Proteolysis-targeting chimeras

Abstract

Compounds of formula (I) are disclosed: HL – (X)a – L –(X1)b – UL (I); wherein HL comprises a HAT-domain recruiting ligand, X and X1 comprise exit vectors, L comprises a linker, and UL comprises an E3 ubiquitin ligase ligand. HL is a group of formula (H1). The compounds are useful as proteolysis-targeting chimeras (PROTACs) and are selective for p300.

Description

[0001] PROTEOLYSIS-TARGETING CHIMERAS

[0002] FIELD OF THE INVENTION

[0003] The present disclosure relates to compounds, in particular those that are useful as proteolysis-targeting chimeras, methods of using such compounds, reagents comprising such compounds and methods for synthesis of such compounds.

[0004] BACKGROUND TO THE INVENTION

[0005] Targeted degradation of a protein can be achieved using chimeric molecules known as proteolysis-targeting chimeras (PROTACs) or heterobifunctional degrader molecules (“degraders”). These compounds contain a target warhead (i.e. a ligand specific for the target of interest) linked to a ligand targeting an E3 ubiquitin ligase. The degrader interacts to induce the heterodimerization of the two bound proteins, thus resulting in the ubiquitination and subsequent proteasomal degradation of the target of interest.

[0006] CREB-binding protein (CBP, CREBBP, KAT3A) and El A-binding protein (EP300, p300, KAT3B) are paralogous multi-domain proteins that act as chromatin regulators and transcriptional co-activators. They contain a histone acetyltransferase (HAT) domain that catalyzes the histone H3, lysine 27 acetylation (H3K27ac) mark at regulatory elements such as enhancers and promoters. Transcription factors associate with stretches of H3K27ac marks (known as “super-enhancer” elements) and result in gene transcription that ultimately establishes cell identity and fate. They are implicated in cancer pathology. Inhibition of the bromodomain (BRD) or HAT domain of CBP / p300 is considered a promising therapeutic strategy for a number of cancer types. CBP and p300 are highly homologous but have distinct roles that are hard to delineate, and known inhibitors are unable to selectively target each protein independently (1-3).

[0007] The majority of high-risk pediatric neuroblastoma (NB) is associated with p300, with a limited role for CBP. Selectivity to p300 for treatment of pediatric NB would be advantageous as it may limit the toxicity associated with concomitant degradation of CBP. There are other cancers where selective p300 degradation may be beneficial as a treatment, including Ewing sarcoma and CIC-DUX4 sarcoma. A bromodomain-recruiting dual CBP / p300 PROTAC Degrader “dCBPl” was recently developed to provide a chemical tool to explore the phenotypic consequences of CBP / p300 chemical knockdown.

[0008] A further study demonstrated that it is possible to degrade p300 with some selectivity by converting a CBP / p300 dual HAT-domain inhibitor into a PROTAC, called “JQAD1”.

[0009] There is nevertheless a need for improved selectivity of p300 over CBP as both a research tool and potentially for therapeutic use.

[0010] The present invention seeks to address this need and to overcome problems associated with the prior art.

[0011] SUMMARY OF THE INVENTION

[0012] The present inventors have surprisingly discovered HAT-domain recruiting ligands and PROTACs that elicit proteasome-mediated degradation of p300 with significantly enhanced selectivity over CBP that were not previously predicted and with a faster onset of action.

[0013] The present invention accordingly provides in a first aspect a compound of formula (I):

[0014] HL - (X)a- L -(Xl)b - UL

[0015] (I) or a salt, solvate or tautomer thereof, wherein;

[0016] HL comprises a HAT-domain recruiting ligand,

[0017] X comprises a divalent exit vector;

[0018] XI comprises a divalent exit vector; a and b are independently selected from 1 or 2;

[0019] L comprises a divalent linker, and

[0020] UL comprises an E3 ubiquitin ligase ligand; wherein HL comprises a group of formula Hl :

[0021] wherein each R’ is independently selected from halo, each R’’ is independently selected from -C(R’)3, or halo; RH is selected from halo, hydroxyl, or -C(=O)-RY; RY is H or C1- C6alkyl; n is 1, 2, 3, 4 or 5, and the wavy line indicates the bond to X. Optionally, n may be 1 and HL may comprise a group of formula H2: Suitably, HLmay comprise a group of formula H3: Suitably, each R’ is independently selected from F or Cl, preferably F.

[0022] Thus, suitably, HL may comprise a group of formula H4:

[0023] Advantageously, the mechanism of action of such PROTACs is event driven such that reduced binding affinity to a target will not necessarily lead to loss of target degradability providing the components are within functional proximity. PROTACs use a catalytic mechanism of action whereby one PROTAC can degrade multiple target proteins. Therefore PROTACs can be used at sub-stoichiometric concentrations relative to the target protein and the E3 ligase. This is greatly advantageous and means that PROTACs according to the invention may have improved function compared to inhibitors which typically rely on a 1 : 1 binding stoichiometry.

[0024] Furthermore, the compound of formula I provides more potent degradation of p300 with improved selectivity over CBP and a faster onset of action.

[0025] The locations of the exit vector on the HL structures and their nature are important in order to provide or retain binding affinity for the protein.

[0026] In some embodiments, a may be 1 and / or b may be 1.

[0027] If a and / or b is 2, each X (e.g. -X-X-) or XI (e.g. -X1-X1-) may be selected independently.

[0028] UL may comprise an E3 ubiquitin ligase targeting ligand selected from a ligand that targets cereblon (CRBN), Von Hippel-Lindau (VHL), tDHU, phenyl dihydrouracil, phenyl glutarimide, inhibitor of apoptosis protein (IAP), mouse double minute

[0029] 2 homolog (MDM2), or Kelch like ECH associated protein 1 (KEAP1).

[0030] Optionally, UL may comprise an E3 ubiquitin ligase targeting ligand selected from a ligand that targets cereblon (CRBN), Von Hippel-Lindau (VHL), inhibitor of apoptosis protein (IAP), mouse double minute 2 homolog (MDM2), or Kelch like ECH associated protein 1 (KEAP1).

[0031] Optionally, UL may comprise a ligand selected from a univalent substituent derived from VH101, VH032, VH298, tDHU, phenyl dihydrouracil, phenyl glutarimide, phenyl amino glutarimide or an immunomodulatory imide drug (IMiD), optionally derivatives of thalidomide, lenalidomide, pomalidomide, or avadomide, differing by exit vector and substitution.

[0032] Thus, UL may comprise a ligand selected from a univalent substituent derived from VH101, VH032, VH298, tDHU, phenyl dihydrouracil, phenyl glutarimide, or an immunomodulatory imide drug (IMiD), optionally thalidomide, lenalidomide, pomalidomide, or avadomide.

[0033] Thus, UL may be selected from a species of the following formulae: wherein R1 is selected from -O-, -NH-, or -CH2-, or is absent; each R2or R5is independently selected from H or -CH3; each R3is independently selected from -CH2- or -C(=O)-; each R4 is independently selected from -CH3; each R8is selected from H or -CH3; each R26or R27is selected from H, or OH; but R26and R27are not the same, each RA is selected from H, C1-6 alkyl, halo and (CH2)t-NR20R21, t is selected from 0, 1, 2, or 3,

[0034] R20 and R21 are each independently selected from H, and C1-6 alkyl; and the wavy line indicates the bond to XI.

[0035] Rs may be methyl and may be positioned at the ortho position of the phenyl ring. Where the CRBN binder is N-methylated (i.e. on the glutarimide group), so that R2 is CH3, or R26 is H and R27 is OH, UL may be a negative control.

[0036] Thus, in one aspect, UL may be a group of formula: wherein R2 is CH3, and the other substituent are as indicated above. Generally, however, R2 may be H.

[0037] Generally, however, R26 is OH and R27 is H.

[0038] Suitably, UL may be selected from a species of the following formulae: wherein RAis selected from H, C1-6alkyl, halo and (CH2)t-NR20R21, t is selected from 0, 1, 2, or 3, R20 and R21 are independently selected from H, and C1-6 alkyl; and the wavy line indicates the bond to X1. The exit vector X may each be such that each X is independently selected from a divalent substituent selected from, -(CH2)zC(=O)-, - CH2(CH2)z-, -(CH2)zO-, -(CH2)zS-, -(CH2)zC(=O)-NR11-; -(CH2)zNR11C(=O)-; -(CH2)zNR11-; -(CH2)zC(=O)-O-; -(CH2)zO- CH2-C(=O)-NR11-; -(CH2)zNR11-C(=O)-CH2-O-; -(CH2)zC(=O)-CH2-O-; wherein each R11is independently selected from H, and C1-6alkyl, and each z is independently 0, 1 or 2, preferably 1; and the bonds, or wavy lines in the formulae, indicate the bonds to HL and L or L and HL. The exit vector may be bonded to HL and L in either orientation by either bond. Suitably, the exit vector X may be -(CH2)zC(=O)-NR11or -(CH2)zNR11C(=O), wherein each z is selected from 0, 1 or 2 and each R11 is independently selected from H, and C1-6 alkyl. Suitably, each z is 1. Suitably each R11 is H. The linker may be flexible or rigid or partially rigid. Thus, L may be a divalent linking group comprising , , C3-8 cycloalkyl, C5-10 heteroarylene, phenylene, a C2-12 alkylene chain which may contain one or more carbon-carbon double or triple bonds, a paraformaldehyde chain –(CH2CH2)n(CH2)m(OCH2)s(CH2CH2)p(CH2)q-, a polyethylene glycol chain –(CH2CH2)n(CH2)m(OCH2CH2)v(CH2CH2)p(CH2)q-, which chains may be interrupted by one, two or three groups selected from -O-, -S-, -NH-, halo, , , C3-8cycloalkyl, C5-10heteroarylene and / or phenylene; wherein n, m, p and q are independently 0, 1 or 2, s and v are independently 1 to 12, optionally 1 to 8, optionally 1 to 6. Suitably, L may be selected from a C2-12alkylene chain, a paraformaldehyde chain –(CH2CH2)n(CH2)m(OCH2)s(CH2CH2)p(CH2)q-, or a polyethylene glycol chain –(CH2CH2)n(CH2)m(OCH2CH2)v(CH2CH2)p(CH2)q-; wherein n, m, p and q are independently 0, 1 or 2, s and v are independently 1 to 12, optionally 1 to 8, optionally 1 to 6. Optionally the linker L has at least three atoms in the chain (e.g. a C3-12 alkylene chain). The exit vector X1 may be such that each X1 is independently selected from - (CH2)zC(=O)-, -CH2(CH2)z-, -(CH2)zO-, -(CH2)zS-, -(CH2)zC(=O)-NR11-; - (CH2)zNR11C(=O)-; -(CH2)zNR11-; -(CH2)zC(=O)-O-; -(CH2)zO-CH2-C(=O)-NR11-; - (CH2)zNR11-C(=O)-CH2-O-; -(CH2)zC(=O)-CH2-O-; wherein each R11 is independently selected from H, and C1-6 alkyl, and each z is independently 0, 1 or 2, preferably 1; and the bonds or wavy lines in the formulae indicate the bonds to ULand L or L and UL. The exit vector may be bonded to ULand L in either orientation by either bond. wherein the wavy line indicates the connection to L. Suitably, each X1 is independently selected from -(CH2)zO-; -(CH2)zC(=O)-NR11-; - (CH2)zNR11C(=O)- or -(CH2)zNR11-; wherein each z is selected from 0, 1 or 2 and each R11 is independently selected from H, and C1-6 alkyl. Suitably, each z is 0. Suitably each R11is H. Preferably, the compound may be selected from compounds of the formulae:

[0039]

[0040]

[0041] (020);

[0042] In a second aspect, there is provided a method (optionally an in vitro method) comprising providing a composition comprising a compound according to the first aspect, and contacting the composition with a source of p300 or CBP.

[0043] In a third aspect, there is provided a method (optionally an in vitro method) of selectively degrading p300 comprising providing a composition comprising a compound according to the first aspect, and contacting the composition with a source of p300 and / or CBP. Optionally, in the method of the third aspect, the compound may be selected from:

[0044]

[0045] In a fourth aspect, there is provided a reagent comprising a compound according to the first aspect and a solvent. Further particular and preferred aspects are set out in the accompanying independent and dependent claims. Features of the dependent claims may be combined with features of the independent claims as appropriate, and in combinations other than those explicitly set out in the claims.

[0046] DEFINITIONS

[0047] “Substituted”, when used in connection with a chemical substituent or moiety (e.g., an alkyl group), means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.

[0048] In this specification, unless the context otherwise suggests, divalent groups may be connected to other parts of the molecule by either bond, thus in either orientation by either bond.

