COMPOUNDS FIELD OF THE INVENTION The present disclosure relates to compounds, combinations comprising such compounds, pharmaceutical compositions comprising such compounds or combinations, and methods and reagents using the compounds. BACKGROUND TO THE INVENTION economy. The coronavirus SARS-CoV-2 that caused the pandemic is therefore an important therapeutic target. The papain-like protease domain (PLpro) of SARS-CoV-2 (SCoV2) is indispensable for viral replication and represents a putative target for pharmacological intervention (Shan et al.; Cell Chemical Biology 28, 855–865, 2021). Shen et al (Journal of Medicinal Chemistry 202265 (4), 2940-2955) determined that SARS-CoV-2 papain-like protease (PLpro), which is one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and de-ubiquitination of host protein substrates. PLpro is a challenging target owing to featureless P1 and P2 sites recognizing glycine. Shin et al. (Nature 587, 657– 662; 2020) performed characterization studies of SARS-CoV-2 PLpro (SCoV2-PLpro) and outlined differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-κB pathways. Inhibitors of the protein have been developed, with potent enzymatic inhibition and cellular antiviral activity. Liu et al., Journal of Medicinal Chemistry, 65(1), 2022 p.876 to 884 discloses the design and evaluation of a Peptide Drug Conjugate (PDC) targeting SARS-CoV‑2 papain-like protease. Sencanski et al., ChemRxiv, 2021, pages 1-12, ISSN: 2573-2293, DOI: 10.26434/chemrxiv-2021-39cd6. Chem. Abs. Acc. No.2021:2089168 discloses drug repurposing for candidate SARS-CoV-2 papain-like protease inhibitors by a combined in silico method. WO-A-2022/169891, WO-A-2022/070048, CN 113735937, and WO-A-2022/189810 disclose papain-like protease inhibitors or modulators. Protein degradation is a useful therapeutic strategy. Targeted degradation of a protein can be achieved using chimeric molecules known as proteolysis-targeting chimeras (PROTACs) or heterobifunctional degrader molecules (“degraders”). These compounds consist of 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. This principle has been successfully applied to several targets, including kinases, and transcriptional enzymes. PROTACs have usually focused on cancer-related targets where degradation of the host proteins leads to more favorable phenotypic outcomes than inhibition of the target. US 9,988,376 discloses compounds including PROTACs which are capable of inhibiting oestrogen receptor function including compounds which degrade the oestrogen receptor. There have recently been attempts to direct degraders to viral proteins. WO-A- 2022/081827 discloses proteolysis targeting chimeras (PROTACs) that target the degradation of viral proteins including coronaviral papain-like protease, and main protease (Mpro). WO-A-2021/231778 discloses compounds and methods useful for the modulation of coronavirus protease via ubiquitination and/or degradation. de Wispelaere et al. (Nat. Commun.10, 3468; 2019) disclose PROTACs that induce proteasomal degradation of viral proteins using telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site which is linked to ligands that recruit the CRL4 CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. There is similar disclosure in WO-A- 2020/069125 which discloses bifunctional compounds (degraders) that target hepatitis C virus (HCV) NS3/4A for degradation. There is nevertheless a need for improved treatments and tools to investigate viruses, in particular coronaviruses. The present invention seeks to address this need and to overcome problem(s) associated with the prior art. SUMMARY OF THE INVENTION The present inventors have developed PROTACs useful against the papain-like protease of SARS-CoV-2. The antiviral mechanism of action of the PROTACs may be driven by proteasomal degradation of the viral proteins. The present invention accordingly provides in a first aspect a compound of formula (I): PL _L – (X) _a – L –(X1) _b – U _L (I) or a salt, solvate or tautomer thereof, wherein; PL _L comprises a SARS-CoV-2 papain-like protease ligand, X comprises a divalent exit vector; X1 comprises a divalent exit vector; a is 0, 1 or 2; b is 1 or 2; L comprises a divalent linker, and U _L comprises an E3 ubiquitin ligase ligand; wherein PL _L is selected from: (P2a);

(P3b); wherein each R ₆ is independently selected from the wavy line indicates the bond to X. 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: using a catalytic mode of action such that one PROTAC can facilitate the degradation of multiple proteins of the same target. 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 and therefore PROTACs can be used at sub-stoichiometric concentrations relative to the target protein and the E3 ligase. The locations of the exit vector on the PL _L structures are important in order to retain binding affinity for PLpro. U _L comprises a ligand targeting a E3 ubiquitin ligase. In some embodiments, a may be 1 and/or b may be 1. If a and/or b is 2, each X (e.g. -X-X-) or X1 (e.g. -X1-X1-) may be selected independently. U _L 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). Thus, U _L may comprise a ligand selected from a univalent substituent derived from VH101, VH032, VH298 or an immunomodulatory imide drug (IMiD), optionally thalidomide, lenalidomide, pomalidomide, avadomide; or 3-phenylpiperidine-2,6- dione. U _L may be selected from a species of the following formulae:

wherein R ₁ is selected from -O-, -NH-, or -CH ₂ -, or is absent; each R ₂ or R ₅ is independently selected from H or -CH ₃ ; each R ₃ is independently selected from -CH ₂ - or -C(=O)-; each R ₄ is independently selected from -CH ₃ ; ; or ; each R ₂₆ and R ₂₇ is selected from H, or OH; but R ₂₆ and R ₂₇ are not the same, R ₈ is selected from H or F, each R _A is selected from H, C _1-6 alkyl, halo and (CH ₂ ) _t -NR ₂₀ R ₂₁ , t is selected from 0, 1, 2, or 3, R ₂₀ and R ₂₁ are independently selected from H, and C _1-6 alkyl; and the wavy line indicates the bond to X1. Where the CRBN binder is N-methylated (i.e. on the glutarimide group), so that R ₂ is CH ₃ , or R ₂₆ is H and R ₂₇ is OH, U _L may be a negative control. Thus, in one aspect, U _L may be a group of formula: wherein R ₂ is CH ₃ , and the other substituent are as indicated above. Generally, however, R ₂ may be H _. Generally, however, R ₂₆ is OH and R ₂₇ is H. Suitably, U _L may be selected from a species of the following formulae:

