Abd-CRBN or Abd-CRBN followed by cell culture for 4, 6, 12, 20, 24 and 30 hours. Cell treated with 1% DMSO in culture medium was control. Data represent mean + SEM (n=3). Panel B. KOPT-K1 and Jurkat cells were treated with 20 pM Abd-CRBN or Abd-CRBN and cultured for 24 or 48 hours. Cell extracts were made and proteins subjected to Western blotting analysis with specific antibodies for detection of LMO2, Caspase3, cleaved-Caspase3, Caspase?, cleaved-caspase?, PARP, and cleaved-PARP. p-actin protein detection was used as an internal loading control for Western blotting analysis.Supplementary Figure 1. Lentivirus infection of Jurkat and KOPT-K1 cells with doxycycline activation

[0325] Jurkat and KOPT-K1 cells were infected with lentivirus-CRBN for 48 hours followed by 2 rounds puromycin selections. The selected cells were treated with 2 pg / ml doxycycline for 24 hours prior FACS analysis of GFP expression and cell lysate preparation. Jurkat cells infected with biodegrader vector (TLCV2-iDAb-L10-CRBN) were grown without doxycycline (panel A) or with 2 pg / ml doxycycline (B). KOPT-K1 cells were infected with biodegrader vector (TLCV2-iDAb-L10-CRBN) and grown without doxycycline (C) or with 2 pg / ml doxycycline (D). (E) Western blot data showed CRBN expression in Jurkat and KOPT-K1 cells after infected with TLCV2-iDAb-L10-CRBN for 48 hours with (+dox) or without (-dox) 2 pg / ml doxycycline, p-actin was used as an internal loading control for Western blotting analysis.Supplementary Figure 2. Viability of KOPT-K1 and Jurkat cells after treatment with Abd compounds and Abd degraders

[0326] Panel A: Chemical structures of LMO2 Abd compounds. Panel B: KOPT-K1 and Jurkat cells were treated at 20 pM of Abd-compounds or degrader Protac compounds from 0 to 48 hours. Cell viability after the treatment was measured by counting viable cells after staining cells with trypan blue. Panel C and D: Cell viability was also determined using trypan blue after the treatment with different concentrations of Abd degrader compounds (0, 5, 10, and 20 pM) for 2, 6, and 24 hours. Panel E and F: CellTiter-Glo viability assays of KOPT-K1 and Jurkat cells treated with a single 20 pM dose of Abd-CRBN (E) or Abd-VHL (F) for upto 48 hours. All the values are presented as the average viable cells per ml. Data represent mean + SEM (n=3).Supplementary Figure 3. Dose response of T cell lines with Abd degraders

[0327] T cells were treated with Abd-CRBN or Abd-VHL in a dose range from 0-25 pM for 24 hours. The effect on viability was measured using CellTiter-Glo assays at 24 hours in Jurkat, KOPT-K1, and MOLT-3 with Abd-CRBN (panels A-C) or with Abd-VHL (panels D-F). Data represent mean + SEM (n=3). EC50 values were determined from dose-response curves generated using Graph Pad Prism 9.0 software.Supplementary Figure 4. Longevity of responses of KOPT-KI cells to single dose treatment with Abd degraders

[0328] KOPT-K1 and Jurkat cells were treated with 20 pM of Abd-compounds and cultured from 0 to 72 hours. Western blot data of LMO2 and RAS expression in cells were treated with Abd-CRBN (A) and Abd-VHL (B). p-actin was used as an internal loading control for Western blotting analysis. Cell viability was determined using CellTiter-Glo assay after the treatment with Abd-CRBN (C) and Abd-VHL (D) at points during the 72 hours. All the values are presented as the average luminescence values. Data represent mean + SEM (n=3). Supplementary Figure 5: Verification of LMO2 non-expressing T cell lines

[0329] Five human T cell lines were verified by Western analysis of total protein extracts and probed with anti-LMO2, anti-RAS and p-actin as an internal loading control. No LMO2 was detectable. In addition, off-target effects, as determined by RAS protein levels, of the Abd-CRBN and Abd-VHL were tested by treating the cells with 20 pM Abd degraders for 24 hours and 48 hours followed by Western blotting.Supplementary Figure 6: RT-PCR analysis of the human T cell ALL panel

[0330] Agarose gel electrophoresis of LMO1 (A), LMO2 (B), and KRAS (C) PCR products the different human T cell lines (KOPT-K1, P12-lchikawa, MOLT-3, PF-382, Jurkat, DND-41, and ALL-SIL). Lane M represents a 1 kb ladder.RT-PCR primer sequences.LMO1: PCR product 410 bpForward GATCCAGCCCAAAGGGAAGCAGReverse GATAAAGGTGCCATTGAGCTGLMO2: PCR product 220 bpForward GATTCCTCGGCCATCGAAAGGReverse GATGTTTGTAGTAGAGGCGCCGKRAS: PCR product 249 bpForward GATATGACTGAATATAAACTTGTGGTAGReverse GATGGCAAATACACAAAGAAAGCSupplementary Figure 7: Caspase? and cleaved-Caspase? in Jurkat and KOPT-K1 cells after the treatment of doxorubicin.

[0331] Western blot data showed Caspase? and cleaved-Caspase? after the treatment with 1 pM doxurubicin from 0-48 hours. At 48 hours treatment, doxorubicin at 1 pM induced 100% cell death in KOPT-K1 cells. (B) Cell viability after the treatment at 4, 6, 12, 20, 24 and 30 hours in Jurkat and KOPT-K1 cells was determined using CellTiter-Glo assay. Data represent mean + SEM (n=3).Supplementary Figure 8: Confirmation of KOPT-KI chromosomal translocation in KOPT-KI tissue culture cells

[0332] The human T-ALL cells carries an LMO2 activating chromosomal translocation t(11;14)(p13;q11). The gPCR forward primers were designed to bind different 3’-end of the breakpoint region and reverse primer was designed to bind at 5’-end of the breakpoint region (A). Agarose gel electrophoresis was used to evaluate the PCR products (B), the different size of PCR products is showed in lane 1 and 2. Lane M represents a 1 kb ladder.

[0333] The sequence of the genomic PCR primers were derived from the published breakpoint has been REF and the relevant germline sequences of chromosomes 11 and 14.Supplementary Figure 9: Amino Acid sequence of anti-LMO2 VH protein (VH576).Supplementary Figure 10: Contacts of Structural Restraint between LMO2 and binding single domain antibody VH576.Materials and MethodsMolecular cloning

[0334] The iDAb LMO2-E3 ligases fusions were generated by polymerase chain reaction (PCR) using Phusion High-Fidelity PCR kit (NEB). pEF-VH576-L10-FLAG-CRBN-mb was used as a template to generate VH576-L10-FLAG-CRBN; pEF-FLAG-CRBN-L5-VH576-myc was used as a template to generate FLAG-CRBN-L5-VH576; pEF-VHL-L5-FLAG-VH576-mb was used as a template to generate VHL-L5-FLAG-VH576; pEF-NtFarn-FLAG-VH576-L10-VHL was used as a template to generate FLAG-VH576-L10-VHL; pEF-UBOX-L5-FLAG-VH576-mb was used as a template to generate UBOX-L5-FLAG-VH576; pEF-NtFarn-FLAG-VH576-L5-UBOX was used as a template to generate FLAG-VH576-L5-UBOX. All the PCR templates were previously described

[0017] , PCR products were cloned into pEF-BOS plasmid and sequenced to confirm inset with the vector.Cell culture

[0335] Human T-ALL cell lines KOPT-K1, Jurkat, MOLT-3, ALL-SIL, DND-41, PF382, SLIPT-1, RPMI8402, and P12-lchikawa cell lines were cultured in RPMI-1640 medium (ThermoFisher) supplemented with 10% foetal bovine serum (FBS) (Pan-Biotech). HEK293T cell line was cultured in DM EM (Life Technologies) supplemented with 10% FBS. Cells were grown at 37°C in a humidified incubator with 5% CO2 and were regularly performed mycoplasma test using a MycoAlert Mycoplasma Detection kit (Lonza). Cells with mycoplasma-free were used for experiments.Transient Transfection

[0336] HEK293T cells were seeded on 6-well plate at 3x105 cells / well and incubated at 37°C with 5% CO2 until 70-80% confluence determined visually. After 24 hours, cells were transfected with Lipofectamine2000 reagent (Invitrogen) according to manufacturer’s instructions. An iDAb LMO2-E3 ligase plasmid (ranging from 0-1.0 pg) was mixed with 1 pg pEF-BOS-LMO2 expression vector

[0036] and diluted in 150 ul Opti-MEM reduced serum medium (ThermoFisher). 10 pl Lipofectamine2000 was diluted in 150 ul Opti-MEM reduced serum medium. The diluted DNA was added to diluted Lipofectamine2000 and incubated for 15 minutes at room temperature. After the incubation, the mixture was added to the HEK293T cells. After 24 hours of transfection, the transfected cells were detached from the plate using trypsin-EDTA (0.05%), phenol red (GibcoTM) and incubated at 37°C for 2 minutes. Two volumes of pre-warmed complete media were added to inactivate trypsin, and dispersal of the medium, by pipetting over the cell layer surface, was used to recovery of >95% of cells. Cell pellets were collected by centrifugation at 100g for 5 minutes at room temperature.Western blotting

[0337] Cells were washed with PBS before lysis with RIPA buffer (Sigma-Aldrich) (50mM Tris-HCL, pH 8.0, 150mM sodium chloride, 1.0% Igepal CA-630 (NP-40), 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulphate) supplemented with PierceTM protease inhibitor tablets, EDTA-free (ThermoFisher). Cells were lysed on ice and vortexed every 5minutes for 30 mins, then centrifuged at 10,000g, 10 minutes at 4 °C. Protein concentrations were quantified using PierceTM BCA Protein assay kit (ThermoFisher) with the BCA standard curve range from 0-2 mg / ml. Equal amounts of protein samples were separated on 10% or 15% SDS-PAGE and subsequently transferred to polyvinylidene fluoride (PVDF) membrane (Amersham, Cytiva) by wet blotting method. The membrane was blocked with 10% non-fat milk (Sigma-Aldrich) in PBST (PBS with 0.1% Tween20 (Sigma-Aldrich)) before incubation with primary antibodies overnight at 4 °C on a roller. After the incubation, the membrane was washed with PBST for 5 minutes and repeating washing step for 5 times. The washed membrane was incubated with horseradish peroxidase-conjugated secondary antibodies at room temperature for 1 hour on a roller and washed with PBST for 5 minutes and repeating the washing step for 5 times. The membrane was incubated with ClarityTM western blotting substrate (Bio-Rad) for 1 minute before exposure to a ChemiDoc imager (Bio-Rad). For quantification, densitometry analysis of protein expression was analysed using Image Lab software.Reverse transcription-PCR (RT-PCR)

[0338] The expression of LMO1 and LMO2 was verified using RT-PCR method using the primers shown in Supplementary Fig. 6. 1x107 cells were harvested and lysed by using 0.5% NP40 lysis buffer (Thermo Scientific). Total cellular RNA was extracted from the supernatant by using water-saturated phenol pH6.6 (InvitrogenTM), 2M NaAc pH5.0 was added to 300mM and 100% ethanol to 70% to precipitate RNA at-20°C for 2 hours. The pellet was washed with 70% aqueous ethanol, dried at room temperature. The RNA precipitate was dissolved in 10mM Tris pH7.5. The final RNA concentration was measured using NanodropTM spectrophotometer (Thermo Scientific). Two pg of RNA was used for first strand cDNA synthesis with 100pmoles oligo(dT)12-18 primer (InvitrogenTM) and 20 units SuperScriptTM II Reverse Transcriptase (InvitrogenTM). Primers for LMO1 were forward 5’-GATCCAGCCCAAAGGGAAGCAG-3’, reverse 5’-GATAAAGGTG CCATTGAGCTG-3’. Primers for LMO2 were forward 5’-GATTCCTCGGCCATCGAAAGG-3’, reverse 5’-GATGTTTGTAGTAGAGGCGCC G-3’. Primers for KRAS were forward 5’-GATATGAC TGAATATAAACTTGTGGTAG-3’, reverse 5’-GATGGCAAATACACAAAGAAAGC-3’. PCR was performed by using DNA Engine Tetrad® Thermal cycler (Bio-Rad). The PCR conditions were 98°C 1 minute 1 cycle for initial denaturation, and 30 cycles of 98°C 10 seconds for denaturation, 65°C 15 seconds for annealing, 72°C 30 seconds per 1 kb for extension, then 72°C 10 minutes for final extension. The PCR products were resolved on 1.0% agarose gel, visualized by SYBR safe staining, and quantified using ChemiDoc imager (Bio-Rad).Genomic PCR

[0339] The presence of the chromosomal translocation t(11; 14)(p13;q11) in KOPT-K1 cells

[0027] was confirmed using genomic PCR. The derived genomic translocation sequence is shown in Supplementary Fig 8. Total DNA was extracted from 1x106 KOPT-K1 cells by using DNeasy Blood& Tissue kit (Qiagen) according to the manufacturer’s instruction. The final DNA concentration was measured using NanodropTM spectrophotometer (Thermo Scientific). One hundred ng of DNA template was used to generate PCR using Phusion High-Fidelity PCR kit (NEB). PCR was performed by using DNA Engine Tetrad® Thermal cycler (Bio-Rad). The forward and reverse primers used to confirm the chromosomal translocation in KOPT-K1 was forward two 5’-GATGAATTCGAAGCTACTGCAGCCATC-3’, forward three 5’-GATGAATTCATGCTATG AGGTAGGTATG-3’, and J delta reverse 5’-GATGGATCCGGTTCCACAGTCACTCGGGTTCC-3’. The PCR condition was 98°C 1 minute 1 cycle for initial denaturation, followed by 98°C 10 seconds for denaturation, 65°C 15 seconds for annealing, 72°C 15 seconds for extension for 30 cycles, then 72°C 10 minutes for final extension. The PCR products were resolved on 1% agarose gel, visualized by SYBR safe staining, and quantified using ChemiDoc imager (Bio-Rad).Cell assays with Abd-CRBN, Abd-VHL and inhibitors

[0340] Assays for the LMO2 PROTAC compounds Abd-CRBN and Abd-VHL were carried out with compounds synthesized by contract with O2H Discovery. All compounds (Abd compounds and epoxomicin, thalidomide, VHL, and MLN4924) were dissolved in 100% DMSO at 10mM and stored in small aliquots -20 °C. The stability of the compounds was evaluated before using for experiments by using Liquid Chromatography-Mass Spectrometry (LC-MS) method using a Xevo TQ Mass spectrometer instrument.Cell viability assays

[0341] The number of viable cells was measured by staining cells with 0.4% Trypan blue solution (InvitrogenTM) and counting with CountessTM Automated Cell Counter (InvitrogenTM). For inhibition studies, KOPT-K1 cells were seeded in 6-well plate at 5x105 cells / well. After the incubation at 37°C in a humidified incubator with 5% CO2 for 24 hours, cells were pre-treated with inhibitor compounds (epoxomicin, thalidomide, or lenalidomide) or Neddylation inhibitor (MLN4924) for 2 hours or proteasome inhibitor (epoxomicin) for 24 hours prior the treatment of Abd compounds for 24 hours. For apoptosis studies, KOPT-K1 cellswere seeded in 6-well plate at 5x105 cells / well. After the incubation at 37°C in a humidified incubator with 5% CO2 for 24 hours, cells were treated with Abd-CRBN or Abd-VHL for 24 or 48 hours.