[0049] “Optionally substituted” refers to a parent group which may be unsubstituted or which may be substituted with one or more substituents. Suitably, unless otherwise specified, when optional substituents are present, the optional substituted parent group comprises from one to three optional substituents. Where a group may be “optionally substituted with 1, 2 or 3 groups”, this means that the group may be substituted with 0, 1, 2 or 3 of the optional substituents. Suitably, the group is substituted with 1, 2 or 3 of the optional substituents. Where a group is “optionally substituted with one or two optional substituents”, this means that the group may be substituted with 0, 1 or 2 of the optional substituents. Suitably, the group may be optionally substituted with 0 or 1 optional substituents. In some aspects, suitably the group is not optionally substituted. In other aspects, suitably the group is substituted with 1 of the optional substituents.

[0050] Optional substituents may be selected from Ci-8 alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-12 alkoxy, C5-20 aryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C3-10 cycloalkynyl, C3-20 heterocyclyl, C3-20 heteroaryl, acetal, acyl, acylamido, acyloxy, amidino, amido, amino, aminocarbonyloxy, azido, carboxy, cyano, ether, formyl, guanidino, halo, hemiacetal, hemiketal, hydroxamic acid, hydroxyl, imidic acid, imino, ketal, nitro, nitroso, oxo, oxycarbonyl, oxycarboyloxy, sulfamino, sulfamyl, sulfate, sulfhydryl, sulfmamino, sulfinate, sulfino, sulfinyl, sulfinyloxy, sulfo, sulfonamido, sulfonamino, sulfonate, sulfonyl, sulfonyloxy, uredio groups. In some aspects, the optional substituents are 1, 2 or 3 optional substituents independently selected from OH, Ci-8 alkyl, OC1-12 alkyl, and halogen. More suitably, the optional substituents are selected from OH, C1-8 alkyl and OC1-12 alkyl; more suitably, the optional substituents are selected from C1-8 alkyl and OC1-12 alkyl.

[0051] “Independently” or “Independently selected” is used in the context of statement that, for example, “each Ri6, R17, is independently H, C1-8 alkyl,...” and means that each instance of the functional group, e.g. Ri6, is selected from the listed options independently of any other instance of Ri6 or R17 in the compound. Hence, for example, H may be selected for the first instance of Ri6 in the compound; methyl may be selected for the next instance of Ri6 in the compound; and ethyl may be selected for the first instance of R17 in the compound.

[0052] “C1-8 alkyl”: refers to straight chain and branched saturated hydrocarbon groups, generally having from 1 to 8 carbon atoms; suitably a C1-7 alkyl; suitably a C1-6 alkyl; suitably a C1-5 alkyl; more suitably a Ci-4 alkyl; more suitably a C1-3 alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-l-yl, pent-2-yl, pent-3 -yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-l-yl, n-hexyl, n-heptyl, n-octyl and the like.

[0053] “Alkylene” refers to a divalent radical derived from an alkane which may be a straight chain or branched, as exemplified by -CH2CH2CH2CH2-. The alkylene may have the number of carbons as discussed above for alkyl groups.

[0054] “Ce-26 aralkyl” refers to an arylalkyl group having 6 to 26 carbon atoms and comprising an alkyl group substituted with an aryl group. Suitably the alkyl group is a C1-6 alkyl group and the aryl group is phenyl. Examples of Ce-26 aralkyl include benzyl and phenethyl. In some cases, the Ce-26 aralkyl group may be optionally substituted, and an example of an optionally substituted Ce-26 aralkyl group is 4-methoxylbenzyl.

[0055] “C5-20 Aryl”: refers to fully unsaturated monocyclic, bicyclic and polycyclic aromatic hydrocarbons having at least one aromatic ring and having a specified number of carbon atoms that comprise their ring members (e.g., C5-20 aryl refers to an aryl group having from 5 to 20 carbon atoms as ring members). The aryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non- hydrogen substituents unless such attachment or substitution would violate valence requirements. Suitably, a Ce-14 aryl is selected from a C6-12 aryl, more suitably, a Ce-io aryl. Examples of aryl groups include phenyl.

[0056] “Arylene” refers to a divalent radical derived from an aryl group, e.g. -CeEU- which is the arylene derived from phenyl.

[0057] “C3-8 cycloalkyl” or “3- to 8-membered cycloalkyl” means a closed ring of carbon atoms having 3 to 8 carbon atoms, preferably 3 to 7 carbon atoms, more preferably 3 to 6 carbon atoms and encompasses, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0058] “C3-8 cycloalkylene” or “3- to 8-membered cycloalkylene” refers to a divalent radical derived from a cycloalkyl group, e.g. -CeHio-.

[0059] “C3-8 cycloalkenylene” refers to a divalent radical derived from a cycloalkenyl group, that is a carbocyclic group with one or more C=C, e.g. -CeHs-.

[0060] Halogen or halo: refers to a group selected from F, Cl, Br, and I. Suitably, the halogen or halo is F or Cl. In some aspects, suitably, the halogen is F. In other aspects, suitably the halogen is Cl.

[0061] “C5-10 heteroaryl” or “5- to 10-membered heteroaryl”: refers to unsaturated monocyclic or bicyclic aromatic groups comprising from 5 to 10 ring atoms, whether carbon or heteroatoms, of which from 1 to 5 are ring heteroatoms. Suitably, any monocyclic heteroaryl ring has from 5 to 6 ring atoms and from 1 to 3 ring heteroatoms. Suitably each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur. The bicyclic rings include fused ring systems and, in particular, include bicyclic groups in which a monocyclic heterocycle comprising 5 ring atoms is fused to a benzene ring. The heteroaryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.

[0062] Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from:

[0063] Ni: pyrrole, pyridine; Oi : furan;

[0064] Si: thiophene;

[0065] N1O1: oxazole, isoxazole, isoxazine;

[0066] N2O1: oxadiazole (e.g. l-oxa-2,3-diazolyl, l-oxa-2,4-diazolyl, l-oxa-2,5-diazolyl, 1- oxa-3,4-diazolyl);

[0067] N3O1: oxatriazole;

[0068] N1S1: thiazole, isothiazole;

[0069] N2: imidazole, pyrazole, pyridazine, pyrimidine, pyrazine;

[0070] N3: triazole, triazine; and,

[0071] N4: tetrazole.

[0072] Examples of heteroaryl which comprise fused rings, include, but are not limited to, those derived from:

[0073] Oi : benzofuran, isobenzofuran;

[0074] Ni: indole, isoindole, indolizine, isoindoline;

[0075] Si: benzothiofuran;

[0076] N1O1: benzoxazole, benzisoxazole;

[0077] N1S1: benzothiazole;

[0078] N2: benzimidazole, indazole;

[0079] O2: benzodioxole;

[0080] N2O1: benzofurazan;

[0081] N2S1: benzothiadiazole;

[0082] N3: benzotriazole; and

[0083] N4: purine (e.g., adenine, guanine), pteridine;

[0084] “heteroarylene” refers to a divalent radical derived from a heteroaryl group (such as those described above) as exemplified by pyridinyl -[C5H3N]-. Heteroarylenes may be monocyclic, bicyclic, or tricyclic ring systems. Representative heteroarylenes, are not limited to, but may be selected from triazolylene, tetrazolylene, oxadi azolylene, pyridylene, furylene, benzofuranylene, thiophenylene, benzothiophenylene, quinolinylene, pyrrolylene, indolylene, oxazolylene, benzoxazolylene, imidazolylene, benzimidazolylene, thiazolylene, benzothiazolylene, isoxazolylene, pyrazolylene, isothiazolylene, pyridazinylene, pyrimidinylene, pyrazinylene, triazinylene, cinnolinylene, phthalazinylene, quinazolinylene, pyrimidylene, azepinylene, oxepinylene, and quinoxalinylene. Heteroarylenes are optionally substituted.

[0085] “Ce-16 heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. Suitably the alkyl is a Ci-6 alkyl group and the heteroaryl group is C5-10 heteroaryl as defined above. Examples of Ce-16 heteroarylalkyl groups include pyrrol-2-ylmethyl, pyrrol-3-ylmethyl, pyrrol-4-ylmethyl, pyrrol -3 -yl ethyl, pyrrol-4-ylethyl, imidazol-2- ylmethyl, imidazol-4-ylmethyl, imidazol-4-ylethyl, thi ophen-3 -ylmethyl, furan-3- ylmethyl, pyridin-2 -ylmethyl, pyridin-2-ylethyl, thiazol-2 -ylmethyl, thiazol-4-ylmethyl, thiazol-2-ylethyl, pyrimidin-2-ylpropyl, and the like.

[0086] “C3-20 heterocyclyl”: refers to saturated or partially unsaturated monocyclic, bicyclic or polycyclic groups having ring atoms composed of 3 to 20 ring atoms, whether carbon atoms or heteroatoms, of which from 1 to 10 are ring heteroatoms. Suitably, each ring has from 3 to 8 ring atoms and from 1 to 4 ring heteroatoms (e.g., suitably C3-5 heterocyclyl refers to a heterocyclyl group having 3 to 5 ring atoms and 1 to 4 heteroatoms as ring members). The ring heteroatoms are independently selected from nitrogen, oxygen, and sulphur.

[0087] As with bicyclic cycloalkyl groups, bicyclic heterocyclyl groups may include isolated rings, spiro rings, fused rings, and bridged rings. The heterocyclyl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.

[0088] Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from:

[0089] Ni : aziridine, azetidine, pyrrolidine, pyrroline, 2H-pyrrole or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine; Oi : oxirane, oxetane, tetrahydrofuran, dihydrofuran, tetrahydropyran, dihydropyran, pyran, oxepin;

[0090] Si: thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, thi epane;

[0091] O2: dioxoiane, dioxane, and dioxepane;

[0092] O3: trioxane;

[0093] N2: imidazoiidine, pyrazolidine, imidazoline, pyrazoline, piperazine:

[0094] N1O1: tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, oxazine;

[0095] N1S1: thiazoline, thiazolidine, thiomorpholine;

[0096] N2O1: oxadiazine;

[0097] O1S1: oxathiole and oxathiane (thi oxane); and

[0098] N1O1S1: oxathiazine.

[0099] Examples of substituted monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses, such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses, such as aliopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.

[0100] L

[0101] As discussed herein, L is a linker group. Suitably, L may comprise an alkylene chain, paraformaldehyde chain or polyethylene glycol chain is interrupted by one or more hetero-atoms (e.g., N, O and S) and / or one or more C5-10 heteroarylene groups (e.g., pyrrolylene, pyrazolylene, pyrazolylene, 1,2,3-triazolylene, pyridinylene) and / or one or more phenylene groups. More suitably, the chains may be interrupted by from one to three hetero-atoms and / or from one to three C5-10 heteroarylene groups and / or from one to three phenylene groups.

[0102] Suitably L is selected from an alkylene chain containing from 2 to 11 carbon atoms, from 2 to 10 carbon atoms, from 2 to 9 carbon atoms, from 2 to 8 carbon atoms, from 2 to 7 carbon atoms, from 2 to 6 carbon atoms, from 2 to 5 carbon atoms, from 2 to 4 carbon atoms, which may contain one or more carbon-carbon double or triple bonds; a paraformaldehyde chain -(OCH2)i-i2-, -(0CH2)i-n-, -(OCH2)I-IO-, -(OCH2)I-9-, - (OCH2)I-8-, -(OCH2)I-7-, -(OCH2)I-6-, -(OCH2)I-5-, -(OCH2)I-4-, -(OCH2)I-3- a polyethylene glycol chain -(OCH2CH2)I-5-, -(OCH2CH2)I-4-, -(OCH2CH2)I-3-; which chain may be interrupted by one or more hetero-atoms and / or C5-9 heteroarylene groups and / or from one to three phenylene groups.

[0103] More suitably, L may be selected from an alkylene chain containing from 2 to 12 carbon atoms which may contain one or more carbon-carbon double or triple bonds.

[0104] More suitably, L may be selected from CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2, and CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2.

[0105] L may be a moiety having 1-200 nonhydrogen atoms selected from C, N, O, S, or halogen, and optionally incorporates ether, oxo, carboxyl, carboxamide, carboxamidyl, urethanyl, branched, cyclic, unsaturated, amino acid, heterocyclyl, aryl or heteroaryl moieties. Linker L may be unbranched or branched, flexible or rigid, short or long and may incorporate any combination of moieties as deemed useful.

