Compounds for targeted protein degradation

Abstract

The present disclosure relates to a novel class of bifunctional molecules that are useful in a targeted or selective degradation of a protein.

Description

[0001] Compounds for Targeted Protein Degradation

[0002] FIELD

[0003] The present disclosure relates to degradation of TEAD proteins. Specifically, the present disclosure relates to novel compounds that are useful in a targeted or selective degradation of TEAD proteins, together with methods of preparing such compounds and therapeutic uses thereof.

[0004] BACKGROUND

[0005] The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signalling pathway.

[0006] The Hippo pathway is a critical transcriptional signalling pathway that regulates cell growth, proliferation and organ development. The Hippo pathway is a kinase cascade which ultimately restricts the activities of (i.e. inactivates) Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). When YAP and TAZ are active, they translocate into the nucleus to bind the TEAD transcription factor family and induce expression of a wide range of genes that are involved in cell proliferation, survival, and migration.

[0007] It has become apparent that the dysregulation and / or overexpression of the Hippo pathway is implicated in a wide range of cancers, including breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer and bone cancer. This suggests that degrading TEAD and thus retarding YAP / TAZ- TEAD activity may provide a beneficial therapeutic impact by reducing growth of tumors resistant to other treatments.

[0008] Targeted Protein Degradation (TPD) is a therapeutic modality, which relies on the use of synthetic molecules to repurpose cellular degradation machinery to induce degradation of specific disease-causing proteins. TPD approaches offer a number of advantages over other drug modalities (e.g. small molecule inhibitors, antibodies & protein-based agents, antisense oligonucleotides & related knockdown approaches) including: potentiated pharmacology due to catalytic protein removal from within cells; ability to inhibit multiple functions of a specific drug target including e.g. scaffolding function through target knockdown; opportunity for systemic dosing with good biodistribution; potent in vivo efficacy due to catalytic potency and long duration of action limited only by de novo protein resynthesis; and facile chemical synthesis and formulation using application of small molecule processes.

[0009] The majority of physiologic post-translational regulation of protein levels as well as removal of damaged, misfolded, or excess proteins is mediated by the ubiquitin-proteasome system (UPS). The UPS can be repurposed to degrade specific proteins using certain compounds as therapeutic agents, which act by inducing the proximity of desired substrates with UPS proteins to initiate a cascade of events which ultimately lead to degradation, and removal from the cell, of the desired targets by the proteasome.

[0010] Proteolysis targeting chimeras (PROTACs) constitute one such class of compounds, which induce proximity of target proteins to the UPS by recruitment of specific ubiquitin E3 ligases. PROTACs are composed of two ligands joined by a linker - one ligand to engage a desired target protein and another ligand to recruit a ubiquitin E3 ligase.

[0011] The E3 ligases used most frequently in PROTACs are von Hippel-Lindau (VHL) and Cereblon (CRBN). PROTACs recruiting VHL are typically based on hydroxyproline-containing ligands, whereas PROTACs recruiting CRBN are typically characterised by the presence of a glutarimide moiety, such as thalidomide, pomalidomide and lenalidomide or close analogues to act as the warhead. Other ligases including mdm2 and the IAP family have also shown utility in PROTAC design.

[0012] However, these approaches suffer from a range of limitations, which restrict their utility to treat a wide range of diseases. For example, limitations of current PROTAC approaches include: inability to efficiently degrade some targets; poor activity of PROTACs in many specific cells due to low and variable expression of E3 ligases and other proteins required for efficient degradation; chemical properties which make it more difficult to prepare degraders with suitable drug-like properties including good drug metabolism & pharmacokinetic profiles; and high susceptibility to induced resistance mechanisms in tumours.

[0013] Because of these limitations, there remains a need to identify novel compounds which show efficient degradation of TEAD proteins.

[0014] SUMMARY

[0015] The present disclosure is based on the identification of novel compounds that are useful in a targeted and / or selective degradation of TEAD proteins.

[0016] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a is 0 to 4; b is 0 or 1 ; c is 0 to 5;

[0017] A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and 0, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;

[0018] G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl, 3- to 7-membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl, wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and O, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -ON, C1-C4 alkyl, and C1-C4 alkoxy;

[0019] G2is selected from -NR10-, -CO-, -CO2-, -0C(0)0-, -CONR11-, -NR12CO-, -OC(O)NR13-, - NR14C(O)O-, -NR15C(O)NR15-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and 0, wherein when G2is -

[0020] CO2-, -OC(O)O-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;

[0021] G3is C(R19)2; each G4is independently selected from O, NR20or C(R21)2, wherein if c is selected from 2 to 5, then adjacent instances of G4may not both be O and / or NR20;

[0022] R1is selected from halogen and methyl;

[0023] R2is selected from halogen and methyl;

[0024] R3is selected from halogen and methyl;

[0025] R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;

[0026] R5is CN or CON(R22)2;

[0027] R6is selected from H and C1-C3 alkyl;

[0028] R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;

[0029] R9is selected from , wherein the wavy line intersects the bond between R9and the rest of the compound;

[0030] R10is selected from H and C1-C4 alkyl;

[0031] R11is selected from H and C1-C4 alkyl;

[0032] R12is selected from H and C1-C4 alkyl;

[0033] R13is selected from H and C1-C4 alkyl;

[0034] R14is selected from H and C1-C4 alkyl;

[0035] R15is selected from H and C1-C4 alkyl;

[0036] R16is selected from H and C1-C4 alkyl;

[0037] R17is selected from H and C1-C4 alkyl;

[0038] R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, -CN, and C1-C4 alkoxy;

[0039] R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O (e.g. R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1- C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl;

[0040] R23Is H;

[0041] R24is H; and

[0042] X1is selected from CH and N.

[0043] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a is 0 to 4; b is 0 or 1 ; c is 0 to 5;

[0044] A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and 0, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;

[0045] G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl (including spiro- and fused bicyclic cycloalkanediyls), 3- to 7-membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl (including spiro- and fused bicyclic heterocycloalkanediyls), wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and 0, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy;

[0046] G2is selected from -NR10-, -CO-, -CO2-, -0C(0)0-, -CONR11-, -NR12CO-, -OC(O)NR13-, -

[0047] NR14C(O)O-, -NR15C(O)NR15-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and 0, wherein when G2is - CO2-, -0C(0)0-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;

[0048] G3is C(R19)2; each G4is independently selected from 0, NR20or C(R21)z, wherein if c is selected from 2 to 6 (e.g. from 2 to 5), then adjacent instances of G4may not both be O and / or NR20;

[0049] R1is selected from halogen and methyl;

[0050] R2is selected from halogen and methyl;

[0051] R3is selected from halogen and methyl;

[0052] R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;

[0053] R5is CN or CON(R22)2;

[0054] R6is selected from H and C1-C3 alkyl;

[0055] R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;

[0056] R9is selected from , wherein the wavy line intersects the bond between R9and the rest of the compound;

[0057] R10is selected from H and C1-C4 alkyl;

[0058] R11is selected from H and C1-C4 alkyl;

[0059] R12is selected from H and C1-C4 alkyl;

[0060] R13is selected from H and C1-C4 alkyl;

[0061] R14is selected from H and C1-C4 alkyl;

[0062] R15is selected from H and C1-C4 alkyl;

[0063] R16is selected from H and C1-C4 alkyl;

[0064] R17is selected from H and C1-C4 alkyl;

[0065] R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, -GN, and C1-C4 alkoxy;

[0066] R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N; or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1- C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl;

[0067] R23is selected from H, C1-C4 alkyl, and -CO-C1-C4-alkyl;

[0068] R24is selected from H and C1-C4 alkyl; and

[0069] X1is selected from CH and N.

[0070] In another aspect, the present invention provides a compound capable of binding to F-box only protein 22 (FBXO22) (e.g. covalently, for example reversibly covalently) and capable of binding to a transcriptional enhanced associate domain (TEAD) protein.

[0071] In another aspect, the present invention provides a compound according to formula (SLA): wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

[0072] In another aspect, the present invention provides an F-box only protein 22 (FBXO22) conjugate comprising an FBXO22 protein covalently (e.g. reversibly covalently) bound to a ligand capable of binding to a transcriptional enhanced associate domain (TEAD) protein.

[0073] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA) or a compound of formula (I) (for example a compound of formula (IA) or a compound of formula (I), e.g. a compound of formula (I)) together with a pharmaceutically acceptable carrier, optionally wherein the compound of formula (SK), the compound of formula (SL), the compound of formula (SLA), the compound of formula (IA) or the compound of formula (I) is present in the composition as a pharmaceutically acceptable salt, solvate or derivative.

[0074] In another aspect, the present invention provides a compound, an FBXO22 conjugate or a pharmaceutical composition as described herein for use in medicine.

[0075] In another aspect, the present invention provides a method of making a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA) or a compound of formula (I) (e.g. a compound of formula (I)).

[0076] BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 provides a Western blot and graph showing the results of Example 7.

[0078] Figure 2 provides an SDS-PAGE showing the results of Example 12.

[0079] DETAILED DESCRIPTION

[0080] F-box only protein 22 (also known as F-box protein 22, FBXO22, FBX22, FISTC1 ; UniProt ID: Q8NEZ5; encoded by FBXO22 gene) is an E3 ligase which is a member of the F-box protein family. F-box only protein 22 is the substrate-recognition component of a ‘SKP1 -CUL1 -F-box protein’-type E3 ubiquitin ligase complex. Recruitment of this protein with a ligand capable of binding to a transcriptional enhanced associate domain (TEAD) protein can promote Targeted Protein Degradation of proteins in the TEAD protein family.