[0342] Cell viability was also assessed by CellTiter-Glo® (Promega) according to the manufacturer’s instruction. Cells were seeded in triplicate in white 96-well plate (PerkinElmer) at 1x104 cells / well. After the treatment with compounds, an equal amount of CellTiter-Glo® reagent was added to each well and incubated at room temperature for 10 minutes before the luminescence signal measurement using PHERAstar® FSX (BMG Labtech).Dose response and EC50 determination

[0343] KOPT-K1, Jurkat, and MOLT-3 cells were seeded in white 96-well plate at 1x104 cells / well and incubated at 37°C in a humidified incubator with 5% CO2. After 24 hours incubation, cells were treated with 5, 10, 15, 20, or 25 pM of Abd-CRBN or Abd-VHL for 24 hours. The viable cells were measured using CellTiter-Glo® assay. The EC50 was calculated using Prism9 GraphPad Software. For dose response by western blotting analysis, KOPT-K1 and Jurkat cells were seeded in 6-well plate at 5x105 cells / well and the incubation at 37°C in a humidified incubator with 5% CO2 for 24 hours. Then, cells were treated with Abd-CRBN or Abd-VHL compounds at concentration of 5, 10, or 20 pM for 2, 6, or 24 hours.Caspase3 / 7 activity assay

[0344] Caspase activity was measured using Caspase-Gio® 3 / 7 (Promega) according to the manufacturer’s instruction. Cells were seeded in triplicate in white 96-well plate (PerkinElmer) at 1x104 cells / well. After the treatment with Abd-CRBN or Abd-VHL compounds for 24 hours, an equal amount of CellTiter-Glo® reagent was added to each well and mixed using a plate shaker at 300 rpm for 30 seconds, incubated the plate at room temperature for 1 hour before the luminescence signal measurement using PHERAstar® FSX (BMG Labtech).Synthesis of Abd-CRBNethyl 2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxylate

[0345] 1-(3-Methoxybenzyl)piperazine (150 mg, 0.728 mmol, 1.2 eq.) was dissolved in 1,4-dioxane / N, N-diisopropylethylamine (4:1, 5 mL) before addition of ethyl 2-chlorooxazole-4-carboxylate (116 mg, 0.661 mmol, 1.0 eq.). The solution was stirred at 60 °C for 48 h, cooled down to room temperature, diluted with EtOAc (20 mL) and washed with H2O / brine (1:1, 20mL). The organic phase was dried (Na2SC>4), filtered and concentrated in vacuo. The crude material was then purified on silica gel on silica gel (4% MeOH in CH2CI2) afford the title compound as a yellow oil (163 mg, 71%), after purification on silica gel (4% MeOH in CH2CI2).ethyl 2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxylate

[0346] Ethyl 2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxylate (200 mg, 0.580 mmol, 1.0 eq.) was dissolved in THF / MeOH (4:1) before addition of NaOH (1M aq.) until pH> 8. The resulting reaction was stirred for 16 h at room temperature and then acidified with HCI (1M aq.) until pH<5. The solution was concentrated in vacuo and the obtained carboxylic acid (184 mg, quant.) used directly in the next step.ethyl 4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamido)benzoate

[0347] 2-(4-(3-Methoxybenzyl)piperazin-1-yl)thiazole-4-carboxylic acid (184 mg, 0.580 mmol, 1.0 eq.) was dissolved in DMF (4 mL) before sequential addition of N, N-diisopropylethylamine (303 pL, 1.74 mmol, 3.0 eq.), benzocaine (115 mg, 0.696 mmol, 1.2 eq.) and HATLI (309 mg, 0.812 mmol, 1.4 eq.). The resulting solution was stirred for 18 h, diluted with EtOAc (10 mL) and washed with brine / water (1:1, 3 x 50 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The title product was obtained as a colourless oil that solidified on standing (247 mg, 92%), after purification on silica gel (4% MeOH in CH2CI2).4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamido)benzoic acid

[0348] Ethyl 4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamido) benzoate (120 mg, 0.252 mmol, 1.0 eq.) was dissolved in THF / MeOH (4:1) before addition of NaOH (1M aq.) until pH> 8. The resulting reaction was stirred for 16 h at room temperature and then acidified with HCI (1M aq.) until pH<5. The solution was concentrated in vacuo and the obtained carboxylic acid (114 mg, quant.) used directly in the next step.N-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamide

[0349] 4-(2-(4-(3-Methoxybenzyl)piperazin-1-yl)oxazole-4-carboxamido)benzoic (65mg, 0.150 mmol, 1.2 eq.) was dissolved in DMF (1 mL) before sequential addition of N, N-diisopropylethylamine (66 pL, 0.381 mmol, 3.0 eq.), 4-((6-aminohexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (47 mg, 0.127 mmol, 1.0 eq.) and HATLI (80 mg, 0.210 mmol, 1.4 eq.). The resulting solution was stirred for 18 h, diluted with EtOAc (10 mL) and washed with brine / water (1:1, 3 x 50 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The title product was obtained as a colourless oil (89 mg, 89%), after purification on silica gel (10% MeOH in CH2CI2).Synthesis of Abd-VHL

[0350] tert-Butyl 2-(2-(2-aminoethoxy)ethoxy)acetate was prepared followed literature precedent.tert-butyl 2-(2-(2-(4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido) benzamido)ethoxy)ethoxy)acetate

[0351] 4-(2-(4-(3-Methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzoic (36 mg, 0.080 mmol, 1.0 eq.) was dissolved in DMF (1 mL) before sequential addition of N, N-diisopropylethylamine (42 pL, 0.240 mmol, 3.0 eq.), tert-butyl 2-(2-(2-aminoethoxy)ethoxy)acetate (20 mg, 0.086 mmol, 1.2 eq.) and HATU (43 mg, 0.112 mmol, 1.4 eq.). The resulting solution was stirred for 18 h, diluted with EtOAc (10 mL) and washed with brine / water (1:1, 3 x 50 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The title product was obtained as a colourless oil (30 mg, 57%), after purification on silica gel (10% MeOH in CH2CI2).2-(2-(2-(4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4 carboxamido)benzamido) ethoxy)ethoxy) acetic acid

[0352] tert-Butyl 2-(2-(2-(4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido) benzamido)ethoxy)ethoxy)acetate (30 mg, 0.046 mmol, 1.0 eq.) was dissolved in CH2CI2 (1 mL) before addition of TFA (10 pL) in one portion. The reaction was stirred for 16 h at room temperature, concentrated in vacuo and the title product was obtained as a yellow oil (27 mg, quant.) and used directly in the next step.VHL ligand:

[0353] The VHL ligand ((2S,4R)-1-((R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide) was prepared following literature precedent with a small modification; the first 2 steps were replaced by a Suzuki reaction. The final product was columned before use (not carried out in the literature).N-(4-((2-(2-(2-(((R)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidine-1 -yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl) carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0354] 2-(2-(2-(4-(2-(4-(3-Methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzamido) ethoxy)ethoxy) acetic acid (20 mg, 0.033 mmol, 1.0 eq.) was dissolved in DMF (1 mL) before sequential addition of N, N-diisopropylethylamine (17 pL, 0.100 mmol, 3.0 eq.), 2S,4R)-1-((R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (17 mg, 0.040 mmol, 1.2 eq.) and HATLI (18 mg, 0.046 mmol, 1.4 eq.). The resulting solution was stirred for 18 h, diluted with EtOAc (10 mL) and washed with brine / water (1:1, 3 x 50 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The title product was obtained as a colourless oil (9 mg, 27%), after purification on silica gel (18% MeOH in CH2CI2), followed by two successive preparative TLC (15% MeOH in CH2CI2 with double elution).ResultsInduced LMO2 degraded by interaction of IDAb biodegraders

[0355] The mouse model of LMO2 tumourigenesis showed that expression of LMO2 in thymus T cells resulted in clonal T cell neoplasia and a differentiation block at the immature CD4-CD8 double negative (DN) stage

[0022] , Expressing the anti-LMO2 iDAb VH576 in clonal tumours from these mice showed that tumour growth was inhibited in a transplantation model

[0015] , It has previously been shown that intracellular antibodies could be engineered to carry warheads of pro-caspase that cause antigen-dependent apoptosis

[0023] and suggested that other fusion proteins could be designed to affect other cellular pathways such as proteolysis

[0024] , This was demonstrated using targeted protein degradation of KRAS

[0025] , In order to improve the efficacy of the anti-LMO2 iDAb, it was fused directly with an E3 ligase to potentially mediate a binary interaction between iDAb-E3 ligase and the target to allow ubiquitination of LMO2 and proteasomal degradation. Previous work with an anti-RAS iDAb and an anti-RAS DARPin successfully fused the intracellular macromolecule with one of two different E3 ligase (VHL or UBOX E3 ligase) to achieve RAS degradation

[0025] , Figure 1 shows the effect similar E3 ligase fusions with the anti-LMO2 iDAb, where the fusions were either at the N- or C-terminus of the iDAb. The fusion-expressing plasmids were transfected into HEK293T host cells along with an LMO2 expressing plasmid, proteins were extracted at 24 hours and separated on SDS-PAGE for Western blotting analysis with the panel of antibodies. Targeted protein degradation of LMO2 was observed in each of the six iDAb-E3 ligase proteins (Fig. 1, panels A, B, D, E, G and H). No detectable loss of control protein RAS was observed (or of the loading controls, cyclophilin-B and p-actin). Conversely, using anti-RAS iDAb-CRBN or anti-KRAS DARPin-UBOX or anti-KRAS DARPin-VHL (Fig. 1, panels C, F and I, respectively) caused turnover of RAS but not LMO2. While precise quantification of E3 ligase efficacy is difficult as this approach used a co-transfection protocol, the iDAb-E3 ligase fusions seem to have different efficacy depending on the E3 ligase chosen. Nonetheless, the VHL-iDAb LMO2 appears as the best degrader compared to the other proteins in this approach (Fig. 1).

[0356] These data demonstrated that the proteasome dependent degradation of LMO2 could be achieved with all three types of iDAb-E3 ligase in HEK293T. As it was found that standard transfection methods were inefficient at introducing expression plasmids into human T cell lines, initial analyses of potential LMO2 biodegraders were conducted with coexpression of LMO2 and biodegraders. It was an objective to reproduce these data in natural LMO2 expression settings (i.e. T-ALL lines), therefore, a lentivirus was produced that conditionally expresses inserted cDNAs via a doxycycline-inducible promoter (TLCV2

[0026] ) and a version was made to express anti-LMO2 iDAb VH576 fused to CRBN E3 ligase (designated TLCV-iDab-CRBN). This lentivirus was used to infect both Jurkat cells (that lack LMO2 expression) and KOPT-K1

[0027] or P12-lchikawa cells

[0028] (expressing LMO2 after chromosomal translocations for 16 hours without doxycycline induction followed by induction for up to 64 hours). Infection was monitored by GFP expression that arises from the induced mRNA from an internal ribosome entry site (IRES) before the GFP coding region (Fig. 2A). Surprisingly, GFP expression was not detected in KOPT-K1 or P12-lchikawa cells when infected cells with TLCV-iDab-CRBN whereas Jurkat cells acquired increasing GFP over the time course of the analysis, the infection efficiency of KOPT-K1 and Jurkat cells was compared using the original TLCV2-cas9-IRES-GFP and the levels were virtually the same (Fig. 2A) showing that the differences are not simply due to the inability to infect KOPT-K1 or P12-Ichikawa with the TLCV2-based virus. In an attempt to make stable lines, the infection time was increased to 48 hours. However, selection of infected cells with puromycin followed by doxycycline induction showed much poorer GFP expression (from the IRES-GFP of the vector) in KOPT-K1 than Jurkat cells (Supplementary Fig. 1A-D). Further, the expression of iDAb-CRBN (as determined by CRBN Western signal, Supplementary Fig. 1E) was low in infected KOPT-K1 compared to Jurkat cells. These data correlate susceptibility of KOPT-K1 and P12-lchikawa cells to TLCV-iDab-CRBN with LMO2 expression since Jurkat cell does notexpress LM02.