[0106] In some embodiments, at least a portion of the linker L may have a polyalkylene oxide polymeric region, which may enhance solubility of the compound of formula (I) or (II). In some embodiments, the linker L may have a repeating unit of ethylene glycol, and may have a number of repeating ethylene glycol units of about 1 to about 6, or any number therebetween. In some embodiments, L may include about 3 to about 20, about 4 to about 15, about 5 to about 12 or about 6 to about 10 ethylene glycol units. In some embodiments, at least a portion of Linker L may include one or more amino acid moieties which may provide enhanced solubility for the compound of formula (I) or (II) Other polymeric types of moieties may be incorporated in the linker L, such as polyacids, polysaccharides, or polyamines. Other moieties such as substituted or unsubstituted cyclic, aromatic or heteroaromatic moieties may be used to enhance rigidity. For example, the linker L can include ethylene glycol repeating units, and / or an amino acid sequence. In some embodiments, linker L2 includes the formula:

[0107] -[CH2CH2O]0-50-

[0108] Any suitable number of ethylene glycol units can be used in the linker L of the present invention. For example, the linker L can include 1, 2, 3, 4, 5, 6 or more ethylene glycol units. In some embodiments, the linker L can include 1 or 3 ethylene glycol units. Several commercially available ethylene glycol groups (polyethylene glycol, PEG) are suitable in the linker L2, such as H2N-dPEG®8-C(O)OH, having a discrete (“d”) polyethylene glycol having 8 ethylene glycol repeating units. Other discrete PEG units are commercially available and known to one of skill in the art, such as by Advanced ChemTech. In some embodiments, the linker L includes the formula:

[0109] -HN-PEG-C(O)- wherein PEG has 1-50 ethylene glycol units, usually 1 to 6 units.

[0110] The term “or pharmaceutically acceptable salts”, means that pharmaceutically acceptable salt, solvate, tautomeric, stereoisomeric forms of the shown structure are also included. “Mixtures thereof’ means that mixture of these forms may be present, for example, the compounds of the invention may include both a tautomeric form and a pharmaceutically acceptable salt.

[0111] “Pharmaceutically acceptable” substances refers to those substances which are within the scope of sound medical judgment suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit-to-risk ratio, and effective for their intended use.

[0112] “Pharmaceutical composition” refers to the combination of one or more drug substances and one or more excipients.

[0113] As used herein, “solvate” refers to a complex of variable stoichiometry formed by a solute (e.g. formulas ( 1 )-( 1 ) (A), (B), (C), (D), or any other compound herein or a salt thereof) and a solvent. Pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. The incorporated solvent molecules can be water molecules or non-aqueous molecules, such as but not limited to, ethanol, isopropanol, dimethyl sulfoxide, acetic acid, ethanolamine, and ethyl acetate molecules. As used herein the term “comprising” means “including at least in part of’ and is meant to be inclusive or open ended. When interpreting each statement in this specification that includes the term “comprising”, features, elements and / or steps other than that or those prefaced by the term may also be present. Related terms such as “comprise” and “comprises” are to be interpreted in the same manner.

[0114] The term “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. When the phrase “consisting essentially of’ appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause.

[0115] The term “consisting of’ excludes any element, step, or ingredient not specified in the claim; “consisting of’ defined as “closing the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consists of’ appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. It should be understood that while various embodiments in the specification are presented using “comprising” language, under various circumstances, a related embodiment is also described using “consisting essentially of’ or “consisting of’ language.

[0116] Other Forms

[0117] Unless otherwise specified, included in the above are the well-known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (-RCOOH) also includes the anionic (carboxylate) form (-RCOO ), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-RN HR1R2), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-O'), a salt or solvate thereof, as well as conventional protected forms.

[0118] Isomers, Salts and Solvates Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, mesomeric stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1- forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; alpha- and beta-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).

[0119] Note that, except as discussed below for tautomeric forms, specifically excluded from the term “isomers”, as used herein, are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, - CH2OH.

[0120] A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g. C1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

[0121] The above exclusion does not apply to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol, imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hyroxyazo, and nitro / aci-nitro.

[0122] As regards the pyrazole group in the structure of HL: the bond leading to the exit vector group X may be attached to either of the N groups in the ring.

[0123] Note that specifically included in the term “isomer” are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 'H,2H (D), and3H (T); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like. Unless otherwise specified, a reference in this specification to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.

[0124] Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

[0125] Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below.

[0126] In some embodiments, the compound of formula (I) and salts and solvates thereof, comprises pharmaceutically acceptable salts of the compounds of formula (I).

[0127] Compounds of formula (I), which include compounds specifically named above, may form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include nontoxic acid addition salts (including di-acids) and base salts.

[0128] If the compound is cationic, or has a functional group which may be cationic (e.g. -NH2 may be -NH3+), then an acid addition salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids hydrochloric acid, nitric acid, nitrous acid, phosphoric acid, sulfuric acid, sulphurous acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphoric acid and phosphorous acids. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2- acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfonate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

[0129] For example, if the compound is anionic, or has a functional group which may be anionic (e.g. -RCOOH may be -RCOO ), then a base salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, metal cations, such as an alkali or alkaline earth metal cation, ammonium and substituted ammonium cations, as well as amines. Examples of suitable metal cations include sodium (Na+) potassium (K+), magnesium (Mg2+), calcium (Ca2+), zinc (Zn2+), and aluminum (Al3+). Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH4+) and substituted ammonium ions (e.g. NH3R , NEER?4, NHR3+, NR4+). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, di ethylamine, di cyclohexylamine, tri ethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CHS)4+. Examples of suitable amines include arginine, N,N'-dibenzylethylene- diamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2- hydroxymethyl-propane-l,3-diol, and procaine. For a discussion of useful acid addition and base salts, see S. M. Berge et al., J. Pharm. Sci. (1977) 66: 1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2011)

[0130] Pharmaceutically acceptable salts may be prepared using various methods. For example, one may react a compound of formula 1 with an appropriate acid or base to give the desired salt. One may also react a precursor of the compound of Formula I with an acid or base to remove an acid- or base-labile protecting group or to open a lactone or lactam group of the precursor. Additionally, one may convert a salt of the compound of Formula 1 to another salt through treatment with an appropriate acid or base or through contact with an ion exchange resin. Following reaction, one may then isolate the salt by filtration if it precipitates from solution, or by evaporation to recover the salt. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.

[0131] It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the active compound. The term “solvate” describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., EtOH). The term “hydrate” is a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., D2O, acetone-d6, DMSO-d6).

[0132] A currently accepted classification system for solvates and hydrates of organic compounds is one that distinguishes between isolated site, channel, and metal-ion coordinated solvates and hydrates. See, e.g., K. R. Morris (H. G. Brittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site solvates and hydrates are ones in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound. In channel solvates, the solvent molecules lie in lattice channels where they are next to other solvent molecules. In metal-ion coordinated solvates, the solvent molecules are bonded to the metal ion.

[0133] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, nonstoichiometry will typically be observed.

[0134] BRIEF DESCRIPTION OF THE DRAWINGS

[0135] Embodiments of the present invention will now be described further, with reference to the accompanying drawings, in which:

[0136] Figure 1. Simple Western data from HAP1 cells incubated with compounds at 3 concentrations (0.1 pM, 1 pM and 1 OpM) for 24 hours prior to lysis. dCBP-1 is a control PROTAC known to degrade both p300 and CBP.

[0137] Figure 2. Results from a p300 and CBP HiBit assay in a HAP1 cell line. PROTACs were dosed from 100 nM to 10 pM and data was recorded for 48 hours following PROTAC treatment. Readout is normalized protein abundance (y axis) versus hours after PROTAC treatment (x axis). Data for dCBPl, a control PROTAC known to degrade both p300 and CBP, is provided for comparison.

[0138] Figure 3. Heatmap summarizing AUC data from the HiBit assay described in Figure 2. O2B here refers to JQAD1.

[0139] Figure 4. Simple Western data from HAP1 cells treated with vehicle (lane 1) or compound 02C (100 nM) for 24 hours (lane 2). In lanes 3 and 4, MLN4924 or Carfilzomib were added after 22 hours incubation with 02C (100 nM) to block neddylation or the 26S proteasome, respectively. Samples were lysed and analyzed after 24 hours.

[0140] DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0141] Synthetic Strategies

[0142] The compounds of Formula (I) may be prepared using the techniques described below. Some of the schemes and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in a number of treatises, including Richard Larock, Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 2nd Ed (2010), and the multi -volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974 et seq.). Starting materials and reagents may be obtained from commercial sources or may be prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO2 from the decarboxylation of a diacid, etc.). In addition, in some instances, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0143] In some of the reaction schemes and examples below, certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry, 4th Edition, (2006) and P. Kocienski, Protective Groups, 3rd Edition (2005).

[0144] Generally, the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78°C. to 0°C.). Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., whether or not expressly using the word "range," also includes the indicated endpoints.

[0145] Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-l-ol, propan-2-ol, butan-l-ol, 2-methyl- propan-l-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-l-ol, 3-methyl-butan-l-ol, hexan-l-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-m ethoxy - ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, di -isopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2- di ethoxy-ethane, 1 -methoxy -2-(2-methoxy-ethoxy)-ethane, 1 -ethoxy-2-(2-ethoxy- ethoxy)-ethane, tetrahydrofuran, 1,4-di oxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene- 1,1, -di oxide); and phosphorus-containing solvents (e.g.,HMPA, hexamethylphosphoramide).

[0146] Chemistry General Methods

[0147] All reagents and solvents were purchased from commercial sources and used without further purification. Nuclear magnetic resonance spectra were recorded on a Bruker Avance III HD spectrometer operating at 400 MHz for!H NMR and 100 MHz for13C NMR.XH NMR and13C NMR chemical shifts (5) are reported in parts per million (ppm) and are referenced to residual protium in solvent and to the carbon resonances of the residual solvent peak respectively. DEPT and correlation spectra were run in conjunction to aid assignment. Coupling constants (J) are quoted in Hertz (Hz), and the following abbreviations were used to report multiplicity: s= singlet, d= doublet, dd= doublet of doublets, ddd= double doublet of doublets, t= triplet, q= quartet, m= multiplet, br s= broad singlet. Purification by flash column chromatography was carried out using Fisher Scientific silica gel 60A (35-70 pm), or by using Biotage Selekt, Biotage Isol era, Grace Reveleris or Buchi Pure systems. Analytical thin layer chromatography was performed on glass plates pre-coated with silica gel (Analtech, UNIPLATE™ 250 μm / UV254), with visualization being achieved using UV light (254 nm) and / or by staining with alkaline potassium permanganate dip. Reaction monitoring LC-MS analyses were conducted using Agilent InfinityLab LC / MSD systems. Chiral GC analysis was conducted using an Agilent 7890A GC system. Optical rotations were recorded on a Bellingham & Stanley ADP450 polarimeter. High resolution mass spectral (HRMS) data was collected in the laboratories of the University of Bath Chemistry Department using an Agilent 6545 LC / Q-TOF system.

[0148] 5,-Bromo-2,.,3,-dihydrosDiro[imidazolidine-4,l,-indene]-2.,5-dione

[0149] A stirred suspension of 5-bromoindan-l-one (60.00 g, 284.29 mmol) in ethanol (246 mL) and water (164 mL) at ambient temperature was treated with ammonium carbonate (83.86 g, 872.76 mmol) and potassium cyanide (27.77 g, 426.43 mmol). The reaction mixture was heated to 70 °C and stirred under a flow of nitrogen at this temperature for a total of 161 hours. During this period it was found to be necessary three times to cool and recharge with further portions of ammonium carbonate (1 eq) and potassium cyanide (0.5 eq) before raising the temperature again. Upon completion of the reaction, and after cooling to ambient temperature, the reaction mixture was treated with water (700 mL) and ethyl acetate (500 mL). The mixture was filtered, and the layers of the filtrate separated. The aqueous component was extracted with ethyl acetate (2 x 200 mL), and the combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by dry flash chromatography, eluting with 2-4% MeOH / DCM, afforded the title compound as a light brown solid (42.80 g, 54%). m / z (ES-): 279.1, 281.1 [M-H+]’

[0150] 1H NMR (DMSO-d6) δ: 10.81 (br s, 1H), 8.44 (br s, 1H), 7.55 (d, J= 1.2, 1H), 7.43 (dd, J= 8.4, 1.2, 1H), 7.12 (d, J= 8.4, 1H), 3.07-2.94 (m, 2H), 2.56-2.50 (m, 1H), 2.21-2.13 (m, 1H).