[0081] Certain compounds described within this patent are able to degrade TEAD using FBXO22 (e.g. using exclusively FBXO22). For example, certain compounds disclosed herein are capable of binding to FBXO22 and capable of binding to a TEAD protein. Without wishing to be bound to theory, such compounds may modulate, facilitate and / or promote proteasomal degradation of a TEAD target protein by inducing proximity of the TEAD target protein to the UPS using FBXO22.

[0082] Accordingly, in one aspect the present invention provides an FBXO22 conjugate comprising a FBXO22 protein covalently (e.g. reversibly covalently) bound to a ligand capable of binding to a TEAD protein.

[0083] In embodiments, the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein at a cysteine residue (for example, a cysteine residue at a position corresponding to residue 117, 226, 227, 326, 365, or 378 of SEQ ID NO: 1 (e.g. residue 326 of SEQ ID NO: 1)).

[0084] In embodiments, the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein via the reaction of an electrophilic group (e.g. acrylamide, cyanoacrylamide, chloroacetamide, iodoacetamide , aldehyde, ketone, epoxide, nitrile, alkyne, alkene, aryl / heteroaryl halide, aryl / heteroaryl vinyl, aryl / heteroaryl acetylene, cyanoacrylamide and sulfonyl fluoride) on the ligand capable of binding to a TEAD protein with the FBXO22 protein.

[0085] In embodiments, the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein via the reaction of an electrophilic group (e.g. acrylamide, cyanoacrylamide, chloroacetamide, iodoacetamide, aldehyde, ketone, epoxide, nitrile, alkyne, alkene, aryl / heteroaryl halide, aryl / heteroaryl vinyl, aryl / heteroaryl acetylene, cyanoacrylamide and sulfonyl fluoride ) on the ligand capable of binding to a TEAD protein with the thiol group of a cysteine residue in the FBXO22 protein (for example, a cysteine residue at a position corresponding to residue 117, 226, 227, 326, 365, or 378 of SEQ ID NO: 1 (e g. residue 326 of SEQ ID NO: 1 )).

[0086] In embodiments, the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein via the reaction of an aldehyde on the ligand capable of binding to a TEAD protein with the FBXO22 protein.

[0087] In embodiments, the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein via the reaction of an aldehyde on the ligand capable of binding to a TEAD protein with the thiol group of a cysteine residue in the FBXO22 protein (for example, a cysteine residue at a position corresponding to residue 117, 226, 227, 326, 365, or 378 of SEQ ID NO: 1 (e.g. residue 326 of SEQ ID NO: 1)).

[0088] In embodiments, the ligand capable of binding to a TEAD protein is a compound capable of binding to F-box only protein 22 (FBXO22) and capable of binding to a transcriptional enhanced associate domain (TEAD) protein. As such, the present invention provides a compound capable of binding to F-box only protein 22 (FBXO22) and capable of binding to a transcriptional enhanced associate domain (TEAD) protein.

[0089] In embodiments, the ligand capable of binding to a TEAD protein is a ligand that is capable of binding to the S site of a TEAD protein. The S site (also referred to as interface 3) of a TEAD protein is the binding site on the surface of the TEAD protein that typically binds the omega loop region of YAP.

[0090] In embodiments, the ligand capable of binding to a TEAD protein is a ligand that is capable of binding to the palmitoylation site of a TEAD protein. The palmitoylation site of a TEAD protein is the pocket of the TEAD protein which typically binds to palmitic acid (e.g. during palmitoylation).

[0091] In embodiments, the ligand capable of binding to a TEAD protein is a synthetic ligand.

[0092] In embodiments, the ligand capable of binding to a TEAD protein is a compound of formula (SK): wherein Lcis a linker, TB is a moiety that is capable of binding to a TEAD protein, and FBX is a moiety that is capable of binding (e.g., covalently, for example reversibly covalently) to FBXO22.

[0093] In embodiments, the ligand capable of binding to a TEAD protein is a compound of formula (SL): wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

[0094] In embodiments, the ligand capable of binding to a TEAD protein is a compound of formula (IA) as defined herein, wherein R9’ is , wherein the wavy line intersects the bond between R9' and the rest of the compound.

[0095] In embodiments, the ligand capable of binding to a TEAD protein is a compound of formula (I) as defined herein, wherein R9is , wherein the wavy line intersects the bond between R9and the rest of the compound.

[0096] Degradation of the TEAD protein can occur via in-situ oxidation of a primary amine attached to a ligand that is capable of binding to a TEAD protein to an aldehyde (e.g. catalysed by a monoamine oxidase). The resulting aldehyde then recruits FBXO22 to a TEAD protein (e.g. at a specific cysteine residue) upon ligand-binding, triggering degradation of the TEAD protein.

[0097] Accordingly, in an aspect, the disclosure provides a compound according to formula (SLA): wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

[0098] In an aspect, the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein

[0099] A’ is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and 0, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;

[0100] R1' is selected from halogen and methyl;

[0101] R2’ is selected from halogen and methyl; R3is selected from halogen and methyl;

[0102] R4’ is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;

[0103] R5is CN or CON(R22)2;

[0104] R6’ is selected from H and C1-C3 alkyl;

[0105] R7’ is selected from H and C1-C4 alkyl;

[0106] R9’ is selected from wherein the wavy line intersects the bond between R9and the rest of the compound; each R22’ is independently selected from H and C1-C4 alkyl; and

[0107] Lcis a linker; and

[0108] X1is selected from CH and N.

[0109] In an embodiment, A’ is phenyl optionally substituted with halogen or C1-C3 haloalkoxy.

[0110] In an embodiment, A’ is phenyl.

[0111] In an embodiment, R1is selected from halogen.

[0112] In an embodiment, R1is F.

[0113] In an embodiment, R2’ is selected from halogen.

[0114] In an embodiment, R2is Cl.

[0115] In an embodiment, R3’ is selected from halogen.

[0116] In an embodiment, R3is F.

[0117] In an embodiment, R1, R2and R3are each independently selected from halogen (e.g. R1is F, R2’ is Cl and R3’ is F).

[0118] In an embodiment, R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-Ci- C4alkoxy.

[0119] In an embodiment, R4is selected from C1-C4 alkoxy and C1-C4 haloalkoxy.

[0120] In an embodiment, R4is selected from C1-C4 alkoxy.

[0121] In an embodiment, R4’ is methoxy.

[0122] In an embodiment, R6is selected from C1-C3 alkyl.

[0123] In an embodiment, R6’ is methyl.

[0124] In an embodiment, R7is H.

[0125] In an embodiment, R9is , wherein the wavy line intersects the bond between R9’ and the rest of the compound.

[0126] In an embodiment, R9’ is , wherein the wavy line intersects the bond between R9’ and the rest of the compound.

[0127] In an embodiment, each R22’ is H.

[0128] As described herein (e.g. with respect to the compounds of formula (SK), formula (SL), formula (SLA) or formula (IA)), Lcis a linker capable of coupling or linking a moiety that is capable of binding to a

[0129] TEAD protein to another part of the compound (e.g. to FBX in compounds of formula (SK), to in compounds of formula (SL), to in compounds of formula (SLA), or to R9in compounds of formula (IA)). Lcmay be a chemical linker (e.g. a chemical linker moiety) and, for example, may be a covalent linker, by which is meant that the linker is coupled on one or both sides to other portions of the compound by a covalent bond. Lcacts to tether the portions of the compound to one another whilst also allowing both of the portions to bind to their respected targets and / or form their respective function (e.g. allowing a portion to bind to a TEAD protein, and / or allowing a portion to bind to FBXO22 or allowing a portion to be metabolized into a portion to bind to FBXO22 as described herein). Additionally or alternatively, Lcmay act to tether the portions of the compound to one another whilst also mitigating the possibility of the two portions disrupting, interfering with and / or inhibiting the cellular interactions of one another.

[0130] In other words, Lcmay function to facilitate targeted protein degradation by allowing each end of the compounds of formulae (SK), (SL), (SLA), and / or (IA) to be available for binding (or another type of cellular interaction) with various components of the cellular environment. For example, Lcmay be configured to allow the moiety TB (or equivalent portion of formula (IA)) to bind to a TEAD protein without interference, disruption and / or inhibition from FBX, , , or R9. Additionally or alternatively, Lcmay be y^. configured to allow FBX, 0 , ,t0interact with the various components in the cellular environment (including FBXO22) to modulate, facilitate and / or promote the proteasomal degradation of the target protein (TEAD) without interference, disruption and / or inhibition from the moiety TB (or equivalent portion of formula (IA)).

[0131] In many cases, a broad range of linkers will be tolerated. The selection of linker may depend upon several factors, including but not limited to the particular portions of the compound tethered by the linker.

[0132] Lcmay be selected to provide a particular length and / or flexibility, e.g. to hold the portions of the compound at a particular distance or in a particular geometry. As will be appreciated by one of skill in the art, the length and / or flexibility of Lcmay be varied dependent upon the structure and / or nature of the other portions of the compound.

[0133] In an embodiment, Lcis represented by formula (LI) wherein a, b, c, R8, G1, G2, G3and G4are as defined herein, and wherein * indicates the position that is attached to , , or R9’, and the wavy line intersects the bond between (CHR8)aand the rest of the compound.