[0357] A possible explanation for the apparent intransigence of KOPT-K1 or P12-Ichikawa cells to stably infect with TLCV-iDab-CRBN is that, despite the tight tetracycline control of the TLCV expression, sufficient iDab-CRBN is produced during infection and selection to differentially inhibit the growth of infected KOPT-K1 or P12-lchikawa, whereas the infection with original TLCV2-cas9-IRES-GFP does not have an effect on either Jurkat and KOPT-K1 cells (Fig. 2B). In addition, the TLCV-iDab-CRBN infection induced cell apoptosis as shown by increasing caspase 3 / 7 activity in KOPT-K1 and P12-lchikawa cells compared to Jurkat cell, while there is no difference in infected KOPT-K1 and Jurkat cells with TLCV2-cas9-IRES-GFP (Fig. 2C). The level of LMO2 expression after infection of Jurkat and KOPT-K1 cells was confirmed by Western blotting, showing infection with TLCV2-cas9-IRES-GFP followed by the induction with doxycycline does not have an effect on LMO2 protein expression (Fig. 2D). However, the infection of TLCV-iDab-CRBN in KOPT-K1 and P12-lchikawa cells caused the reduction of LMO2 protein expression, although iDab-CRBN could not be detected (Fig. 2E).

[0358] This suggested that chemical compounds equivalent to the biodegrader format, i.e. in PROTACs format

[0029] , could lead to a potent, drug-precursor inhibitor of LMO2. The inventors developed a chemical series that bind to LMO2 in cells and the chemical matter was identified using an intracellular antibody binding site

[0017] to compete compounds in a method called ‘Antibody derived technology’ (Abd technology)

[0030] , Exemplified compounds are shown in Supplementary Fig. 2A. Abd-L21 and Abd-L27 were used, based on previously described SAR

[0017] as starting points for the PROTAC design.

[0359] PROTACs comprise a ligand binding moiety and a ligand binding an E3 ligase held via a linker. The challenges in PROTACs synthesis thus include the choice of exit vector for attachment on the ligand for the protein of interest, the length, composition and conformational properties of the linker, and the choice of E3 ligase ligand. LMO2 is a disordered protein and soluble protein for structural studies have not been produced, except when co-expressed with the iDAb

[0016] that was used for the competitive screen of the compound library

[0017] , In the absence of structural data to indicate potential exit vectors for linker / E3 ligase ligand attachment, compounds were prepared bearing substituents on different positions of the structure to assess where LMO2 binding was maintained or diminished. Representative examples of the Abd library are shown in Supplementary Fig. 2A

[0017] , In summary, it was found that there was a broad tolerance of a range of para-substituents on the right-hand side arene ring. Similarly on the left-hand side, meta-substituted arenes were preferred with a range of substituents tolerated. Piperazine was preferred to the imidazolidin-2-one, seen in Abd-L9, for activity, stability, and ease of synthesis, and was therefore selectedfor PROTACs design. Thiazole and oxazole were found to be interchangeable without any noticeable difference in activity, although the thiazole series were found to be easier to synthesize with higher chemical stability and better yields. It was decided to use a medium length linker as a starting point, namely two PEG units for the VHL-binding ligand and a six carbon alkyl unit for the CRBN-binding ligand. Accordingly, two Abd E3 ligase ligand bifunctional molecules, designated Abd-VH Land Abd-CRBN, were synthesized with either the VHL or thalidomide E3 ligase ligand respectively (Fig. 3).

[0360] Initial cell viability assays with the compound Abd-L9, L17, L19 and L21 consistently showed evidence of LMO2-independent toxicity since both LMO2-expressing KOPT-K1 and non-expressing Jurkat cells lost viability after about 24 hours (Supplementary Fig. 2B). This affect was less pronounced when the Abd-VHL and Abd-CRBN compounds were assayed as the KOPT-K1 cells exhibited lower viability (Supplementary Fig. 2B). This difference was clearer when titrating the Abd-VHL and Abd-CRBN compounds over a concentration range during a 24 hours assay period since Jurkat cells were largely unaffected, while KOPT-K1 showed greater loss of viability with increased PROTACs concentration (Supplementary Fig. 2C). In addition, 20 pM Abd-CRBN or Abd-VHL showed a larger effect on viability between the two cell lines up to 48 hours incubation (Supplementary Fig. 2E, F, respectively). The effect of the Abd-CRBN or Abd-VHL compounds on LMO2 protein levels was assessed in a dose response in KOPT-K1 and Jurkat cells. Cells were treated with a single dose of the compound, ranging from 0-20 pM, for 2, 6 or 24 hours followed by analysis of protein levels by Western blotting analysis or cell growth (Fig. 4). LMO2 levels are reduced following treatment by either Abd-CRBN (panels A-C) or Abd-VHL (panels D-F) whereas control protein RAS levels are unaffected. There is also a progressive loss of LMO2 protein from 6 hours onwards up to the end point of 24 hours. This finding was paralleled with loss of cell viability over the 24 hours period when KOPT-K1 cells were treated with 15 pM of either compound (Fig. 4G, H). The half-maximal degradation dose (DC50) was determined by treating KOPT-K1 with Abd-CRBN (Fig. 4I) or Abd-VHL (Fig. 4J) in a dose range from 0-25 pM for 24 hours. The analysis was showed that the DC50 in KOPT-K1 was 14 pM and 12 pM for Abd-CRBN and Abd-VHL, respectively. The half-maximal effective concentration (EC50) values were in a comparable range with the DC50 when we evaluated the effects on KOPT-K1 and MOLT-3 cells (another LMO2 expressing cell line) (Supplementary Fig. 3). In both these LMO2-expressing cells it was found that Abd-CRBN has a lower improved EC50 compared to Abd-VHL and Jurkat cells were largely resistance to either compound at the 24 hours points and in the dose range (Supplementary Fig. 4). The longevity of degradation response was followed using CellTitre-Glo assays and showed lower viability in KOPT-K1 and MOLT-3 during the 72 hours of cell culture after a single dose of compounds (using 20 pM).Little or no effect was observed in the LMO2 non-expressing Jurkat cells range (Supplementary Fig. 4C and D).

[0361] The involvement of proteasome machinery in the LMO2 protein turnover was confirmed in KOPT-K1 cells using either proteosome inhibitors or by competing the potential of the Abd degraders with free E3 ligase ligands (Fig. 5). Treating KOPT-K1 cells with Abd-CRBN causes LMO2 degradation, as shown in Western blotting analysis, and this is partly reduced by addition of the proteasome inhibitor epoxomicin, and by the CBRN ligand thalidomide, and its derivative lenalidomide (Fig. 5A, quantified in panel B). Conversely, thalidomide does not compete the effects of LMO2 protein shown by incubated cells with Abd-VHL (Fig. 5C, quantified in panel D) while free VHL ligand does restore LMO2 protein levels in cells treated with Abd-VHL but has no effect on those treated with Abd-CRBN (Fig. 5E, quantified in panel F). Accompanying these data, we observed that cell viability was only affected in cells treated with one of the Abd degraders alone or with a heterologous ligand (Fig. 5, G-l), suggesting that addition of the Abd degrader compounds alone does not cause loss of KOPT-K1 cell viability but rather requires the associated loss of the LMO2 protein. Treating the KOPT-K1 cells with single doses of Abd-CRBN with or without the MLN4924 Neddylation inhibitor for 24 hours showed similar effects on the LMO2 protein degradation (Fig. 5J) whereas Abd-VHL with MLN4924 restored the LMO2 protein levels (Fig. 5K) The correlation between cell viability with loss of LMO2 by targeted protein is quantified in Figure 5, panels L, M.

[0362] The lack of LMO2 protein was confirmed in the latter by Western blotting analysis (Supplementary Fig. 5) and RT-PCR analysis (Supplementary Fig. 6). Those expressing LMO1 were confirmed by RT-PCR (Jurkat, SUP-T1, RPMI8402 (which has an LMO1 chromosomal translocation t(11; 14)(p15;q11) and LOUCY has mRNA for both LMO1 and LMO2, Supplementary Fig. 6). All the cell cultures were treated with 20 pM of either Abd degrader in a single dose and the culture continued for 24 and 48 hours. At time 0 and at the two culture time points, cells were split and part taken from the LMO2 expressing cells for whole cell protein extracts and Western blotting analysis (Fig. 6), and part used for growth analysis for all the cells (Fig. 6). All the LMO2 expressing T cell lines show progressive LMO2 protein degradation when cultured in the presence of the Abd-CRBN or the Abd-VHL. No effect was observed in any of these cells on RAS protein levels (Fig. 6) and p-actin was used for loading control.

[0363] Comparing the effects on the cell growth showed marked differences in response of cells with LMO2 and those lacking LMO2. Those with LMO2 expression, in which the Abd compounds are associated with targeted protein degradation, displayed a significant reduction (p<0.001) in cell growth over 48 hours compared to cells treated with DMSO vehicleonly (Fig. 6, G-L). Conversely, those without LMO2 showed little difference in growth of cells with only DMSO and those with the Abd degraders (Fig. 6, M-Q). Thus non-expressing cell lines do not appear to show toxicity when treated with 20 pM compounds (also indicated in Supplementary Fig. 5).

[0364] These data support the conclusion that the Abd degrader targeted protein degradation of LMO2 has a consequence for cell division and viability of the T cell lines.

[0365] Since the cell growth is reduced by the LMO2 degradation, it was investigated whether this was occurring by programmed cell death (PCD). KOPT-K1 or Jurkat cells were treated with a single 20 pM dose of either Abd-CRBN or Abd-VHL for up to 30 hours and caspase 3 and 7 activation determined at various time points (Fig. 7A). Increased levels of caspases were found in LMO2-expressing KOPT-K1 treated with either Abd compound, rising 10 fold (from 23325 RLU at 4 hours to 228865 RLU at 30 hours) using Abd-CRBN and 25 fold increase (from 19460 RLU at 4 hours to 476843 RLU at 30 hours) using Abd-VHL. This rise in activated caspases mirrors loss of LMO2 as judged by Western blotting analysis (Fig. 7B) and with appearance of cleaved caspase 3, cleaved caspase 7 and cleaved poly(ADP-ribose) polymerase (PARP). The increase is caspase 3 / 7 in KOPT-K1 cells treated with Abd-CRBN is lower than observed with Abd-VHL, reflected by relatively low levels of protein detected in Western blot.

[0366] Conversely, the effect of both compounds on the LMO2-negative Jurkat cells was a small increase in caspase 3 / 7 levels over the time course of the experiment. This increased 2.6 fold (from 16223 RLU at 4 hours to 43651 RLU at 30 hours) using Abd-CRBN and 4.5 fold (from 20309 RLU at 4 hours to 92683 RLU at 30 hours) using Abd-VHL. Western blotting analysis up to 48 hours of treatment with compounds did not show significant levels of activated, cleaved caspase 3 and only small amounts of activated, cleaved caspase 7 at 48 hours after treatment with Abd-CRBN (Fig. 7B). Similarly, Abd-VHL treatment of Jurkat cells did not induce detectable cleaved caspase 3 or 7 in the Western blotting analysis. Small amounts of cleaved PARP were detected in the Western blotting analysis for treatment with both Abd compounds. Cells treated with only DMSO in culture medium showed essentially no detectable activated caspase 3 / 7 during this growth period (Fig. 7A) nor activated, cleaved caspase or PARP (Fig. 7B). Both Jurkat and KOPT-K1 cells were treated with the chemotherapy reagent doxorubicin to induced PCD to corroborate the detection system for cleaved caspase 7 and this was confirmed using both the luminescence assay and Western blotting analysis (Supplementary Fig. 7).Discussion

[0367] Transcription factors have been considered as hard to drug targets because they are involved in protein-protein or DNA interaction and most often have large intrinsically disordered regions or else they are fully disordered, as in the case of LMO2. Indeed, it has been estimated up to 20% of intracellular proteins are the former type while up to 30% cellular proteins are the latter type

[0031] , This means that chromosomal translocation encoded proteins in acute cancers, which are predominantly transcription regulators [3,4], will mostly exhibit large intrinsically disordered regions. Therefore, using intracellular antibodies as inhibitors is a convenient starting point for drug discovery with these intrinsically disordered proteins. Further, intracellular antibodies can be developed with high affinity and as potent PPI inhibitors. Their efficacy as therapeutics is limited by at least two factors. First, the occupancy time with which the target is engaged by the intracellular antibody is important in inducing a phenotypic effect and second, the current difficulty in delivery macromolecules of this type to specified cells. While the latter problem is awaiting a solution in the future, enhancing intracellular antibody potency by addition of warheads is valuable adjunct to function.

[0368] The use of direct fusion of E3 ligases or procaspase 3 warheads to anti-RAS intracellular antibodies and DARPins showed that the discriminating sensitivity of these macromolecules can be exploited for isoform specific effects

[0025] , Similarly, the anti-LMO2 iDAb used in the current study distinguishes the LMO2 from its three other LIM-only protein paralogues

[0015] , In the initial investigations of the anti-LMO2 iDAb, we showed that it could induce targeted protein degradation of LMO2, whether one of three E3 ligase fusions was engineered at the amino or carboxy termini of the iDAb (Fig. 1). In the binary interaction assay, there appear differences between VHL-iDAb or iDAb-VHL degraders compared to the other E3 fusions, indicating that VHL E3 ligase engineered proteins are better at depletion of LMO2 protein (Fig. 1). In the potential future use of these macromolecules as drugs, this would need to be evaluated in an amendable T cell assay because co-expression of LMO2 was used with the iDAb-E3 ligase fusion in initial analysis, since T cells are intransigent to standard transfection methods. Nonetheless the data show that protein degradation of this transcription factor is achievable when a binary interaction of the iDAb-warhead occurs with LMO2.

[0369] To obviate the technical problem of iDAb delivery into cells, the inventors previously described the Antibody-derived (Abd) technology to screen chemical libraries to derive surrogates of the iDAb paratope

[0017] , The two LMO2 PROTACs are based on the same LMO2-binding Abd compound and differ with a different E3 ligase ligand and linker. Despite this, the two compounds have similar properties of LMO2 degradation and effects of cell growth of T cells with LMO2 proteins (Figs. 4 and 6). The VHL-based PROTAC has a higher molecular weight and lower solubility than the thalidomide version but during the main times in the analysis, the two compounds have similar effects. However, the VHL degrader appearsto induce cell death and inhibit cell proliferation with more efficiency than CRBN degrader (Figs. 6 and 7).