; wherein R _A is selected from H, C _1-6 alkyl, halo and (CH ₂ ) _t -NR ₂₀ R ₂₁ , t is selected from 0, 1, 2, or 3, R ₂₀ and R ₂₁ are independently selected from H, and C _1-6 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 a single covalent bond (e.g. is null or absent), - C(=O)-, -CH ₂ -, -O-, -S-, -C(=O)-NR ₁₁ -; -NR ₁₁ C(=O)-; -NR ₁₁ -; -C(=O)-O-; -O-CH ₂ -C(=O)- NR ₁₁ -; -NR ₁₁ -C(=O)-CH ₂ -O-; -C(=O)-CH ₂ -O-; wherein each R ₁₁ is independently selected from H, and C _1-6 alkyl, and the bonds, or wavy lines in the formulae, indicate the bonds to M _PL and L or L and M _PL . The exit vector may be bonded to M _PL and L in either orientation by either bond. The linker may be flexible or rigid or partially rigid. Thus, L may be a divalent linking group comprising , , C _3-8 cycloalkyl, C _5-10 heteroarylene, phenylene, a C _1-12 alkylene chain which may contain one or more carbon-carbon double or triple bonds, a paraformaldehyde chain –(CH ₂ CH ₂ ) _n (CH ₂ ) _m (OCH ₂ ) _s (CH ₂ CH ₂ ) _p (CH ₂ ) _q -, a polyethylene glycol chain –(CH ₂ CH ₂ ) _n (CH ₂ ) _m (OCH ₂ CH ₂ ) _v (CH ₂ CH ₂ ) _p (CH ₂ ) _q -, which chains may be interrupted by one, two or three groups selected from -O-, -S-, -NH-, halo, , C _3-8 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. The exit vector X1 may each be such that each X1 is independently selected from a single covalent bond (e.g. is null or absent), -C(=O)-,-CH ₂ -, -O-, -S-, -C(=O)-NR ₁₁ -; - NR ₁₁ C(=O)-; -NR ₁₁ -; -C(=O)-O-; -O-CH ₂ -C(=O)-NR ₁₁ -; -NR ₁₁ -C(=O)-CH ₂ -O-; -C(=O)- CH ₂ -O-; ; ; ; o ; wherein each R ₁₁ is independently selected from H, and C _1-6 alkyl, and the bonds or wavy lines in the formulae indicate the bonds to U _L and L or L and U _L . The exit vector may be bonded to U _L and L in either orientation by either bond. Preferably, the compound may be selected from compounds of the formulae as set out in claim 10. In a further aspect, there is provided a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, for use as a medicament. In a further aspect, there is provided a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, for use as a medicament in the treatment of a viral disease. In a further aspect, there is provided a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, for use as a medicament in the treatment of a coronavirus disease. In a further aspect, there is provided a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, for use as a medicament in the treatment of SARS-CoV-2. In a second aspect, there is provided a combination comprising a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, and at least one other active agent. In a third aspect, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a combination according to the second aspect, and a pharmaceutically acceptable excipient, carrier or diluent. In a fourth aspect there is provided a method of treatment of a subject suffering from a viral disease, the method comprising administering to said subject a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect. In a fifth aspect there is provided a method (preferably an in vitro method) comprising providing a composition comprising a compound according to the first aspect, and contacting the composition with a source of a viral protease, optionally corono-viral protease; optionally SAR-CoV-2 PLpro. In a sixth aspect there is provided a reagent comprising a compound according to the first aspect and a solvent. Thus, in one aspect the invention provides a compound according to the first aspect, being a compound of formula: . In a further aspect the invention provides a compound according to the first aspect, being a compound of formula: . In a further aspect the invention provides a compound according to the first aspect, being a compound of formula: 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. DEFINITIONS “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. 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. “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. Optional substituents may be selected from C _1-8 alkyl, C _2-7 alkenyl, C _2-7 alkynyl, C _1-12 alkoxy, C _5-20 aryl, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _3-10 cycloalkynyl, C _3-20 heterocyclyl, C _3-20 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, sulfinamino, 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, C _1-8 alkyl, OC _1-12 alkyl, and halogen. More suitably, the optional substituents are selected from OH, C _1-8 alkyl and OC _1-12 alkyl; more suitably, the optional substituents are selected from C _1-8 alkyl and OC _1-12 alkyl. “Independently” or “Independently selected” is used in the context of statement that, for example, “each R ₁₆ , R _17, is independently H, C _1-8 alkyl,...” and means that each instance of the functional group, e.g. R ₁₆ , is selected from the listed options independently of any other instance of R ₁₆ or R ₁₇ in the compound. Hence, for example, H may be selected for the first instance of R ₁₆ in the compound; methyl may be selected for the next instance of R ₁₆ in the compound; and ethyl may be selected for the first instance of R ₁₇ in the compound. “C _1-8 alkyl”: refers to straight chain and branched saturated hydrocarbon groups, generally having from 1 to 8 carbon atoms; suitably a C _1-7 alkyl; suitably a C _1-6 alkyl; suitably a C _1-5 alkyl; more suitably a C _1-4 alkyl; more suitably a C _1-3 alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, n-heptyl, n-octyl and the like. “Alkylene” refers to a divalent radical derived from an alkane which may be a straight chain or branched, as exemplified by –CH ₂ CH ₂ CH ₂ CH ₂ -. The alkylene may have the number of carbons as discussed above for alkyl groups. “C _6-26 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 C _1-6 alkyl group and the aryl group is phenyl. Examples of C _6-26 aralkyl include benzyl and phenethyl. In some cases, the C _6-26 aralkyl group may be optionally substituted, and an example of an optionally substituted C _6-26 aralkyl group is 4-methoxylbenzyl. “C _5-20 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., C _5-20 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 C _6-14 aryl is selected from a C _6-12 aryl, more suitably, a C _6-10 aryl. Examples of aryl groups include phenyl. “Arylene” refers to a divalent radical derived from an aryl group, e.g. –C ₆ H ₄ - which is the arylene derived from phenyl. “C _3-8 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. “C _3-8 cycloalkylene” or “3- to 8-membered cycloalkylene” refers to a divalent radical derived from a cycloalkyl group, e.g. –C ₆ H ₁₀ -. “C _3-8 cycloalkenylene” refers to a divalent radical derived from a cycloalkenyl group, that is a carbocyclic group with one or more C=C, e.g. –C ₆ H ₈ -. 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. “C _5-10 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. Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N ₁ : pyrrole, pyridine; O ₁ : furan; S ₁ : thiophene; N ₁ O ₁ : oxazole, isoxazole, isoxazine; N ₂ O ₁ : oxadiazole (e.g.1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa- 3,4-diazolyl); N ₃ O ₁ : oxatriazole; N ₁ S ₁ : thiazole, isothiazole; N ₂ : imidazole, pyrazole, pyridazine, pyrimidine, pyrazine; N ₃ : triazole, triazine; and, N ₄ : tetrazole. Examples of heteroaryl which comprise fused rings, include, but are not limited to, those derived from: O ₁ : benzofuran, isobenzofuran; N ₁ : indole, isoindole, indolizine, isoindoline; S ₁ : benzothiofuran; N ₁ O ₁ : benzoxazole, benzisoxazole; N ₁ S ₁ : benzothiazole; N ₂ : benzimidazole, indazole; O ₂ : benzodioxole; N ₂ O ₁ : benzofurazan; N ₂ S ₁ : benzothiadiazole; N ₃ : benzotriazole; and N ₄ : purine (e.g., adenine, guanine), pteridine; “heteroarylene” refers to a divalent radical derived from a heteroaryl group (such as those described above) as exemplified by pyridinyl –[C ₅ H ₃ N]-. Heteroarylenes may be monocyclic, bicyclic, or tricyclic ring systems. Representative heteroarylenes, are not limited to, but may be selected from triazolylene, tetrazolylene, oxadiazolylene, 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. “C _6-16 heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. Suitably the alkyl is a C _1-6 alkyl group and the heteroaryl group is C _5-10 heteroaryl as defined above. Examples of C _6-16 heteroarylalkyl groups include pyrrol-2-ylmethyl, pyrrol-3-ylmethyl, pyrrol-4-ylmethyl, pyrrol-3-ylethyl, pyrrol-4-ylethyl, imidazol-2- ylmethyl, imidazol-4-ylmethyl, imidazol-4-ylethyl, thiophen-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. “C _3-20 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 C _3-5 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. 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. Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from: N ₁ : aziridine, azetidine, pyrrolidine, pyrroline, 2H-pyrrole or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine; O ₁ : oxirane, oxetane, tetrahydrofuran, dihydrofuran, tetrahydropyran, dihydropyran, pyran, oxepin; S ₁ : thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, thiepane; O ₂ : dioxoiane, dioxane, and dioxepane; O ₃ : trioxane; N ₂ : imidazoiidine, pyrazolidine, imidazoline, pyrazoline, piperazine: N ₁ O ₁ : tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, oxazine; N ₁ S ₁ : thiazoline, thiazolidine, thiomorpholine; N ₂ O ₁ : oxadiazine; O ₁ S ₁ : oxathiole and oxathiane (thioxane); and N ₁ O ₁ S ₁ : oxathiazine. 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. L 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 C _5-10 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 C _5-10 heteroarylene groups and/or from one to three phenylene groups. Suitably L is selected from an alkylene chain containing from 1 to 11 carbon atoms, from 1 to 10 carbon atoms, from 1 to 9 carbon atoms, from 1 to 8 carbon atoms, from 1 to 7 carbon atoms, from 1 to 6 carbon atoms, from 1 to 5 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, which may contain one or more carbon- carbon double or triple bonds; a paraformaldehyde chain –(OCH ₂ ) _1-12 -, –(OCH ₂ ) _1-11 -, – (OCH ₂ ) _1-10 -, –(OCH ₂ ) _1-9 -, –(OCH ₂ ) _1-8 -, –(OCH ₂ ) _1-7 -, –(OCH ₂ ) _1-6 -, –(OCH ₂ ) _1-5 -, –(OCH ₂ ) _{1- 4} -, –(OCH ₂ ) _1-3 - a polyethylene glycol chain -(OCH ₂ CH ₂ ) _1-5 -, -(OCH ₂ CH ₂ ) _1-4 -, - (OCH ₂ CH ₂ ) _1-3 -; which chain may be interrupted by one or more hetero-atoms and/or C _5-9 heteroarylene groups and/or from one to three phenylene groups. More suitably, L may be selected from an alkylene chain containing from 1 to 12 carbon atoms which may contain one or more carbon-carbon double or triple bonds. More suitably, L may be selected from CH=CH, CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ . 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. 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 L ₂ includes the formula: -[CH ₂ CH ₂ O] _0-50 - 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 5 ethylene glycol units. Several commercially available ethylene glycol groups (polyethylene glycol, PEG) are suitable in the linker L ₂ , such as H ₂ N-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: -HN-PEG-C(O)- wherein PEG has 1-50 ethylene glycol units, usually 1 to 6 units. 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. “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. “Pharmaceutical composition” refers to the combination of one or more drug substances and one or more excipients. 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. The term “subject” as used herein refers to a human or non-human mammal. Examples of non-human mammals include livestock animals such as sheep, horses, cows, pigs, goats, rabbits and deer; and companion animals such as cats, dogs, rodents, and horses. “Therapeutically effective amount” of a drug refers to the quantity of the drug or composition that is effective in treating a subject and thus producing the desired therapeutic, ameliorative, inhibitory, or preventative effect. The therapeutically effective amount may depend on the weight and age of the subject and the route of administration, among other things. “Treating” refers to reversing, alleviating, inhibiting the progress of, or preventing a disorder, disease or condition to which such term applies, or to reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of such disorder, disease or condition. “Treatment” refers to the act of “treating”, as defined immediately above. 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. 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. 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. Administration & Dose Compounds of formula I may be administered alone or in combination with one or another or with one or more pharmacologically active compounds which are different from the compounds of formula I. Compounds of the invention may suitably be combined with various components to produce compositions of the invention. Suitably the compositions are combined with a pharmaceutically acceptable carrier or diluent to produce a pharmaceutical composition (which may be for human or animal use). Suitable carriers and diluents include isotonic saline solutions, for example phosphate-buffered saline. Useful pharmaceutical compositions and methods for their preparation may be found in standard pharmaceutical texts. See, for example, Handbook for Pharmaceutical Additives, 3rd Edition (eds. M. Ash and I. Ash), 2007 (Synapse Information Resources, Inc., Endicott, New York, USA) and Remington: The Science and Practice of Pharmacy, 21st Edition (ed. D. B. Troy) 2006 (Lippincott, Williams and Wilkins, Philadelphia, USA) which are incorporated herein by reference. The compounds of the invention may be administered by any suitable route. Suitably the compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. The compounds of the invention, their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compounds of the invention or salts or solvates thereof can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, controlled-release or pulsatile delivery applications. The compounds of the invention may also be administered via fast dispersing or fast dissolving dosages forms. Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device. Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. Release rate modifying excipients maybe present both within the dosage form i.e. within the matrix, and/or on the dosage form i.e. upon the surface or coating. Fast dispersing or dissolving dosage formulations (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The compounds of the invention can also be administered parenterally, for example, intravenously, intra-arterially, or they may be administered by infusion techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Suitably formulation of the invention is optimised for the route of administration e.g. oral, intravenously, etc. Administration may be in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) during the course of treatment. Methods of determining the most effective means and dosage are well known to a skilled person and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and the dose regimen being selected by the treating physician, veterinarian, or clinician. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses. For example, a typical dosage for an adult human may be 100 ng to 25 mg (suitably about 1 µg to about 10 mg) per kg body weight of the subject per day. Suitably guidance may be taken from studies in test animals when estimating an initial dose for human subjects. For example when a particular dose is identified for mice, suitably an initial test dose for humans may be approx.0.5x to 2x the mg/Kg value given to mice. Other Forms 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 ⁺ HR ¹ R ² ), 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. 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 l- 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”). 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, -OCH ₃ , is not to be construed as a reference to its structural isomer, a hydroxymethyl group, - CH ₂ OH. A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g. C _1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). 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. 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 ¹ H, ² H (D), and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; O may be in any isotopic form, including ¹⁶ O and ¹⁸ O; 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. 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. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below. In some embodiments, the compound of formula (I) and salts and solvates thereof, comprises pharmaceutically acceptable salts of the compounds of formula (I). 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. If the compound is cationic, or has a functional group which may be cationic (e.g. -NH ₂ may be -NH ₃ ⁺ ), 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, methylsulfonate, 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. 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 (Mg ²⁺ ), calcium (Ca ²⁺ ), zinc (Zn ²⁺ ), and aluminum (Al ³⁺ ). Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH4 ⁺ ) and substituted ammonium ions (e.g. NH ₃ R ⁺ , NH ₂ R ₂ ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, 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(CH ₃ ) 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-1,3-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) 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. 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., D ₂ O, acetone-d6, DMSO-d6). 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. 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, non- stoichiometry will typically be observed. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the present invention will now be described further, with reference to the accompanying drawings, in which: Figure 1 shows in (a) the structure of the PROTAC according to the invention C10778A; (b) the parent inhibitor compound C10778B; graphs of results of inhibitory potency studies using a binary IC50 in vitro inhibitory assay against SARS-CoV-2 PLpro for the (c) PROTAC and (d) parent compound. Figure 2 shows in (a) the structure of the parent inhibitor compound TS440; (b) the structure of the PROTAC according to the invention TS445; graphs of results of inhibitory potency studies using a binary IC50 in vitro inhibitory assay against SARS- CoV-2 PLpro for (c) TS440 and (d) TS445. Figure 3 shows in (a) the structure of the parent inhibitor compound GRL-0617; (b) the PROTAC according to the invention TS128; graphs of results of inhibitory potency studies using a binary IC50 in vitro inhibitory assay against SARS-CoV-2 PLpro for the (c) GRL-0617; and (d) TS128. Figure 4 shows in vitro biology of PROTACs. (A) Chemical structure of PROTAC TS516. (B) Antiviral assay with Vero E6 cells infected with SARS-CoV-2 at an MOI of 0.05, following dosing with TS516 or the parent inhibitor TS440. EC ₅₀ value for TS516 = 4.4 µM. (C) A plaque reduction assay performed in Vero E6 cells demonstrating that TS516 efficiently reduces viable virus. DESCRIPTION OF THE PREFERRED EMBODIMENTS An advantage of PROTACs according to the invention, is that they may not bind within the active site of a protein where loss of efficacy mutations can occur. Typical antiviral small molecules inhibitors employ an occupancy driven mechanism of action where the binding affinity plays a large part in the efficacy of the compound. For example, in small molecule inhibitors against HIV protease, it has been shown that the accumulation of several mutations results in drug resistance to clinically approved compounds. PROTACs operate via an event driven process whereby sub-stoichiometric amounts of the degrader can be used because the process of degradation is catalytic and PROTACs are recycled. Further, mutations that reduce the affinity of the PROTAC for the target may still lead to degradation of the target providing the compound still induces proximity between the E3 ligase and the target protein. An additional benefit of antiviral PROTACs is that the portion of the compound binding to the target protein does not need to be within the active site which is often the site where resistance mutations are present. An antiviral PROTAC could bind to a location on the target that is distal to the active site and still lead to effective degradation. SYNTHETIC STRATEGIES 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, CO ₂ 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). 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). 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. 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-1-ol, propan-2-ol, butan-1-ol, 2- methyl-propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1- ol, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy- 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- diethoxy-ethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy- ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); 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,-dioxide); and phosphorus-containing solvents (e.g.,HMPA, hexamethylphosphoramidep). EXAMPLES Synthesis of PLproTACs based on GRL0617 (P1a P1b) GRL0617 was synthesized adapting a procedure from the literature [Nat. Commun. 2021, 12, 743]. Oxalyl chloride (1.15 mL, 13.2 mmol, 1.2 eq.) and catalytic amounts of DMF (~20 drops) were added dropwise at 0 °C to a suspension of 5-nitro-o-toluic acid (2.0 g, 11.0 mmol, 1.0 eq.) in CH ₂ Cl ₂ (50 mL). After stirring at 0 °C for 30 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ before (R)-(+)-1-(1-naphthyl)ethylamine (2.35 mL, 14.4 mmol, 1.3 eq.) and Et ₃ N (3.05 mL, 22.1 mmol, 2.0 eq.) were added at room temperature. After stirring at room temperature for 1 h, the reaction was quenched by the dropwise addition of 1 M HCl. The mixture was diluted with CH ₂ Cl ₂ and the phases were separated. The organic phase was washed with 1 M KOH, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by recrystallization from CH ₂ Cl ₂ to afford the amide intermediate (2.09 g, 57%) as a white solid. The intermediate was suspended in MeOH and Pd/C was added. The atmosphere was exchange by three times evacuation and purging with H ₂ . The reaction was stirred at room temperature for 3 h under an H ₂ atmosphere. After complete conversion, the reaction mixture was filtered through Celite and washed thoroughly with EtOAc. The filtrate was concentrated in vacuo to afford GRL0617 (1.55 g, 46% over 2 steps) as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.22 (d, J = 8.5 Hz, 1H), 7.88 (dd, J = 8.2, 1.4 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.63 – 7.42 (m, 4H), 6.91 (d, J = 8.1 Hz, 1H), 6.62 – 6.52 (m, 2H), 6.13 – 6.06 (m, 2H), 3.68 (s, 2H), 2.28 (s, 3H), 1.76 (d, J = 6.5 Hz, 3H). General Procedures: General Procedure A The carboxylic acid building blocks are synthesized adapting a procedure from the literature [Org. Lett. 2019, 21, 3838]. 4-Fluorothalidomide (1.0 eq.) and the respective amine (1.3 eq.) are dissolved in NMP (0.2-0.5 M) in a microwave tube. DIPEA (3.0 eq.) is added and the tube is sealed. The reaction mixture is stirred under microwave irradiation at 110 °C for 2 h. Afterwards the mixture is diluted with EtOAc and washed with brine. The organic phase is dried over Na ₂ SO ₄ and concentrated in vacuo at 55 °C to remove NMP completely. Purification by flash column chromatography (silica gel) affords the tert-butyl ester intermediate as a bright yellow-green solid. This intermediate is stirred in a mixture of CH ₂ Cl ₂ and TFA (1:1) for 1 h at room temperature. The reaction mixture is concentrated in vacuo and co-evaporated with EtOAc to afford the carboxylic acid as a bright yellow-green solid. General Procedure B The carboxylic acid building blocks are synthesized adapting a procedure from the literature [Org. Lett.2019, 21, 3838]. Lenalidomide (1.0 eq.) and the respective bromide (1.2 eq.) are dissolved in NMP (0.2-0.5 M) in a microwave tube. DIPEA (3.0 eq.) is added and the tube is sealed. The reaction mixture is stirred under microwave irradiation at 110 °C for 12 h. Afterwards the mixture is diluted with EtOAc and washed with brine. The organic phase is dried over Na ₂ SO ₄ and concentrated in vacuo at 55 °C to remove NMP completely. Purification by flash column chromatography (silica gel) affords the tert-butyl ester intermediate as a white solid. This intermediate is stirred in a mixture of CH ₂ Cl ₂ and TFA (1:1) for 1 h at room temperature. The reaction mixture is concentrated in vacuo and co-evaporated with EtOAc to afford the carboxylic acid as a white solid. General Procedure C Step 1: 6-bromo-2-(2,6-dioxopiperidin-3-yl)-1H-benzo[de]isoquinoline -1,3(2H)-dione was synthesized adapting a procedure from the literature [WO202000626A1]. To a suspension of 6-bromo-1H,3H-benzo[de]isochromene-1,3-dione (1.50 g, 5.4 mmol, 1.0 eq.) and 3-aminopiperidine-2,6-dione hydrochloride (0.89 g, 5.4 mmol, 1.0 eq.) in THF (30 mL) was added Et ₃ N (2.25 mL, 16.2 mmol, 3.0 eq.) and the reaction mixture was refluxed overnight. The mixture was concentrated in vacuo, then suspended in Ac ₂ O (20 mL) and heated at 130 °C for 30 min. It was cooled to 80 °C and EtOH (10 mL) was added. After 20 min the mixture was cooled to room temperature and filtered. The solid was thoroughly washed with EtOAc and dried in vacuo to afford the bromide intermediate as a grey solid that hardly dissolves in any solvent. It was used without further purification in step 2. Step 2: The bromide (1.0 eq.), the respective amine (1.3 eq.) and DIPEA (3.0 eq.) are suspended in DMSO (0.2-0.5 M) and the mixture is stirred for 24-48 h at 120 °C. Afterwards the mixture is diluted with EtOAc and washed with brine. The organic phase is dried over Na ₂ SO ₄ and concentrated in vacuo at 60 °C to remove DMSO completely. Purification by flash column chromatography (silica gel) affords the tert-butyl ester intermediate as a bright orange solid. This intermediate is stirred in a mixture of CH ₂ Cl ₂ and TFA (1:1) for 1 h at room temperature. The reaction mixture is concentrated in vacuo and co-evaporated with EtOAc to afford the carboxylic acid as a bright orange solid. General Procedure D VH032 (1.0 eq.), the respective carboxylic acid (1.2 eq.), HATU (1.3 eq.) and HOAt (1.0 eq.) are dissolved in DMF (0.1-0.2 M). DIPEA (2.5 eq.) is added at room temperature and the reaction mixture is stirred until LCMS analysis indicates complete conversion of the starting material. The reaction mixture is diluted with EtOAc and washed with sat. NaHCO ₃ , 1 M HCl and brine. The organic phases are dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel) affords the tert-butyl ester intermediate as a white solid. This intermediate is stirred in a mixture of CH ₂ Cl ₂ and TFA (1:1) for 1 h at room temperature. The reaction mixture is concentrated in vacuo and co-evaporated with EtOAc to afford the carboxylic acid as a white solid. General Procedure E VH101 (1.0 eq.) is dissolved in DMF (0.1-0.2 M) and the respective bromide (1.5 eq.) and K ₂ CO ₃ (2.5 eq.) are added. The reaction mixture is heated at 70 °C until LCMS analysis indicates complete conversion of the starting material. The reaction is quenched with sat. NH ₄ Cl and extracted with EtOAc (3x). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel) affords the tert-butyl ester intermediate as a white solid. This intermediate is stirred in a mixture of CH ₂ Cl ₂ and TFA (1:1) for 1 h at room temperature. The reaction mixture is concentrated in vacuo and co-evaporated with EtOAc to afford the carboxylic acid as a white solid. General Procedure F GRL0617 (1.0 eq.), the respective carboxylic acid (1.2 eq.) and HATU (1.3 eq.) are dissolved in DMF (0.1-0.2 M). DIPEA (3.0 eq.) is added at room temperature and the reaction mixture is stirred until LCMS analysis indicates complete conversion of the starting material. The crude reaction mixture is directly purified by RP-HPLC (10-95% MeCN/H ₂ O + 0.1% formic acid). The product containing fractions are lyophilized to dryness to yield the respective PROTACs.