[0134] In another aspect, the present invention provides a compound of formula (I)

[0135] or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a is 0 to 4; b is 0 or 1 ; c is 0 to 5;

[0136] A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and O, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;

[0137] G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl (including spiro- and fused bicyclic cycloalkanediyls), 3- to 7-membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl (including spiro- and fused bicyclic heterocycloalkanediyls), wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and O, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy;

[0138] G2is selected from -NR10-, -CO-, -CO2-, -0C(0)0-, -CONR11-, -NR12CO-, -OC(O)NR13-, - NR14C(O)O-, -NR15C(O)NR15-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and O, wherein when G2is - CO2-, -00(0)0-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;

[0139] G3is C(R19)2; each G4is independently selected from O, NR20or C(R21)2, wherein if c is selected from 2 to 5, then adjacent instances of G4may not both be O and / or NR20;

[0140] R1is selected from halogen and methyl;

[0141] R2is selected from halogen and methyl;

[0142] R3is selected from halogen and methyl;

[0143] R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;

[0144] R5is CN or CON(R22)2;

[0145] R6is selected from H and C1-C3 alkyl;

[0146] R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;

[0147] R9is selected from , wherein the wavy line intersects the bond between R9and the rest of the compound;

[0148] R10is selected from H and C1-C4 alkyl;

[0149] R11is selected from H and C1-C4 alkyl;

[0150] R12is selected from H and C1-C4 alkyl;

[0151] R13is selected from H and C1-C4 alkyl;

[0152] R14is selected from H and C1-C4 alkyl;

[0153] R15is selected from H and C1-C4 alkyl;

[0154] R16is selected from H and C1-C4 alkyl;

[0155] R17is selected from H and C1-C4 alkyl;

[0156] R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, -CN, and C1-C4 alkoxy;

[0157] R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O (e.g. R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1- C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl;

[0158] R23is selected from H, C1-C4 alkyl, and -CO- C1-C4-alkyl;

[0159] R24is selected from H and C1-C4 alkyl; and

[0160] X1is selected from CH and N.

[0161] In embodiments: a is 0 to 4; b is 0 or 1 ; c is 0 to 5; A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and O, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;

[0162] G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl (including spiro- and fused bicyclic cycloalkanediyls), 3- to 7-membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl (including spiro- and fused bicyclic heterocycloalkanediyls), wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and O, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -ON, C1-C4 alkyl, and C1-C4 alkoxy;

[0163] G2is selected from -NR10-, -CO-, -CO2-, -0C(0)0-, -CONR11-, -NR12CO-, -OC(O)NR13-, - NR14C(O)O-, -NR15C(O)NR15-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and O, wherein when G2is - C02-, -0C(0)0-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;

[0164] G3is C(R19)2; each G4is independently selected from 0, NR20or C(R21)2, wherein if c is selected from 2 to 6 (e.g. 2 to 5), then adjacent instances of G4may not both be O and / or NR20;

[0165] R1is selected from halogen and methyl;

[0166] R2is selected from halogen and methyl;

[0167] R3is selected from halogen and methyl;

[0168] R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;

[0169] R5is CN or CON(R22)2;

[0170] R6is selected from H and C1-C3 alkyl;

[0171] R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;

[0172] R9is selected from wherein the wavy line intersects the bond between R9and the rest of the compound;

[0173] R10is selected from H and C1-C4 alkyl;

[0174] R11is selected from H and C1-C4 alkyl;

[0175] R12is selected from H and C1-C4 alkyl;

[0176] R13is selected from H and C1-C4 alkyl;

[0177] R14is selected from H and C1-C4 alkyl;

[0178] R15is selected from H and C1-C4 alkyl;

[0179] R16is selected from H and C1-C4 alkyl;

[0180] R17is selected from H and C1-C4 alkyl;

[0181] R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and Cs-Co cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, -CN, and C1-C4 alkoxy; R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N; or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1- C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl;

[0182] R23is selected from H, C1-C4 alkyl, and -CO-C1-C4-alkyl;

[0183] R24is selected from H and C1-C4 alkyl; and

[0184] X1is selected from CH and N.

[0185] In embodiments: a is 0 to 4; b is 0 or 1 ; c is 0 to 5;

[0186] A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and O, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;

[0187] G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl (including spiro- and fused bicyclic cycloalkanediyls), 3- to 7-membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl (including spiro- and fused bicyclic heterocycloalkanediyls), wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and O, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy;

[0188] G2is selected from -NR10-, -CO-, -CO2-, -0C(0)0-, -CONR11-, -NR12CO-, -OC(O)NR13-, - NR14C(O)O-, -NR15C(O)NR15-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and O, wherein when G2is - C02-, -0C(0)0-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;

[0189] G3is C(R19)2; each G4is independently selected from O, NR20or C(R21)2, wherein if c is selected from 2 to 5, then adjacent instances of G4may not both be O and / or NR20;

[0190] R1is selected from halogen and methyl;

[0191] R2is selected from halogen and methyl; R3is selected from halogen and methyl;

[0192] R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;

[0193] R5is CN or CON(R22)2;

[0194] R6is selected from H and C1-C3 alkyl;

[0195] R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;

[0196] R9is selected from

[0197] R23and '10 , wherein the wavy line intersects the bond between R9and the rest of the compound;

[0198] R10is selected from H and C1-C4 alkyl;

[0199] R11is selected from H and C1-C4 alkyl;

[0200] R12is selected from H and C1-C4 alkyl;

[0201] R13is selected from H and C1-C4 alkyl;

[0202] R14is selected from H and C1-C4 alkyl;

[0203] R15is selected from H and C1-C4 alkyl;

[0204] R16is selected from H and C1-C4 alkyl;

[0205] R17is selected from H and C1-C4 alkyl;

[0206] R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, -CN, and C1-C4 alkoxy;

[0207] R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and 0 (e.g. R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and 0, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and 0, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1- C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl; R23is H;

[0208] R24is H; and

[0209] X1is selected from CH and N.

[0210] In an embodiment, a is 0.

[0211] In an embodiment, b is 1.

[0212] In an embodiment, the total of b and c is from 1 to 5 (i.e. b + c = from 1 to 5), for example the total of b and c is 1 , or the total of b and c is 2, the total of b and c is 3, the total of b and c is 4, or the total of b and c is 5. In an embodiment, b is 0 and c is 0 to 5. In an embodiment, b is 0 and c is 0 to 4. In an embodiment, b is 0 and c is 0 to 3. In an embodiment, b is 0 and c is 0 to 2. In an embodiment, b is 0 and c is 0 or 1. In an embodiment, b is 0 and c is 1 to 5. In an embodiment, b is 0 and c is 1 to 4. In an embodiment, b is 0 and c is 1 to 3. In an embodiment, b is 0 and c is 1 or 2. In an embodiment, b is 0 and c is 2 to 5. In an embodiment, b is 0 and c is 2 to 4. In an embodiment, b is 0 and c is 2 or 3. In an embodiment, b is 0 and c is 3 to 5. In an embodiment, b is 0 and c is 3 or 4. In an embodiment, b is 0 and c is 4 or 5. In an embodiment, b is 1 and c is 0 to 5. In an embodiment, b is 1 and c is 0 to 4. In an embodiment, b is 1 and c is 0 to 3. In an embodiment, b is 1 and c is 0 to 2. In an embodiment, b is 1 and c is 0 or 1. In an embodiment, b is 1 and c is 1 to 5. In an embodiment, b is 1 and c is 1 to 4. In an embodiment, b is 1 and c is 1 to 3. In an embodiment, b is 1 and c is 1 or 2. In an embodiment, b is 1 and c is 2 to 5. In an embodiment, b is 1 and c is 2 to 4. In an embodiment, b is 1 and c is 2 or 3. In an embodiment, b is 1 and c is 3 to 5. In an embodiment, b is 1 and c is 3 or 4. In an embodiment, b is 1 and c is 4 or 5. In an embodiment, b is 0 and c is 1. In an embodiment, b is 0 and c is 2. In an embodiment, b is 0 and c is 3. In an embodiment, b is 0 and c is 4. In an embodiment, b is 0 and c is 5. In an embodiment, b is 1 and c is 0. In an embodiment, b is 1 and c is 1 . In an embodiment, b is 1 and c is 2. In an embodiment, b is 1 and c is 3. In an embodiment, b is 1 and c is 4. In an embodiment, b is 1 and c is 5.

[0213] In an embodiment, A is phenyl optionally substituted with halogen or C1-C3 haloalkoxy.

[0214] In an embodiment, A is phenyl.

[0215] In an embodiment, G1is one of the following groups: wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and R56are each independently selected from H, halogen, -OH, -ON, C1-C4 alkyl, and C1-C4 alkoxy; and

[0216] X2is selected from CH or N; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound. wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R35, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and R56are each independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0217] In an embodiment, G1is one of the following groups: wherein R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, and R47are each independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0218] In an embodiment, G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0219] In an embodiment, G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0220] In an embodiment, G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0221] In an embodiment, G1is: wherein indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0222] In an embodiment, G1is: wherein indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0223] In an embodiment, G2is selected from wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0224] In an embodiment, G2is selected from

[0225] ¥ ¥

[0226] 0 J O wherein the wavy line intersects the bond be indicates the position that is attached to G3.

[0227] In an embodiment, G2is selected from

[0228] R11

[0229] ¥ ¥-

[0230] 0 O wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0231] In an embodiment, G2is

[0232] ¥

[0233] 0 wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0234] In an embodiment, G2is

[0235] R11

[0236] ¥'■ o 5 wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0237] In an embodiment, when G1is:

[0238] In an embodiment, each G4is independently selected from 0 and C(R21)z.