[0370] In particular for potential drug development, the inhibitory effect on the growth of T cell ALL lines that express LMO2 protein with no discernible effect on T-ALL cell lines that lack LMO2. Normal LMO2 protein has a half-life due protein metabolism around 6 hours

[0032] and the effects of both LMO2 PROTACs lasts at least for 48 hours such that re-establishment of LMO2 protein pool does not make a discernible difference to effects on cell growth. One cell line that may not obey this situation is RPM 18402 (Fig. 6). This line also carries a chromosomal translocation of chromosome 11 at band p15 (t(11; 14)(p15;q11)) which activates the LMO1 paralogue of LMO2 [33,34], Treating the line with the LMO2 Abd degrader PROTACs results in a small but reproducible inhibition of growth (Fig. 6). While the anti-LMO2 iDAb has highly specific discrimination of the LMO family proteins, it is possible that LMO2 Abd degraders may cross react with LMO1 in RPMI8402 and cause its degradation thus affecting growth but this is difficult to directly assess as there are no reliable anti-LMO1 antibodies.

[0371] PROTACs are potential compounds for drug development

[0029] and the two compounds here may be progenitors for specifically treating T-ALL expressing LMO2, but extending to potentially include T-ALL with chromosomal 11 band p13 translocations but also to those with aberrant LMO2 expression

[0035] , T-ALL is a sub-type of ALL that occurs in 10% to 15% of paediatric and about 20% of adult ALLs. While survival of children and younger adults is about 80% where treatment regimens involve high dose of chemotherapy, this therapy has longer term side effects such as growth retardations and sterility. Eradication of such treatment-related side effects would clearly be a major advantage as well as the harshness of treatment itself. Further, adults with T-ALL have a median survival of about 50% in the five-year post treatment period, in part due to loss of the T cell repertoire and lack of replacement from thymus T cell precursors in older patients. As a consequence relapsed T-ALL is only successfully treated with less 7% for adult patients surviving at 5 years. The survival in paediatric cases is higher but still only about 20% of relapsed cases. Refractory T-ALL is separate that resists even first stage treatments. The data with the new LMO2 PROTACs suggest that improving the potency and drug-like properties of these LMO2 Abd degraders will lead to new medicines for T-ALL treatment.

[0372] These data also illustrate a strategy for drug discovery for intrinsically disordered proteins such as transcription factors and other chromosomal translocation proteins that were considered as hard-to-drug targets. Employing a human intracellular single domain antibody (iDAb) that inhibits the LMO2-mediated protein complex function

[0015] , the inventors previously used for selecting LMO2-binding compounds

[0017] , The inventors havenow converted these Abd compounds into degrader compounds (PROTACs) that affect the growth of T cell leukaemia lines that express LMO2. This was achieved without the need for recombinant protein and can be applied to any intrinsically disordered proteins, or partly structured protein, without the need for structural information on the protein or the interacting inhibitory iDAb. Affinity manipulation of iDAbs can be achieved simply by mutational analysis of the CDRs (known from primary sequence data). This is a general approach for hard to drug, disordered proteins, such as transcription factors.PART BFiguresFigure 8. Warheads of the PROTAC compounds.Figure 9. BRET data for a variety of warheads.Figure 10. Variable alkyl linker size on the PROTAC compounds.Figure 11. Targeted protein degradation data for a variety of PROTAC compounds at 5 pM, 10 pM, 15 pM and 20 pM.Figure 12. Targeted protein degradation data for a variety of PROTAC compounds at 2.5 pM, 1.25 pM and 0.625 pM.Figure 13. Variable rigid linkers on the PROTAC compounds.Figure 14. Variable alkyl linker size on the PROTAC compounds.Figure 15. Targeted protein degradation data for a variety of PROTAC compounds at 2.5 pM, 1.25 pM and 0.625 pM.Figure 16. Further PROTAC compounds.General Procedure A: Basic Ester Hydrolysis

[0373] Lithium hydroxide monohydrate (5.0 eq.) was added to a solution of requisite ethyl ester (1.0 eq.) in THF (50 mL), water (10 mL) and methanol (5 mL) at room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate and subsequently acidified to pH 2 with 1 M HCI. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified on silica gel togive the desired compound.General Procedure B - Amide coupling

[0374] To a solution of requisite carboxylic acid (1.0 eq.) in DMF (2 mL) was added the corresponding amine (1.2 eq.), DI PEA (3.0 eq.), and HATU (1.4 eq.). The reaction mixture was stirred for 18 h at room temperature before addition of EtOAc (20 mL). The mixture was washed with FW / brine (1:1, 20 mL) and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified on silica gel to give the desired compound.General Procedure C: Synthesis of substituted piperazines■Cr~"O~

[0375] Boc-piperazine (1.1 eq.) was dissolved in CH3CN, before the sequential addition of K2CO3 (2.5 eq.) and the requisite substituted benzyl bromide (1.0 eq.). The resultant mixture was stirred at room temperature for 18 h. After this, H2O (50 mL) and EtOAc (50 mL) were added, and the organic layer separated and washed with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified on silica gel (0-100% EtOAc in pentane) to give the N-Boc benzyl piperazine. The product was dissolved in CH2CI2 (20 mL) before the addition of 4N HCI in 1,4-dioxane (1 mL). The resultant mixture was stirred for 18 h at room temperature and concentrated in vacuo. The compound was used directly in the next step without further purification,General Procedure D: SuAr

[0376] To a solution of the corresponding amine hydrochloride salt (1.2 eq.) in 1,4-dioxane / A / , A / -diisopropylethylamine (4:1, 1 mL) was added the requisite thiazole (1.0 eq.) and was stirred for 24 h at 100 °C. The reaction mixture was then cooled to room temperature, diluted with EtOAc (10 mL) and washed with FW / brine (1:1, 3 x 20mL). The organic phase was then dried over Na2SO4, filtered, and concentrated in vacuo. The compound was purified on silica gel.General Procedure E: Basic hydrolysis of the ester moiety and subsequent amide coupling

[0377] NaOH (1 M aq.) was added to a solution of the ester (1.0 eq.) in a mixture of THF: MeOH (4:1) until pH>8. The resultant mixture was stirred for 18 h at room temperature. After this, the reaction mixture was acidified with HCI (1 M aq.) until pH<5. The solution was concentrated in vacuo and the resultant carboxylic acid was used directly in the next step without further purification. The carboxylic acid was dissolved in DMF (2 mL) before the sequential addition of / V, / V-diisopropylethylamine (3.0 eq.), the requisite amine (1.2 eq.) and HATU (1.4 eq.). The resultant solution was stirred for 18 h, diluted with EtOAc (10 mL) and washed with brine (3x 50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified on silica gel to give the title compound.General Procedure F - Fluoro thalidomide synthesis

[0378] Sodium acetate (2.0 eq.) and 3-aminopiperidine-2, 6-dione hydrochloride (1.0 eq.) were added to a solution of the requisite phthalic anhydride (1.0 eq.) in acetic acid (50 mL). The resulting mixture was heated to 120°C and stirred for 18 h. After cooling to room temperature, the solution was poured onto ice water and filtered. The resultant solid was purified on silica gel to give the desired compound.General Procedure G: A / -Boc deprotection and subsequent SNAR

[0379] 4N HCI in 1,4-dioxane (0.5 mL) was added to a solution of the corresponding Boc-protected amine (1.0 eq.) in CH2Ch(2 mL) and the resultant mixture was stirred for 18 h at room temperature then concentrated in vacuo and the resultant residue was used directly in the next step. / V, / V-Diisopropylethylamine (4.0 eq.) and the requisite fluorothalidomide (1.2 equiv.) were added to a solution of the deprotected product in DMF (1 mL) and the resultant mixture was heated to 100°C for 18 h. After this time, the solution was diluted with EtOAc, and washed with brine (3 x 15 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified on silica gel to give the title product.Experimental data[1] 2-chlorothiazole-4-carboxylic acid

[0380] Following General Procedure A using ethyl 2-chlorothiazole-4-carboxylate ( 3.0 g, 15.7 mmol) and lithium hydroxide monohydrate (3.3 g, 78.3 mmol), the title compound 1 was obtained as a white solid (1.15 g, 45%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0381] m / z LRMS (ESI+): 164 (100%) [M+H]+[2] 2-chlorothiazole-5-carboxylic acid

[0382] Following General Procedure A using ethyl 2-chlorothiazole-5-carboxylate (5.0 g, 26.1 mmol) and lithium hydroxide monohydrate (5.47 g, 130.5 mmol), the title compound 1 was obtained as a white solid (2.88 g, 68%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0383] m / z LRMS (ESI+): 164 (100%) [M+H]+[3] ethyl 4-(2-chlorothiazole-5-carboxamido)benzoate

[0384] Following General Procedure B using carboxylic acid 2 (1.62 g, 9.91 mmol) and benzocaine (1.96 g, 11.88 mmol), the title compound was obtained as a yellow solid (1.92 g, 63%) after purification on silica gel (0-10% MeOH in CH2CI2).[4] ethyl 4-(2-chlorothiazole-4-carboxamido)benzoate

[0385] Following General Procedure B using carboxylic acid 1 (100 mg, 0.61 mmol) and benzocaine (121 mg, 0.73 mmol), the title compound was obtained as a white solid (77 mg, 41%) after purification on silica gel (0-10% MeOH in CH2CI2).

[0386] m / z LRMS (ESI+): 311 (100%) [M+H]+HRMS (ESI+): calc, for CI3HI2CIN2O3S+311.0256 [M+H]+found 311.0252.[5] ethyl 3-(2-chlorothiazole-4-carboxamido)benzoate

[0387] Following General Procedure B using carboxylic acid 1 (100 mg, 0.61 mmol) and ethyl 3-aminobenzoate (121 mg, 0.73 mmol), the title compound was obtained as a white solid (148 mg, 78%) after purification on silica gel (0-10% MeOH in CH2CI2).

[0388] m / z LRMS (ESI+): 333 (100%) [M+Na]+. HRMS (ESI+): calc, for Ci3HnCIN2O3SNa+[M+Na]+333.0062, found 333.0071.[6] 1-(3-methoxybenzyl)piperazine

[0389] Following General Procedure C using N-Boc piperazine (1.02 g, 5.47 mmol) and 1-(bromomethyl)-3-methoxybenzene (1.00 g, 4.97 mmol), the title compound was obtained as a colourless oil (1.50 g, 98%), after purification on silica gel (0-100% EtOAc in pentane).

[0390] m / z LRMS (ESI+): 307 (100%) [M+H]+

[0391] The product was dissolved in CH2CI2 (20 mL) before the addition of 4N HCI in 1,4-dioxane (1 mL). The resultant mixture was stirred for 18 h at room temperature and concentrated in vacuo. The compound was used directly in the next step without further purification (1.18 g, quant.).

[0392] m / z LRMS (ESI+): 207 (100%) [M+H]+[7] 1-(3-(trifluoromethoxy)benzyl)piperazine

[0393] Following General Procedure C using N-Boc piperazine (1.00 g, 5.36 mmol) and 1-(bromomethyl)-3-(trifluoromethoxy)benzene (0.79 mL, 4.88 mmol), the title compound was obtained as a colourless oil (1.45 g, 82%), after purification on silica gel (0-100% EtOAc in pentane).

[0394] m / z LRMS (ESI+): 361 (100%) [M+H]+

[0395] The product was dissolved in CH2CI2 (20 mL) before the addition of 4N HCI in 1,4-dioxane (1 mL). The resultant mixture was stirred for 18 h at room temperature and concentrated in vacuo. The compound was used directly in the next step without further purification (1.19 g, quant.).

[0396] m / z LRMS (ESI+): 261 (100%) [M+H]+[8] 3-(piperazin-1 -ylmethyl)benzonitrile

[0397] Following General Procedure C using N-Boc piperazine (1.00 g, 5.36 mmol) and 3-cyanobenzylbromide (0.97 g, 4.88 mmol), the title compound was obtained as acolourless oil (1.36 g, 74%), after purification on silica gel (0-100% EtOAc in pentane).

[0398] m / z LRMS (ESI+): 302 (100%) [M+H]+

[0399] The product was dissolved in CH2CI2 (20 mL) before the addition of 4N HCI in 1,4-dioxane (1 mL). The resultant mixture was stirred for 18 h at room temperature and concentrated in vacuo. The compound was used directly in the next step without further purification (1.05 g, quant.).

[0400] m / z LRMS (ESI+): 202 (100%) [M+H]+[9] ethyl 4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzoate

[0401] Following General Procedure D using amine 6 (0.47 g, 1.93 mmol) and thiazole 4 (0.50 g, 1.61 mmol), the title was obtained as a brown solid (0.66 g, 85%) after purification on silica gel (0-10% MeOH in CH2CI2).

[0402] m / z LRMS (ESI+): 481 (100%) [M+H]+. HRMS (ESI+): calc, for C25H29N4O4S+481.1910 [M+H]+found 481.1911.

[0010] ethyl 3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzoate

[0403] Following General Procedure D using amine 6 (0.47 g, 1.93 mmol) and thiazole 5 (0.50 g, 1.61 mmol), the title was obtained as a brown solid (0.57 g, 73%) after purification on silica gel (0-10% MeOH in CH2CI2).

[0404] m / z LRMS (ESI+): 481 (100%) [M+H]+. HRMS (ESI+): calc, for C25H29N4O4S+481. 1910 [M+H]+found 481.1905

[0011] ethyl 4-(2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamido)benzoate

[0405] Following General Procedure D using amine 7 (0.23g, 0.772 mmol) and thiazole 4 (0.20 g, 0.644 mmol), the title was obtained as a brown oil (0.33 g, 96%) after purification on silica gel (0-10% MeOH in CH2CI2).