Table 1 Synthesis of PLproTACs based on Inhibitor 19 (P2a P2b) The carboxylic acid building block was synthesized according to procedures from the literature [Tetrahedron 2005, 61, 593–598; J. Med. Chem.2010, 53, 4968–4979]. To a solution of dimethyl malonate (4.3 mL, 37.8 mmol, 1.0 eq.) in DMSO (100 mL) was added KOt-Bu (5.09 g, 45.4 mmol, 1.2 eq.) and the reaction mixture was stirred for 1 h at room temperature. 2-(bromomethyl)-1,3-dioxolane (4.7 mL, 45.4 mmol, 1.2 eq.) was added and the mixture was stirred at 80 °C overnight. Afterwards KOt-Bu (5.09 g, 45.4 mmol, 1.2 eq.) was added again and the mixture was stirred for 1 h at room temperature. 2-(bromomethyl)-1,3-dioxolane (4.7 mL, 45.4 mmol, 1.2 eq.) was added and the mixture was stirred again at 80 °C overnight. The reaction was quenched by the addition of H ₂ O (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel, 40% EtOAc/petrol ether) afforded the product (5.1 g, 44%) as a colorless oil. m/z (ESI): 305.2 [M+H ⁺ ] ⁺ , 327.2 [M+Na ⁺ ] ⁺ To a solution of dimethyl 2,2-bis((1,3-dioxolan-2-yl)methyl)malonate (5.1 g, 16.7 mmol, 1.0 eq.) in THF (100 mL) was added aq. HCl (10%, 92 mL, 251 mmol, 15 eq.) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized by the portion wise addition of solid NaHCO ₃ at 0 °C. A solution of (R)-(+)- 1-(1-naphthyl)ethylamine (2.70 mL, 16.7 mmol, 1.0 eq.) in THF (50 mL) was added and the reaction was stirred overnight at room temperature. H ₂ O (100 mL) was added and the aqueous phase was extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel, 10% EtOAc/petrol ether + 2% Et ₃ N) afforded the product (2.15 g, 37%) as a colorless oil. m/z (ESI): m/z (ESI): 352.2 [M+H ⁺ ] ⁺ , 374.2 [M+Na ⁺ ] ⁺ Step 1: To a solution of dimethyl (R)-1-(1-(naphthalen-1-yl)ethyl)pyridine-4,4(1H)- dicarboxylate (2.15 g, 6.18 mmol, 1.0 eq.) in EtOAc (100 mL) was added PtO ₂ (138 mg, 0.61 mmol, 0.1 eq.). The atmosphere was exchange by three times evacuation and purging with H ₂ . The reaction was stirred at room temperature for 2 h under an H ₂ atmosphere. After complete conversion, the reaction mixture was filtered through Celite and washed thoroughly with EtOAc. The filtrate was concentrated in vacuo to afford the piperidine diester intermediate as a colorless oil. m/z (ESI): 356.2 [M+H ⁺ ] ⁺ The crude product was used without further purification in step 2. Step 2: To a solution of the intermediate in DMF (50 mL) was added NaCN (450 mg, 9.18 mmol, 1.5 eq.) and the reaction mixture was stirred at 70 °C overnight. The reaction was quenched by the addition of H ₂ O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel, 10% EtOAc/petrol ether + 2% Et ₃ N) afforded the piperidine methylester intermediate (1.45 g, 80%) as a colorless oil. m/z (ESI): 298.2 [M+H ⁺ ] ⁺ Step 3: To a solution of the piperidine methylester (1.45 g, 4.87 mmol, 1.0 eq.) in THF (18 mL), MeOH (6 mL) and H ₂ O (6 mL) was added LiOH∙H ₂ O (307 mg, 7.31 mmol, 1.5 eq.) at 0 °C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, dissolved in sat NaHCO ₃ and washed with Et ₂ O. The aqueous phase was acidified by the addition of 1 M HCl upon which as solid precipitated. The solid was collected by filtration and washed with Et ₂ O. The filtrate was concentrated in vacuo upon which more solid precipitated. The combined solids were dried in vacuo to yield the product (1.10 g, 79%) as a white solid. m/z (ESI): 284.3 [M+H ⁺ ] ⁺ The amine building block was synthesized adapting procedures from the literature [Cell Chem. Biol.2021, 28, 855-865]. To a solution of 3-amino-5-fluorobenzonitrile (2.50 g, 13.4 mmol, 1.0 eq.) in CH ₂ Cl ₂ (100 mL) was added a solution of triphosgene (2.72 g, 9.18 mmol, 0.5 eq.) in CH ₂ Cl ₂ (25 mL) dropwise at room temperature. After stirring for 6 h at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (100 mL) and N-Boc-piperazine (3.40 g, 18.4 mmol, 1.0 eq.) was added. The reaction mixture was stirred at room temperature overnight and was then concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel) to afford the product (4.0 g, 62%) as a colorless oil. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.11 (s, 1H), 7.75 – 7.69 (m, 2H), 7.38 (ddd, J = 8.3, 2.4, 1.4 Hz, 1H), 3.47 – 3.42 (m, 4H), 3.38 – 3.34 (m, 4H), 1.42 (s, 9H). m/z (ESI): 371.2 [M+Na ⁺ ] ⁺ To a solution of tert-butyl 4-((3-cyano-5-fluorophenyl)carbamoyl)piperazine-1- carboxylate (4.02 g, 11.5 mmol, 1.0 eq.) in ammonia (7 M in MeOH, 100 mL) was added Raney-Nickel (slurry in H ₂ O, ~1 g). The atmosphere was exchange by three times evacuation and purging with H ₂ . The reaction was stirred at room temperature overnight under an H ₂ atmosphere. After complete conversion, the reaction mixture was filtered through Celite and washed thoroughly with MeOH. The filtrate was concentrated in vacuo to afford the product (3.97 g, 98%) as a colorless oil. m/z (ESI): 353.3 [M+H ⁺ ] ⁺ Step 1: To a solution of the carboxylic acid (1.04 g, 3.65 mmol, 1.0 eq.), EDC∙HCl (840 mg, 4.38 mmol, 1.2 eq.) and HOBt (592 mg, 4.38 mmol, 1.2 eq.) in CH ₂ Cl ₂ (50 mL) was added a solution of the amine (1.29 g, 3.65 mmol, 1.0 eq.) and DIPEA (3.2 mL, 18.3 mmol, 5.0 eq.) in CH ₂ Cl ₂ (20 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of H ₂ O (50 mL) and extracted with CH ₂ Cl ₂ (3 x 100 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel) afforded the Boc-protected intermediate (1.80 g, 79%) as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.78 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.28 (t, J = 6.0 Hz, 1H), 7.92 (dd, J = 7.6, 1.9 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.57 – 7.45 (m, 4H), 7.29 (dt, J = 11.8, 2.2 Hz, 1H), 7.10 (s, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 4.20 – 4.12 (m, 1H), 3.43 – 3.39 (m, 4H), 3.36 – 3.30 (m, 4H), 3.08 (d, J = 10.9 Hz, 1H), 2.82 – 2.76 (m, 1H), 2.19 – 2.10 (m, 1H), 2.05 – 1.96 (m, 2H), 1.76 – 1.69 (m, 1H), 1.64 – 1.50 (m, 3H), 1.42 (s, 9H), 1.41 (d, J = 6.6 Hz, 3H). m/z (ESI): 618.4 [M+H ⁺ ] ⁺ Step 2: The Boc-protected intermediate (1.80 g, 2.91 mmol, 1.0 eq.) was stirred in a solution of HCl (4 M, 11.0 mL, 43.7 mmol, 15 eq.) in dioxane for 1 h at room temperature. The reaction mixture was concentrated in vacuo to afford the amine hydrochloride (1.49 g, 87%) as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 9.38 (s, 2H), 9.12 (s, 1H), 8.53 (t, J = 6.1 Hz, 1H), 8.42 (d, J = 8.7 Hz, 1H), 8.24 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.68 – 7.57 (m, 3H), 7.31 (dt, J = 11.7, 2.2 Hz, 1H), 7.17 (s, 1H), 6.60 (ddd, J = 9.5, 2.6, 1.4 Hz, 1H), 5.38 (t, J = 7.1 Hz, 1H), 4.18 (dd, J = 6.0, 3.9 Hz, 2H), 3.96 (d, J = 11.9 Hz, 1H), 3.69 (t, J = 5.4 Hz, 4H), 3.21 – 2.96 (m, 6H), 2.83 – 2.74 (m, 1H), 2.46 – 2.34 (m, 1H), 2.23 – 2.11 (m, 1H), 2.02 (d, J = 14.1 Hz, 1H), 1.91 – 1.72 (m, 2H), 1.78 (d, J = 6.6 Hz, 3H). m/z (ESI): 259.7 [M+2H ⁺ ] ²⁺ , 518.4 [M+H ⁺ ] ⁺ General Procedures General Procedure G Step 1: 4-Hydroxythalidomide (1.0 eq.), the linker (1.2 eq.), NaHCO ₃ (2.0 eq.) and NaI (1.0 eq.) are stirred in DMF at 70 °C overnight. The reaction is quenched with sat NH ₄ Cl and extracted with EtOAc (3x). The combined organic phase are dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel) affords the desired intermediate. Step 2: The first step can be performed with a free hydroxyl group or using a TBS protected linker. The application of a TBS protecting group significantly increases the yield of step 1. The TBS protecting group can be remove by stirring the intermediate from step 1 (1.0 eq.) in 1 M HCl in MeOH (5-10 eq.) for 30 min. The reaction mixture is then concentrated in vacuo to afford the alcohol intermediate. Step 3: To a solution of the alcohol intermediate (1.0 eq.) in CH ₂ Cl ₂ are added Et ₃ N (3.0 eq.) and TsCl (1.5 eq.). The reaction mixture is stirred at room temperature until LCMS or TLC analysis indicates complete conversion of the starting material. The reaction is quenched by the addition of sat NH ₄ Cl and extracted with CH ₂ Cl ₂ (3x). The combined organic phases are dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel) affords the desired tosylate. General Procedure H O = C ₂ , G To a solution of the starting alcohol (1.0 eq.) in CH ₂ Cl ₂ is added Dess-Martin periodinane (1.2 eq.) and the resulting mixture is stirred at room temperature until LCMS or TLC analysis indicates complete conversion of the starting material. The reaction is quenched by the addition of i-PrOH and concentrated in vacuo. The residue is filtered and purified by flash column chromatography (silica gel) to afford the desired aldehyde. General Procedure I The starting material was synthesized according to the literature [Angew. Chem. Int. Ed. 2021, 60, 26663-26670; ACS Med. Chem. Lett.2023, 14, 141–145]. To a solution of the starting piperazine (1.0 eq.), the carboxylic acid (1.3 eq) and HATU (1.3 eq.) in DMF is added DIPEA (3.0 eq.) and the resulting mixture is stirred overnight at room temperature. The reaction is quenched by the addition of sat. NaHCO ₃ and extracted with EtOAc (3x). The combined organic phases are washed with 1M HCl and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel) affords the desired amide. General Procedure J The starting material was synthesized according to the literature [Angew. Chem. Int. Ed. 2021, 60, 26663-26670; ACS Med. Chem. Lett.2023, 14, 141–145]. To a solution of the starting piperazine (1.0 eq.), the amine (1.3 eq) and HATU (1.3 eq.) in DMF is added DIPEA (3.0 eq.) and the resulting mixture is stirred overnight at room temperature. The reaction is quenched by the addition of sat. NaHCO ₃ and extracted with EtOAc (3x). The combined organic phases are washed with 1M HCl and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash column chromatography (silica gel) affords the desired amide. General Procedure K To a solution of amine hydrochloride (1.0 eq.) in DMF (0.1-0.2 M) is added DIPEA (3.0 eq.). Subsequently the tosylate (1.1 eq.) and NaI (1.0 eq.) are added and the reaction mixture was stirred at room temperature for 24 – 48 h until LCMS analysis indicates complete conversion of the starting material. The reaction is quenched by the addition of sat NH ₄ Cl and extracted with EtOAc (3x). The combined organic phase are dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product is purified by RP-HPLC (10-95% MeCN/H ₂ O + 0.1% TFA). The product containing fractions are lyophilized to dryness. In order to obtain the free amine the product from the HPLC is further purified by preparative TLC (silica gel, MeOH/CH ₂ Cl ₂ + 1% Et ₃ N). The free amine is treated with 4M HCl in dioxane and concentrated in vacuo to obtain the amine hydrochloride. General Procedure L To a solution of amine hydrochloride (1.0 eq.) and the aldehyde (1.5 eq.) in DMF is added 3-5 drops of AcOH followed by the addition of NaBH(OAc) ₃ (2.0 eq.). The reaction mixture is stirred at room temperature until LCMS analysis indicates complete conversion and then filtered through a syringe filter. The crude product is purified by RP-HPLC (10-95% MeCN/H ₂ O + 0.1% TFA). The product containing fractions are lyophilized to dryness. In order to obtain the free amine the product from the HPLC is further purified by preparative TLC (silica gel, MeOH/CH ₂ Cl ₂ + 1% Et ₃ N). The free amine is treated with HCl (4M) in dioxane and concentrated in vacuo to obtain the amine hydrochloride.