[0239] In an embodiment, each G4is independently selected from O and CHR21.

[0240] In an embodiment, one instance of G4is 0.

[0241] In an embodiment, one or more instance of G4is C(R21)z.

[0242] In an embodiment, each G4is C(R21)a.

[0243] In an embodiment, one or more instance of G4is CHR21. In an embodiment, each G4is CHR21.

[0244] In an embodiment, R1is selected from halogen.

[0245] In an embodiment, R1is F.

[0246] In an embodiment, R2is selected from halogen.

[0247] In an embodiment, R2is Cl.

[0248] In an embodiment, R3is selected from halogen.

[0249] In an embodiment, R3is F.

[0250] In an embodiment, R1, R2and R3are each independently selected from halogen (e.g. R1is F, R2is Cl and R3is F).

[0251] In an embodiment, R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy- C1- C4alkoxy, each optionally substituted by -OH.

[0252] In an embodiment, R4is selected from C1-C4 alkoxy and C1-C4alkoxy- Ci-C+alkoxy, each optionally substituted by -OH.

[0253] In an embodiment, R4is selected from C1-C4alkoxy and C1-C4alkoxy-C1-C4alkoxy, wherein C1-C4 alkoxy is optionally substituted by -OH.

[0254] In an embodiment, R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-Ci- C4alkoxy.

[0255] In an embodiment, R4is selected from C1-C4 alkoxy and C1-C4 haloalkoxy.

[0256] In an embodiment, R4is selected from C1-C4 alkoxy, optionally substituted by -OH.

[0257] In an embodiment, R4is selected from C1-C4 alkoxy.

[0258] In an embodiment, R4is methoxy.

[0259] In an embodiment, R4is C1-C4alkoxy-C1-C4alkoxy.

[0260] In an embodiment, R4is wherein the wavy line intersects the bond between R4and the rest of the compound.

[0261] In an embodiment, R4is wherein the wavy line intersects the bond between R4and the rest of the compound.

[0262] In an embodiment, the compound of formula (I) is a compound of formula (la), (lb), or (Ic)

[0263] wherein R57is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; and b, c, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R9, and X1are as defined for compounds of formula (I).

[0264] In an embodiment, R6is selected from C1-C3 alkyl.

[0265] In an embodiment, R6is methyl.

[0266] In an embodiment, R7is H; and each R8is H.

[0267] In an embodiment, R9is wherein the wavy line intersects the bond between R9' and the rest of the compound. In an embodiment, R9is wherein the wavy line intersects the bond between R9and the rest of the compound. In an embodiment, R9is

[0268] "V^NH2wherein the wavy line intersects the bond between R9and the rest of the compound.

[0269] In an embodiment, R10, R12, R13, R14, R15, R16, R17and R18are each H.

[0270] In an embodiment, R10, R11, R12, R13, R14, R15, R16, R17and R18are each H.

[0271] In an embodiment,

[0272] R11is selected from H and C1-C4 alkyl; each R19is H or halogen;

[0273] R20is selected from H, halogen, and C1-C4 alkyl; each R21is independently selected from H and C1-C4 alkyl; or R11and one instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O; or one instance of R19and one instance of R21, together with the atoms to which they are connected, form cyclobutanediyl.

[0274] In an embodiment,

[0275] R11is selected from H and C1-C4 alkyl; each R19is H;

[0276] R20is selected from H and C1-C4 alkyl; each R21is independently selected from H and C1-C4 alkyl; or R11and one instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N; or one instance of R19and one instance of R21, together with the atoms to which they are connected, form cyclobutanediyl.

[0277] In an embodiment,

[0278] R11is selected from H and methyl; each R19is H;

[0279] R20is H; each R21is independently selected from H and C1-C4 alkyl; or R11and one instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N; or one instance of R19and an instance of R21, together with the atoms to which they are connected, form cyclobutanediyl.

[0280] In an embodiment, the compound of formula (I) is a compound of formula (Id), (le), (lei), (If), (Ifi), (Ig), (Igi) or (Igii) (e.g. a compound of formula (Id), (le), (If) or (lg))

[0281] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, and X1are as defined for compounds of formula (I).

[0282] In an embodiment, the compound of formula (I) is a compound of formula (Ih), (Ij), (Iji), (Ik), or (Im) (e.g. a compound of formula (Ih), (Ij), (Ik) or (Im))

[0283]

[0284] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined for compounds of formula (I).

[0285] In an embodiment, the compound of formula (I) is a compound of formula (In), (Ip), (Ipi), (Ipii), (Iq), (Iqi), (Iqii), (Iqiii), (Iqiv), (Iqv), (Iqvi), (Ir), (Iri), (Irii), or (Is) (e.g. a compound of formula (In), (Ip), (Iq), (Ir) or

[0286] (Is))

[0287]

[0288] 10

[0289] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11and X1are as defined for compounds of formula (I).

[0290] In an embodiment of the compound of formula (I), a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0291] In an embodiment of the compound of formula (I), a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0292] In an embodiment, the compound of formula (I) is a compound of formula (It), (lu), (Iv), (Iw), or (lx)

[0293] wherein A, R1, R2, R3, R4, R5, R6, R7, R9, R11, and X1are as defined for compounds of formula (I).

[0294] In an embodiment, one instance of R22is H and the other is selected from H and C1-C4 alkyl.

[0295] In an embodiment, each R22is H.

[0296] In an embodiment, R23is selected from H and C1-C4 alkyl.

[0297] In an embodiment, R23is H.

[0298] In an embodiment, R24is H.

[0299] In an embodiment, R23and R24are both H.

[0300] In an embodiment, R25is H.

[0301] In an embodiment, one of R26and R27is H, and the other is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0302] In an embodiment, both of R26and R27are H.

[0303] In an embodiment, one of R28and R29is H, and the other is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0304] In an embodiment, both of R28and R29are H.

[0305] In an embodiment, one of R30, R31, and R32is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0306] In an embodiment, each of R30, R31, and R32are H.

[0307] In an embodiment, one of R33, R34, and R35, is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0308] In an embodiment, each of R33, R34, and R35are H.

[0309] In an embodiment, one of R36, R37, R38, and R39is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0310] In an embodiment, each of R36, R37, R38, and R39are H.

[0311] In an embodiment, one of R40, R41, R42, and R43is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0312] In an embodiment, each of R40, R41, R42, and R43are H.

[0313] In an embodiment, one of R44, R45, R46, and R47is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0314] In an embodiment, each of R44, R45, R46, and R47are H.

[0315] In an embodiment, one of R48, R49, R50, and R51is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H. In an embodiment, each of R48, R49, R50, and R51are H.

[0316] In an embodiment, one of R52, R53, R54, R55, and R56is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0317] In an embodiment, each of R52, R53, R54, R55, and R56are H. In an embodiment, R57is H.

[0318] In an embodiment, X1is N.

[0319] In an embodiment, X1is N and R4is C1-C4alkoxy-C1-C4alkoxy.

[0320] In an embodiment, X1is CH.

[0321] In an embodiment, the compound of formula (I) is a compound of formula (laa) wherein a, b, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R7, R8, R9, and X1are as defined for compounds of formula (I).

[0322] In an embodiment of the compound of formula (laa), G1is one of the following groups: wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R35, R37, R38, R39, R40, R41, R42, R43, R44,

[0323] R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and R56are each independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; and X2is selected from CH or N; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0324] In an embodiment of the compound of formula (laa), G1is one of the following groups: wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R35, R37, R38, R39, R40, R41, R42, R43, R44,

[0325] R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and R56are each independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound. In an embodiment of the compound of formula (laa), G1is one of the following groups: wherein R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, and R47are each independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound. In an embodiment of the compound of formula (laa), R25is H.

[0326] In an embodiment of the compound of formula (laa), one of R26and R27is H, and the other is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0327] In an embodiment of the compound of formula (laa), both of R26and R27are H. In an embodiment of the compound of formula (laa), one of R28and R29is H, and the other is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0328] In an embodiment of the compound of formula (laa), both of R28and R29are H.

[0329] In an embodiment of the compound of formula (laa), one of R30, R31, and R32is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0330] In an embodiment of the compound of formula (laa), each of R30, R31, and R32are H.

[0331] In an embodiment of the compound of formula (laa), one of R33, R34, and R35, is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0332] In an embodiment of the compound of formula (laa), each of R33, R34, and R35are H.

[0333] In an embodiment of the compound of formula (laa), one of R36, R37, R38, and R39is selected from

[0334] H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0335] In an embodiment of the compound of formula (laa), each of R36, R37, R38, and R39are H.

[0336] In an embodiment of the compound of formula (laa), one of R40, R41, R42, and R43is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0337] In an embodiment of the compound of formula (laa), each of R40, R41, R42, and R43are H.

[0338] In an embodiment of the compound of formula (laa), one of R44, R45, R46, and R47is selected from

[0339] H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0340] In an embodiment of the compound of formula (laa), each of R44, R45, R46, and R47are H.

[0341] In an embodiment of the compound of formula (laa), one of R48, R49, R50, and R51is selected from

[0342] H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0343] In an embodiment of the compound of formula (laa), each of R48, R49, R50, and R51are H.

[0344] In an embodiment of the compound of formula (laa), one of R52, R53, R54, R55, and R56is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0345] In an embodiment of the compound of formula (laa), each of R52, R53, R54, R55, and R56are H.