[0151] 5,-BromosDiro[imidazolidine-4,l,-indene]-2.,3,.,5(2,H)-trione

[0152] A stirred mixture of 5'-bromo-2',3'-dihydrospiro[imidazolidine-4,l'-indene]-2, 5-dione (38.70 g, 137.67 mmol), tetrabutylammonium hydrogen sulfate (9.35 g, 27.53 mmol) and sodium 2-iodobenzenesulfonic acid (2.11 g, 6.88 mmol) in acetonitrile (1450 mL) at ambient temperature was treated with potassium peroxymonosulfate (126.95 g, 413.01 mmol) in portions. The reaction mixture was heated to 65 °C and stirred for a total of 56 hours. During this period it was found necessary to periodically cool and recharge with further portions of potassium peroxymonosulfate (eventually up to a total of 8 equivalents were added) before raising the temperature again. Upon completion of the reaction, and after cooling to ambient temperature, the reaction mixture was filtered and washed with acetone (900 mL). The collected solid was treated with hot acetone (5 x 500 mL), these extracts being concentrated to a solid and triturated with ethyl acetate to give an initial crop of product. All the filtrates were combined and concentrated and purified by flash column chromatography, eluting with 3% MeOH / DCM, to afford a second crop of product. This process afforded the title compound as a white solid (22.15 g, 55%). m / z (ES+): 295.1, 297.1 [M+H+]+

[0153] 1H NMR (DMSO-d6) δ: 11.19 (br s,lH), 8.56 (br s, 1H), 7.96 (dd, J= 8.2, 2.0, 1H), 7.90 (d, J= 2.0, 1H), 7.62 (d, J= 8.2, 1H), 3.15 (d, J= 18.6, 1H), 2.92 (d, J= 18.6, 1H).

[0154] (51-1,1, l-Trifluoro-A-(4-fluorobenzyl)DroDan-2-amine

[0155] To a stirred solution of (25)-l,l,l-trifhroropropan-2-amine hydrochloride (34.50 g, 230.70 mmol, [a]o22= +5.8° (c=1.0, MeOH)) and potassium carbonate (127.54 g, 922.81 mmol) in DMF (345 mL) at ambient temperature was added l-(bromomethyl)-4-fluoro- benzene (34.50 mL, 276.84 mmol) in a dropwise fashion over a period of 10 minutes, and the resulting reaction mixture was stirred for 18 hours. The reaction mixture was poured into water (2.8 L) and extracted with ethyl acetate (3 - I L). The combined organic extracts were washed with water (3 ^ 1 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a colourless oil. Purification by flash column chromatography, eluting with 4% ethyl actetate / petroleum ether (40:60), afforded the title compound as a colourless oil (30.79 g, 60%).1H NMR (CDC13) δ: 7.33-7.28 (m, 2H), 7.04-6.99 (m, 2H), 3.93-3.84 (m, 2H), 3.22-3.11 (m, 1H), 1.26-1.24 (m, 3H). Chiral GC (P-DEX™ 120, 30 m x 250 mm, 0.25 μm): 99.7%ee. [a]D26= +22.5° (c = 1, CHCI3).

[0156] To a stirred solution of (5)-l,l,l-trifluoro-M(4-fluorobenzyl)propan-2-amine (30.50 g, 137.89 mmol) in DCM (350 mL) at ambient temperature was added a solution of bromoacetyl bromide (55.66 g, 275.78 mmol) in DCM (50 mL) in a dropwise fashion over a period of 15 minutes, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. After treatment with NaHCCh (sat. aq.) (470 mL) and a further hour of stirring, the organic phase was separated. The aqueous component was extracted with DCM (2 x 200mL), and the combined organics were washed with NaHCCh (sat. aq.) (250 mL), brine (250 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a pale yellow oil. Purification by flash column chromatography, eluting with 4-10% ethyl actetate / petroleum ether (40:60), afforded the title compound as a colourless oil (16.90 g, 36%). m / z (ES+): 367.3 [M+Na+]+

[0157] 1H NMR (DMSO-d6) δ: 7.32-7.10 (m, 4H), 5.34-5.28 (m, 0.5H), 4.96-4.88 (m, 0.5H), 4.81-4.66 (m, 1.5H), 4.56 (d, J= 12.0, 0.5H), 4.38 (d, J= 16.4, 0.5H), 4.26 (d, J= 12.0, 0.5H), 4.09-3.95 (m, 1H), 1.39-1.29 (m, 3H). Observed as a mixture of rotamers.

[0158] 2-((S)-5,-Bromo-2.,3\5-trioxo-2\3,-dihvdrosDiro|imidazolidine-4.,r-inden]-l-yr)-2V- (4-fluorobenzyl)-A^-((5)-l,l,l-trifluoroDroDan-2-yl)acetamide

[0159] To a stirred solution of 5'-bromospiro[imidazolidine-4,T-indene]-2,3',5(2'H)-trione (22.70 g, 76.93 mmol) and potassium carbonate (21.26 g, 153.85 mmol) in DMF (200 mL) at 2 °C was dropwise added a solution of (.S')-2-brorno- / V-(4-fluorobenzyl)- / V-( l ,L I - trifluoropropan-2-yl)acetamide (26.32 g, 76.93 mmol) in DMF (50 mL) at such a rate so as to keep the temperature below 5 °C during the course of the addition. The reaction mixture was then allowed to warm to ambient temperature and stirred for 6 hours before being partitioned between water (450 mL) and ethyl acetate (450 mL). The organic phase was separated, and the aqueous component was extracted with ethyl acetate (3 x 200 mL). The combined organics were washed with brine (4 x 200 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 1-2% MeOH / DCM afforded an off-white solid which was triturated with diethyl ether / petroleum ether (40:60) (1 : 1) to give the title compound as a white solid (33.08 g, 77%). Separation by preparative chromatography afforded the desired (^-(^ / -diastereomer (12.49g). m / z (ES+): 578.1, 580.1 [M+Na+]+1H NMR (DMSO-d6, 120 °C) δ: 8.58 (br s, 1H), 7.98-7.92 (m, 1H), 7.88-7.86 (m, 1H), 7.67-7.63 (m, 1H), 7.36-7.33 (m, 2H), 7.13 (t, J= 8.8, 2H), 5.22-5.15 (m, 1H), 4.82 (d, J= 17.6, 1H), 4.65-4.50 (m, 2H), 4.35-4.28 (m, 1H), 3.13 (d, J= 18.6, 1H), 2.98 (d, J= 18.6, 1H), 1.37 (d, J= 7.2, 3H). [a]D21= +23.6° (c = 1, MeOH) Butyl 2-(4-((5)-l-(2-((4-fluorobenzyl)((5)-l,l,l-trifluoroDroDan-2-yl)amino)-2- oxoethyl)-2.,3,.,5-trioxo-2,.,3,-dihydrosDiro[imidazolidine-4,l,-inden]-5,-yl)-lH- pyrazol-l-vDacetate

[0160] To a stirred solution of 2-((S)-5'-bromo-2,3',5-trioxo-2',3'-dihydrospiro[imidazolidine- 4, 1 '-inden]- 1 -yl)-A^-(4-fluorobenzyl)-A^-((5')- 1,1,1 -trifluoropropan-2-yl)acetamide (3.00 g, 5.39 mmol) and tert-butyl 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol- l-yl]acetate (2.08 g, 6.74 mmol) in 1,4-dioxane (45 mL) at ambient temperature was added water (9 mL), and the resulting reaction mixture was degassed with nitrogen. Potassium carbonate (2.24 g, 16.18 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedi chloropalladium (II) DCM complex (0.35 g, 0.43 mmol) were added, nitrogen was bubbled through the reaction mixture for 5 minutes, and then the entire reaction mixture was transferred to a sealed stainless-steel vessel and stirred under nitrogen atmosphere at 95 °C for 12 hours. Upon cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography, eluting with 2% MeOH / DCM, afforded the title compound as a light brown solid (2.86 g, 81%). m / z (ES+): 658.30 [M+H+]+1H NMR (DMSO-d6, 100°C) δ: 8.64 (s, 1H), 8.26 (s, 1H), 8.03 - 7.97 (m, 2H), 7.87 (d, J= 1.4, 1H), 7.67 (d, J= 8.1, 1H), 7.40 - 7.31 (m, 2H), 7.14 (t, J= 8.6, 2H), 5.21 (br s, 1H), 4.92 (s, 2H), 4.84 (d, J= 17.4, 1H), 4.69 - 4.44 (m, 2H), 4.30 (d, J= 16.0, 1H), 3.11 (d, J= 18.4, 1H), 2.95 (d, J= 18.4, 1H), 1.46 (s, 9H), 1.37 (d, J= 7.0, 3H).

[0161] / f / 7- Butyl 2-(4-((3’5.,45)-l-(2-((4-fluorobenzyl)((5)-l,l,l-trifluoroDroDan-2- yr)amino)-2-oxoethyl)-3,-hvdroxy-2.,5-dioxo-2,.,3,-dihvdrosDiro[imidazolidine-4.,r- indenl-S’-vD-lH-pyrazol-l-vDacetate To a stirred solution of tert-butyl 2-(4-((S)-l-(2-((4-fluorobenzyl)((5')- 1,1,1- trifluoropropan-2-yl)amino)-2-oxoethyl)-2,3', 5-tri oxo-2', 3'-dihydrospiro[imidazolidine- 4,l'-inden]-5'-yl)-lH-pyrazol-l-yl)acetate (2.80 g, 4.26 mmol) in THF (87 mL) and MeOH (87 mL) at 0°C was added sodium borohydride (0.96 g, 25.42 mmol) in a portion-wise fashion. After stirring at 0°C for 30 minutes, the reaction mixture was allowed to warm to ambient temperature with acetone (5 mL) being added, before being concentrated under reduced pressure. Purification by flash column chromatography, eluting with 2% MeOH / DCM, afforded the title compound as a beige solid (2.18 g, 78%). m / z (ES+): 660.30 [M+H+]+1H NMR (DMSO-d6, 100°C) δ: 8.46 (s, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.52 (d, J= 8.8, 1H), 7.40 - 7.33 (m, 2H), 7.29 (d, J= 8.0, 1H), 7.15 (t, J= 8.8, 2H), 5.34 (t, J= 6.5, 1H), 5.22 (br s, 1H), 4.92 - 4.81 (m, 3H), 4.68 - 4.45 (m, 2H), 4.29 (d, J= 16.3, 1H), 2.55 (dd, J= 13.5, 6.3, 1H), 2.40 (dd, J= 13.5, 6.3, 1H), 1.45 (s, 9H), 1.37 (d, J= 7.0, 3H).

[0162] / cr / - Butyl 2-(4-((3'.R .,45)-3'-fluoro-l-(2-((4-fluorobenzyl)((5)-l ,1 ,1-trifluoropropan-

[0163] 2-yl)amino)-2-oxoethyl)-2.,5-dioxo-2'.,3'-dihvdrospiro[imidazolidine-4,l'-inden]-5'- yl)-lH-pyrazol-l-yl)acetate

[0164] To a stirred solution of tert-butyl 2-(4-((3'S,4S)-l-(2-((4-fhiorobenzyl)((S)-l,l,l- trifluoropropan-2-yl)amino)-2-oxoethyl)-3'-hydroxy-2,5-dioxo-2',3'- dihydrospiro[imidazolidine-4,l'-inden]-5'-yl)-lH-pyrazol-l-yl)acetate (2.10 g, 3.18 mmol) in DCM (140 mL) at -70°C was added DAST (1.03 g, 6.37 mmol) in a dropwise fashion, and stirring was maintained at this temperature for 30 minutes. The reaction mixture was allowed to warm to -30°C over 10 minutes, at which point calcium carbonate (1.00 g) was added. The reaction mixture was warmed to ambient temperature and then concentrated under reduced pressure. Purification by flash column chromatography, eluting with 1% MeOH (5% NH40H) / DCM, afforded the title compound as a white solid (1.43 g, 68%)._m / z (ES+): 662.10 [M+H+]+1H NMR (DMSO-de, 100°C) δ: 8.73 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.75 - 7.68 (m, 2H), 7.40 - 7.31 (m, 3H), 7.14 (t, J= 8.4, 2H), 6.16 (ddd, J= 57.7, 6.6, 4.9, 1H), 5.21 (s, 1H), 4.92 (s, 2H), 4.83 (d, J= 17.8, 1H), 4.67 - 4.41 (m, 2H), 4.26 (d, J= 17.8, 1H), 3.08 (ddd, J= 14.3, 12.8, 6.9, 1H), 2.42 (ddd, J= 25.7, 14.5, 4.6, 1H), 1.46 (s, 9H), 1.36 (d, J= 7.0, 3H).