Table 2. TS445: ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 8.69 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.25 (t, J = 6.0 Hz, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.82 (dd, J = 8.5, 7.3 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.57 – 7.44 (m, 6H), 7.28 (dt, J = 11.8, 2.2 Hz, 1H), 7.13 – 7.10 (m, 1H), 6.56 (ddd, J = 9.4, 2.5, 1.3 Hz, 1H), 5.08 (dd, J = 12.9, 5.5 Hz, 1H), 4.34 (t, J = 5.5 Hz, 2H), 4.20 – 4.14 (m, 3H), 3.42 (t, J = 5.1 Hz, 4H), 3.09 (d, J = 11.0 Hz, 1H), 2.88 (ddd, J = 17.2, 14.0, 5.5 Hz, 1H), 2.79 (t, J = 5.6 Hz, 3H), 2.63 – 2.50 (m, 6H), 2.14 (tt, J = 11.6, 4.0 Hz, 1H), 2.07 – 1.98 (m, 3H), 1.77 – 1.70 (m, 1H), 1.65 – 1.52 (m, 3H), 1.40 (d, J = 6.7 Hz, 3H). ¹³ C NMR (176 MHz, DMSO-d ₆ ) δ = 174.5, 172.8, 170.0, 166.8, 165.4, 162.6 (d, J = 239.5 Hz), 155.8, 154.6, 142.8 (d, J = 12.0 Hz), 142.6 (d, J = 8.7 Hz), 140.2, 137.0, 133.7, 133.2, 131.3, 128.5, 127.2, 125.6, 125.4, 125.4, 124.4, 124.2, 119.9, 116.3, 115.4, 113.5, 107.0 (d, J = 21.9 Hz), 104.7 (d, J = 26.7 Hz), 67.7, 60.7, 56.2, 53.1, 51.3, 48.8, 48.4, 43.8, 42.1, 41.7, 31.0, 28.9, 22.0, 17.7. TS446: ¹ H NMR (700 MHz, DMSO-d ₆ ) δ = 11.10 (s, 1H), 8.67 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.27 – 8.23 (m, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.83 – 7.77 (m, 2H), 7.57 – 7.42 (m, 6H), 7.27 (dt, J = 11.8, 2.2 Hz, 1H), 7.10 (s, 1H), 6.55 (d, J = 8.6 Hz, 1H), 5.07 (dd, J = 12.9, 5.5 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 4.16 (d, J = 6.0 Hz, 2H), 4.18 – 4.10 (m, 1H), 3.39 (s, 4H), 3.07 (d, J = 11.0 Hz, 1H), 2.88 (ddd, J = 17.2, 13.9, 5.5 Hz, 1H), 2.78 (d, J = 11.1 Hz, 1H), 2.61 – 2.56 (m, 1H), 2.55 – 2.48 (m, 1H), 2.37 – 2.20 (m, 6H), 2.17 – 2.10 (m, 1H), 2.05 – 1.97 (m, 3H), 1.79 – 1.69 (m, 3H), 1.63 – 1.51 (m, 3H), 1.49 – 1.41 (m, 4H), 1.40 (d, J = 6.7 Hz, 3H), 1.37 – 1.25 (m, 6H). ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ = 174.9, 173.3, 170.5, 167.3, 165.8, 162.6 (d, J = 239.3 Hz), 156.5, 155.0, 142.7 (d, J = 14.5 Hz), 142.6 (d, J = 8.6 Hz), 137.5, 134.1, 133.7, 131.7, 129.0, 127.7, 126.1, 125.9, 125.0, 124.7, 120.2, 116.7, 115.6, 113.9, 107.0 (d, J = 22.3 Hz), 104.7 (d, J = 26.5 Hz), 70.2, 69.2, 61.2, 58.1, 53.0, 49.2, 48.9, 44.0, 42.1, 31.4, 29.3, 29.1, 28.9, 27.3, 26.5, 25.7, 22.5, 18.2, 14.4. TS499: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.70 (s, 1H), 8.50 – 8.37 (m, 1H), 8.26 (s, 1H), 7.96 – 7.87 (m, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.82 – 7.74 (m, 1H), 7.70 – 7.41 (m, 5H), 7.37 (dd, J = 8.4, 2.3 Hz, 1H), 7.28 (d, J = 11.8 Hz, 1H), 7.15 – 7.07 (m, 1H), 6.56 (dt, J = 9.0, 2.0 Hz, 1H), 5.12 (dd, J = 12.8, 5.5 Hz, 1H), 4.32 (t, J = 5.6 Hz, 2H), 4.17 (d, J = 5.9 Hz, 2H), 4.18 – 4.09 (m, 1H), 3.43 (s, 4H), 3.36 – 3.31 (m, 4H), 3.12 – 3.02 (m, 1H), 2.89 (ddd, J = 16.8, 13.8, 5.4 Hz, 1H), 2.81 – 2.74 (m, 3H), 2.65 – 2.52 (m, 2H), 2.21 – 1.93 (m, 3H), 1.84 – 1.49 (m, 4H), 1.39 (d, J = 6.7 Hz, 3H). ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ = 175.0, 173.3, 170.4, 167.4, 167.3, 164.4, 162.6 (d, J = 239.3 Hz), 155.0, 142.8 (d, J = 12.2 Hz), 138.0, 134.4, 134.1, 131.7, 129.0, 128.5, 127.6, 126.0, 125.9, 125.8, 124.8, 124.7, 123.5, 121.4, 114.0, 109.4, 107.0 (d, J = 21.5 Hz), 104.7 (d, J = 26.4 Hz), 67.1, 61.3, 56.7, 53.3, 51.9, 49.4, 48.8, 46.2, 42.7, 42.1, 31.4, 29.4, 22.5, 21.3, 18.2. TS516: ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 8.67 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.25 (t, J = 6.1 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.55 – 7.44 (m, 4H), 7.42 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.3, 2.3 Hz, 1H), 7.27 (dt, J = 11.8, 2.3 Hz, 1H), 7.10 (s, 1H), 6.55 (d, J = 9.4 Hz, 1H), 5.11 (dd, J = 12.9, 5.5 Hz, 1H), 4.19 – 4.11 (m, 5H), 3.42 – 3.37 (m, 4H), 3.07 (d, J = 11.1 Hz, 1H), 2.88 (ddd, J = 17.1, 13.9, 5.5 Hz, 1H), 2.78 (d, J = 11.4 Hz, 1H), 2.61 – 2.57 (m, 1H), 2.56 – 2.51 (m, 1H), 2.34 – 2.30 (m, 4H), 2.28 – 2.24 (m, 2H), 2.16 – 2.11 (m, 1H), 2.07 – 1.99 (m, 3H), 1.78 – 1.69 (m, 3H), 1.62 – 1.50 (m, 3H), 1.46 – 1.40 (m, 4H), 1.40 (d, J = 6.6 Hz, 3H), 1.36 – 1.25 (m, 6H). ¹ C NMR ( 6 MHz, DMSO-d ₆ ) δ = 173.3, 170.4, 167.4, 167.3, 164.6, 162.6 (J = 239.6 Hz), 155.0, 142.7, 142.6, 134.4, 134.1, 131.7, 129.0, 127.6, 125.9, 125.8, 124.8, 124.7, 123.3, 121.2, 113.9, 109.3, 106.9, 104.8, 104.6, 70.2, 69.3, 53.1, 51.8, 49.4, 48.8, 44.2, 42.7, 42.1, 31.4, 29.4, 29.1, 28.8, 27.3, 25.8, 22.5, 18.2. TS526: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 8.71 (s, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.16 – 7.98 (m, 1H), 7.95 – 7.88 (m, 1H), 7.84 – 7.76 (m, 1H), 7.69 – 7.42 (m, 4H), 7.28 (d, J = 11.8 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 14.6 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.56 (d, J = 9.0 Hz, 1H), 4.45 (s, 2H), 4.17 (d, J = 5.9 Hz, 2H), 4.18 – 4.10 (m, 1H), 3.79 (dd, J = 11.6, 4.9 Hz, 1H), 3.39 (s, 8H), 3.19 – 3.11 (m, 2H), 3.11 – 3.02 (m, 1H), 2.86 – 2.74 (m, 1H), 2.65 (ddd, J = 17.1, 11.8, 5.3 Hz, 1H), 2.49 – 2.44 (m, 1H), 2.41 – 2.22 (m, 4H), 2.20 – 2.10 (m, 2H), 2.06 – 1.94 (m, 3H), 1.83 – 1.49 (m, 4H), 1.49 – 1.36 (m, 5H). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 8.73 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.28 (s, 1H), 8.08 (t, J = 5.9 Hz, 1H), 7.95 – 7.87 (m, 1H), 7.84 – 7.75 (m, 1H), 7.62 – 7.39 (m, 4H), 7.28 (d, J = 11.9 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.13 – 7.08 (m, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.56 (d, J = 10.6 Hz, 1H), 4.44 (s, 2H), 4.16 (d, J = 6.0 Hz, 2H), 4.19 – 4.09 (m, 1H), 3.79 (dd, J = 11.6, 4.9 Hz, 1H), 3.49 – 3.33 (m, 6H), 3.15 – 3.00 (m, 3H), 2.85 – 2.73 (m, 1H), 2.65 (ddd, J = 17.2, 11.8, 5.3 Hz, 1H), 2.50 – 2.44 (m, 1H), 2.43 – 2.08 (m, 6H), 2.06 – 1.92 (m, 3H), 1.79 – 1.49 (m, 4H), 1.49 – 1.33 (m, 6H), 1.31 – 1.20 (m, 5H). ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ = 175.8, 174.9, 173.9, 167.9, 162.6 (d, J = 239.5 Hz), 157.1, 155.0, 142.7, 135.3, 134.1, 132.3, 131.7, 130.0, 129.0, 127.6, 125.9, 124.8, 115.0, 114.0, 107.0 (d, J = 20.8 Hz), 104.7 (d, J = 26.9 Hz), 70.2, 67.5, 53.0, 51.8, 48.8, 47.0, 46.0, 44.2, 42.1, 38.7, 31.9, 29.5, 29.4, 27.0, 26.7, 26.5, 18.2. TS530 ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 8.75 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.29 (s, 1H), 8.09 – 7.88 (m, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.86 – 7.73 (m, 1H), 7.68 – 7.41 (m, 4H), 7.44 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 8.3, 2.3 Hz, 1H), 7.29 (d, J = 11.8 Hz, 1H), 7.12 (s, 1H), 6.56 (d, J = 8.7 Hz, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 4.17 (d, J = 5.9 Hz, 2H), 4.23 – 4.07 (m, 1H), 3.38 (d, J = 35.7 Hz, 6H), 3.13 – 2.99 (m, 1H), 2.89 (ddd, J = 16.8, 13.8, 5.4 Hz, 1H), 2.84 – 2.72 (m, 1H), 2.63 – 2.51 (m, 2H), 2.47 – 2.10 (m, 5H), 2.09 – 1.93 (m, 3H), 1.83 – 1.32 (m, 11H). ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ = 173.3, 170.4, 167.4, 167.3, 164.5, 162.6 (d, J = 239.5 Hz), 155.0, 142.7, 134.4, 134.1, 131.7, 129.1, 125.9, 125.8, 124.7, 123.4, 121.2, 114.0, 109.3, 107.0 (d, J = 20.7 Hz), 104.7 (d, J = 26.3 Hz), 70.2, 69.0, 52.9, 49.4, 48.8, 43.9, 42.1, 31.4, 29.4, 26.6, 22.5, 18.2. TS534 ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 8.74 (s, 1H), 8.49 – 8.41 (m, 1H), 8.29 (s, 1H), 8.11 – 7.88 (m, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.83 – 7.76 (m, 1H), 7.70 – 7.43 (m, 4H), 7.42 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.3, 2.3 Hz, 1H), 7.29 (d, J = 11.8 Hz, 1H), 7.12 (s, 1H), 6.57 (d, J = 9.2 Hz, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.24 – 4.08 (m, 5H), 3.49 – 3.23 (m, 6H), 3.11 – 3.00 (m, 1H), 2.89 (ddd, J = 16.9, 13.8, 5.4 Hz, 1H), 2.82 – 2.72 (m, 1H), 2.66 – 2.51 (m, 2H), 2.45 – 2.19 (m, 5H), 2.09 – 1.94 (m, 3H), 1.82 – 1.67 (m, 4H), 1.65 – 1.27 (m, 11H). ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ = 173.3, 170.4, 167.4, 167.3, 164.6, 162.6 (d, J = 239.6 Hz), 155.0, 142.6, 134.4, 134.1, 131.7, 129.0, 127.6, 126.0, 125.9, 125.8, 124.8, 123.3, 121.2, 113.9, 109.3, 107.0 (d, J = 25.9 Hz), 104.7 (d, J = 27.6 Hz), 70.2, 69.2, 53.1, 51.9, 49.4, 48.8, 44.1, 42.7, 42.1, 31.4, 29.5, 29.4, 28.8, 25.7, 22.5, 18.2. TS535 ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.74 (s, 1H), 8.51 – 8.20 (m, 2H), 7.91 (t, J = 51.9 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.65 – 7.41 (m, 4H), 7.35 – 7.26 (m, 2H), 7.23 (dd, J = 8.8, 2.3 Hz, 1H), 7.13 (s, 1H), 6.56 (d, J = 11.3 Hz, 1H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.17 (d, J = 5.9 Hz, 2H), 4.24 – 3.86 (m, 1H), 4.05 (d, J = 12.9 Hz, 2H), 3.49 – 3.37 (m, 4H), 3.18 – 2.70 (m, 5H), 2.62 – 2.52 (m, 2H), 2.46 – 2.27 (m, 4H), 2.24 – 2.09 (m, 3H), 2.05 – 1.93 (m, 3H), 1.90 – 1.31 (m, 12H). ¹³ C NMR (126 MHz, DMSO-d ₆ ) δ = 173.3, 170.6, 168.1, 167.4, 162.6 (d, J = 239.3 Hz), 155.5, 155.0, 142.8, 134.5, 134.1, 131.7, 125.9, 125.5, 118.1, 117.8, 114.0, 108.2, 107.0 (d, J = 23.5 Hz), 104.7 (d, J = 26.1 Hz), 70.2, 64.1, 53.5, 49.2, 48.8, 47.7, 45.9, 44.2, 42.1, 32.8, 31.5, 30.0, 29.4, 22.7, 18.3. Synthesis of compounds relating to P3a and P3b 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 ¹ H NMR and 100 MHz for ¹³ C NMR. ¹ H NMR and ¹³ C NMR chemical shifts (δ) 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 60Å (35-70 μm), or by using Biotage Selekt, Biotage Isolera, 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 HPLC analysis was conducted using an Agilent 1100 series LC equipped with DAD (G1315B), Column Oven (G1316A), Autosampler (G1313A) with 100 μL loop, Quaternary Pump (G1311A) and an Agilent 1200 series Degasser (G1322A). Data collection and processing was conducted using Agilent Technologies Chemstation B.04.03. SFC purity analyses were conducted using a Waters ACQUITY UPC ² system with Binary Solvent Manager (K17C2B854M), Sample Manager (L17C2S782M), Convergance Manager (K17C2M838M), Column Manager (E18AZ3268M) and PDA Detector (M17C2P349A). Data were collected and processed using Empower 3 Build 3471 software. Optical rotations were recorded on a Bellingham & Stanley ADP450 polarimeter. 5-((1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)-2-methylben zoic acid To a stirred solution of 5-amino-2-methylbenzoic acid (10.00 g, 66.15 mmol) in methanol (120 mL) at ambient temperature was added tert-butyl 4-oxopiperidine-1- carboxylate (39.54 g, 198.46 mmol) followed by acetic acid (16.66 mL), and the reaction mixture was stirred at 50 ^C for 3 hours. After this time, the reaction mixture was cooled to ambient temperature before sodium triacetoxyborohydride (32.25 g, 152.15 mmol) was added in a portionwise fashion, and the resulting mixture was stirred at ambient temperature for 72 hours. Water (200 mL) was slowly added, and the mixture was extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 20-50% EtOAc/petroleum ether (40:60) afforded the title compound as a white solid (18.00g, 81%). ¹ H NMR (DMSO-d6) δ: 12.52 (br s, 1H), 7.07 (d, J= 2.6, 1H), 6.97 (d, J= 8.4, 1H), 6.67 (dd, J= 8.4, 2.6, 1H), 5.49 (d, J= 6.0, 1H), 3.85 (d, J= 13.0, 2H), 3.43-3.29 (m, 1H), 3.00-2.85 (m, 2H), 2.33 (s, 3H), 1.85 (dd, J= 12.8, 2.9, 3H), 1.40 (s, 9H), 1.25-1.15 (m, 2H). m/z (ES-): 333.30 [M-H ⁺ ]-