[0406] m / z LRMS (ESI+): 535 (100%) [M+H]+. HRMS (ESI+): calc, for C25H26F3N4O4S+535.1627 [M+H]+found: 535.1622

[0012] ethyl 4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-5-carboxamido)benzoate

[0407] Following General Procedure D using amine 6 (0.47 g, 1.93 mmol) and thiazole 3 (0.50 g, 1.61 mmol), the title was obtained as a white solid (0.59 g, 76%) after purification on silica gel (0-10% MeOH in CH2CI2).

[0408] m / z LRMS (ESI+): 481 (100%) [M+H]+. HRMS (ESI+): calc, for C25H29N4O4S+481.1910 [M+H]+found 481.1912.

[0013] ethyl 4-(2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-5-carboxamido)benzoate

[0409] Following General Procedure D using amine 7 (0.84 g, 2.5 mmol) and thiazole 3 (0.68 g, 2.2 mmol), the title was obtained as a white solid (1.16 g, 99) after purification on silica gel (0-10% MeOH in CH2CI2).

[0410] m / z LRMS (ESI+): 573 (100%) [M+K]+. HRMS (ESI+): calc, for C25H25 F3N4O4SK+573.1185 [M+K]+found 573.1189.

[0014] ethyl 4-(2-(4-(3-cyanobenzyl)piperazin-1-yl)thiazole-5-carboxamido)benzoate

[0411] Following General Procedure D using amine 8 (0.69 g, 2.5 mmol) and thiazole 3 (0.65 g, 2.2 mmol), the title was obtained as a white solid (0.90 g, 90%) after purification on silica gel (0-10% MeOH in CH2CI2).

[0412] m / z LRMS (ESI+): 476 (100%) [M+H]+. HRMS (ESI+): calc, for C25H26N5O3S+476.1756 [M+H]+found 476.1756

[0015] tert-butyl (6-(3-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzamido)hexyl)carbamate

[0413] Following General Procedure E, using thiazole 10 and tert-Butyl (7-aminohept-1-yl)carbamate, the title compound was obtained as a yellow oil (87 mg, 51%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0414] m / z LRMS (ESI+): 651 (100%) [M+H]+. HRMS (ESI+): calc, for C₃₅H₄₇N₆O₅S⁺ 651.3329 [M+H]+found 651.3330

[0016] tert-butyl (2-(4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzamido)ethyl)carbamate

[0415] Following General Procedure E, using thiazole 9 and tert-Butyl A / -(2-aminoethyl)carbamate, the title compound was obtained as a yellow oil (77 mg, 46%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0416] m / z LRMS (ESI+): 595 (100%) [M+H]+. HRMS (ESI+): calc, for C₃₀H₃₉N₆O₅S⁺ 595.2703 [M+H]+found 595.2701

[0017] tert-butyl (3-(4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzamido)propyl)carbamate

[0417] Following General Procedure E, using thiazole 9 and tert-Butyl A / -(3-aminopropyl)carbamate, the title compound was obtained as a yellow oil (115 mg, 67%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0418] m / z LRMS (ESI+): 609 (100%) [M+H]+. HRMS (ESI+): calc, for C3iH4iN6O5S+609.2860 [M+H]+found 595.2855

[0018] tert-butyl (4-(4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzamido)butyl)carbamate

[0419] Following General Procedure E, using thiazole 9 and tert-Butyl N-(4-aminobutyl)carbamate, the title compound was obtained as a yellow oil (91 mg, 71%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0420] m / z LRMS (ESI+): 623 (100%) [M+H]+. HRMS (ESI+): calc. C32H43N6O5S+623.3016 [M+H]+found 623.3010

[0019] tert-butyl (5-(4-(2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamido)benzamido)pentyl)carbamate

[0421] Following General Procedure E, using thiazole 9 and tert-Butyl N-(5-aminopentyl)carbamate, the title compound was obtained as a yellow oil (99 mg, 37%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0422] m / z LRMS (ESI+): 637 (100%) [M+H]+. HRMS (ESI+): calc. Css^sNeOsS*637.3172[M+H]+found 637.3167

[0020] tert-butyl (6-(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzamido)hexyl)carbamate

[0423] Following General Procedure E, using thiazole 9 and tert-Butyl-N-(6-aminohexyl)carbamate, the title compound was obtained as a yellow oil (105 mg, 38%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0424] m / z LRMS (ESI+): 651 (100%) [M+H]+. HRMS (ESI+): calc. C34H47N6O5S+651.3329 [M+H]+found 651.3333

[0021] tert-butyl (7-(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzamido)heptyl)carbamate

[0425] Following General Procedure E, using thiazole 9 and tert-Butyl (7-aminohept-1-yl)carbamate, the title compound was obtained as a yellow oil (72 mg, 46%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0426] m / z LRMS (ESI+): 665 (100%) [M+H]+. HRMS (ESI+): calc. C35H49N6O5S+665.3485 [M+H]+found 665.3489

[0022] tert-butyl (8-(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzamido)octyl)carbamate

[0427] Following General Procedure E, using thiazole 9 and tert-Butyl (8-aminooct-1-yl)carbamate, the title compound was obtained as a yellow oil (131 mg, 51%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0428] m / z LRMS (ESI+): 679 (100%) [M+H]+. HRMS (ESI+): calc. CseHsiNeOsS+679.3642 [M+H]+found 679.3647

[0023] tert-butyl (6-(4-(2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamido)benzamido)hexyl)carbamate

[0429] Following General Procedure E, using thiazole 11 and tert-Butyl-N-(6-aminohexyl)carbamate, the title compound was obtained as a yellow oil (135 mg, 61%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0430] m / z LRMS (ESI+): 705 (100%) [M+H]+. HRMS (ESI+): calc. C34H44F3N6O5S+705.3046 [M+H]+found 705.3050

[0024] tert-butyl (3-(4-(2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamido)benzamido)propyl)carbamate

[0431] Following General Procedure E, using thiazole 11 and tert- Butyl A / -(3-aminopropyl)carbamate, the title compound was obtained as a yellow oil (125 mg, 45%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0432] m / z LRMS (ESI+): 663 (100%) [M+H]+. HRMS (ESI+): calc. C31H38F3N6O5S+663.2577 [M+H]+found 663.2572

[0025] tert-butyl (3-(4-(2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-5-carboxamido)benzamido)propyl)carbamate

[0433] Following General Procedure E, using thiazole 13 and tert- Buty I N- (3-aminopropyl)carbamate, the title compound was obtained as a yellow oil (180 mg, 67%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0434] m / z LRMS (ESI+): 663 (100%) [M+H]+. HRMS (ESI+): calc. C31H38F3N6O5S+663.2577 [M+H]+found 663.2571

[0026] tert-butyl (3-(4-(2-(4-(3-cyanobenzyl)piperazin-1-yl)thiazole-5-carboxamido)benzamido)propyl)carbamate

[0435] Following General Procedure E, using thiazole 14 and tert- Buty I N- (3-aminopropyl)carbamate, the title compound was obtained as a yellow oil (111 mg, 36%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0436] m / z LRMS (ESI+): 604 (100%) [M+H]+. HRMS (ESI+): calc. C31H38N7O4S+604.2706 [M+H]+found 604.2709

[0027] tert-butyl 9-(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0437] Following General Procedure E, using thiazole 9 and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, the title compound was obtained as a yellow oil (154 mg, 69%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0438] m / z LRMS (ESI+): 689 (100%) [M+H]+. HRMS (ESI+): calc. C37H49N6O5S+689.3485 [M+H]+found 689.3486

[0028] tert-butyl 4-(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzoyl)piperazine-1 -carboxylate

[0439] Following General Procedure E, using thiazole 9 and N-Boc piperazine, the title compound was obtained as a yellow oil (82 mg, 54%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0440] m / z LRMS (ESI+): 621 (100%) [M+H]+. HRMS (ESI+): calc C32H4iN6O5S+621.2859 [M+H]+found 621.2864

[0029] tert-butyl 4-(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzamido)piperidine-1 -carboxylate

[0441] Following General Procedure E, using thiazole 9 and l-(terf-butoxycarbonyl)-4-aminopiperidine, the title compound was obtained as a yellow oil (182 mg, 76%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0442] m / z LRMS (ESI+): 635 (100%) [M+H]+. HRMS (ESI+): calc Css^sNeOsS* 635.3016 [M+H]+found 635.3021

[0030] tert-butyl ((1 -(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzoyl)azetidin-3-yl)methyl)carbamate

[0443] Following General Procedure E, using thiazole 9 and tert-butyl (azetidin-3-ylmethyl)carbamate, the title compound was obtained as a yellow oil (132 mg, 65%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0444] m / z LRMS (ESI+): 621 (100%) [M+H]+. HRMS (ESI+): calc C32H4iN6O5S+621.2859 [M+H]+found 621.2864

[0031] tert-butyl 3-((4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzamido)methyl)azetidine-1 -carboxylate

[0445] Following General Procedure E, using thiazole 9 and tert-butyl 3-(aminomethyl)azetidine-l-carboxylate, the title compound was obtained as a yellow oil (140 mg, 56%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0446] m / z LRMS (ESI+): 621 (100%) [M+H]+. HRMS (ESI+): calc C32H4IN6O5S+621.2859 [M+H]+found 621.2857

[0031] tert-butyl 5-(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0447] Following General Procedure E, using thiazole 9 and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, the title compound was obtained as a yellow oil (112 mg, 39%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0448] m / z LRMS (ESI+): 647 (100%) [M+H]+. HRMS (ESI+): calc C34H43N6O5S+647.3016 [M+H]+found 647.3010

[0032] tert-butyl 6-(4-(2-(4-(3-methoxybenzyl)piperazin-1 -yl)thiazole-4-carboxamido)benzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0449] Following General Procedure E, using thiazole 9 and terf-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, the title compound was obtained as a yellow oil (167 mg, 42%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0450] m / z LRMS (ESI+): 633 (100%) [M+H]+. HRMS (ESI+): calc C33H4IN6O5S+633.2859 [M+H]+found 633.2866

[0037] 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1, 3-dione

[0451] Following General Procedure F, using 3-fluorophthalic anhydride and 3-aminopiperidine-2, 6-dione hydrochloride, the title compound was obtained as a purple solid (1.10 g, 81%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0452] m / z LRMS (ESI+): 277 (100%) [M+H]+. HRMS (ESI+): calc Ci3Hi0FN2O4+277.0625 [M+H]+found 277.0629

[0038] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1, 3-dione

[0453] Following General Procedure F, using 4-fluorophthalic anhydride and 3-aminopiperidine-2, 6-dione hydrochloride, the title compound was obtained as a purple solid (0.82 g, 77%), after purification on silica gel (0-10% MeOH in CH2CI2).

[0454] m / z LRMS (ESI+): 277 (100%) [M+H]+. HRMS (ESI+): calc Ci3HioFN204+277.0625 [M+H]+found 277.0631

[0039] N-(3-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0455] Following General Procedure G, using thiazole 15 and fluorothalidomide 37, the title compound was obtained as a yellow solid (21 mg, 54%), after purification on silica (0-10% MeOH in CH2CI2).

[0456] m / z LRMS (ESI+): 807 (100%) [M+H]+. HRMS (ESI+): calc C42H47N8O7S+807.3288 [M+H]+found 807.3291

[0040] N-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0457] Following General Procedure G, using thiazole 16 and fluorothalidomide 37, the title compound was obtained as a yellow solid (18 mg, 42%), after purification on silica (0-10% MeOH in CH2CI2).

[0458] m / z LRMS (ESI+): 751 (100%) [M+H]+. HRMS (ESI+): calc C38H39N8O7S+751.2662 [M+H]+found 751.2657

[0041] N-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0459] Following General Procedure G, using thiazole 16 and fluorothalidomide 38, the title compound was obtained as a yellow solid (15 mg, 48%), after purification on silica (0-10% MeOH in CH2CI2).

[0460] m / z LRMS (ESI+): 751 (100%) [M+H]+. HRMS (ESI+): calc CssHsgNsOyS* 751.2662 [M+H]+found 751.2664

[0042] N-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0461] Following General Procedure G, using thiazole 17 and fluorothalidomide 37, the title compound was obtained as a yellow solid (24 mg, 68%), after purification on silica (0-10% MeOH in CH2CI2).

[0462] m / z LRMS (ESI+): 765 (100%) [M+H]+. HRMS (ESI+): calc C39H4IN8O7S+765.2819 [M+H]+found 765.2812

[0043] N-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0463] Following General Procedure G, using thiazole 17 and fluorothalidomide 38, the title compound was obtained as a yellow solid (14 mg, 61%), after purification on silica (0-10% MeOH in CH2CI2).

[0464] m / z LRMS (ESI+): 765 (100%) [M+H]+. HRMS (ESI+): calc C39H4IN8O7S+765.2819 [M+H]+found 765.2824

[0044] N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0465] Following General Procedure G, using thiazole 18 and fluorothalidomide 38, the title compound was obtained as a yellow solid (8 mg. 22%, after purification on silica (0-10% MeOH in CH2CI2).

[0466] m / z LRMS (ESI+): 780 (100%) [M+H]+. HRMS (ESI+): calc C4oH44N807S+780.3054 [M+H]+found 780.3049

[0045] N-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0467] Following General Procedure G, using thiazole 18 and fluorothalidomide 37, the title compound was obtained as a yellow solid (12 mg, 41%), after purification on silica (0-10% MeOH in CH2CI2).

[0468] m / z LRMS (ESI+): 780 (100%) [M+H]+. HRMS (ESI+): calc C4oH44N807S+780.3054 [M+H]+found 780.3051

[0046] N-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0469] Following General Procedure G, using thiazole 19 and fluorothalidomide 38, the title compound was obtained as a yellow solid (18 mg, 41%), after purification on silica (0-10% MeOH in CH2CI2).

[0470] m / z LRMS (ESI+): 793 (100%) [M+H]+. HRMS (ESI+): calc C41H45N8O7S+793.3132 [M+H]+found 793.3132

[0047] N-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0471] Following General Procedure G, using thiazole 19 and fluorothalidomide 37 the title compound was obtained as a yellow solid (9 mg, 15%), after purification on silica (0-10% MeOH in CH2CI2).