[0165] 2-(4-((3’R,,45)-3,-Fluoro-l-(2-((4-fluorobenzyl)((5)-l,l,l-trifluoropropan-2- yl)amino)-2-oxoethyl)-2.,5-dioxo-2,.,3,-dihvdrospiro[imidazolidine-4,l,-inden]-5,-yl)-

[0166] IH-pyrazol-l-vDacetic acid tert-Butyl 2-(4-((3 'R, 45)-3 '-fluoro- 1 -(2-((4-fluorobenzyl)((S)- 1,1,1 -trifluoropropan-2- yl)amino)-2-oxoethyl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH- pyrazol-l-yl)acetate (0.11 g, 0.17 mmol) was treated with hydrogen chloride (2 mL, 4M solution in 1,4-di oxane) and the resulting solution was stirred at ambient temperature for 6 hours before being concentrated under reduced pressure to give the title compound as a white solid (100 mg, quant), m / z (ES+): 606.10 [M+H+]+1H NMR (DMSO-de, 100°C) δ: 8.73 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.75 - 7.67 (m, 2H), 7.40 - 7.31 (m, 3H), 7.14 (t, J= 8.9, 2H), 6.16 (ddd, J= 57.2, 6.3, 4.7, 1H), 5.21 (br s, 1H), 4.95 (s, 2H), 4.83 (d, J= 17.7, 1H), 4.68 - 4.41 (m, 2H), 4.26 (d, J= 18.1, 1H), 3.13 - 3.02 (m, 1H), 2.47 - 2.34 (m, 1H), 1.36 (d, J= 6.9, 3H). tert- Butyl (7-((2-(2,6-dioxoDiDeridin-3-yl)-l.,3-dioxoisoindolin-5- yl)amino)heptyl)carbamate

[0167] To a stirred mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (0.25 g, 0.91 mmol) and DIPEA (0.23 g, 1.81 mmol) in NMP (5 mL) was added tert-butyl N-(7- aminoheptyl)carbamate (0.23 g, 0.99 mmol) and the reaction mixture was stirred at 90°C for 19.5 hours. After cooling to ambient temperature, the dark green reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were sequentially washed with water (20 mL) and brine (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 1 % MeOH / DCM (containing 0.1% NH4OH), afforded the title compound as a thick oil (118 mg, 41%). m / z (ES+): 387.20 [M-BOC+H+]+1H NMR (CDCh) δ: 7.95 (s, 1H), 7.63 (d, J= 8.3, 1H), 7.01 (d, J= 1.7, 1H), 6.80 (d, J= 8.1, 1H), 4.99 - 4.86 (m, 1H), 4.50 (s, 2H), 3.32 - 3.19 (m, 2H), 3.11 (t, J= 6.8, 2H), 2.93 - 2.63 (m, 3H), 2.16 - 2.08 (m, 2H), 1.75 - 1.57 (m, 2H), 1.54 - 1.23 (m, 16H).

[0168] 5-((7-AminoheDtyl)amino)-2-(2.,6-dioxoDiDeridin-3-yl)isoindoline-l.,3-dione hydrochloride tert-Butyl (7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)heptyl)carbamate (113 mg) was treated with hydrogen chloride (1.2 mL, 4M solution in 1,4-di oxane) and the reaction mixture was stirred at ambient temperature for 16 hours. The resulting suspension was treated with diethyl ether (5 mL) before being filtered, washed with further diethyl ether (2 mL) and dried, to afford the title compound as a yellow-green solid (110 mg) which was used directly in the next stage without further purification, m / z (ES+): 387.20 [Mfreebase+H+]+

[0169] 1H NMR (DMSO-d6) δ: 11.05 (br s, 1H), 7.85 (br s, 3H), 7.56 (d, J= 8.4, 1H), 6.95 (d, J= 1.8, 1H), 6.85 (dd, J= 8.4, 1.8, 1H), 5.02 (dd, J= 8.4, 2.0, 1H), 3.16 (t, J= 8.4, 2H), 2.93-2.82 (m, 1H), 2.80-2.71 (m, 2H), 2.61-2.45 (m, 2H), 2.04-1.95 (m, 1H), 1.62-1.50 (m, 4H), 1.40-1.28 (m, 6H).

[0170] / c / 7- Butyl (7-((2-(l-methyl-2.,6-dioxoDiDeridin-3-yl)-l.,3-dioxoisoindolin-5- yl)amino)heDtyl)carbamate To a stirred mixture of 5-fluoro-2-(l-methyl-2,6-dioxo-3-piperidyl)isoindoline-l, 3-dione (5.00 g, 17.2 mmol) and DIPEA (6.00 mL g, 34.45 mmol) in NMP (50 mL) was added tert-butyl A-(7-aminoheptyl)carbamate (4.36 g, 18.95 mmol) and the reaction mixture was stirred at 90°C for 17 hours. After cooling to ambient temperature, the dark green reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were sequentially washed with water (2 x 250 mL) and brine (3 x 250 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 1-3% MeOH / DCM (with 0.1% NELOH) afforded the title compound as a green solid (1.1 g) which was used directly in the next stage without further purification, m / z (ES+): 401.3 [M-BOC+H+]+1H NMR (DMSO-d6) δ: 7.61 (d, J= 8.3, 1H), 6.96 (d, J= 2.0, 1H), 6.75 (dd, J= 8.3, 2.0, 1H), 4.95 - 4.88 (m, 1H), 4.51 (s, 1H), 3.24 - 3.18 (m, 4H), 3.15 - 3.05 (m, 2H), 2.99 - 2.90 (m, 1H), 2.84 - 2.68 (m, 2H), 2.12 - 2.06 (m, 1H), 1.70 - 1.59 (m, 2H), 1.53 - 1.28 (m, 19H).

[0171] 5-((7-. i-2-(l-methyl-2,6-di idin-3-yl)isoindoline-l,3- dione tert-Butyl(7-((2-(l-methyl-2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)heptyl) carbamate (378 mg, 0.76 mmol) was treated with hydrogen chloride (3.78 mL, 4M solution in 1,4-dioxane) and the resulting mixture was stirred for 2 hours, treated with diethyl ether and filtered, affording the title compound as a pale blue solid (265 mg, 80%) which was used directly in the next stage without further purification, m / z (ES+): 401.2 [M(free base) +H+]+

[0172] 1H NMR (DMSO-d6) δ: 7.81 (br s, 1H), 7.56 (d, J= 8.4, 1H), 6.95 (s, 1H), 6.85 (dd, J= 8.4, 2.0, 1H), 5.09 (dd, 7= 13.0, 5.4, 1H), 4.25 (s, 1H), 3.16 (t, J= 7.0, 2H), 3.02 - 2.88 (m, 4H), 2.79 - 2.70 (m, 3H), 2.60 - 2.52 (m, 1H), 2.05 - 1.97 (m, 1H), 1.62 - 1.50 (m, 5H), 1.41 - 1.24 (m, 7H).

[0173] GENERAL PROCEDURE A To a stirred solution of 2-(4-((3' / ?,4.S')-3'-fluoro- l -(2-((4-fluorobenzyl)((.S')- l , 1 , 1 - trifluoropropan-2-yl)amino)-2-oxoethyl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine- 4,l'-inden]-5'-yl)-lH-pyrazol-l-yl)acetic acid (1 eq) in DMF was added the amine coupling partner (1 eq), DIPEA (2.5 to 4.5 eq) and HATU (1.1 eq) and the reaction mixture stirred at ambient temperature until the reaction was complete. The reaction mixture was diluted with water (10 volumes) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography followed by lyophilisation afforded the product.

[0174] 2-((37?.-kS)-5'-(l-(2-((7-((2-(2.6-l)ioxopipei idiii-3-xl)-1.3-dioxoisoindoliii-5- yljaminojheptxljainiiioj^l^oxoedixDzlHzEXi^zoM^xDzSlzfluoro^ljS^dioxo^l^S^ dihydrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A-((5)-l,l,l- trifluoroDroDan-2-yl)acetamide (02C)

[0175] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihy drospiro[imidazolidine-4,l'-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (95.0 mg, 0.16 mmol) was coupled with 5-((7-aminoheptyl)amino)-2- (2, 6-dioxopiperidin-3-yl)isoindoline-l, 3-dione hydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 3% MeOH / DCM, the residue was lyophilised from MeCN / EEO to afford the title compound as a yellow solid (97 mg, 64%, >99% LCMS purity), m / z (ES+): 974.30 [M+H+]+1H NMR (DMSO-d6, 120 °C) δ 1:0.51 (br s, 1H), 8.61 (s, 1H), 8.13 (s, 1H), 7.88 (d, J= 0.67, 1H), 7.71 (m, 1H), 7.69 - 7.66 (m, 1H), 7.54 (d, J= 8.2, 1H), 7.38 - 7.32 (m, 3H),

[0176] 7.13 (t, J= 8.7, 2H), 6.98 (d, J= 2.1, 1H), 6.87 (dd J= 8.4, 2.2, 1H), 6.62, (t, J= 5.2, 1H),

[0177] 6.14 (ddd, J= 57.7, 6.8, 4.6, 1H), 5.18 (m, 1H), 4.96 (m, 1H), 4.82 (d, J= 17.2, 1H), 4.78 (s, 2H) 4.61 (d, J= 17.6, 1H), 4.47 (d, J= 17.6, 1H), 4.26 (d, J= 16.7, 1H), 3.23 - 3.12 (m, 4H), 3.08 (ddd, J= 14.4, 12.4, 6.8, 1H), 2.90 - 2.79 (m, 1H), 2.67 - 2.52 (m, 2H), 2.42 (ddd, J= 25.5, 14.4, 4.6, 1H), 2.09 - 2.01 (m, 1H), 1.66 - 1.58 (m, 1H), 1.54 -

[0178] 1.45 (m, 1H), 1.44 - 1.28 (m, 6H), 1.37 (d, J= 7.1, 3H)

[0179] HRMS (ES+) calculated for [C48H48F5N9O8+H+]+974.9670, found: 974.3638

[0180] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihy drospiro[imidazolidine-4,l'-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (100 mg, 0.17 mmol) was coupled with 4-((3-aminopropyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione hydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 3% MeOH / DCM, the residue was lyophilised from MeCN / FEO to afford the title compound as a yellow solid (77 mg, 51%, 99% LCMS purity), m / z (ES+): 918.30 [M+H+]+1H NMR (DMSO-d6, 120 °C) δ 1:0.56 (br s, 1H), 8.63 (s, 1H), 8.14 (d, 7= 0.65, 1H), 7.89 (d, J= 0.76, 1H), 7.78 - 7.71 (m, 1H),7.72 (m, 1H), 7.70 - 7.66 (m, 1H), 7.57 (dd, J= 8.4, 7.1, 1H), 7.39 - 7.33 (m, 3H), 7.13 (t, J= 8.8, 2H), 7.07 (d, J= 8.5, 1H), 7.03 (d, J= 7.1, 1H), 6.45 (t, J= 6.2, 1H), 6.15 (ddd, J= 57.5, 6.7, 4.5, 1H), 5.19 (m, 1H), 5.00 (m, 1H), 4.83 (d, J= 17.2, 1H), 4.82 (s, 2H), 4.62 (d, J= 17.2, 1H), 4.48 (d, J= 17.2, 1H), 4.27 (d, J= 16.7, 1H), 3.38 (q, J= 6.7, 2H), 3.28 (q, J= 6.7, 2H), 3.08 (ddd, J= 14.4, 12.4, 6.8, 1H), 2.91 - 2.81 (m, 1H), 2.68 - 2.53 (m, 2H), 2.42 (ddd, J= 25.5, 14.4, 4.6, 1H), 2.13 - 2.04 (m, 1H), 1.87 - 1.78 (m, 1H), 1.37 (d, J= 6.9, 3H)

[0181] HRMS (ES+) calculated for [C44H40F5N9O8+HT 918.2998, found: 918.3005

[0182] 2-((37?.4tS)-5'-(l-(2-((5-((2-(2.6-l)ioxopiperidin-3-yl)-1.3-dioxoisoindolin-4- yljaminojEentxljainiiioj^^^oxoedixDzlHzEXi^zoM^xDzSlzfluoro^^jS^dioxo^^S^ dihvdrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A-((5)-l,l,l-

[0183] I-2--

[0184] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (80 mg, 0.13 mmol) was coupled with 4-((5-aminopentyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione hydrochloride according to general procedure A. After purification by flash column chromatography, eluting with EtOAc, the residue was lyophilised from MeCN / EEO to afford the title compound as a yellow solid (43 mg, 34%, 96% LCMS purity), m / z (ES+): 946.20 [M+H+]+1H NMR (DMSO-d6, 100 °C) δ: 10.67 (s, 1H), 8.71 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.73 - 7.66 (m, 3H), 7.57 (dd, J= 8.3, 7.3, 1H), 7.39-7.33 (m, 2H), 7.13 (t, J= 8.3, 2H), 7.07 (d, J= 8.5, 1H), 7.02 (d, J= 7.0, 1H), 6.42 - 6.35 (m, 1H), 6.14 (ddd, J= 58.4, 6.9, 4.7, 1H), 5.19 (br s, 1H), 5.00 (dd, J= 12.5, 5.5, 1H), 4.86 - 4.77 (m, 3H), 4.66 - 4.42 (m, 2H), 4.26 (d, J= 16.3, 1H), 3.31 (dd, J= 12.8, 6.5, 2H), 3.16 (dd, J= 12.8, 6.6, 2H), 3.12 - 3.01 (m, 1H), 2.91 - 2.80 (m, 2H), 2.67 - 2.55 (m, 2H), 2.41 (ddd, J= 25.0, 14.1, 4.4, 1H), 2.11 - 2.02 (m, 1H), 1.65 - 1.59 (m, 2H), 1.58 - 1.49 (m, 2H), 1.46 - 1.39 (m, 2H), 1.36 (d, J= 7.0, 3H).