tert-Butyl (R)-4-((3-((1-(3-bromophenyl)ethyl)carbamoyl)-4- methylphenyl)amino)piperidine-1-carboxylate To a stirred solution of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2- methylbenzoic acid (11.60 g, 34.69 mmol) and (R)-1-(3-bromophenyl)ethan-1-amine (7.00 g, 34.99 mmol, [ ^] _D ²² = 13.2 ^ (c=1 EtOH)) in DMF (250 mL) at ambient temperature was sequentially added TEA (7.30 mL, 52.37 mmol), DMAP (1.00 g, 8.19 mmol) and HATU (13.19 g, 34.69 mmol) in a portion-wise fashion in that order, and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was diluted with EtOAC (300 mL) and the mixture was washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to a brown oil. Purification by flash column chromatography, eluting with 20- 40% EtOAc/petroleum ether (40:60), afforded the title compound as a pale yellow oil (15.00 g, 70%). ¹ H NMR (DMSO-d6) δ: 8.62 (d, J= 8.1, 1H), 7.59-7.56 (m, 1H), 7.45- 7.37 (m, 2H), 7.33-7.28 (m, 1H), 6.92 (d, J= 7.9, 1H), 6.56 (d, J= 2.4, 1H), 6.54 (br s, 1H) 5.46 (d, J= 8.4, 1H), 5.10-5.03 (m, 1H), 3.85 (d, J= 12.9, 2H), 3.43-3.35 (m, 1H), 2.99-2.85 (m, 2H), 2.09 (s, 3H), 1.90-1.82 (m, 2H), 1.42-1.37 (m, 12H), 1.25-1.15 (m, 2H). m/z (ES+): 518.10 [M+H ⁺ ] ⁺ . General Procedure A To a flask containing tert-butyl 4-[3-[[(1R)-1-(3-bromophenyl)ethyl]carbamoyl]-4- methyl-anilino]piperidine-1-carboxylate (1 eq.) and the relevant boronic acid (1.5eq) which had been degassed and purged with argon was added XPhos-Pd-G2 (5 mol%), K ₃ PO ₄ (2.4 eq.). Following this was added DMF (4 mL/mmol SM), EtOH (4 mL/mmol) and H ₂ O (2 mL/mmol), and the vessel was again degassed and backfilled with argon. The resulting mixture was stirred at 100 ^C for 20 hours, and then upon cooling to ambient temperature, stirring was maintained for a further 3 days. The reaction mixture was diluted with EtOAc, and then partially concentrated under reduced pressure at 40 ^C. The residue was diluted with brine and water and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by flash column chromatography afforded the title compound. tert-Butyl (R)-4-((3-((1-(3-(5-formylthiophen-2- yl)phenyl)ethyl)carbamoyl)-4-methylphenyl)amino)piperidine-1 - carboxylate tert-Butyl (R)-4-((3-((1-(3-bromophenyl)ethyl)carbamoyl)-4- methylphenyl)amino)piperidine-1-carboxylate (12.00 g, 19.28 mmol) and (5-formyl-2- thienyl)boronic acid (4.60 g, 29.49 mmol) were coupled following General Procedure A. After purification by flash column chromatography, eluting with 30-70% EtOAc/petroleum ether (40:60), the title compound was obtained as a pale yellow solid (7.30 g, 66%). ¹ H NMR (DMSO-d6) δ: 9.91 (s, 1H), 8.67 (d, J= 8.2, 1H), 8.05 (d, J= 4.0, 1H), 7.82 (br s, 1H), 7.73 (d, J= 4.0, 1H), 7.71-7.67 (m, 1H), 7.45 (d, J= 4.9, 2H), 6.92 (d, J= 8.0, 1H), 6.57-6.54 (m, 2H), 5.44 (d, J= 8.4, 1H), 5.29-5.11 (m, 1H), 3.83 (d, J= 13.2, 2H), 3.43-3.35 (m, 1H), 2.99-2.82 (m, 2H), 2.10 (s, 3H), 1.89-1.80 (m, 2H), 1.44 (d, J= 7.0, 3H), 1.40 (s, 9H), 1.25-1.115 (2H). m/z (ES+): 570.30 [M+Na ⁺ ] ⁺