[0472] m / z LRMS (ESI+): 793 (100%) [M+H]+. HRMS (ESI+): calc C41H45N8O7S+793.3132 [M+H]+found 793.3137

[0048] N-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0473] Following General Procedure G, using thiazole 20 and fluorothalidomide 37, the title compound was obtained as a yellow solid (7 mg, 22%), after purification on silica (0-10% MeOH in CH2CI2).

[0474] m / z LRMS (ESI+): 807 (100%) [M+H]+. HRMS (ESI+): calc C42H47N8O7S+807.3288 [M+H]+found 807.3293

[0049] N-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0475] Following General Procedure G, using thiazole 20 and fluorothalidomide 38, the title compound was obtained as a yellow solid (7 mg, 22%), after purification on silica (0-10% MeOH in CH2CI2).

[0476] m / z LRMS (ESI+): 807 (100%) [M+H]+. HRMS (ESI+): calc C42H47N8O7S+807.3288 [M+H]+found 807.3291

[0050] N-(4-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0477] Following General Procedure G, using thiazole 21 and fluorothalidomide 37, the title compound was obtained as a yellow solid (14 mg, 51%), after purification on silica (0-10% MeOH in CH2CI2).

[0478] m / z LRMS (ESI+): 821 (100%) [M+H]+. HRMS (ESI+): calc C43H49N8O7S+821.3445 [M+H]+found 821.3441

[0051] N-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0479] Following General Procedure G, using thiazole 22 and fluorothalidomide 37, the title compound was obtained as a yellow solid (21 mg, 54%), after purification on silica (0-10% MeOH in CH2CI2).

[0480] m / z LRMS (ESI+): 835 (100%) [M+H]+. HRMS (ESI+): calc C44H51N8O7S+835.3601 [M+H]+found 835.3607

[0052] N-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0481] Following General Procedure G, using thiazole 22 and fluorothalidomide 38, the title compound was obtained as a yellow solid (13 mg, 51%), after purification on silica (0-10% MeOH in CH2CI2).

[0482] m / z LRMS (ESI+): 835 (100%) [M+H]+. HRMS (ESI+): calc C44H51N8O7S+835.3601 [M+H]+found 835.3604

[0053] N-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamide

[0483] Following General Procedure G, using thiazole 23 and fluorothalidomide 37, the title compound was obtained as a yellow solid (45 mg, 75%), after purification on silica (0-10% MeOH in CH2CI2).

[0484] m / z LRMS (ESI+): 861 (100%) [M+H]+. HRMS (ESI+): calc C42H44F3N8O7S+861.3006 [M+H]+found 861.3012

[0054] N-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamide

[0485] Following General Procedure G, using thiazole 24 and fluorothalidomide 37, the title compound was obtained as a yellow solid (25 mg, 68%), after purification on silica (0-10% MeOH in CH2CI2).

[0486] m / z LRMS (ESI+): 819 (100%) [M+H]+. HRMS (ESI+): calc C39H38F3N8O7S+819.2536 [M+H]+found 819.2541

[0055] N-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-5-carboxamide

[0487] Following General Procedure G, using thiazole 25 and fluorothalidomide 37, the title compound was obtained as a yellow solid (18 mg, 34%), after purification on silica (0-10% MeOH in CH2CI2).

[0488] m / z LRMS (ESI+): 819 (100%) [M+H]+. HRMS (ESI+): calc C39H38F3N8O7S+819.2536 [M+H]+found 819.2532

[0056] 2-(4-(3-cyanobenzyl)piperazin-1-yl)-N-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)thiazole-5-carboxamide

[0489] Following General Procedure G, using thiazole 26 and fluorothalidomide 37, the title compound was obtained as a yellow solid (11 mg, 23%), after purification on silica (0-10% MeOH in CH2CI2).

[0490] m / z LRMS (ESI+): 760 (100%) [M+H]+. HRMS (ESI+): calc C38H35N9O6S+760.2666 [M+H]+found 760.2661

[0057] N-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0491] Following General Procedure G, using thiazole 27 and fluorothalidomide 37, the title compound was obtained as a yellow solid (21 mg, 37%), after purification on silica (0-10% MeOH in CH2CI2).

[0492] m / z LRMS (ESI+): 845 (100%) [M+H]+. HRMS (ESI+): calc C45H49N8O7S+845.3445 [M+H]+found 845.3441

[0058] N-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0493] Following General Procedure G, using thiazole 27 and fluorothalidomide 38, the title compound was obtained as a yellow solid (16 mg, 31%), after purification on silica (0-10% MeOH in CH2CI2).

[0494] m / z LRMS (ESI+): 845 (100%) [M+H]+. HRMS (ESI+): calc C45H49N8O7S+845.3445 [M+H]+found 845.3443

[0059] N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0495] Following General Procedure G, using thiazole 28 and fluorothalidomide 37, the title compound was obtained as a yellow solid (6 mg, 21%), after purification on silica (0-10% MeOH in CH2CI2).

[0496] m / z LRMS (ESI+): 777 (100%) [M+H]+. HRMS (ESI+): calc C40H41N8O7S+777.2819 [M+H]+found 777.2822

[0060] N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0497] Following General Procedure G, using thiazole 28 and fluorothalidomide 38, the title compound was obtained as a yellow solid (6 mg, 21%), after purification on silica (0-10% MeOH in CH2CI2).

[0498] m / z LRMS (ESI+): 777 (100%) [M+H]+. HRMS (ESI+): calc C40H41N8O7S+777.2819 [M+H]+found 777.2824

[0061] N-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0499] Following General Procedure G, using thiazole 29 and fluorothalidomide 38, the title compound was obtained as a yellow solid (26 mg, 65%), after purification on silica (0-10% MeOH in CH2CI2).

[0500] m / z LRMS (ESI+): 791 (100%) [M+H]+. HRMS (ESI+): calc C41H43N8O7S+791.2975 [M+H]+found 791.2977

[0062] N-(4-((1 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0501] Following General Procedure G, using thiazole 29 and fluorothalidomide 37, the title compound was obtained as a yellow solid (31 mg, 71%), after purification on silica (0-10% MeOH in CH2CI2).

[0502] m / z LRMS (ESI+): 791 (100%) [M+H]+. HRMS (ESI+): calc C41H43N8O7S+791.2975 [M+H]+found 791.2979

[0063] N-(4-(3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)azetidine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0503] Following General Procedure G, using thiazole 30 and fluorothalidomide 38, the title compound was obtained as a yellow solid (18 mg, 36%), after purification on silica (0-10% MeOH in CH2CI2).

[0504] m / z LRMS (ESI+): 777 (100%) [M+H]+. HRMS (ESI+): calc C40H41N8O7S+777.2819 [M+H]+found 777.2824

[0064] N-(4-(3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)azetidine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0505] Following General Procedure G, using thiazole 30 and fluorothalidomide 37, the title compound was obtained as a yellow solid (18 mg, 36%), after purification on silica (0-10% MeOH in CH2CI2).

[0506] m / z LRMS (ESI+): 777 (100%) [M+H]+. HRMS (ESI+): calc C40H41N8O7S+777.2819 [M+H]+found 777.2814

[0065] N-(4-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0507] Following General Procedure G, using thiazole 31 and fluorothalidomide 38, the title compound was obtained as a yellow solid (28 mg, 65%), after purification on silica (0-10% MeOH in CH2CI2).

[0508] m / z LRMS (ESI+): 777 (100%) [M+H]+. HRMS (ESI+): calc C40H41N8O7S+777.2819 [M+H]+found 777.2825

[0066] N-(4-(((1 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0509] Following General Procedure G, using thiazole 31 and fluorothalidomide 37, the title compound was obtained as a yellow solid (22 mg, 52%), after purification on silica (0-10% MeOH in CH2CI2).

[0510] m / z LRMS (ESI+): 777 (100%) [M+H]+. HRMS (ESI+): calc C40H41N8O7S+777.2819 [M+H]+found 777.2821

[0067] N-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0511] Following General Procedure G, using thiazole 31 and fluorothalidomide 38, the title compound was obtained as a yellow solid (19 mg, 45%), after purification on silica (0-10% MeOH in CH2CI2).

[0512] m / z LRMS (ESI+): 803 (100%) [M+H]+. HRMS (ESI+): calc C42H43N8O7S+803.2975 [M+H]+found 803.2981

[0068] N-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0513] Following General Procedure G, using thiazole 31 and fluorothalidomide 37, the title compound was obtained as a yellow solid (25 mg, 49%), after purification on silica (0-10% MeOH in CH2CI2).

[0514] m / z LRMS (ESI+): 803 (100%) [M+H]+. HRMS (ESI+): calc C42H43N8O7S+803.2975 [M+H]+found 803.2972

[0069] N-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0515] Following General Procedure G, using thiazole 32 and fluorothalidomide 38, the title compound was obtained as a yellow solid (24 mg, 41%), after purification on silica (0-10% MeOH in CH2CI2).

[0516] m / z LRMS (ESI+): 789 (100%) [M+H]+. HRMS (ESI+): calc C41H41N8O7S+789.2819 [M+H]+found 789.2826

[0070] N-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide

[0517] Following General Procedure G, using thiazole 32 and fluorothalidomide 37, the title compound was obtained as a yellow solid (31 mg, 48%), after purification on silica (0-10% MeOH in CH2CI2).