[0185] HRMS (ES+) calculated for [C46H44F5N9O8+HT 946.3311, found: 946.3320

[0186] 2- -5,-(l-(2-((7-((2-(2.,6-DioxoDiDeridin-3-yl)-l.,3-dioxoisoindolin-4- yljaminojheptxljainiiioj^^^oxoedixDzlHzEXi^zoM^xDzSlzfluoro^^jS^dioxo;^^ dihvdrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A-((5)-l,l,l- trifluoroDroDan-2-yl)acetamide (02F)

[0187] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (80 mg, 0.13 mmol) was coupled with 4-((5-aminoheptyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione hydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 50% EtOAc / petroleum ether (40:60) increased to 100% EtOAc, the residue was lyophilised from MeCN / EEO to afford the title compound as a yellow solid (79 mg, 61%, >95% LCMS purity), m / z (ES+): 974.10 [M+H+]+1H NMR (DMSO-d6, 100 °C) δ: 10.69 (s, 1H), 8.72 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.73 - 7.65 (m, 3H), 7.57 (dd, J= 8.2, 7.5, 1H), 7.39 - 7.30 (m, 3H), 7.13 (t, J= 8.6, 2H), 7.07 (d, J= 8.6, 1H), 7.02 (d, J= 7.0, 1H), 6.38 (t, J= 5.8, 1H), 6.14 (ddd, J= 58.0, 7.2, 5.0, 1H), 5.20 (br s, 1H), 5.00 (dd, J= 12.4, 5.6, 1H), 4.86 - 4.76 (m, 3H), 4.69 - 4.37 (m, 2H), 4.25 (d, J= 15.8, 1H), 3.31 (dd, J= 13.2, 6.7, 2H), 3.16 - 3.02 (m, 3H), 2.91 - 2.81 (m, 1H), 2.67 - 2.52 (m, 2H), 2.40 (ddd, J= 25.5, 14.4, 4.5, 1H), 2.13 - 1.99 (m, 1H), 1.67 - 1.57 (m, 2H), 1.51 - 1.43 (m, 2H), 1.43 - 1.22 (m, 9H).

[0188] HRMS (ES+) calculated for [C48H48F5N9O8+H+]+974.3624, found: 974.3632

[0189] 2-((37?.4tS)-5'-(l-(2-((2-(2-((2-(2.6-Dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4- yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)-lH-Dyrazol-4-yl)-3,-fluoro-2.,5-dioxo-

[0190] 2,,3,-dihvdrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A-((5)-l,l,l- trifluoroDroDan-2-yl)acetamide (02G)

[0191] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (80 mg, 0.13 mmol) was coupled with 4-[2-(2-aminoethoxy)ethylamino]- 2-(2,6-dioxo-3-piperidyl)isoindoline-l, 3-dione hydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 3% MeOH / DCM, the residue was lyophilised from MeCN / FFO to afford the title compound as a yellow solid (88 mg, 70%, 99% LCMS purity), m / z (ES+): 948.30 [M+H+]+1H NMR (DMSO-d6, 120 °C) δ: 10.56 (br s, 1H), 8.62 (s, 1H), 8.12 (d, J= 0.5, 1H), 7.87 (d, J= 0.7, 1H), 7.70 (s, 1H), 7.67, (dt, J= 8.0, 1.7, 1H), 7.64 (br s, 1H), 7.57 (dd, J= 8.5, 7.2, 1H), 7.39 - 7.32 (m, 3H) 7.13 (m, 3H), 7.04 (d, J= 7.0, 1H), 6.51 (t, J= 5.2, 1H), 6.14 (ddd, J= 57.6, 6.7, 4.5, 1H), 5.18 (m, 1H), 5.00 (m, 1H), 4.82 (d, J= 17.2, 1H), 4.82 (s, 2H), 4.62 (d, J= 17.2, 1H), 4.48 (d, J= 17.2, 1H), 4.27 (d, J= 16.7, 1H), 3.68 (t, J= 5.5, 2H), 3.56 (t, J= 5.5, 2H), 3.49 (q, J= 5.6, 2H), 3.34 (q, J= 5.6, 2H), 3.08 (ddd, J= 14.4, 12.4, 6.8, 1H), 2.90 - 2.80 (m, 1H), 2.67 - 2.53 (m, 2H), 2.42 (ddd, J= 25.5, 14.4, 4.6, 1H), 2.12 - 2.03 (m, 1H), 1.37 (d, J= 6.9, 3H)

[0192] HRMS (ES+) calculated for [C45H42F5N9O9+HT 948.3104, found: 948.3113

[0193] 2-( -5'-( l-( 14-((2-(2.6-Dioxopiperidin-3-yl)-l .3-dioxoisoiiidoliii-4-yl):imino)-

[0194] 2zoxoz629J2ztnoxaz3zazateti^decxl)zlIl^Xi^zol2£^l)z3^fliioi^2225zdioxo22^3^ dihvdrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A-((5)-l,l,l- trifluoroDroDan-2-yl)acetamide (02H)

[0195] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (80 mg, 0.13 mmol) was coupled with 4-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-l,3- dione hydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 2.5% MeOH / DCM, the residue was lyophilised from MeCN / FEO to afford the title compound as a yellow solid (67 mg, 49%, 98% LCMS purity), m / z (ES+): 1036.40 [M+H+]+

[0196] 1H NMR (DMSO-d6, 120 °C) δ 1: 0.55 (br s, 1H), 8.61 (s, 1H), 8.13 (d, J= 0.5, 1H), 7.88 (d, J= 0.7, 1H), 7.71 (s, 1H), 7.67, (dt, J= 8.0, 1.7, 1H), 7.57 (br s, 1H), 7.56 (dd, J= 8.8, 7.1, 1H), 7.38 - 7.32 (m, 3H) 7.12 (m, 3H), 7.03 (d, J= 7.0, 1H), 6.50 (t, J= 5.7, 1H), 6.14 (ddd, J= 57.8, 6.8, 4.7, 1H), 5.18 (m, 1H), 4.99 (m, 1H), 4.82 (d, J= 17.5, 1H), 4.81 (s, 2H), 4.61 (d, J= 17.2, 1H), 4.47 (d, J= 17.2, 1H), 4.26 (d, J= 16.6, 1H), 3.68 (t, J= 5.5, 2H), 3.62 - 3.56 (m, 4H), 3.56 - 3.53 (m, 4H), 3.52 - 3.46 (m, 4H), 3.30 (q, J= 5.8, 2H), 3.08 (ddd, J= 14.4, 12.4, 6.8, 1H), 2.90 - 2.80 (m, 1H), 2.68 - 2.52 (m, 2H), 2.42 (ddd, J= 25.5, 14.4, 4.6, 1H), 2.12 - 2.04 (m, 1H), 1.37 (d, J= 7.1, 3H)

[0197] HRMS (ES+) calculated for [C49H50F5N9O11+HT 1036.3628, found: 1036.3637

[0198] (25,4 / ?)-l-((5)-2-(3-(2-(4-((3, / ?,45)-3,-Fluoro-l-(2-((4-fluorobenzyl)((5)-l,ia- dihvdrosDiro[imidazolidine-4,l,-inden]-5,-yl)-lH-Dyrazol-l- yl)acetamido)DroDanamido)-3,3-dimethylbutanoyl)-4-hvdroxy-A-(4-(4- methylthiazol-5-yl)benzyl)Dyrrolidine-2-carboxamide (021)

[0199]

[0200] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (80 mg, 0.13 mmol) was coupled with (2S,4R)~ 1 -((S)-2-(3- aminopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-yV-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide dihydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 0-10% MeOH / DCM, the residue was lyophilised from MeCN / FEO to afford the title compound as a white solid (110 mg, 76%, 98.5% LCMS purity), m / z (ES+): m / z (ES+): 1111.20 [M+Na+]+1H NMR (DMSO-d6, 100 °C) δ: 8.89 (s, 1H), 8.72 (s, 1H), 8.14 (s, 1H), 8.07 (br s, 1H), 7.89 (s, 1H), 7.74 - 7.65 (m, 3H), 7.50 (br d, J= 9.3, 1H), 7.44 - 7.31 (m, 7H), 7.13 (t, J= 8.6, 2H), 6.14 (ddd, J= 57.6, 6.7, 4.7, 1H), 5.20 (br s, 1H), 4.87 - 4.74 (m, 4H), 4.67 - 4.20 (m, 9H), 3.68 (dd, J= 23.6, 10.0, 1H), 3.36 (dd, J= 12.5, 6.5, 2H), 3.07 (ddd, J= 14.2, 12.7, 6.8, 1H), 2.48 - 2.35 (m, 6H), 2.03 (s, 2H), 1.35 (d, J= 7.0, 3H), 0.96 (s, 9H).

[0201] HRMS (ES+) calculated for [C53H57F5N10O8S+HT 1089.4080, found: 1089.4080

[0202] (25,4 / ?)-l-((5)-2-(5-(2-(4-((3, / ?,45)-3,-Fluoro-l-(2-((4-fluorobenzyD((5)-iaa- dihvdrosDiro[imidazolidine-4,l,-inden]-5,-yl)-lH-Dyrazol-l- yl)acetamido)Dentanamido)-3.,3-dimethylbutanoyl)-4-hvdroxy-A-(4-(4- methylthiazol-5-yl)benzyl)Dyrrolidine-2-carboxamide (02J)

[0203]

[0204] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (80 mg, 0.13 mmol) was coupled with (2S,47?)-1 -((5)-2-(5- aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-yV-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide dihydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 0-10% MeOH / DCM, the residue was lyophilised from MeCN / FFO to afford the title compound as a white solid (78 mg, 53%, 95% LCMS purity), m / z (ES+): 1117.20 [M+H+]+1H NMR (DMSO-d6, 100 °C) δ: 8.90 (s, 1H), 8.72 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.74 - 7.66 (m, 3H), 7.43 - 7.30 (m, 8H), 7.14 (t, J= 8.4, 2H), 6.15 (ddd, J= 57.8, 6.7, 4.7, 1H), 5.20 (br s, 1H), 4.86 - 4.72 (m, 4H), 4.68 - 4.56 (m, 1H), 4.57 - 4.45 (m, 3H), 4.44 - 4.33 (m, 2H), 4.33 - 4.19 (m, 2H), 3.75 - 3.62 (m, 2H), 3.17 - 3.02 (m, 3H), 2.45 (s, 3H), 2.43 - 2.34 (m, 1H), 2.30 - 2.13 (m, 3H), 2.06 - 1.98 (m, 2H), 1.60 - 1.44 (m, 4H), 1.35 (d, J= 7.0, 3H), 0.96 (s, 9H).