tert-Butyl (R)-4-((3-((1-(3-(5-(((tert- butoxycarbonyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)carba moyl)-4- methylphenyl)amino)piperidine-1-carboxylate tert-Butyl (R)-4-((3-((1-(3-bromophenyl)ethyl)carbamoyl)-4- methylphenyl)amino)piperidine-1-carboxylate (5.50 g, 8.84 mmol) and [5-[(tert- butoxycarbonylamino)methyl]-2-thienyl]boronic acid (3.48 g, 13.52 mmol) were coupled following General Procedure A. After purification by flash column chromatography, eluting with 30-70% EtOAc/petroleum ether (40:60), the title compound was obtained as a cream solid (5.74 g, 96%). ¹ H NMR (DMSO-d6) δ: 8.64 (d, J= 8.2, 1H, 7.61 (br s, 1H), 7.52-7.44 (m, 2H), 7.37-7.28 (m, 3H), 6.93-6.89 (m, 2H), 6.57-6.53 (m, 2H), 5.44 (d, J= 8.4, 1H), 5.15-5.07 (m, 1H), 4.27 (d, J= 6.0, 2H), 3.84 (d, J= 13.1, 2H), 3.43-3.32 (m, 1H), 2.99-2.82 (m, 2H), 2.10 (s, 3H), 1.89-1.81 (m, 2H), 1.42 (d, J= 7.0, 3H), 1.40 (m, 18H), 1.25-1.18 (m, 2H). m/z (ES+): 649.30 [M+H ⁺ ] ⁺ (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5- (piperidin-4-ylamino)benzamide dihydrochloride To a stirred solution of tert-butyl (R)-4-((3-((1-(3-(5-(((tert- butoxycarbonyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)carba moyl)-4- methylphenyl)amino)piperidine-1-carboxylate (5.74 g, 8.85 mmol) in DCM (125 mL) at ambient temperature was dropwise added hydrogen chloride (21.53 mL, 86.10 mmol, 4M solution in 1,4-dioxane). The resulting yellow solution was stirred at ambient temperature for 30 minutes, during which time a thick suspension formed. The solid was collected by filtration, being washed with DCM and then dried under high vacuum. This afforded the title compound as a cream solid (4.90 g, quant.). ¹ H NMR (DMSO-d6) δ: 9.07 (m, 1H), 8.92 (d, J= 10.1, 1H), 8.81 (d, J= 7.0, 1H), 8.51 (br s, 2H), 7.66 (s, 1H), 7.51 (d, J= 7.4, 1H), 7.47-7.34 (m, 3H), 7.28 (d, J= 3.7, 1H), 7.12 (br s, 1H), 6.93 (br s, 1H), 5.18-5.11 (m, 1H), 4.61 (br s, 3H), 4.25 (q, J= 5.4, 2H), 3.66-3.58 (m, 1H), 3.30 (d, J= 12.4, 2H), 2.93 (d, J= 10.4, 2H), 2.19 (s, 3H), 2.09-2.01 (m, 2H), 1.80-1.66 (m, 2H), 1.46 (d, J= 7.0, 3H). m/z (ES+): 449.30 [M _{(free base)} +H ⁺ ] ⁺ . General Procedure B To a stirred solution of carboxylic acid (0.8-1eq) in DMF (10 mL/mmol) was sequentially added (R)-N-(1-(3-(5-(aminomethyl)thiophen-2-yl)phenyl)ethyl)-2- methyl-5-(piperidin-4-ylamino)benzamide dihydrochloride (1 eq.) followed by DIPEA (up to 4 eq.) and HATU (1 eq.) in that order, and the resulting mixture was stirred at ambient temperature for up to 24 hours. After this time, the solution was either concentrated under reduced pressure, or diluted with ethyl acetate and successively washed with portions of brine, with the organic phase then being dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by flash column chromatography afforded the title compound. (R)-N-(1-(3-(5-(Acetamidomethyl)thiophen-2-yl)phenyl)ethyl)- 2-methyl-5- (piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.60 g, 1.08 mmol) was coupled with acetic acid (0.06 g, 1.08 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (68 mg, 13%). ¹ H NMR (DMSO-d6) δ: ¹ H NMR (400 MHz, DMSO) δ 8.64 (d, J = 8.2 Hz, 1H), 8.51 (t, J = 5.8 Hz, 1H), 7.62 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.32 – 7.24 (m, 2H), 6.96 (d, J = 3.6 Hz, 1H), 6.93 – 6.84 (m, 1H), 6.58 – 6.47 (m, 2H), 5.38 (d, J = 8.2 Hz, 1H), 5.11 (p, J = 6.9 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.19 (m, 1H), 2.97 – 2.82 (m, 2H), 2.42-2.45 (m, 1H), 2.10 (s, 3H), 1.82 (m, 5H), 1.43 (d, J = 7.1 Hz, 3H), 1.29 – 1.02 (m, 2H). m/z (ES+): 491.10 [M+H ⁺ ] ⁺ N-((1R)-1-(3-(5-((4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoi soindolin-4- yl)oxy)butanamido)methyl)thiophen-2-yl)phenyl)ethyl)-2-methy l-5- (piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.20 g, 0.38 mmol) was coupled with thalidomide 4’-ether-alkylC3-acid (0.14 g, 0.38 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (40 mg, 13%). ¹ H NMR (DMSO-d6) δ: 1H NMR (400 MHz, DMSO) δ: 8.63 (d, J = 8.2 Hz, 1H), 8.54 (m, 1H), 7.83 – 7.69 (m, 1H), 7.60 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.43 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.31 – 7.24 (m, 2H), 6.95 (d, J = 3.6 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.51 (m, 2H), 5.38 (d, J = 8.2 Hz, 1H), 5.17 – 4.95 (m, 2H), 4.42 (d, J = 5.7 Hz, 2H), 4.23 (t, J = 6.3 Hz, 2H), 3.23 – 3.10 (m, 1H), 2.99 – 2.74 (m, 3H), 2.59 (m, 1H), 2.36 (t, J = 7.3 Hz, 2H), 2.07 (d, J = 15.7 Hz, 3H), 2.07 – 1.93 (m, 3H), 1.84 (d, J = 25.9 Hz, 2H), 1.42 (d, J = 7.0 Hz, 3H), 1.19 (dd, J = 23.4, 11.7 Hz, 3H). m/z (ES+): 791.40 [M+H ⁺ ] ⁺ N-((1R)-1-(3-(5-((6-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoi soindolin-4- yl)oxy)hexanamido)methyl)thiophen-2-yl)phenyl)ethyl)-2-methy l-5- (piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.35 g, 0.67 mmol) was coupled with thalidomide 4’-ether-alkylC5-acid (0.22 g, 0.57 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (96 mg, 18%). m/z (ES+): 819.30 [M+H ⁺ ] ⁺ Pomalidomide 5’-alkylC5-acid To a stirred solution of 5’-fluorothalidomide (3.29 g, 11.91 mmol) in NMP (70 mL) was added tert-butyl 6-aminohexanoate (2.45 g, 13.10 mmol) and DIPEA (4.15 mL, 23.82 mmol), and the resulting mixture was stirred at 90 °C for 18 hours. After cooling to ambient temperature, the mixture was poured into water (700 mL) and extracted with EtOAc. The combined organic extracts were washed successively with portions of brine before being dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 30-60% EtOAc/petroleum ether (40:60), afforded tert-butyl 6-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)amino)hexanoate as a yellow-green gum (1.44 g, 27%). ¹ H NMR (DMSO-d6) δ: 11.05 (br s, 1H), 7.55 (d, J= 8.4, 1H), 7.09 (t, J= 5.4, 1H), 6.94 (d, J= 1.9, 1H), 6.84 (dd, J= 8.4, 1.9, 1H), 5.02 (dd, J= 12.9, 5.4, 1H), 3.18-3.11 (m, 2H), 2.93-2.80 (m, 1H), 2.62-2.45 (m, 1H), 2.19 (t, J= 7.3, 2H), 2.03-1.95 (m, 1H), 1.60-1.49 (m, 4H), 1.40-1.34 (m, 11H). m/z (ES+): 444.30 [M+H ⁺ ] ⁺ tert-Butyl 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ami no)hexanoate (1.43 g, 3.22 mmol) was treated with DCM (15 mL) followed by TFA (7.5 mL), and the resulting yellow solution was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was reconcentrated three times from DCM/heptane to afford a viscous brown gum. Trituration with EtOAc afforded a yellow suspension, and after dilution of the mixture with 3 volumes of petroleum ether (40:60), the solid was collected by filtration, washed with petroleum ether (40:60) and dried under vacuum. This afforded the title compound as a pale yellow solid (1.08 g, 86%). ¹ H NMR (DMSO-d6) δ: 11.98 (br s, 1H), 11.05 (br s, 1H), 7.55 (d, J= 8.4, 1H), 7.13-7.07 (m, 1H), 6.94 (d, J= 1.9, 1H), 6.84 (dd, J= 8.4, 1.9, 1H), 5.02 (dd, J= 12.9, 5.4, 1H), 3.17-3.11 (m, 2H), 2.93-2.81 (m, 1H), 2.62-2.45 (m, 1H), 2.22 (t, J= 7.3, 2H), 2.03-1.95 (m, 1H), 1.61-1.50 (m, 4H), 1.41-1.33 (m, 2H). m/z (ES+): 410.10 [M+Na ⁺ ] ⁺ N-((1R)-1-(3-(5-((6-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoi soindolin-5- yl)amino)hexanamido)methyl)thiophen-2-yl)phenyl)ethyl)-2-met hyl-5- (piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.25 g, 0.48 mmol) was coupled with pomalidomide 5’-alkylC5-acid (0.19 g, 0.48 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (93 mg, 24%). m/z (ES+): 818.20 [M+H ⁺ ] ⁺ Pomalidomide 5’-alkylC3-acid To a stirred solution of 5’-fluorothalidomide (6.52 g, 23.60 mmol) in NMP (130 mL) was added tert-butyl 4-aminohexanoate hydrochloride (5.08 g, 25.96 mmol) and DIPEA (12.33 mL, 70.81 mmol), and the resulting mixture was stirred at 90 °C for 24 hours. After cooling to ambient temperature, the mixture was poured into water (1 L) and extracted with EtOAc. The combined organic extracts were washed successively with portions of brine before being dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 30-60% EtOAc/petroleum ether (40:60), afforded tert-butyl 4-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanoat e as a yellow-green gum (1.44 g, 27%). ¹ H NMR (DMSO-d6) δ: 11.05 (br s, 1H), 7.56 (d, J= 8.4, 1H), 7.14 (t, J= 5.5, 1H), 6.95 (d, J= 1.9, 1H), 6.85 (dd, J= 8.4, 1.9, 1H), 5.03 (dd, J= 12.9, 5.4, 1H), 3.22-3.14 (m, 2H), 2.93-2.80 (m, 1H), 2.60-2.45 (m, 2H), 2.32 (t, J= 7.4, 2H), 2.03-1.95 (m, 1H), 1.81-1.72 (m, 2H), 1.40 (s, 9H). m/z (ES+): 438.10 [M+Na ⁺ ] ⁺ tert-Butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ami no)butanoate (2.79 g, 6.04 mmol) was treated with DCM (20 mL) followed by TFA (10 mL), and the resulting yellow solution was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was reconcentrated three times from DCM/heptane to afford a viscous brown gum. Trituration with EtOAc afforded a yellow suspension, and after dilution of the mixture with an equal volume of petroleum ether (40:60), the solid was collected by filtration. The solid was directly adsorbed onto silica from DCM/MeOH, and then purified by flash column chromatography, initially eluting with 5% 7M methanolic ammonia solution/DCM until the by-product eluted, followed afterwards by 5% MeOH/DCM with 0.5% AcOH added to the eluent until the product finished eluting. Clean product fractions were concentrated under reduced pressure and then three times re-concentrated from 5% MeOH/DCM:heptane (1:1) to afford the title compound as a pale yellow solid (0.78 g, 36%). ¹ H NMR (DMSO-d6) δ: 11.05 (m, 2H), 7.56 (d, J= 8.4, 1H), 7.19-7.14 (m, 1H), 6.95 (d, J= 1.9, 1H), 6.85 (dd, J= 8.4, 1.9, 1H), 5.03 (dd, J= 12.9, 5.4, 1H), 3.22-3.14 (m, 2H), 2.93-2.82 (m, 1H), 2.62-2.45 (m, 2H), 2.33 (t, J= 7.4, 2H), 2.03-1.95 (m, 1H), 1.82-1.73 (m, 2H). m/z (ES-): 358.20 [M-H ⁺ ]- N-((1R)-1-(3-(5-((4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoi soindolin-5- yl)amino)butanamido)methyl)thiophen-2-yl)phenyl)ethyl)-2-met hyl-5- (piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.30 g, 0.58 mmol) was coupled with pomalidomide 5’-alkylC3-acid (0.21 g, 0.58 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (48 mg, 11%). m/z (ES+): 790.20 [M+H ⁺ ] ⁺ 5-(2-(4-(2,6-Dioxopiperidin-3-yl)phenoxy)acetamido)pentanoic acid To a stirred solution of phenyl glutarimide 4’-oxyacetic acid (1.50 g, 5.70 mmol) in DMF (20 mL) cooled in an ice-bath was added tert-butyl 5-aminopentanoate (1.00 g, 5.77 mmol), DIPEA (3.02 mL, 17.32 mmol) and HATU (2.41 g, 6.35 mmol) in that order, and the resulting reaction mixture was warmed to ambient temperature and stirred for 20 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 200 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 50-70% EtOAc/petroleum ether (40:60), afforded tert-butyl 5-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]pentano ate as a white solid (2.03 g, 94%). ¹ H NMR (DMSO-d6) δ: 10.79 (br s, 1H), 8.08 (t, J= 5.8, 1H), 7.16-7.12 (m, 2H), 6.93-6.89 (m, 2H), 4.44 (s, 2H), 3.79 (dd, J= 11.5, 4.9, 1H), 3.14- 3.08 (m, 2H), 2.70-2.60 (m, 1H), 2.49-2.44 (m, 1H), 2.22-2.10 (m, 3H), 2.05-1.97 (m, 1H), 1.50-1.41 (m, 4H), 1.39 (s, 9H). m/z (ES+): 441.10 [M+Na ⁺ ] ⁺ To a stirred solution of tert-butyl 5-[[2-[4-(2,6-dioxo-3- piperidyl)phenoxy]acetyl]amino]pentanoate (2.03 g, 4.85 mmol) in DCM (60 mL) was added TFA (10 mL), and the reaction mixture was stirred at ambient temperature for 7 hours before being concentrated under reduced pressure. Trituration with EtOAc provided an initial crop of product. Purification of the concentrated filtrate by flash column chromatography, eluting with 10-15% MeOH/DCM, afforded a second crop of the title compound which was obtained as a white solid after combining both crops in solution and concentrating to dryness (0.65 g, 37%). ¹ H NMR (DMSO-d6) δ: 11.97 (br s, 1H), 10.79 (br s, 1H), 8.08 (t, J = 5.8, 1H), 7.14 (d, J = 8.7, 2H), 6.91 (d, J = 8.7, 2H), 4.44 (s, 2H), 3.79 (dd, J = 11.5, 4.9, 1H), 3.16-3.08 (m, 2H), 2.70-2.60 (m, 1H), 2.49- 2.44 (m, 1H), 2.23-2.10 (m, 3H), 2.04 – 1.97 (m, 1H), 1.52-1.40 (m, 4H). m/z (ES+): 385.10 [M+Na ⁺ ] ⁺ N-((1R)-1-(3-(5-((5-(2-(4-(2,6-Dioxopiperidin-3- yl)phenoxy)acetamido)pentanamido)methyl)thiophen-2-yl)phenyl )ethyl)- 2-methyl-5-(piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.25 g, 0.48 mmol) was coupled with 5-(2-(4- (2,6-dioxopiperidin-3-yl)phenoxy)acetamido)pentanoic acid (0.18 g, 0.48 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (98 mg, 28%). m/z (ES+): 815.40 [M+Na ⁺ ] ⁺ . 6-(2-(4-(2,6-Dioxopiperidin-3-yl)phenoxy)acetamido)hexanoic acid To a stirred solution of phenyl glutarimide 4’-oxyacetic acid (1.30 g, 4.94 mmol) in DMF (20 mL) cooled in an ice-bath was added tert-butyl 6-aminohexanoate (0.93 g, 4.94 mmol), DIPEA (2.58 mL, 14.82 mmol) and HATU (1.97 g, 5.19 mmol) in that order, and the resulting reaction mixture was warmed to ambient temperature and stirred for 20 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 200 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 50-70% EtOAc/petroleum ether (40:60), afforded tert-butyl 6-[[2-[4-(2,6-dioxo-3-piperidyl)phenoxy]acetyl]amino]hexanoa te as a white solid (2.10 g, quant.). ¹ H NMR (DMSO-d6) δ: 10.79 (br s, 1H), 8.04 (t, J= 5.8, 1H), 7.16-7.12 (m, 2H), 6.93-6.89 (m, 2H), 4.43 (s, 2H), 3.79 (dd, J= 11.5, 4.9, 1H), 3.13- 3.07 (m, 2H), 2.70-2.60 (m, 1H), 2.49-2.44 (m, 1H), 2.21-2.10 (m, 3H), 2.04-1.95 (m, 1H), 1.52-1.36 (m, 13H), 1.26-1.20 (m, 2H). m/z (ES+): 455.20 [M+Na ⁺ ] ⁺ To a stirred solution of tert-butyl 6-[[2-[4-(2,6-dioxo-3- piperidyl)phenoxy]acetyl]amino]hexanoate (2.10 g, 4.85 mmol) in DCM (100 mL) was added TFA (10.8 mL), and the reaction mixture was stirred at ambient temperature for 7 hours before being concentrated under reduced pressure. Trituration with EtOAc afforded the title compound as a white solid (1.07 g, 59%). ¹ H NMR (DMSO-d6) δ: 11.97 (br s, 1H), 10.79 (br s, 1H), 8.05 (t, J = 5.7, 1H), 7.14 (d, J = 8.7, 2H), 6.91 (d, J = 8.7, 2H), 4.44 (s, 2H), 3.79 (dd, J = 11.5, 4.9, 1H), 3.14-3.07 (m, 2H), 2.70-2.60 (m, 1H), 2.49-2.44 (m, 1H), 2.22-2.10 (m, 3H), 2.04 – 1.97 (m, 1H), 1.52-1.38 (m, 4H), 1.27-1.20 (m, 2H). m/z (ES+): 399.30 [M+Na ⁺ ] ⁺ N-((1R)-1-(3-(5-((6-(2-(4-(2,6-Dioxopiperidin-3- yl)phenoxy)acetamido)hexanamido)methyl)thiophen-2-yl)phenyl) ethyl)-2- methyl-5-(piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.25 g, 0.45 mmol) was coupled with 6-(2-(4- (2,6-Dioxopiperidin-3-yl)phenoxy)acetamido)hexanoic acid (0.17 g, 0.45 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (98 mg, 27%). m/z (ES+): 829.50 [M+Na ⁺ ] ⁺ N-((1R)-1-(3-(5-((6-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoi soindolin-4- yl)amino)hexanamido)methyl)thiophen-2-yl)phenyl)ethyl)-2-met hyl-5- (piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.30 g, 0.58 mmol) was coupled with pomalidomide 4’-alkylC5-acid (0.22 g, 0.58 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (90 mg, 19%). m/z (ES+): 840.40 [M+Na ⁺ ] ⁺ N-((1R)-1-(3-(5-((4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoi soindolin-4- yl)amino)butanamido)methyl)thiophen-2-yl)phenyl)ethyl)-2-met hyl-5- (piperidin-4-ylamino)benzamide (R)-N-(1-(3-(5-(Aminomethyl)thiophen-2-yl)phenyl)ethyl)-2-me thyl-5-(piperidin-4- ylamino)benzamide dihydrochloride (0.11 g, 0.21 mmol) was coupled with pomalidomide 4’-alkylC3-acid (0.08 g, 0.21 mmol) according to General Procedure B. Purification by flash column chromatography, eluting with 7-15% MeOH/DCM, followed by lyophilisation from MeCN/H ₂ O (1:1), afforded the title compound as a white solid (21 mg, 13%). m/z (ES+): 790.20 [M+H ⁺ ] ⁺ P11068GBWO P2 PROTAC Synthesis: 1. PtO ₂ , H ₂ , EtOAc, r.t. 2. NaCN, DMF, 90 °C O O 3. LiOH•H ₂ O O ^{O O} KOt-Bu THF, MeOH, HO, r.t. M _eO O HCl, ₂ + _Br Me N MeO OMe O DMSO, r.t. O O CO then NaH A ₂ Me CO ₃ , , r.t. O O CO ₂ Me F F F 1. triphosgene, CH ₂ Cl ₂ , r.t. O H ₂ , Raney-Ni, NH ₃ O H + N NC MeOH, r ₂ N NC NH ₂ ^{2. N-Boc-piperazine, CH} ₂ ^Cl ₂ ^{, r.t. N} H ^N .t. ^{N N} N _{Boc H} NBoc ^CO2H F F O ^{TsO Linker E3 Ligase} t _{argeted Ligand} O 1. EDC, HOBt, DIPEA N ^{N N} N ^{N N} CH ₂ Cl ₂ , 0 °C NH _H N NH _H NH E ^{DIPEA, DMF, r.t.} 2. HCl, dioxane, r.t. O _Linker ^{3 Ligase} t _{argeted Ligand} O P1 PROTAC Synthesis: O ^{E3 Ligase} H _O ^Linker _{targeted Ligand} H HATU, DIPEA N ^{H O} E3 NH _{N 2 DMF, r.t.} ^{N Linker} Ligase targeted Ligand O O _H e 1: Synthetic routes to PLpro targeting PROTACs according to this invention. 61