[0346] In an embodiment of the compound of formula (laa), G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0347] In an embodiment of the compound of formula (laa), G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0348] In an embodiment of the compound of formula (laa), G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0349] In an embodiment of the compound of formula (laa), G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0350] In an embodiment of the compound of formula (laa), the compound is a compound of formula (lab), (lac), or (lad) wherein R57is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; and b, c, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R9, and X1are as defined for compounds of formula

[0351] (I).

[0352] In an embodiment of the compounds of formulae (lab), (lac), and (lad), R57is H.

[0353] In an embodiment of the compound of formula (laa), the compound is a compound of formula (lae), (laf), (lafi), (lag), (lagi) , (lah), or (lahi) (e.g. a compound of formula (lae), (laf), (lag), (lah))

[0354]

[0355] (lahii) wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, and X1are as defined for compounds of formula (I).

[0356] In an embodiment of the compound of formula (laa), the compound is a compound of formula (laj), (lak), (laki), (lam), or (Ian) (e.g. a compound of formula ((aj), (lak), (lam), or (Ian))

[0357] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined for compounds of formula (I).

[0358] In an embodiment of the compound of formula (laa), the compound is a compound of formula (lap), (laq), (laqi), (laqii), (lar), (lari), (larii), (lariii), (lariv), (larv), (larvi), (las), (Iasi), (lasii), or (lat) (e.g. a compound of formula (lap), (laq), (lar), (las), or (lat))

[0359]

[0360] 10

[0361] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined for compounds of formula (I).

[0362] In an embodiment of the compound of formula (laa), a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0363] In an embodiment of the compound of formula (laa), a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0364] In an embodiment of the compound of formula (laa), the compound is a compound of formula (lau), (lav), (law), (lax), or (lay)

[0365]

[0366] In an embodiment, the compound of formula (I) is a compound of formula (Ilia) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; d is 0 or 1 ; each G4is independently selected from O and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0367] R4is selected from C1-C4 alkoxy and C1-C4alkoxy-C1-C4alkoxy, each optionally substituted by -OH;

[0368] R5is CONH2;

[0369] R9is selected from , wherein the wavy line intersects the bond between R9and the rest of the compound;

[0370] R11is H or methyl; and

[0371] R15is H; each R21is independently selected from H, halogen, and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or R11and an instance of R21, together with the atoms to which they are connected, form a 4- to 6- membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O (e.g. R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl;

[0372] X1is selected from CH and N;

[0373] X2is selected from CH and N.

[0374] In an embodiment, the compound of formula (Ilia) is a compound of formula (Ilia!)

[0375] (Ilia!) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c, d, R4, R5, R9, R11, R19, X1, X2, G4are as defined for compounds of formula (Ilia).

[0376] In an embodiment, the compound of formula (Ilia) is a compound of formula (lliaii)

[0377]

[0378] (lliaii) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c, d, R4, R5, R9, R11, R19, X1, X2, G4are as defined for compounds of formula (Ilia).

[0379] In an embodiment of the compound of formula (Ilia), (Ilia!) or (lliaii), c, R4, R5, R9, R11, R19, X1, X2, G4are as defined elsewhere herein (e.g. as defined for compounds of formula (I) and / or formula (IA)).

[0380] In an embodiment of the compound of formula (Ilia), (lliai) or (lliaii) when X2is CH, d is 1 .

[0381] In an embodiment of the compound of formula (Ilia), (lliai) or (lliaii), when X2is N, d is 0.

[0382] In an embodiment, the compound of formula (I) is a compound of formula (III) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; each G4is independently selected from O and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0383] R4is selected from C1-C4 alkoxy and C1-C4alkoxy-C1-C4alkoxy, each optionally substituted by -OH;

[0384] R5is CONH2;

[0385] R9is selected from anc|z X0 wherein the wavy line intersects the bond between R9and the rest of the compound;

[0386] R11is H or methyl; and

[0387] R15is H; each R21is independently selected from H, halogen, and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or R11and an instance of R21, together with the atoms to which they are connected, form a 4- to 6- membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O (e.g. R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl;

[0388] X1is selected from CH and N;

[0389] X2is selected from CH and N.

[0390] In an embodiment, the compound of formula (I) is a compound of formula (llii) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; each G4is independently selected from O and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0391] R5is CONH2;

[0392] R9is selected from anc|z XO wherein the wavy line intersects the bond between R9and the rest of the compound; and

[0393] R15is H; each R21is independently selected from H, halogen, and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl.

[0394] In an embodiment, the compound of formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; each G4is independently selected from O and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0395] R5is CONH2;

[0396] R9is selected from , wherein the wavy line intersects the bond between R9and the rest of the compound;

[0397] R12is H or methyl; and

[0398] R15is H; each R21is independently selected from H, halogen, and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or R11and an instance of R21, together with the atoms to which they are connected, form a 4- to 6- membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O (e.g. R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl.

[0399] In an embodiment of the compound of formula (II), (III), or (Illi) each R21is independently selected from H, and C1-C4 alkyl.

[0400] In an embodiment of the compound of formula (II), (III) or (Illi) each G4is independently selected from O and C(R21)z.

[0401] In an embodiment of the compound of formula (II), (III) or (llii) each G4is independently selected from O and CH(R21). In an embodiment of the compound of formula (II), (Hi) or (llii) one instance of G4is O.

[0402] In an embodiment of the compound of formula (II), (Hi) or (llii) each G4is CHR21.

[0403] In an embodiment of the compound of formula (II), (Hi) or (llii),

[0404] R11(where present) and an instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N; or an instance of R19and an instance of R21, together with the atoms to which they are connected, form cyclobutanediyl.

[0405] In an embodiment of the compound of formula (Hi), the compound is a compound of formula (llaia), (llaiia) or (llaiiia)

[0406] (llaiia)

[0407] wherein c, G4, R5, R9, R11and R19are as defined for compounds of formula (Hi).

[0408] In an embodiment of the compound of formula (Ili), the compound is a compound of formula (llai), (llaii) or (Halil)

[0409] (llaii)

[0410] wherein c, G4, R5, R9, R11and R19are as defined for compounds of formula (III).

[0411] In an embodiment of the compound of formula (Ili), the compound is a compound of formula (I Ibi), 5 (llbii) or (llbiii)

[0412]

[0413] (llbiii) wherein b, G4, R5, R9, R11and R19are as defined for compounds of formula (Hi).

[0414] In an embodiment of the compound of formula (llii), the compound is a compound of formula (llaiv)

[0415] (llaiv) wherein c, G4, R5, R9, R11and R19are as defined for compounds of formula (llii).

[0416] In an embodiment, the compound may be a compound of formula (llavii)

[0417] (llavii) wherein c, G4, R5, R9, R11and R19are as defined for compounds of formula (llai).

[0418] In an embodiment, the compound may be a compound of formula (llaviii)

[0419]

[0420] (llaviii) wherein c, G4, R5, R9, R11and R19as defined for compounds of formula (llai).

[0421] In an embodiment of the compound of formula (II), the compound is a compound of formula (llav) wherein c, G4, R5, R9, R11and R19are as defined for compounds of formula (II).

[0422] In an embodiment of the compound of formula (II), the compound is a compound of formula (llbv) wherein c, G4, R5, R9, R11and R19are as defined for compounds of formula (II).

[0423] In an embodiment of the compound of formula (Ili), the compound is a formula (llavi) wherein c, G4, R5, R9, R11and R19are as defined for compounds of formula (Ili).

[0424] In an embodiment of the compound of formula (Ili), the compound is a compound of formula (llabi) wherein b, G4, R5, R9, R11and R19are as defined for compounds of formula (Ili).

[0425] In an embodiment of the compound of formula (II), the compound is a compound of formula (Ila)

[0426] wherein c, G4, R5, R9, R11and R19are as defined for compounds of formula (II).

[0427] In embodiments of the compound of formula (II), the compound is a compound of formula (lib) wherein b, G4, R5, R9, R11and R19are as defined for compounds of formula (II).

[0428] In an embodiment, the compound of formula (I) is selected from a compound in Table 1 .

[0429] Table 1 : Exemplary compounds of formula (l) / compounds of formula (IA) In an embodiment, the compound of formula (IA) or the compound of formula (I) is selected from compounds 1 to 26 and 30 to 34 shown in Table 1 . In an embodiment, the compound of formula (IA) or the compound of formula (I) is selected from compounds 1 to 25 and 30 to 34 in Table 1 . In an embodiment, the compound of formula (IA) or the compound of formula (I) is selected from compounds 1 to 24 and 30 to 34 in Table 1 . In an embodiment, the compound of formula (IA) or the compound of formula (I) is selected from compounds 1 to 10 and 17 (e.g. from compounds 1 to 10) shown in Table 1. In an embodiment, the compound of formula (IA) or the compound of formula (I) is selected from compounds 1 to 16, 18 to 26 and 34 shown in Table 1. In such embodiments wherein the compound of formula (IA) or the compound of formula (I) is selected from compounds 1 to 16, 18 to 26 and 34 shown in Table 1 , the compound may be considered a pro-drug. In other embodiments, the compound of formula (IA) or the compound of formula (I) is selected from compounds 17 and 30 to 33 in Table 1.

[0430] In another aspect, the present invention provides a compound capable of binding to F-box only protein 22 (FBXO22) (e.g., covalently, for example reversibly covalently) and capable of binding to a transcriptional enhanced associate domain (TEAD) protein.