[0205] HRMS (ES+) calculated for [CssHeiFsNioOsS+HT 1117.4393, found: 1117.4405

[0206] (2.S.4 / ?)-.\-(2-(4-(2-(4-((37?.4.S)-3'-l liioro-l-(2-((4-niiorobenzyl)((S)-l.l.l- trifluoroDroDan-2-yl)amino)-2-oxoethyl)-2.,5-dioxo-2'.,3'- dihydrosDiro[imidazolidine-4,l,-inden]-5,-yl)-lH-Dyrazol-l-yl)acetamido)butoxy)-

[0207] 4-(4-methylthiazol-5-yl)benzyl)-l-((S)-2-(l-fluorocvcloDroDane-l-carboxamido)-

[0208] 3,3-dimethylbutanoyl)-4-hvdroxyDyrrolidine-2-carboxamide (02K)

[0209]

[0210] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (80 mg, 0.13 mmol) was coupled with (2S,47?)-A-[[2-(4-aminobutoxy)-4- (4-methylthiazol-5-yl)phenyl]methyl]- 1 -[(2S)-2-[( 1 - fluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidine-2- carboxamide dihydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 2.5% MeOH / DCM, the residue was lyophilised from MeCN / EEO to afford the title compound as a white solid (98mg, 62%, >99% LCMS purity), m / z (ES-): 1189.4 [M-H+]+1H NMR (DMSO-d6, 120 °C) δ: 8.87 (s, 1H), 8.61 (br s, 1H), 8.13 (s, 1H), 7.87 (s, 1H),

[0211] 7.82 (m, 1H), 7.71 (s, 1H), 7.67 (dt, J= 8.0, 1.7, 1H), 7.65 (br s, 1H), 7.41 - 7.32 (m, 4H), 7.13 (t, J= 8.6, 2H), 7.06 (br s, 1H), 7.02 (d, J= 1.4, 1H), 6.98 (d, J= 8.0, 1H6.14 (ddd, J= 57.7, 6.8, 4.6, 1H), 5.18 (m, 1H), 4.82 (d, J= 18.1, 1H), 4.79 (s, 2H), 4.70 (br s, 1H), 4.65 - 4.58 (m, 3H), 4.47 (d, J= 16.6, 1H), 4.41 (br s, 1H), 4.34 (br s, 2H), 4.27 (d, J= 16.6, 1H), 4.10 (t, J= 6.4, 2H), 3.77 - 3.56 (m, 2H), 3.24 (q, J= 6.8, 2H), 3.08 (ddd, J= 14.4, 12.4, 6.8, 1H), 2.47 (s, 3H), 2.42 (ddd, J= 25.5, 14.4, 4.6, 1H), 2.08 (m, 1H),

[0212] 1.83 (m, 2H), 1.69 (m, 2H), 1.37 (d, J= 7.2, 3H), 1.37 - 1.21 (m, 5H), 0.99 (s, 9H) HRMS (ES+) calculated for [C58H64F6NIO09S+H+]+1191.4561, found: 1191.4576

[0213] (2.S.4 / ?)-.\-(2-(4-(2-(4-((37?.4.S)-3'-l liioro-l-(2-((4-niiorobenzyl)((S)-l.l.l- trifluoroDroDan-2-yl)amino)-2-oxoethyl)-2.,5-dioxo-2'.,3'- dihydrosDiro[imidazolidine-4,l,-inden]-5,-yl)-lH-Dyrazol-l-yl)acetamido)butoxy)-

[0214] 4-(4-methylthiazol-5-yl)benzyl)-l-((S)-2-(l-fluorocvcloDroDane-l-carboxamido)-

[0215] 3,3-dimethylbutanoyl)-4-hvdroxyDyrrolidine-2-carboxamide (02L)

[0216]

[0217] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (80 mg, 0.13 mmol) was coupled with (2S,47?)-A-[[2-(6-aminohexoxy)-4- (4-methylthiazol-5-yl)phenyl]methyl]- 1 -[(2S)-2-[( 1 - fluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidine-2- carboxamide dihydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 2.5% MeOH / DCM, the residue was lyophilised from MeCN / FFO to afford the title compound as a white solid (108 mg, 67%, >98% LCMS purity), m / z (ES+): 1219.4 [M+H+]+1H NMR (DMSO-d6, 120 °C) δ: 8.88 (s, 1H), 8.62 (br s, 1H), 8.13 (s, 1H), 7.88 (d, J= 0.7, 1H), 7.82 (m, 1H), 7.71 (s, 1H), 7.68 (dt, J= 8.0, 1.7, 1H), 7.58 (br s, 1H), 7.41 - 7.32 (m, 4H), 7.13 (t, J= 8.6, 2H), 7.07 (br s, 1H), 7.02 (d, J= 1.6, 1H), 6.98 (d, J= 8.0, 1H), 6.15 (ddd, J= 57.7, 6.7, 4.6, 1H), 5.19 (m, 1H), 4.83 (d, J= 17.7, 1H), 4.79 (s, 2H), 4.70 (br s, 1H), 4.66 - 4.58 (m, 3H), 4.48 (d, J= 16.6, 1H), 4.41 (br s, 1H), 4.34 (br s, 2H), 4.27 (d, J= 16.6, 1H), 4.09 (t, J= 6.5, 2H), 3.76 - 3.57 (m, 2H), 3.17 (q, J= 6.8, 2H), 3.08 (ddd, J= 14.4, 12.4, 6.8, 1H), 2.48 (s, 3H), 2.42 (ddd, J= 25.5, 14.4, 4.6, 1H), 2.09 (m, 1H), 1.81 (m, 2H), 1.58 - 1.46 (m, 4H) 1.45 - 1.22 (m, 7H), 1.37 (d, J= 7.2, 3H), 1.00 (s, 9H)

[0218] HRMS (ES+) calculated for [CeoHesFeNioCfcS+HT 1219.4874, found: 1219.4884

[0219] 2- 1 -( 2-(4-( (4-(2-( 2.6- Dioxopiper idin-3-vI )-6-fl uoro- 1.3-dioxoisoiiidol in-

[0220] 5-yl)DiDerazin-l-yl)methyl)DiDeridin-l-yl)-2-oxoethyl)-lH-Dyrazol-4-yl)-3,-fluoro-

[0221] 2,5-dioxo-2,,3,-dihvdrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A- ((5)-l,l,l-trifluoroDroDan-2-yl)acetamide (02M)

[0222] 2-(4-((3 R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihydrospiro[imidazolidine-4,r-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (63 mg, 0.10 mmol) was coupled with 2-(2,6-dioxo-3-piperidinyl)-5- fluoro-6- [4-(4-piperidinylmethyl)- 1 -piperazinyl] - 1 H-i soindole- 1 , 3 (277)-dione dihydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 2.5% MeOH / DCM, the residue was lyophilised from MeCN / FEO to afford the title compound as a white solid (97 mg, 89%, >99% LCMS purity), m / z (ES+): 1067.30 [M+Na+]+1H NMR (DMSO-d6, 100 °C) δ: 10.70 (s, 1H), 8.72 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.74 - 7.66 (m, 2H), 7.60 (d, J= 11.7, 1H), 7.43 (d, J= 7.6, 1H), 7.39-7.30 (m, 3H), 7.13 (t, J= 8.3, 2H), 6.15 (ddd, J= 57.3, 5.9, 4.7, 1H), 5.28-5.13 (m, 1H), 5.11 - 5.00 (m, 3H), 4.82 (d, J= 18.4, 1H), 4.66-4.42 (m, 2H), 4.30 - 4.02 (m, 4H), 3.35-3.27 (m, 4H), 3.12 - 3.02 (m, 2H), 2.89 - 2.80 (m, 1H), 2.68-2.53 (m, 5H), 2.46-2.31 (m, 2H), 2.27 (d, J= 6.7, 2H), 2.12 - 2.02 (m, 1H), 1.89-1.75 (m, 3H), 1.35 (d, J= 7.1, 3H), 1.20-1.06 (m, 2H). HRMS (ES+) calculated for [CsiHsoFeNioOs+HT 1045.3796, found: 1045.3786

[0223] 2-( -5'-( l-(2-(4-((4-(4-(2.4-l)ioxotetr:ihvdropyriinidin-l (211)- in-1- in-l-vl)-2-i fluoro-2.,5-dioxo-2'.,3'-dihvdrosDiro[imidazolidine-4,l'-inden]-l-yl)-A-(4-

[0224] 2-(4-((3 R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihy drospiro[imidazolidine-4,l'-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (63 mg, 0.10 mmol) was coupled with l-[4-[4-(4- piperidylmethyl)piperazin-l-yl]phenyl]hexahydropyrimidine-2, 4-dione trihydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 5% MeOH / DCM, the residue was lyophilised from MeCN / FEO to afford the title compound as a white solid (41 mg, 42%, 97% LCMS purity), m / z (ES+): 959.40 [M+H+]+1H NMR (DMSO-d6, 100 °C) δ: 9.79 (s, 1H), 8.73 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.74 - 7.66 (m, 2H), 7.39 - 7.30 (m, 3H), 7.21 - 7.09 (m, 4H), 6.93 (d, J= 7.9, 2H), 6.15 (ddd, J= 57.5, 6.7, 4.4, 1H), 5.20 (br s, 1H), 5.09 (s, 2H), 4.83 (d, J= 17.8, 1H), 4.68-4.40 (m, 2H), 4.30-4.01 (m, 3H), 3.71 (t, J= 6.7, 2H), 3.25 - 3.02 (m, 5H), 2.70 (t, J= 6.7, 2H), 2.65-2.50 (m, 4H), 2.47 - 2.17 (m, 4H), 1.82 (d, J= 12.5, 3H), 1.35 (d, J= 7.1, 3H), 1.22-1.05 (m, 2H).

[0225] HRMS (ES+) calculated for [C48H5iF5NioOe+H+]+959.3991, found: 959.3975

[0226] 2 2.,6-DioxoDiDeridin-3-yl)amino)Dhenyl)DiDerazin-l- xUmedixllEiEendiii^lzxlh^^oxoedixDzlHzEXi^zoM^xDzSlzfluoro^^jS^dioxo;^^ dihvdrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A-((5)-l,l,l- trifluoroDroDan-2-yl)acetamide (020)

[0227] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihy drospiro[imidazolidine-4,l'-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (63 mg, 0.10 mmol) was coupled with 3-[4-[4-(4- piperidylmethyl)piperazin-l-yl]anilino]piperidine-2, 6-dione trihydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 30-100% acetone / DCM, the residue was lyophilised from MeCN / FEO to afford the title compound as a white solid (21 mg, 91%, >99% LCMS purity), m / z (ES+): 973.40 [M+H+]+1H NMR (DMSO-d6, 100 °C) δ: 10.34 (s, 1H), 8.72 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.74 - 7.67 (m, 2H), 7.44 - 7.25 (m, 3H), 7.14 (t, J= 8.0, 2H), 6.93 (t, J= 8.1, 1H), 6.32 - 6.28 (m, 1H), 6.25 - 6.05 (m, 3H), 5.31 (d, J= 6.6, 1H), 5.20 (br s, 1H), 5.08 (s, 2H), 4.82 (d, J= 17.4, 1H), 4.71-4.41 (m, 2H), 4.31 - 3.97 (m, 4H), 3.14 - 3.01 (m, 5H), 2.80 - 2.59 (m, 2H), 2.55 - 2.50 (m, 4H), 2.48-2.34 (m, 2H), 2.27 - 2.15 (m, 3H), 1.95-1.76 (m, 4H), 1.35 (d, 7= 7.1, 3H), 1.22 - 1.02 (m, 2H).

[0228] HRMS (ES+) calculated for [C49H53F5N10O6 + H+]+973.4148, found: 973.4128

[0229] 2-( -5'-( l-(2-(4-((4-(2-(2.6-l)ioxopipei idin-3-xl)-l .3-dioxoisoindoliii-5- yl)DiDerazin-l-yl)methyl)DiDeridin-l-yl)-2-oxoethyl)-lH-Dyrazol-4-yl)-3,-fluoro- 2„5-dioxo-2,.,3,-dihvdrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A- ((5)-l,l,l-trifluoroDroDan-2-yl)acetamide (02P)

[0230] 2-(4-((3 'R, 4S)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihy drospiro[imidazolidine-4,l'-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (63 mg, 0.10 mmol) was coupled with 2-(2,6-dioxo-3-piperidinyl)-5-[4- (4-piperidinylmethyl)-l-piperazinyl]-l / / -isoindole-l,3(2 / / )-dione dihydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 3-5% MeOH / DCM, the residue was lyophilised from MeCN / FEO to afford the title compound as a white solid (54.4 mg, 51%, 98% LCMS purity), m / z (ES+): 1027.4 [M+H+]+1H NMR (DMSO-d6, 100 °C) δ: 10.67 (s, 1H), 8.72 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.74 - 7.63 (m, 3H), 7.38 - 7.28 (m, 4H), 7.23 (dd, J= 8.6, 1.7, 1H), 7.14 (t, J= 8.1, 2H), 6.15 (ddd, J= 57.7, 5.8, 4.5, 1H), 5.28 - 5.14 (m, 1H), 5.09 (s, 2H), 5.01 (dd, J= 12.5, 5.2, 1H), 4.83 (d, J= 17.5, 1H), 4.67 - 4.41 (m, 2H), 4.32 - 4.00 (m, 3H), 3.50 - 3.42 (m, 4H), 3.07 (ddd, J= 13.7, 12.7, 6.9, 1H), 2.91 - 2.81 (m, 2H), 2.69 - 2.53 (m, 7H), 2.41 (ddd, J= 25.9, 14.6, 4.8, 1H), 2.26 (d, J= 6.7, 2H), 2.10 - 2.02 (m, 1H), 1.92 - 1.76 (m, 3H), 1.35 (d, J= 7.0, 3H), 1.19 - 1.06 (m, 2H).