Scheme 2: Synthetic routes to PLpro targeting PROTACs Inhibitory Concentration (IC50), Antiviral and Plaque Reduction Assays Assay Methods IC ₅₀ assay The inhibitory activities of compounds against SARS-CoV-2 PLpro were determined in a reaction buffer containing 20 mM HEPES, 40 mM NaCl, 5% glycerol, 2 mM DTT (freshly added before the measurements), pH 8.1, at 37 °C. A fluorescent substrate of SARS-CoV-2 PLpro (Z-Arg-leu-Arg-Gly-Gly-RLRGG-AMC; Biosyntan, Berlin) was used, and the fluorescence signal of the cleaved substrate was monitored using a Tecan Spark® fluorescence spectrophotometer at an emission/excitation wavelength of 460 / 360 nm. SARS-CoV-2 PLpro (10 µL per well) was pipetted into a 96-well plate together with reaction buffer reaction buffer (50 μL per well, final enzyme concentration: 0.1 µM). Compounds (10 µL per well) were added at varying concentrations, and plates incubated at 37 °C for 10 mins. Finally, the reaction was initiated by adding 30 μL of the substrate (final concentration: 10 µM) dissolved in the reaction buffer. Antiviral assay Vero E6 cells (2x10 ⁴ /well) were seeded in 96 well plates one day before the experiment. Pre-treatment, the medium was removed and compounds were added at concentrations varying from 0.1-100 µM. After 24h incubation, the medium was removed and cells were infected with MOI 0.05 SARS-CoV-2 SARS-CoV2/ZG/297–20. After 1h infection, the viruses were removed and the same concentration of compounds were added back into the cells. After 72h incubation at 37 °C, EC ₅₀ measurements were made using ATP quantification (Cell Titer Glo). Plaque Reduction Assay Vero E6 cells (5x10 ⁵ /well) were seeded in 12 well plates and pre-treated with compounds one day prior to infection. After 24h incubation, the medium was removed and cells were infected with MOI 0.1 SARS-CoV-2 SARS-CoV2/ZG/297–20. The same concentrations of compounds were then added back to the cells and incubated for 24 hours. The supernatant was then harvested for the plaque reduction assay, performed as follows: Vero E6 cells were seeded with 80% confluence one day before the experiment in 48 well plates. The supernatant was serially diluted 10-fold in DMEM with 2% FBS. Cells were infected with the diluted supernatant at 37 °C for 1h. After incubation, the supernatant was removed and the cells were washed with PBS once. 1.5% overlay (1:13% CMC and 2X DMEM) was added prior to incubation at 37 °C for 4- 5 days. Cells were fixed with 4% formalin and stained with crystal violet. Assay Results Figures 1, 2, 3 and 4 show examples of PROTACs inhibiting SARS-CoV-2 from warhead ligands C10778B, TS440, and GRL-0617. The design of the PROTACs is improved by validation of the exit vector on the parent ligand such that the E3 targeting portion of the compound does not perturb binding to the target protein. The IC50 experiments demonstrate the ligands and PROTACs have similar potency, thus validating the exit vector for this series of PROTACs. It can be seen that the PROTACs (particularly those in Figures 1 and 2) function equally well as inhibitors, however the additional mechanism of action (degradation) may lead to improved potency. Figure 1: PROTAC and parent ligand for SARS-CoV-2 PLpro in a binary IC50 experiment. C10778A PROTAC (top left), comprising a SARS-CoV-2 PLpro targeting ligand C10778B (bottom left) connected to thalidomide via a C3 alkyl linker. IC50 values have been determined in an in vitro inhibitory binding assay whereby the fluorescence signal resulting from cleavage of a fluorogenic substrate by PLpro is measured. Inhibition of PLpro is associated with reduced cleavage of the fluorogenic substrate. The PROTAC C10778A retains nM activity for PLpro, similar to the parent compound C10778B, thus validating the amide exit vector used on the targeting ligand. Assay conditions: experiments were performed in 20 mM HEPES buffer containing 40 mM NaCl 5% glycerol, 2 mM DTT at pH 8.1. A fluorogenic substrate for PLpro (Z-Arg- leu-Arg-Gly-Gly-AMC) was used to determine the inhibition rate of compounds. Final DMSO concentration in each reaction was 1%. Measurements were performed in triplicate. Figure 2: Additional example of a PROTAC of different structure for SARS-CoV-2 PLpro in a binary IC50 experiment. Similarly to Figure 1, the parent PLpro ligand TS440 (top left) and the PROTAC TS445 (bottom left) show similar potency in an in vitro inhibitory binding assay validating the piperazine exit vector as an attachment point for PROTAC construction. Assay conditions were as described in Figure 1. Figure 3: Additional example of a PROTAC of different structure for SARS-CoV-2 PLpro in a binary IC50 experiment. Similarly to Figure 1 and 2, the parent PLpro ligand GRL-0617 (top left) and the PROTAC TS128 (bottom left) show similar potency in an in vitro inhibitory binding assay validating the exit vector as an attachment point for PROTAC construction. Assay conditions were described as in Figure 1. Figure 4 shows in vitro biology of PROTACs with Antiviral assay with Vero E6 cells infected with SARS-CoV-2 at an MOI of 0.05, following dosing with TS516 or the parent inhibitor TS440. EC ₅₀ value for TS516 = 4.4 µM. Figure 4 also shows the results of a plaque reduction assay performed in Vero E6 cells demonstrating that TS516 efficiently reduces viable virus. Further results are set out in Table 3, below. It should be noted that the assay results in the Figures and Table 3 were obtained under the conditions tested and are indicative but are not exhaustive. The performance of the compounds under other conditions may be even better.