[0518] m / z LRMS (ESI+): 789 (100%) [M+H]+. HRMS (ESI+): calc C41H41N8O7S+789.2819 [M+H]+found 789.2824REFERENCES1 Rowley, J. D. Genetics. A story of swapped ends. Science 340, 1412-1413, (2013).2 Rabbitts, T. H. Commonality but diversity in cancer gene fusions. Cell 137, 391-395, (2009).3 Cleary, M. L. Oncogenic conversion of transcription factors by chromosomal translocations. Cell 66, 619-622, (1991).4 Rabbitts, T. H. Translocations, master genes, and differences between the origins of acute and chronic leukemias. Cell 67, 641-644, (1991).5 Williams, D. L. et al. New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia. Cell 36, 101-109, (1984). 6 Boehm, T., Foroni, L., Kaneko, Y., Perutz, M. F. & Rabbitts, T. H. The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proceedings of the National Academy of Sciences of the United States of America 88, 4367-4371, (1991).7 Royer-Pokora, B., Loos, U. & Ludwig, W. D. TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). Oncogene 6, 1887-1893, (1991).8 Warren, A. J. et al. The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell 78, 45-57, (1994).9 Yamada, Y. et al. The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Proceedings of the National Academy of Sciences of the United States of America 95, 3890-3895, (1998).10 Yamada, Y., Pannell, R., Forster, A. & Rabbitts, T. H. The oncogenic LIM-only transcription factor Lmo2 regulates angiogenesis but not vasculogenesis in mice. Proceedings of the National Academy of Sciences of the United States of America 97, 320-324, (2000).11 Yamada, Y., Zhong, Y., Miki, S., Taura, A. & Rabbitts, T. H. The transcription factor complex LMO2 / TAL1 regulates branching and endothelial cell migration in sprouting angiogenesis. Scientific reports 12, 7226, (2022).12 Wadman, I. A. et al. The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1 / NLI proteins. The EMBO journal 16, 3145-3157, (1997).13 El Omari, K. et al. Structural basis for LMO2-driven recruitment of the SCL: E47bHLH heterodimer to hematopoietic-specific transcriptional targets. Cell Rep 4, 135-147, (2013).14 Winter, G. P. Antibody engineering. Philos Trans R Soc Lond B Biol Sci 324, 537-546; discussion 547, (1989).15 Tanaka, T., Sewell, H., Waters, S., Phillips, S. E. & Rabbitts, T. H. Single domain intracellular antibodies from diverse libraries: emphasizing dual functions of LMO2 protein interactions using a single VH domain. The Journal of biological chemistry 286, 3707-3716, (2011).16 Sewell, H. et al. Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex. Scientific reports 4, 3643, (2014).17 Bery, N. et al. A cell-based screening method using an intracellular antibody for discovering small molecules targeting the translocation protein LMO2. Sci Adv 7, (2021). 18 Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proceedings of the National Academy of Sciences of the United States of America 98, 8554-8559, (2001).19 Bekes, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nature reviews. Drug discovery 21, 181-200, (2022).20 Paiva, S. L. & Crews, C. M. Targeted protein degradation: elements of PROTAC design. Curr Opin Chem Biol 50, 111-119, (2019).21 Burslem, G. M. & Crews, C. M. Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell 181, 102-114, (2020).22 Larson, R. C., Osada, H., Larson, T. A., Lavenir, I. & Rabbitts, T. H. The oncogenic LIM protein Rbtn2 causes thymic developmental aberrations that precede malignancy in transgenic mice. Oncogene 11, 853-862, (1995).23 Tse, E. & Rabbitts, T. H. Intracellular antibody-caspase-mediated cell killing: an approach for application in cancer therapy. Proceedings of the National Academy of Sciences of the United States of America 97, 12266-12271, (2000).24 Lobato, M. N. & Rabbitts, T. H. Intracellular antibodies and challenges facing their use as therapeutic agents. Trends Mol Med 9, 390-396, (2003).25 Bery, N., Miller, A. & Rabbitts, T. A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS. Nat Commun 11, 3233, (2020).26 Barger, C. J., Branick, C., Chee, L. & Karpf, A. R. Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer. Cancers (Basel) 11, (2019).27 Dong, W. F. et al. Molecular characterization of a chromosome translocation breakpoint t(11; 14)(p13;q11) from the cell line KOPT-K1. Leukemia 9, 1812-1817, (1995).28 Watanabe, S. et al. Leukemic distribution of a human acute lymphocytic leukemia cell line (Ichikawa strain) in nude mice conditioned with whole-body irradiation. Cancer Res 38, 3494-3498, (1978).29 Li, K. & Crews, C. M. PROTACs: past, present and future. Chem Soc Rev 51, 5214-5236, (2022).30 Quevedo, C. E. et al. Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat Commun 9, 3169, (2018).31 Deiana, A., Forcelloni, S., Porrello, A. & Giansanti, A. Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell. PloS one 14, e0217889, (2019).32 Layer, J. H. et al. LDB1 Enforces Stability on Direct and Indirect Oncoprotein Partners in Leukemia. Mol Cell Biol 40, (2020).33 Boehm, T. et al. The mechanism of chromosomal translocation t(11; 14) involving the T-cell receptor C delta locus on human chromosome 14q11 and a transcribed region of chromosome 11 p15. The EMBO journal 7, 385-394, (1988).34 McGuire, E. A. et al. The t(11;14)(p15;q11) in a T-cell acute lymphoblastic leukemia cell line activates multiple transcripts, including Ttg-1, a gene encoding a potential zinc finger protein. Mol Cell Biol 9, 2124-2132, (1989).35 Abraham, B. J. et al. Small genomic insertions form enhancers that misregulate oncogenes. Nat Commun 8, 14385, (2017).36 Osada, H., Grutz, G., Axelson, H., Forster, A. & Rabbitts, T. H. Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. Proceedings of the National Academy of Sciences of the United States of America 92, 9585-9589, (1995).The following paragraphs are not claims, but are intended to assist in the understanding of the present invention, and identify subject matter for which protection may be sought in connection with the present disclosure.Numbered paragraphs:1. A chimaeric protein comprising a ubiquitin ligase domain and an LMO2-specific endogenous targeting portion, wherein the ubiquitin ligase domain is a IIBOX domain of CHIP, or a fragment or variant thereof having ubiquitin ligase activity and wherein the protein shares at least 85% identity with the amino acid sequence of SEQ ID NO: 1 or 2.2. A chimaeric protein according to paragraph 1, comprising the amino acid sequence of SEQ ID NO: 1 or 2.3. A chimaeric protein according to paragraph 1, consisting of the amino acid sequence of SEQ ID NO: 1 or 2.4. A chimaeric protein according to any of paragraphs 1 or 2, wherein the LMO2-specific endogenous targeting portion is an LMO2-specific intracellular antibody.5. A chimaeric protein according to any preceding paragraph, wherein the ubiquitin ligase domain consists of a single domain.6. A chimaeric protein according to any preceding paragraph, wherein the LMO2-specific endogenous targeting portion consists of a single domain.7. A chimaeric protein according to any preceding paragraph, wherein the ubiquitin ligase domain consists of a single domain and the LMO2-specific endogenous targeting portion consists of a single domain.8. A nucleic acid molecule comprising a nucleic acid sequence encoding a chimaeric proteinaccording to paragraphs 1-7.9. A nucleic acid molecule according to paragraph 8, wherein the nucleic acid molecule is provided in the form of a vector comprising the nucleic acid molecule.10. A nucleic acid molecule according to paragraph 9, wherein the nucleic acid molecule is provided in the form of a lentivirus vector comprising the nucleic acid molecule.11. A pharmaceutical composition, comprising a chimaeric protein according to any of paragraphs 1 to 7 and / or a nucleic acid molecule according to any of paragraphs 8 to 10.12. A method of preventing or treating a LMO2-associated disorder, the method comprising providing a therapeutically effective amount of a chimaeric protein according to any of paragraphs 1 to 7 to a subject in need thereof.13. A method according to paragraph 12, wherein the chimaeric protein is provided by administration of the protein to the subject.14. A method according to paragraph 12, wherein the chimaeric protein is provided by administration of a nucleic acid according to any one of paragraphs 8 to 10 to the subject.15. A method according to any of paragraphs 12 to 14, wherein the protein or nucleic acid molecule is provided by administration of a pharmaceutical composition according to paragraph 11 to the subject.16. A method according to any of paragraphs 12 to 15, wherein the LMO2-associated disorder is selected from the group consisting of: T-cell acute lymphoblastic leukaemia (T-ALL); LMO2+ breast cancer; LMO2+ prostate cancer; and LMO2+ diffuse large B cell lymphoma.17. A chimaeric protein according to any of paragraphs 1 to 7, nucleic acid according to paragraphs 8 to 10 or a pharmaceutical composition according to paragraph 11 for use as amedicament.18. A chimaeric protein, nucleic acid or pharmaceutical composition for use according to paragraph 17 in the prevention and / or treatment of a LMO2-associated disorder.19. A chimaeric protein, nucleic acid or pharmaceutical composition for use according to paragraph 18, wherein the LMO2-associated disorder is selected from the group consisting of: T-cell acute lymphoblastic leukaemia (T-ALL); LMO2+ breast cancer; LMO2+ prostate cancer; and LMO2+ diffuse large B cell lymphoma.20. A nucleic acid molecule for use according to paragraph 19, wherein the LMO2-associated disorder is an LMO2-associated cancer.21. A chimaeric protein, nucleic acid or pharmaceutical composition for use according to paragraph 20 in the prevention and / or treatment of an LMO2-associated cancer selected from the group consisting of: LMO2-associated lung cancer; LMO2-associated pancreatic cancer; LMO2-associated colorectal cancer; adrenocortical carcinoma; bladder urothelial carcinoma; breast invasive carcinoma; cervical squamous cell carcinoma or endocervical adenocarcinoma; cholangiocarcinoma; colon adenocarcinoma; lymphoid neoplasm diffuse large B-cell lymphoma; oesophageal carcinoma; glioblastoma multiforme; head and neck squamous cell carcinoma; kidney chromophobe; kidney renal clear cell carcinoma; kidney renal papillary cell carcinoma; acute myeloid leukaemia; brain lower grade glioma; liver hepatocellular carcinoma; lung adenocarcinoma; lung squamous cell carcinoma; ovarian serous cystadenocarcinoma; pancreatic adenocarcinoma; pheochromocytoma or paraganglioma; prostate adenocarcinoma; rectum adenocarcinoma; sarcoma; skin cutaneous melanoma; stomach adenocarcinoma; testicular germ cell tumours; thyroid carcinoma; thymoma; uterine corpus endometrial carcinoma; uterine carcinosarcoma; and uveal melanoma.

Claims

CLAIMS1. A compound, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula I shown below:Formula Iwherein:Ri is selected from:(i) (1-6C)alkylene which is optionally substituted by one or more Ra; (ii) a group of the formula:whereindenotes the point of attachment;n is 0 or 1;Ria and R are selected from hydrogen or methyl;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N;(iii) a group of the formula:whereindenotes the point of attachment;n, Ria and R are as defined above;Ring B is a saturated or partially unsaturated ring; one X7, Xs and Xg is a group C-LRI- and the others are selected from C-H, C-Raor N if a bond connecting them to an adjacent atom is an unsaturated double bond, or C-H2, C-HRa, C-(Ra)2, N-H, N-Rb, S or O if the bonds attaching them to adjacent atoms are single bonds;wherein each Rais independently selected from (1-4C)alkyl (including deuterated (1-4C)alkyl), halo, (1 -4C)haloalkyl, (1-4C)haloalkoxy, cyano, nitro, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, (CH2)qiNRabRac, (CH2)qiORab, (CH2)qiC(O)Rab, (CH2)qiC(O)ORab, (CH2)qiOC(O)Rab, (CH2)qiC(O)N(Rac)Rab, (CH2)qiN(Rac)C(O)Rab, (CH2)qiS(O)PRab(where p is 0, 1 or 2), (CH2)qiSO2N(Rac)Riab, or (CH2)qiN(Rac)SO2Rab,and wherein:q1 is 0, 1, 2 or 3;Rab is selected from hydrogen, (1-4C)alkyl (including deuterated (1- 4C)alkyl), (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1- 2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl,and wherein Rab is optionally further substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl (including deuterated (1 -4C)alkyl), halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, nitro, NRadRae, ORad, C(O)Rad, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(Rae)C(O)Rad, S(O)pRad(where p is 0, 1 or 2), SO2N(Rae)Rad, N(Rae)SO2Rad,or (CH2)q2NRadRae(where q2 is 1, 2 or 3); wherein Rad and Raeare each independently selected from hydrogen or (1 -6C)alkyl; and Racis selected from hydrogen or (1 -2C)alkyl (including deuterated (1-2C)alkyl);or where Rab and Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 memberedheterocyclic ring, each of which is optionally substituted as for Rab above;wherein Rb is independently selected from (1 -4C)alkyl (including deuterated (1- 4C)alkyl), (1-4C)haloalkyl or-C(O)Rba, wherein Rba is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl, and wherein Rba is optionally further substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl (including deuterated (1- 4C)alkyl), halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1- 4C)hydroxyalkyl, cyano, nitro, NRbdRbe, ORbd, C(O)Rbd, C(O)ORbd, OC(O)Rbd, C(O)N(Rbe)Rbd, N(Rbe)C(O)Rbd, S(O)pRbd (where p is 0, 1 or 2), SO2N(Rbe)Rbd, N(Rbe)SC>2Rbd, or (CH2)qsNRbdRbe (where q3 is 1, 2 or 3); wherein Rbd and Rbe are each independently selected from hydrogen or (1-6C)alkyl (including deuterated (1 -4C)alkyl);LRI is a bond or a linking group that connects Ri to L which is optionally selected from (1-4C)alkylene, (3-6C)cycloalkylene, (3-6C)cycloalkyl(1-2C)alkylene, (CH2)qi-NRLRi-, -(CH2)qi-O-, -(CH2)qi-C(O)-, -(CH2)qi-C(O)O-, -(CH2)qi-OC(O)-, -(CH2)qi-C(O)NRLRi-, -(CH2)qiN(RLRi)C(O)-, -(CH2)qi-S(O)P- (where p is 0, 1 or 2), -(CH2)qi-SO2NRLRi-, -(CH2)qi-N(R LRI)SO2-, or -(CH2)qi-[triazole]-;and wherein:q1 is as defined above;RLRI is selected from hydrogen or (1 -4C)alkyl;Xi, X2and X3 are selected from N, N-R5, O, S and CRe, wherein R5 is hydrogen or methyl and Re is hydrogen, methyl or halo, with the proviso that at least one of Xi, X2and X3 is selected from N, N-R5, O and S;Q is a group of the formula:or -X12-CH2-CH2-NR7- or -Xi3-C(O)-NR8-;wherein:X and Xu are selected from N or CH;X12 and X13 are selected from NRg, CH2, CHRg or C(Rg)2; andR7, Rs and Rg are selected from hydrogen or (1 -2C)alkyl (including deuterated (1-2C)alkyl);R2 and R3 are selected from hydrogen (including deuterium) or (1-2C)alkyl (including deuterated (1 -2C)alkyl);R4 is a phenyl, heteroaryl, or heterocyclyl ring optionally substituted by (1-4C)alkyl (including deuterated (1-4C)alkyl), halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, nitro, NR4aR4b, OR4a, C(O)R4a, C(O)OR4a, OC(O)R4a, C(O)N(R4b)R4a, N(R4b)C(O)R4a, S(O)pR4a(where p is 0, 1 or 2), SO2N(R4b)R4a, N(R4b)SO2R4a,or (CH2)q4NR4aR4b (where q4 is 1, 2 or 3); wherein R4ais selected from hydrogen, (1-4C)alkyl (including deuterated (1-4C)alkyl), (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl, and wherein:R4ais optionally further substituted by (1-4C)alkyl (including deuterated (1-4C)alkyl), halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, nitro, NR4aaR4ab, OR4aa, C(O)R4aa, C(O)OR4aa, OC(O)R4aa, C(O)N(R4ab)R4aa, N(R4ab)C(O)R4aa, S(O)pR4aa(where p is 0, 1 or 2), SO2N(R4ab)R4aa, N(R4ab)SO2R4aa, or (CH2)q5NR4aaR4ab (where q5 is 1, 2 or 3) and R4aaand R4abare hydrogen or (1-2C)alkyl (including deuterated (1-2C)alkyl);R4bis selected from hydrogen or (1 -2C)alkyl (including deuterated (1 -2C)alkyl); or, when R4aand R4bare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for R4above;L is a bivalent linker group covalently linking R1 to E3; andE3 is an E3 ubiquitin ligase-binding moiety.

2. A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:A) R1 is selected from:(i) (1-4C)alkylene which is optionally substituted by one or more Ra;(ii) a group of the formula:whereindenotes the point of attachment;n is 0 or 1;Ria and R are hydrogen;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N;(iii) a group of the formula:whereindenotes the point of attachment;n, Ria and R are as defined above;Ring B is a saturated ring;one X7, Xs and Xg is a group C-LRI- and the others are C-H;wherein each Rais independently selected from methyl, halo, cyano, phenyl, (CH2)q1 N RabRac, (CH2)qlORab, (CH2)q1 C(O) Rab Or (CH2)qlC(O)ORab,and wherein:q1 is 0;Rab is selected from hydrogen, (1-4C)alkyl, aryl, aryl(1-2C)alkyl,and wherein Rab is optionally further substituted by one or more substituent groups independently selected from oxo, methyl, halo, or cyano;and Racis selected from hydrogen;or where Rab and Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for Rab above;LRI is a bond or a linking group that connects Ri to L which is optionally selected from (1-2C)alkylene, -NRLRI-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NRLRI-, -N(RLRI)C(O)-, - S(O)P- (where p is 0, 1 or 2), -SO2NR1. R1-, or -N(R LRI)SC>2-;and wherein RLRI is selected from hydrogen or (1 -2C)alkyl;B) Ri is selected from:(1-4C)alkylene which is optionally substituted by one or more Ra;whereindenotes the point of attachment;n is 0 or 1;Ria and R are hydrogen;one of X4, X5 and Xe is a group C-LRI- and the others are selected from C-H, C-Raor N;whereindenotes the point of attachment;n, Riaand R are as defined above;Ring B is a saturated ring;one X7, Xs and Xg is a group C-LRI- and the others are C-H; wherein each Rais independently selected from methyl, halo, (CH2)qiNRabRac, (CH2)qiORab, (CH2)qiC(O)Rabor (CH2)qiC(O)ORab,and wherein:q1 is 0;Rabis selected from hydrogen, (1-4C)alkyl, aryl, aryl(1-2C)alkyl, and wherein Rabis optionally further substituted by one or more substituent groups independently selected from, halo;and Racis hydrogen;or where Raband Racare linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 membered heteroaryl ring or a 5 or 6 membered heterocyclic ring, each of which is optionally substituted as for Rababove;LRI is a bond that connects R1 to L;C) R1 is selected from:whereindenotes the point of attachment to the NH group of formula I; anddenotes the point of attachment to L; orD) Ri is:whereindenotes the point of attachment to the NH group of formula I; anddenotes the point of attachment to L.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:A) Xi, X2 and X3 are selected from N, O, S and CRe, wherein Re is hydrogen (including deuterium), methyl (including CD3), or halo, with the proviso that at least one of Xi, X2 and X3 is selected from N, O and S;B) Xi is N; X2 is O or S; and X3 is CRe, wherein Re is hydrogen; orC) Xi is O or S; X2 is N; and X3 is CRe, wherein Re is hydrogen.