[0231] HRMS (ES+) calculated for [CsiHsiFsNioOs+HT 1027.3890, found: 1027.3882

[0232] 2- -3,-Fluoro-5,-(l-(2-((7-((2-(l-methyl-2.,6-dioxoDiDeridin-3-yl)-l.,3- dioxoisoindolin-5-yl)amino)heDtyl)amino)-2-oxoethyl)-lH-Dyrazol-4-yl)-2.,5-dioxo- 2,,3,-dihvdrosDiro[imidazolidine-4,l,-inden]-l-yl)-A-(4-fluorobenzyl)-A-((5)-l,l,l- trifluoroDroDan-2-yl)acetamide (02C-N)

[0233] 2-(4-((3 'R, 45)-3 '-Fluoro- 1 -(2-((4-fluorob enzyl)((S)- 1,1,1 -trifluoropropan-2-yl)amino)-2- oxoethyl)-2,5-di oxo-2', 3'-dihy drospiro[imidazolidine-4,l'-inden]-5'-yl)-lH-pyrazol-l- yl)acetic acid (58 mg, 0.10 mmol) was coupled with 5-(7-aminoheptylamino)-2-(l- methyl-2,6-dioxo-3-piperidyl)isoindoline-l,3-dione;hydrochloride according to general procedure A. After purification by flash column chromatography, eluting with 3-5% MeOH / DCM, the residue was lyophilised from MeCN / H20 to afford the title compound as a white solid (14 mg, 15%, 98% LCMS purity), m / z (ES+): 988.4 [M+H+]+1H NMR (DMSO-d6, 100 °C) δ: 8.72 (s, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.74 - 7.65 (m, 3H), 7.54 (d, J= 8.4, 1H), 7.39 - 7.31 (m, 3H), 7.13 (t, J= 8.8, 2H), 6.97 (d, J= 2.0, 1H), 6.87 (dd, J= 8.4, 2.1, 1H), 6.74 (t, J= 5.2, 1H), 6.14 (ddd, J= 57.8, 6.8, 5.0, 1H), 5.19 (br s, 1H), 5.05 (dd, J= 12.5, 5.6, 1H), 4.86 - 4.76 (m, 3H), 4.67 - 4.41 (m, 2H), 4.25 (d, J= 17.7, 1H), 3.16 (ddd, J= 19.3, 12.9, 6.7, 4H), 3.10 - 3.02 (m, 4H), 2.94 - 2.87 (m, 1H), 2.81 - 2.73 (m, 1H), 2.63 - 2.52 (m, 1H), 2.41 (ddd, J= 25.8, 14.6, 4.6, 1H), 2.08 - 2.01 (m, 1H), 1.65 - 1.56 (m, 2H), 1.53 - 1.44 (m, 2H), 1.35 (d, J= 7.2, 3H), 1.37 - 1.31 (m, 6H).

[0234] HRMS (ES+) calculated for [C49H50F5N9O8+HT 988.3781 found: 988.3804.

[0235] EXAMPLES

[0236] In the examples, compounds 02C to 02L comprising components of HL (HAT-domain recruiting ligand), X (a divalent exit vector), a linker, XI (a divalent exit vector), and an E3 ubiquitin ligase ligand were synthesised.

[0237] A possible synthesis of 02E is shown in Scheme 1

[0238] The compounds were tested to assess degradation of p300 versus CBP in HAP1 cells by automated western blot (Simple Western), the results are provided in Figure 5. The compounds were benchmarked against a PROTAC known to target both p300 and CBP non-selectively (dCBPl) as well as the PROTAC, JQAD1. The results in Figure 5 show that compounds 02C, 02F and 02H disclosed herein, demonstrate selective degradation of p300.

[0239] The compounds were also tested in a HiBit assay in a HAP1 cell line. The HiBit assay tags the proteins of interest (CBP and p300) to provide a luminescent-based kinetic readout of protein levels in live cells. The results, in Figure 6, show that compounds 02C and 02H demonstrate enhanced selectivity for p300 over CBP with a faster onset of action. The data from this assay is summarized for all compounds in the heatmaps shown in Figure 7. Compounds tested in Figure 7 demonstrate significant and selective degradation of p300.

[0240] To demonstrate that the degradation of p300 is mediated by the ubiquitin proteasome system, a control experiment was performed with a representative compound, 02C. Degradation of p300 induced by 02C treatment could be ‘rescued’ by co-treatment with an inhibitor of neddylation or a direct inhibitor of the 26S proteasome (Figure 8).

[0241] REFERENCES

[0242] 1. Lasko, L., et al. Discovery of a selective catalytic p300 / CBP inhibitor that targets lineage-specific tumours. Nature 550, 128-132 (2017). https: / / doi.org / 10.1038 / nature24Q28.

[0243] 2. WO-A-2016 / 044770.

[0244] 3. Bosnakovski, D., et al. Inactivation of the CIC-DUX4 oncogene through P300 / CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma. Oncogenesis 10, 68 (2021). https: / / d0i.0rg / l 0, 1038 / s41389-021 -00357-4.

[0245] 4. Durbin et al. (2022) Cancer Discov., 12, 730-751 doi: 10.1158 / 2159-8290.CD-

[0246] 21-0385

[0247] 5. EP3873898

[0248] 6. W02020092907 7. Cheng- Sanchez, I.; Gossele, K. A.; Palaferri, L.; Kirillova, M. S.; Nevado, C. Discovery and Characterization of Active CBP / EP300 Degraders Targeting the HAT Domain. ACS Med. Chem. Lett. 2024, acsmedchemlett.3c00490. https : / / doi . org / 10.1021 / acsmedchemlett.3 c00490.

[0249] 8. Chang, Q.; Li, J.; Deng, Y.; Zhou, R.; Wang, B.; Wang, Y.; Zhang, M.; Huang, X.; Li, Y. Discovery of Novel PROTAC Degraders of P300 / CBP as Potential Therapeutics for Hepatocellular Carcinoma. J. Med. Chem. 2024, acs.j medchem.3 cO 1468. https : / / doi . org / 10.1021 / acs .j medchem .3 cP 1468.

[0250] 9. Thomas, J. E.; Wang, M.; Jiang, W .; Wang, M.; Wang, L.; Wen, B.; Sun, D.; Wang, S. Discovery of Exceptionally Potent, Selective, and Efficacious PROTAC Degraders of CBP and P300 Proteins. J. Med. Chem. 2023, 66 (12), 8178-8199. https : / / doi . org / 10.1021 / acs .j medchem .3 c00492.

[0251] All publications mentioned in the above specification are herein incorporated by reference. Although illustrative embodiments of the invention have been disclosed in detail herein, with reference to the accompanying drawings, it is understood that the invention is not limited to the precise embodiment and that various changes and modifications can be effected therein by one skilled in the art without departing from the scope of the invention as defined by the appended claims and their equivalents.

[0252]

[0253] Scheme 1. Synthetic strategy for 02E. Reagents & Conditions: [a] Pd(dppf)2DCM, K2CO3, dioxane, water, 95 °C; [b] NaBEU, MeOH; [c] DAST DCM, -78 °C; [d] HC1 (4M in 1,4-dioxane); [e] 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione, HC1, HATU, DIPEA DMF.

Claims

CLAIMS1. A compound of formula (I):HL - (X)a- L -(Xl)b - UL(I) or a salt, solvate or tautomer thereof, wherein;HL comprises a HAT-domain recruiting ligand,X comprises a divalent exit vector;XI comprises a divalent exit vector; a and b are independently selected from 1 or 2;L comprises a divalent linker, andUL comprises an E3 ubiquitin ligase ligand; wherein HL comprises a group of formula:wherein each R’ is selected from halo, each R” is independently selected from -C(R’)3, or halo; RH is selected from halo, hydroxyl, or -C(=O)-RY; RY is H or Ci-Ce alkyl; n is 1, 2, 3, 4 or 5 and the wavy line indicates the bond to X.

2. A compound as claimed in claim 1, wherein n is 1 and HL comprises a group of formula:A compound as claimed in either claim 1 or claim 2, wherein HL comprises a group of formula:

4. A compound as claimed in any one of the preceding claims, wherein UL comprises an E3 ubiquitin ligase targeting ligand selected from a ligand that targets cereblon (CRBN), Von Hippel-Lindau (VHL), inhibitor of apoptosis protein (IAP), mouse double minute 2 homolog (MDM2), or Kelch like ECH associated protein 1 (KEAP1).

5. A compound as claimed in any one of the preceding claims, wherein UL comprises a ligand selected from a univalent substituent derived from VH101, VH032,VH298, tDHU, phenyl dihydrouracil, phenyl glutarimide, phenyl amino glutarimide or an immunomodulatory imide drug (IMiD), optionally derivatives of thalidomide, lenalidomide, pomalidomide, or avadomide, differing by exit vector and substitution.

6. A compound as claimed in any one of the preceding claims, wherein UL is selected from a species of the following formulae:wherein Ri is selected from -O-, -NH-, or -CH2-, or is absent; each R2 or Rs is independently selected from H or -CH3; each R3 is independently selected from -CH2- or -C(=O)-;F^ / each R4 is independently selected from -CH3; ; oreach Rs is selected from H or -CH3; each R26 or R27 is selected from H, or OH; but R26 and R27 are not the same, each RA is selected from H, C1-6 alkyl, halo and (CH2)t-NR2oR2i, t is selected from 0, 1, 2, or 3, R20 and R21 are independently selected from H, and C1-6 alkyl; and the wavy line indicates the bond to XI.

7. A compound as claimed in any one of the preceding claims, wherein UL is selected from a species of the following formulae:wherein RA is selected from H, Ci-6 alkyl, halo and (CH2)t-NR2oR2i, t is selected from 0, 1, 2, or 3,R20 and R21 are independently selected from H, and C1-6 alkyl; and the wavy line indicates the bond to XI.

8. A compound as claimed in any one of the preceding claims, wherein each X is independently selected from a divalent substituent selected from, -(CH2)zC(=O)-, - CH2(CH2)Z-, -(CH2)ZO-, -(CH2)ZS-, -(CH2)ZC(=O)-NRH-; -(CH2)ZNRHC(=O)-; - (CH2)zNRn-; -(CH2)ZC(=O)-O-; -(CH2)ZO-CH2-C(=O)-NRII-; -(CH2)ZNRH-C(=O)- CH2-O-; -(CH2)ZC(=O)-CH2-O-;wherein each Rn is independently selected from H, and C1-6 alkyl, and each z is independently 0, 1 or 2, preferably 1 ; and the bonds, or wavy lines in the formulae, indicate the bonds to HL and L or L and HL.

9. A compound as claimed in any one of the preceding claims, wherein L is a N— divalent linking group comprising, C3-8 cycloalkylene, C5-10 heteroarylene, phenylene, a Cs-i2alkylene chain which may contain one or more carbon-carbon double or triple bonds, a paraformaldehyde chain-(CH2CH2)n(CH2)m(OCH2)s(CH2CH2)P(CH2)q-, a polyethylene glycol chain-(CH2CH2)n(CH2)m(OCH2CH2)v(CH2CH2)P(CH2)q-, which chains may be interrupted by N— one, two or three groups selected from -O-, -S-, -NH-, halo,C3-8 cycloalkyl, C 5- 10 heteroarylene and / or phenylene; wherein n, m, p and q are independently 0, 1 or 2, s and v are independently 1 to 12, optionally 1 to 8, optionally 1 to 6.

10. A compound as claimed in any one of the preceding claims, wherein each XI is independently selected from a divalent substituent selected from, -(CH2)ZC(=O)-, - CH2(CH2)Z-, -(CH2)ZO-, -(CH2)ZS-, -(CH2)ZC(=O)-NRH-; -(CH2)ZNRHC(=O)-; - (CH2)zNRn-; -(CH2)ZC(=O)-O-; -(CH2)ZO-CH2-C(=O)-NRH-; -(CH2)ZNRH-C(=O)- CH2-O-; -(CH2)ZC(=O)-CH2-O-;wherein each Rn is independently selected from H, and Ci-6 alkyl, and each z is independently 0, 1 or 2, preferably 1 ; and the bonds, or wavy lines in the formulae, indicate the bonds to UL and L or L and UL.

11. A compound as claimed in any one of the preceding claims, wherein the compound is selected from compounds of the following formulae:

12. A method comprising providing a composition comprising a compound of any one of claims 1 to 11, and contacting the composition with a source of p300 and / or CBP.

13. A method of selectively degrading p300 comprising providing a composition comprising a compound of any one of claims 1 to 11, and contacting the composition with a source of p300 and / or CBP.

14. A method as claimed in claim 13, wherein the compound is selected from:

15. A reagent comprising a compound of any one of claims 1 to 11 and a solvent.

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