[0431] In an embodiment, the compound is a compound of formula (SK):

[0432] AC

[0433] TB FBX

[0434] (SK) wherein Lcis a linker,

[0435] TB is a moiety that is capable of binding to a TEAD protein, and

[0436] FBX is a moiety that is capable of binding to FBXO22.

[0437] In an embodiment, the compound of formula (SK) is a compound of formula (Ixx): or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein

[0438] A, R1to R7, R22, and X1are as defined elsewhere herein (e.g. as for compounds of formula (I) and / or formula (IA));

[0439] FBX is a moiety that is capable of binding (e.g., covalently, for example reversibly covalently) to FBXO22; and

[0440] Lcis a linker.

[0441] In an embodiment, Lcis as defined elsewhere herein. For example, Lcis as defined for compounds of formula (IA).

[0442] In an embodiment, the compound of formula (SK) is a compound of formula (Ixy):

[0443] or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a, b, c, A, R1to R22, X1, G1, G2, G3, G4, are as defined elsewhere herein (e.g. as for compounds of formula (I) and / or formula (IA)); and

[0444] FBX is a moiety that is capable of binding (e.g., covalently, for example reversibly covalently) to FBXO22;

[0445] In embodiments of formula (SK), formula (Ixx), and formula (Ixy), FBX is an electrophilic group (e.g. acrylamide, cyanoacrylamide, chloroacetamide, iodoacetamide, aldehyde, ketone, epoxide, nitrile, alkyne, alkene, aryl / heteroaryl halide, aryl / heteroaryl vinyl, aryl / heteroaryl acetylene, cyanoacrylamide and sulfonyl fluoride).

[0446] In an embodiment, the compound of formula (SK) is a compound of formula (SL): wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

[0447] In an embodiment, the compound of formula (SK), (Ixx), (Ixy) or (SL) is a compound according to formula (I) or formula (IA) where R9or R9’ is example, the the compound of formula (SK), (Ixx),

[0448] (Ixy) or (SL) is a compound according to formula (I) where R9is .

[0449] It will be appreciated that the compounds of the present disclosure may exist in different stereoisomeric forms. The present disclosure includes within its scope the use of all stereoisomeric forms, or the use of a mixture of stereoisomers of the compounds, By way of example, where the compound comprises one or more chiral centres, the present disclosure encompasses each individual enantiomer of the compound as well as mixtures of enantiomers including racemic mixtures of such enantiomers. By way of further example, where the compound comprises two or more chiral centres, the present disclosure encompasses each individual diastereomer of the compound, as well as mixtures of the various diastereomers.

[0450] Unless otherwise indicated, the various structures shown herein encompass all isomeric (e.g. enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure). For example, the present disclosure embraces the R and S configurations for each asymmetric centre, and Z and E double bond isomers. A wavy bond from a double bond encompasses the Z or E double bond isomer, and any mixture thereof. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are to be understood to be within the scope of the present disclosure. Additionally, unless otherwise stated, where present, all tautomeric forms of the compounds described herein are to be understood to be within the scope of the present disclosure.

[0451] It should be understood that throughout this specification, the terms “comprise”, “comprising” and / or “comprises” is / are used to denote that aspects, embodiments and examples of this disclosure “comprise” a particular feature or features. It should be understood that this / these terms may also encompass aspects, embodiments and / or examples which “consist essentially of’ or “consist of’ the relevant feature or features.

[0452] The disclosure also includes various deuterated forms of the compounds disclosed herein, or of any of the formulae disclosed herein, including formula (IA) or formula (I) and corresponding subgeneric formulae defined herein, respectively, or a pharmaceutically acceptable salt, solvate or derivative thereof and / or a corresponding tautomer form thereof (including subgeneric formulas, as defined above) of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of any of the formulae disclosed herein, including formula and corresponding subgeneric formulae defined herein, respectively, or a pharmaceutically acceptable salt, solvate or derivative thereof and / or a corresponding tautomer form thereof (including subgeneric formulae, as defined above) of the present disclosure. For example, deuterated materials, such as alkyl groups may be prepared by conventional techniques (see for example: methyl-cfe -amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).

[0453] The disclosure also includes isotopically-labelled compounds which are identical to those recited in any of the formulae disclosed herein, including formula (IA) or formula (I) and corresponding subgeneric formulae defined herein, respectively, or a pharmaceutically acceptable salt, solvate or derivative thereof and / or a corresponding tautomer form thereof (including subgeneric formulae, as defined above) of the present disclosure but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as3H,11C,14C,18F,123l or125l. Compounds of the present disclosure and pharmaceutically acceptable salts, solvates or derivatives of said compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Isotopical ly labelled compounds of the present disclosure, for example those into which radioactive isotopes such as3H or14C have been incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.3H, and carbon-14, i.e.14C, isotopes are particularly preferred for their ease of preparation and detectability.11C and18F isotopes are particularly useful in PET (positron emission tomography).

[0454] Degradation may be determined by measuring the amount of a TEAD target protein (for example a TEAD paralog e.g. TEAD1 , TEAD2, TEAD3, TEAD4) in the presence of a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae as defined herein, and / or comparing this to the amount of the TEAD target protein observed in the absence of the compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae as defined herein. For example, the amount of TEAD target protein in a cell that has been contacted and / or treated with a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae as defined herein may be determined. This amount may be compared to the amount of TEAD target protein in a cell that has not been contacted and / or treated with the compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae as defined herein (e.g. as a control). If the amount of TEAD target protein is decreased in the cell contacted and / or treated with the compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae, the compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae may be considered as facilitating and / or promoting the degradation and / or proteolysis of the TEAD target protein.

[0455] The amount of the TEAD target protein can be determined using methods known in the art, for example, by performing immunoblotting assays, immunofluorescence assays, Western blot analysis and / or ELISA with cells that have been contacted and / or treated with a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae.

[0456] Selective degradation and / or increased proteolysis may be considered to have occurred if at least a 10% decrease in the amount of a TEAD target protein is observed compared to the control, for example, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% following administration of the compound of formula (I) or corresponding subgeneric formulae to the cell.

[0457] For example, selective degradation and / or increased proteolysis may be considered to have occurred if at least a 10% decrease in the amount of a TEAD target protein is observed, (e.g. at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% decrease) within 2 hours or more, or within 4 hours or more, (e.g. 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 66 hours and 72 hours) following administration of the compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae to the cell. In some embodiments, selective degradation and / or increased proteolysis may be considered to have occurred if at least a 50% decrease in the amount of a TEAD target protein is observed within 24 hours. The compound of formula (IA) or the compound of formula (I) or corresponding subgeneric formulae may be administered at any concentration, e.g. a concentration between 0.01 nM to 10 mM , such as 0.01 nM, 0.1 nM, 1 nM, 10nM, 100 nM, 1 mM, and 10 mM. In some instances, an increase of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or approximately 100% in the degradation of the TEAD target protein is observed following administration of the compound of formula (IA) or the compound of formula (I) or corresponding subgeneric formulae at a concentration of approximately 100 nM (e.g. following an incubation period of approximately 8 hours).

[0458] One measure of degrader activity of the compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae is the DCso value. As used herein, DCso is the concentration required to reach 50% of the maximal degradation of the TEAD target protein. The compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae described herein may exhibit a DCso of less than or equal to 10000 nM, less than or equal to 1000 nM, less than or equal to 500 nM, less than or equal to 100 nM or less than or equal to 75 nM. In some cases, the compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae exhibit a DC50 less than or equal to 50 nM, less than or equal to 25 nM, or less than or equal to 10 nM.

[0459] Another measure of the degrader activity of the compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae is the Dmax value. As used herein, Dmax represents the maximal percentage of TEAD target protein degradation. For example, Dmaxmay represent the maximal percentage of TEAD target protein degradation within a particular time period, such as the time period described above. Accordingly, Dmax may represent the maximal percentage of TEAD target protein degradation within 2 hours or more, or within 4 hours or more, (e.g. 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 66 hours and 72 hours). The compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae described herein may exhibit a Dmax of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or about 100%.

[0460] Yet another measure of the efficacy of the described compounds of formula (IA) or the described compounds of formula (I) or corresponding subgeneric formulae may be their effect on cell viability and / or their IC50 value. For example, an anti-proliferative effect of a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae as described herein may be assessed in a cell viability assay to provide an IC50 value. As used herein, the IC50 value represents the concentration at which 50% cell viability was observed in the cell viability assay (following administration of a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae as described herein). In terms of cell viability, the compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae described herein may exhibit an IC50 of less than 1000nM, less than 500nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 20 nM, or less than 10 nM. In some cases, the compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae described herein may exhibit an IC50 value of less than 5 nM.

[0461] The present disclosure provides a pharmaceutical composition comprising the compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae described herein. In such compositions, the compound of formula (IA) or the compound of formula (I) or corresponding subgeneric formulae may be suitably formulated such that it can be introduced into the environment of the cell by a means that allows for a sufficient portion of the molecule to enter the cell to induce degradation of the TEAD target protein.