4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:A) Q is a group of the formula:or -X12-CH2-CH2-NR7- or -Xi3-C(O)-NR8-;wherein:X and Xu are selected from N;X12 and X13 are selected from NRg; andR?, Rs and Rg are selected from hydrogen; orB) Q is selected fromwhereindenotes the point of attachment.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:A) R2 and R3 are selected from hydrogen (including deuterium) or methyl (including CD3); orB) R2 and R3 are hydrogen (including deuterium).

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:A) R4 is a phenyl, heteroaryl, or heterocyclyl ring optionally substituted by (1-2C)alkyl (including deuterated (1 -2C)alkyl),, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, (1-2C)hydroxyalkyl, cyano, nitro, NR4aR4b, OR4a, C(O)R4a, C(O)OR4a, OC(O)R4a, C(O)N(R4b)R4a, N(R4b)C(O)R4a, S(O)pR4a (where p is 0, 1 or 2), SO2N(R4b)R4a, N(R4b)SO2R4a, or (CH2)q4NR4aR4b (where q4 is 1, 2 or 3); wherein R4a is selected from hydrogen, (1-2C)alkyl deuterated (1-2C)alkyl, phenyl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl and heterocyclyl(1-2C)alkyl, and wherein:R4a is optionally further substituted by (1-2C)alkyl (including deuterated (1-2C)alkyl), halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, nitro;R4bis selected from hydrogen or (1 -2C)alkyl (including deuterated (1 -2C)alkyl); or R4a and R4b are linked to a common N atom, they may be linked such that, together with the N atom to which they are attached, they form a 5 or 6 membered heteroaryl ring or a 5 to 7 membered heterocyclic ring, each of which is optionally substituted as for R4 above;B) R4 is a phenyl or heteroaryl ring optionally substituted by (1 -2C)alkyl, halo, cyano, nitro, NR4aR4b, OR4a, C(O)R4a, N(R4b)C(O)R4a; wherein R4a is selected from hydrogen, (1-2C)alkyl (including deuterated (1 -2C)alkyl), (1-2C)haloalkyl, phenyl(1-2C)alkyl; and R4b is hydrogen; or C) R4 is selected fromwhereindenotes the point of attachment.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:A) L is a linker comprising 2 to 40 chain atoms (or 3 to 41 bond lengths), or 3 to 30 chain atoms (or 4 to 31 bond lengths), or 3 to 25 chain atoms (or 4 to 26 bond lengths), or 3 to 20 chain atoms (or 4 to 21 bond lengths), or 3 to 15 chain atoms (or 4 to 16 bond lengths), or 3 to 12 chain atoms (or 4 to 13 bond lengths);B) L is a straight chain alkylene group of 3 to 40, 5 to 30, 10 to 25 or 13 to 23 carbon atoms wherein one or more carbon atoms are optionally replaced by one or moreC) L is a straight chain alkylene group of 3 to 40, 5 to 30, 10 to 25 or 13 to 23 carbon atoms wherein one or more carbon atoms are replaced by a group each independently selected from: -O-, -NH-, -N(CHs)-, CO, carbocyclyl or heterocyclyl (e.g.D) L is a straight chain alkylene group of 3 to 40, 5 to 30, 10 to 25 or 13 to 23 carbon atoms wherein one or more carbon atoms are replaced by a group each independently selected from: -O-, -NH-, CO,E) L is a linker of the formula:*-XL1 - ALI - RLI -XL2- AL2-XL3- RL2-AL3-XL4-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3;XLI is absent or -O-, NRxn, -C(O)-, -C(O)NRXLI-, -NRXLIC(O)- or(2-4C)alkynyl; wherein Rxn is hydrogen or methyl;ALI is absent or (1-15C)alkylene, (2-8C)alkenylene, (2-8C)alkynylene, -(CH2)ai-[O- CH2CH2]a2- or -[O-CH2CH2]a2-(CH2)ai-;RLI is absent, a 5- or 6-membered heteroaryl, phenyl, carbocyclyl, heterocyclyl or:wherein YLI and YL2are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo;XL2is either absent or, when YL2is N, XL2may be selected from -C(O)- or -C(O)NRXL2-; or when YL2 is CH, XL2 may be selected from -O-, NRXL2, -C(O)-, -C(O)NRXL2 or - NRXL2C(O)-; wherein RXL2 is hydrogen or methyl;A 2is absent or (1-15C)alkylene, -(CH2)a3-[O-CH2CH2]a4- or -[O-CH2CH2]a4-(CH2)a3- XLS is absent or -O-, NRXLS, -C(O)-, -C(O)NRXL3- or -NRXL3C(O)- or (2-4C)alkynyl; wherein RXLS is hydrogen or methyl;RL2 is absent, a 5- or 6-membered heteroaryl, phenyl, carbocyclyl or heterocyclyl or:wherein YLS and YL4 are both independently CH or N; Riband RL4 are selected from H or methyl, or Riband RL4 are linked to form a piperidinyl or piperazinyl ring, which is optionally substituted by halo;AI_3 is absent or (1-15C)alkylene, -(CH2)a5-[O-CH2CH2]a6- or -[O-CH2CH2]a6-(CH2)a5- XL4 is absent or-O-, -C(O)-, -C(O)NRXL4- or-NRxL4C(O)- or (2-4C)alkynyl; wherein RXL4 is hydrogen or methyl;integers a1, a3 and a5 are each independently 1 to 4; andintegers a2, a4 and a6 are each independently 1 to 7; orF) L is selected from:*-XLI-[CH2]2-IO-0-***-XLI-[CH2]2-IO-NH-***-XLI-[CH2CH2O]2-8-O-***-XLI-[CH2CH2O]2-8-NH-***-XLI-[CH2]2-IO-0-***-XLI-[CH2]2-IO-NH-***-XLi-[CH2CH2O]2-8-O-(3-4C)alkynyl-***-XLi-[CH2CH2O]2-8-NH-(3-4C)alkynyl-***-XLi-[CH2]i-8-(2-4C)alkynyl-***-XLI-HET-[CH2]O-6-NH-***-XLI-[CH2]O-6-HET-**wherein:*denotes the point of attachment to Ri;** denotes the point of attachment to E3;XLI is absent or -O-, NRxn, -C(O)-, -C(O)NRXLI-; wherein Rxn is hydrogen or methyl; andHET is a nitrogen-containing 4- to 12-memebered heterocyclyl.

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:A) E3 is a small molecule or peptide E3 ubiquitin ligase-binding moiety;B) E3 is a small molecule E3 ubiquitin ligase-binding moiety;C) E3 is an E3 ubiquitin ligase-binding moiety capable of binding an E3 ubiquitin ligase selected from the group consisting of: von Hippel-Lindau (VHL); cereblon, XIAP, E3A; MDM2; Anaphase-promoting complex; EIBR5 (EDDI); SOCS / BC-box / eloBC / CLIL5 / RING; LNXp80; CBX4; CBLL1; HACE1; HECTD1; HECTD2; HECTD3; HECW1; HECW2; HERC1; HERC2; HERC3; HERC4; HUWE1; ITCH; NEDD4; NEDD4L; PPIL2; PRPF19; PIAS1; PIAS2; PIAS3; PIAS4; RANBP2; RNF4; RBX1; SMURF 1; SMURF2; STUB1; TOPORS; TRIP 12; UBE3A; UBE3B; UBE3C; UBE4A; UBE4B; UBOXS; UBR5; WWP1; WWP2; Parkin; A20 / TNFAIP3; AMFR / gp78; ARA54; beta- TrCPI / BTRC; BRCA1; CBL; CHIP / STUB 1; E6; E6AP / UBE3A; F-box protein 15 / FBX015; FBXW7 / Cdc4; GR AIL / RNF 128; HOIP / RNF31; clAP-l / HIAP-2; clAP- 2 / HIAP-l; clAP (pan); ITCH / AIP4; KAP1; MARCH8, Mind Bomb 1 / MIB1; Mind Bomb 2 / MIB2; MuRF 1 / TRIM63; NDFIP1; NEDD4; NieL; Parkin; RNF2; RNF4; RNF8; RNF168; RNF43; SART1; Skp2; SMURF2; TRAF-I; TRAF-2; TRAF-3; TRAF-4; TRAF- 5; TRAF-6; TRIMS; TRIM21; TRIM32; UBR5; ZNRF3 DCAF15, DCAF16, KEAP, AhR, FEM1B, or Cullin ring.D) E3 is an E3 ubiquitin ligase-binding moiety capable of binding an E3 ubiquitin ligase selected from the group consisting of: von Hippel-Lindau (VHL); or cereblon.E) E3 is an E3 ubiquitin ligase-binding moiety capable of binding the E3 ubiquitin ligase cereblon.F) E3 is selected from thalidomide, pomalidomide, lenalidomide, VHL ligand, methyl- bestatin or nutlin, or a derivative thereof.G) E3 is selected from thalidomide, pomalidomide, lenalidomide or VHL ligand.H) E3 is selected from:wherein:denotes the point of attachment to L;Rqis hydrogen or fluoro;RVHL is cyclopropyl optionally substituted by fluoro;X2 is selected from -CH2- or -C(O)-;R100 is fluoro or CF3; andR101 is hydrogen or methyl.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from:A / -(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)oxazole-4- carboxamide;A / -(4-((2-(2-(2-(((R)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl) carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(3-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4- carboxamide;A / -(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4- carboxamide;A / -(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4- carboxamide;A / -(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4- carboxamide;A / -(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4- carboxamide;A / -(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)thiazole-5-carboxamide;2-(4-(3-cyanobenzyl)piperazin-1-yl)- / V-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)carbamoyl)phenyl)thiazole-5-carboxamide;A / -(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide; A / -(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide; A / -(4-(3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)azetidine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)azetidine-1-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide;A / -(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4- carboxamide;A / -(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptane- 2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide; or A / -(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2,6-diazaspiro[3.3]heptane- 2-carbonyl)phenyl)-2-(4-(3-methoxybenzyl)piperazin-1-yl)thiazole-4-carboxamide.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

11. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 10, for use in:(i) therapy;(ii) a method of inhibiting cell proliferation, such as the treatment of cancer;(iii) the treatment of cancer;(iv) the treatment of a haematological cancer;(v) the treatment of lymphomas (including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), which includes T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)) and multiple myeloma;(vi) the treatment of Diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), angioimmunoblastic T-cell lymphoma (AITL), T-cell acute lymphoblastic leukaemia (T-ALL), and acute myeloid leukaemia (AML);(vii) the treatment of T-cell acute lymphoblastic leukaemia (T-ALL); or(viii) angiogenesis.

12. A m ethod of treati ng:(i) a proliferative disorder, such as cancer;(ii) cancer;(iii) a haematological cancer;(iv) lymphomas (including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL), which includes T-cell acute lymphoblastic leukaemia (T-ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)) and multiple myeloma;(v) diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic lymphoma (B-ALL), angioimmunoblastic T-cell lymphoma (AITL), T-cell acute lymphoblastic leukaemia (T-ALL), and acute myeloid leukaemia (AML);(vi) T-cell acute lymphoblastic leukaemia (T-ALL); or(vii) angiogenesis;in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 10.

13. A chimaeric protein comprising a ubiquitin ligase domain and an LMO2-specific endogenous targeting portion, wherein the ubiquitin ligase domain is a UBOX domain of CHIP, or a fragment or variant thereof having ubiquitin ligase activity and wherein the protein shares at least 85% identity with the amino acid sequence of SEQ ID NO: 1 or 2.

14. A chimaeric protein according to claim 13, comprising the amino acid sequence of SEQ ID NO: 1 or 2.

15. A chimaeric protein according to claim 13, consisting of the amino acid sequence of SEQ ID NO: 1 or 2.

16. A chimaeric protein according to any of claims 13 to 15, wherein the LMO2-specificendogenous targeting portion is an LMO2-specific intracellular antibody.

17. A nucleic acid molecule comprising a nucleic acid sequence encoding a chimaeric protein according to claims 13-16.

18. A pharmaceutical composition, comprising a chimaeric protein according to any of claims 13 to 16 and / or a nucleic acid molecule according to claim 17.

19. A method of preventing or treating a LMO2-associated disorder, the method comprising providing a therapeutically effective amount of a chimaeric protein according to any of claims 13 to 16 to a subject in need thereof.

20. A method according to claim 19, wherein the LMO2-associated disorder is selected from the group consisting of: angiogenesis, T-cell acute lymphoblastic leukaemia (T-ALL); LMO2+ breast cancer; LMO2+ prostate cancer; LMO2+ acute myeloid leukaemia (AML) and LMO2+ diffuse large B cell lymphoma.

21. A chimaeric protein according to any of claims 13 to 16, a nucleic acid molecule according to claim 17 or a pharmaceutical composition according to claim 18 for use as a medicament.

22. A chimaeric protein, nucleic acid or pharmaceutical composition for use according to claim 21 in the prevention and / or treatment of a LMO2-associated disorder.

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