P11068GBWO 1 1 1 66

1 1

1 1 1

1 2

2 2

2 3 3

3 4

4 5 4

4 4 5

₅ 4 4

4 5 5

555

5 5 5

5 5 5

O O O

O O O

P11068GBWO 0 0 le 3. IC50 and antiviral data for compounds. Key: IC50: <0.1 uM = A, <1 uM = B, <10 uM = C, 10-25 uM = D, Not obtained or >25 uM = E.viral Activity by cell viability assay: Not obtained = F, <0% = E, <25% = D, <50% = C, <75%= B, >75% = A 84

REFERENCES 1) de Wispelaere, M., et al.; Nat Commun 10, 3468 (2019); https://doi.org/10.1038/s41467-019-11429-w 2) Naoya Kitamura, et al; Journal of Medicinal Chemistry 202265 (4), 2848- 2865; DOI: 10.1021/acs.jmedchem.1c00509 3) Zhang et al.; Science (2020) Vol 368, Issue 6489 pp.409-412 DOI: 10.1126/science.abb3405 4) Andreas Luttens et al.; Journal of the American Chemical Society 2022144 (7), 2905-2920; DOI: 10.1021/jacs.1c08402) 5) Shan et al; Cell Chemical Biology 28, 855–865, 2021; https://doi.org/10.1016/j.chembiol.2021.04.020 6) Shen et al.; Journal of Medicinal Chemistry 202265 (4), 2940-2955; DOI: 10.1021/acs.jmedchem.1c01307 7) Shin, et al.; Nature 587, 657–662 (2020). https://doi.org/10.1038/s41586- 020-2601-5. 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.