[0462] Accordingly, there is provided a pharmaceutical composition comprising a compound of formula (SK), formula (SL), a compound of formula (SLA), a compound of formula (IA), a compound of formula (I) or corresponding subgeneric formulae as described herein (e.g. a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae as described herein) together with a pharmaceutically acceptable carrier. In an embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae together with a pharmaceutically acceptable carrier, optionally wherein the compound is present in the composition as a pharmaceutically acceptable salt, solvate or derivative. Optionally the compound of formula (SK), formula (SL), the compound of formula (SLA), the compound of formula (IA) or the compound of formula (I) or corresponding subgeneric formulae (e.g. the compound of formula (IA) or the compound of formula (I) or corresponding subgeneric formulae) is present in the pharmaceutical composition as a pharmaceutically acceptable salt, solvate or derivative. For example, there is provided a pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae as described herein together with a pharmaceutically acceptable carrier. Optionally the compound of formula (I) or corresponding subgeneric formulae is present in the pharmaceutical composition as a pharmaceutically acceptable salt, solvate or derivative.

[0463] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, phosphate buffer solutions and / or saline. Pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.

[0464] In addition to the aforementioned carrier ingredients the pharmaceutical compositions described above may alternatively or additionally include, an appropriate one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

[0465] Pharmaceutical compositions may be present in any formulation typical for the administration of a pharmaceutical compound to a subject. Representative examples of typical formulations include, but are not limited to, capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc.

[0466] A pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, transdermal, topical, transmucosal, vaginal and rectal administration. The pharmaceutical composition may be formulated to be administered with a pre-loaded syringe.

[0467] The pharmaceutical compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), topical (including dermal, buccal and sublingual), rectal, nasal and pulmonary administration e.g., by inhalation. The composition may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. Methods typically include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0468] Pharmaceutical compositions suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope. The compounds of formula (IA) or the compounds of formula (I) or corresponding subgeneric formulae may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet. Compositions suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion. Compositions for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release controlling matrix, or is coated with a suitable release controlling film.

[0469] Pharmaceutical compositions suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles. Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers, which are sealed after introduction of the formulation until required for use. Alternatively, the compound of formula (IA) or the compound of formula (I) or corresponding subgeneric formulae may be in powder form, which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.

[0470] The pharmaceutical composition may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins.

[0471] Pharmaceutical compositions suitable for topical formulation may be provided for example as gels, creams or ointments.

[0472] The compound of formula (IA) or the compound of formula (I) or corresponding subgeneric formulae described herein may be present in the pharmaceutical compositions as a pharmaceutically and / or physiologically acceptable salt, solvate or derivative.

[0473] As used herein, the term “pharmaceutically acceptable salt” refers to those salts, which are generally considered suitable for use in medicine (including in a veterinary context). For example, pharmaceutically acceptable salts may be those which can be contacted with the tissues of a mammalian subject (e.g. humans) without undue toxicity, irritation, allergic response or the like. By way of further example of suitable pharmaceutically acceptable salts, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the entire contents of which are incorporated herein by reference.

[0474] Representative examples of pharmaceutically and / or physiologically acceptable salts of the compounds of the disclosure may include, but are not limited to, acid addition salts formed with organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, malonic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric and sulfamic acids. Other pharmaceutically acceptable salts include (but are not limited to) adipate, alginate, ascorbate, aspartate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate salts, and the like.

[0475] In some examples, salts that may be derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts may include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0476] Pharmaceutically and / or physiologically functional derivatives of compounds of the present invention are derivatives, which may be converted in the body into the parent compound. Such pharmaceutically and / or physiologically functional derivatives may also be referred to as “pro-drugs” or “bioprecursors”. Pharmaceutically and / or physiologically functional derivatives of compounds of the present disclosure may include hydrolysable esters or amides or oxidisable amines in vivo.

[0477] It may be convenient or desirable to prepare, purify, and / or handle a corresponding pharmaceutically and / or physiologically acceptable solvate of the compounds described herein, which may be used in the any one of the uses / methods described. The term solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.

[0478] The compounds of the compounds of formula (I) or corresponding subgeneric formulae (e.g. wherein R9is”" 0 ), the compounds of formula (IA) (e.g. wherein R9’ is the compounds of formula (SL), and the compounds of formula (SK), of the present disclosure may modulate, facilitate and / or promote proteasomal degradation of a TEAD target protein. For example, the compounds of formula (IA) (e.g. wherein R9is ), the compounds of formula (I) or corresponding subgeneric formulae (e.g. wherein R9 ), the compounds of formula (SL), or the compounds of formula (SK), of the present disclosure may modulate, facilitate and / or promote proteasomal degradation of a TEAD target protein by inducing proximity of the TEAD target protein to the UPS using FBXO22. Accordingly, in some embodiments of the disclosure, the compounds of formula (IA) (e.g. wherein R9’ the compounds of formula (I) or corresponding subgeneric formulae (e.g. wherein ), the compounds of formula (SL), or the compounds of formula (SK), of the present disclosure may be capable of binding FBXO22 and capable of binding to a TEAD protein, (e.g. at a cysteine residue).

[0479] In other embodiments, the compounds of the compounds of formula (IA) (e.g. wherein R9’ is the compounds of formula (I) or corresponding subgeneric formulae (e.g. wherein R9is

[0480] R

[0481] -VN'R24r23, e.g. wherein R23and R24are both H), or the compounds of formula (SLA) of the present disclosure may be metabolized (e.g. oxidised, for example in vivo) to produce a compound (e.g. an aldehyde) capable of binding FBXO22 and capable of binding to a TEAD protein. As such, there is provided a method of selectively degrading and / or increasing proteolysis of a TEAD target protein in a cell, the method comprising contacting and / or treating the cell with a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae or a pharmaceutical composition comprising a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae as described herein. The method may be carried out in vivo or in vitro. In particular, there is provided a method of selectively degrading and / or increasing proteolysis of a TEAD target protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae or a pharmaceutical composition comprising a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA) or a compound of formula (I) or corresponding subgeneric formulae of the present disclosure. For example, there is provided a method of selectively degrading and / or increasing proteolysis of a TEAD target protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or corresponding subgeneric formulae or a pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae of the present disclosure.

[0482] As such, a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA), or the compounds of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA), or a compound of formula (I) or corresponding subgeneric formulae) of the present disclosure may find application in medicine and / or therapy. In some embodiments, a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA) or a compound of formula (I), an FBXO22 conjugate as described herein or a pharmaceutical composition comprising compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA) or a compound of formula (I) is for use in medicine. For example, the compound of formula (I) or corresponding subgeneric formulae, or the pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae, may be for use in medicine. For example, the compound of formula (SK), the compound of formula (SL), the compound of formula (SLA), the compound of formula (IA), or the compound of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA), or a compound of formula (I) or corresponding subgeneric formulae) of the present disclosure may find use in the treatment and / or prevention of any disease or condition, which is modulated through the TEAD target protein. For example, the compounds of formula (SK), the compounds of formula (SL), the compounds of formula (SLA), the compounds of formula (IA), or the compounds of formula (I) or corresponding subgeneric formulae of the present disclosure may be useful in the treatment of any disease, which is modulated through the TEAD target protein by lowering the level of that protein in the cell, e.g. cell of a subject. For example, the compounds of formula (I) or corresponding subgeneric formulae of the present disclosure may be useful in the treatment of any disease, which is modulated through the TEAD target protein by lowering the level of that protein in the cell, e.g. cell of a subject. Reduction of TEAD target protein levels in a cell following administration of a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA), or a compound of formula (I) or corresponding subgeneric formulae of the present invention wherein activity of the selected TEAD protein is implicated in a disease state or a disorder, then it is to be understood that the compound of formula (SK), the compound of formula (SL), the compound of formula (SLA), the compound of formula (IA), or the compound of formula (I) or corresponding subgeneric formulae is useful in the treatment of that disease. The compound of formula (SK), the compound of formula (SL), the compound of formula (SLA), the compound of formula (IA), or the compound of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA), or a compound of formula (I) or corresponding subgeneric formulae) of the present disclosure may also find use in the treatment and / or prevention of any disease or condition, which is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ- TEAD interaction. For example, the compound of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae) of the present disclosure may also find use in the treatment and / or prevention of any disease or condition, which is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction. For example, the compounds of formula (SK), the compounds of formula (SL), the compounds of formula (SLA), the compounds of formula (IA), or the compounds of formula (I) or corresponding subgeneric formulae of the present disclosure may be useful in the treatment of any disease, which is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction by lowering the level of a TEAD protein in the cell, e.g. cell of a subject. For example, the compounds of formula (I) or corresponding subgeneric formulae of the present disclosure may be useful in the treatment of any disease, which is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction by lowering the level of a TEAD protein in the cell, e.g. cell of a subject.

[0483] There is further provided the use of the compounds of formula (SK), the compounds of formula (SL), the compounds of formula (SLA), the compounds of formula (IA), or the compounds of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae) as described herein in the manufacture of a medicament for the treatment and / or prevention of any disease or condition, which is modulated through the TEAD target protein. For example, the use of the compounds of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae) as described herein in the manufacture of a medicament for the treatment and / or prevention of any disease or condition, which is modulated through the TEAD target protein. There is also provided the use of the compounds of formula (SK), the compounds of formula (SL), the compounds of formula (SLA), the compounds of formula (IA), or the compounds of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae) as described herein in the manufacture of a medicament for the treatment and / or prevention of any disease or condition, which is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction. For example, the use of the compounds of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae) as described herein in the manufacture of a medicament for the treatment and / or prevention of any disease or condition, which is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction.

[0484] Diseases and / or conditions that may be treated and / or prevented by the compounds of formula (SK), the compounds of formula (SL), the compounds of formula (SLA), the compounds of formula (IA), or the compounds of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA), or a compound of formula (I) or corresponding subgeneric formulae) of the disclosure include any disease, which is associated with and / or is caused by an abnormal level of TEAD protein activity. For example, diseases and / or conditions that may be treated and / or prevented by the compounds of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a formula (I) or corresponding subgeneric formulae) of the disclosure include any disease, which is associated with and / or is caused by an abnormal level of TEAD protein activity.

[0485] Such diseases and conditions include those whose pathology is related at least in part to an abnormal (e.g. elevated) level of a TEAD protein and / or the overexpression of a TEAD protein. For example, the compounds of formula (SK), the compounds of formula (SL), the compounds of formula (SLA), the compounds of formula (IA), or the compounds of formula (I) or corresponding subgeneric formulae (e.g. the compounds of formula (I) or corresponding subgeneric formulae) may find use in the treatment and / or prevention of diseases where an elevated level of a TEAD protein is observed in a subject suffering from the disease. In other examples, the diseases and / or conditions may be those whose pathology is related at least in part to inappropriate TEAD protein expression (e.g., expression at the wrong time and / or in the wrong cell), or excessive TEAD protein expression.

[0486] Accordingly, there is provided a method of treating and / or preventing a disease or condition, which is associated with and / or is caused by an abnormal level of TEAD protein activity, which comprises administering a therapeutically effective amount of a compound of formula (SK), a compound of formula (SL), a compound of formula (SLA), a compound of formula (IA), or a compound of formula (I) or corresponding subgeneric formulae e.g. the compounds of formula (I) or corresponding subgeneric formulae) as described herein.

[0487] Representative examples of the diseases and / or conditions that may be treated and / or prevented by the use of the described compounds of formula (SK), the described compounds of formula (SL), the described compounds of formula (SLA), the described compounds of formula (IA), or the described compounds of formula (I) or corresponding subgeneric formulae (or a pharmaceutical composition comprising a compound of formula (SK), formula (SL), formula (SLA), formula (IA), formula (I) or corresponding subgeneric formulae) include (but are not limited to) cancer. For example, the described compounds of formula (I) or corresponding subgeneric formulae, or the pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae, may be for use in medicine, wherein the disease or condition is cancer.

[0488] Representative examples of cancers that may be treated and / or prevented using the described compounds of formula (SK), the described compounds of formula (SL), the described compounds of formula (SLA), the described compounds of formula (IA), or the described compounds of formula (I) or corresponding subgeneric formulae (e.g. the described compounds of formula (I) or corresponding subgeneric formulae) include, but are not limited to breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer. For example, the described compounds of formula (I) or corresponding subgeneric formulae, or the pharmaceutical composition comprising a compound of formula (I) or corresponding subgeneric formulae, may be for use in medicine, wherein the disease or condition is cancer and wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer and bone cancer. The disclosure also provides treatment of any tumor expressing relevant biomarkers, including but not limited to large tumour suppressor kinase 1 (LATS1), LATS2, neurofibromatosis type II (NF2) loss-of-function mutations and YAP / TAZ mutations, for example fusions.

[0489] In an aspect, the invention provides a method of treating and / or preventing a disease or condition, which is associated with and / or is caused by an abnormal level of TEAD protein activity, which comprises administering a therapeutically effective amount of a compound of formula (SL) as described herein to a patient, wherein the compound of formula (SL) forms in vivo a FBXO22 conjugate wherein the FBXO22 protein is covalently bound (e.g. reversibly covalently bound) to the compound of formula (SL).

[0490] In embodiments, the diseases and / or conditions that may be treated and / or prevented by this method include (but are not limited to) cancer.

[0491] Representative examples of cancers that may be treated and / or prevented using this method include, but are not limited to breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer. The disclosure also provides treatment of any tumor expressing relevant biomarkers, including but not limited to large tumour suppressor kinase 1 (LATS1 ), LATS2, neurofibromatosis type II (NF2) loss-of-function mutations and YAP / TAZ mutations, for example fusions.

[0492] In this method, the compound of formula (SL) may be administered in capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc. Furthermore, the compound of formula (SL) may be administered parenterally, e.g., intravenously, intradermally, subcutaneously, orally, transdermally, topically, transmucosally, vaginally or rectally. The pharmaceutical composition may be formulated to be administered with a pre-loaded syringe.

[0493] In an aspect, the invention provides a method of treating and / or preventing a disease or condition, which is associated with and / or is caused by an abnormal level of TEAD protein activity, which comprises administering a therapeutically effective amount of a compound of formula (I ) as described herein to a patient, wherein the compound of formula (IA) (e.g s in vivo an FBXO22 conjugate wherein the FBXO22 protein is covalently bound (e.g. reversibly covalently bound) to the compound of formula (IA) (e.g. wherein

[0494] In embodiments, the diseases and / or conditions that may be treated and / or prevented by this method include (but are not limited to) cancer.

[0495] Representative examples of cancers that may be treated and / or prevented using this method include, but are not limited to breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer. The disclosure also provides treatment of any tumor expressing relevant biomarkers, including but not limited to large tumour suppressor kinase 1 (LATS1 ), LATS2, neurofibromatosis type II (NF2) loss-of-function mutations and YAP / TAZ mutations, for example fusions.

[0496] In this method, the compound of formula (IA) (e.g. wherein R9’ is may peadministered in capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc. Furthermore, the compound of formula (SL) may be administered parenterally, e.g., intravenously, intradermally, subcutaneously, orally, transdermally, topically, transmucosally, vaginally or rectally. The pharmaceutical composition may be formulated to be administered with a pre-loaded syringe.

[0497] In an aspect, the invention provides a method of treating and / or preventing a disease or condition, which is associated with and / or is caused by an abnormal level of TEAD protein activity, which comprises administering a therapeutically effective amount of a compound of formula (I) (e.g. wherein R9is ) or corresponding subgeneric formulae as described herein to a patient, wherein the compound of formula (I) (e.g. wherein R9is or corresponding subgeneric formulae forms in vivo an FBXO22 conjugate wherein the FBXO22 protein is covalently bound (e.g. reversibly covalently bound) to the compound of formula (I) (e.g. wherein R9is ) or corresponding subgeneric formulae.

[0498] In embodiments, the diseases and / or conditions that may be treated and / or prevented by this method include (but are not limited to) cancer.

[0499] Representative examples of cancers that may be treated and / or prevented using this method include, but are not limited to breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer. The disclosure also provides treatment of any tumor expressing relevant biomarkers, including but not limited to large tumour suppressor kinase 1 (LATS1 ), LATS2, neurofibromatosis type II (NF2) loss-of-function mutations and YAP / TAZ mutations, for example fusions.

[0500] In this method, the compound of formula (I) (e.g. wherein R9is ) or corresponding subgeneric formulae may be administered in capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc. Furthermore, the compound of formula (SL) may be administered parenterally, e.g., intravenously, intradermally, subcutaneously, orally, transdermally, topically, transmucosally, vaginally or rectally. The pharmaceutical composition may be formulated to be administered with a pre-loaded syringe.

[0501] In an aspect, the invention provides a method of treating and / or preventing a disease or condition, which is associated with and / or is caused by an abnormal level of TEAD protein activity, which comprises administering a therapeutically effective amount of a compound of formula (SLA) as described herein to a patient, wherein the compound of formula (SLA) forms in vivo a FBXO22 conjugate wherein the FBXO22 protein is covalently bound (e.g. reversibly covalently bound) to the compound of formula (SLA). In embodiments of this method, a monoamine oxidase catalyses the in situ oxidation of the primary amine of the compound of formula (SLA) to an aldehyde, and the aldehyde recruits FBXO22 to a TEAD protein, triggering degradation of the TEAD protein.

[0502] In embodiments, the diseases and / or conditions that may be treated and / or prevented by this method include (but are not limited to) cancer.

[0503] Representative examples of cancers that may be treated and / or prevented using this method include, but are not limited to breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer. The disclosure also provides treatment of any tumor expressing relevant biomarkers, including but not limited to large tumour suppressor kinase 1 (LATS1 ), LATS2, neurofibromatosis type II (NF2) loss-of-function mutations and YAP / TAZ mutations, for example fusions. In this method, the compound of formula (SK) or the compound of formula (SL) (e.g. the compound of formula (SL)) may be administered in capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc. Furthermore, the compound of formula (SK) or the compound of formula (SL) (e.g. the compound of formula (SL)) may be administered parenterally, e.g., intravenously, intradermally, subcutaneously, orally, transdermally, topically, transmucosally, vaginally or rectally. The pharmaceutical composition may be formulated to be administered with a pre-loaded syringe.

[0504] In an aspect, the invention provides a method of treating and / or preventing a disease or condition, which is associated with and / or is caused by an abnormal level of TEAD protein activity, which comprises administering a therapeutically effective amount of a compound of formula (IA) (e.g. wherein R9’ is asdescribed herein to a patient, wherein the compound of formula (IA) (e.g. wherein R9' is forms in vivo an FBXO22 conjugate wherein the FBXO22 protein is covalently bound (e.g. reversibly covalently bound) to the compound of formula (IA) (e.g. wherein R9’ is ). In embodiments of this method, a monoamine oxidase catalyses the in situ oxidation of the primary amine of the compound of formula (IA) wherein R9' is ,and the resulting aldehyde recruits FBXO22 to a TEAD protein, triggering degradation of the TEAD protein.

[0505] In embodiments, the diseases and / or conditions that may be treated and / or prevented by this method include (but are not limited to) cancer.

[0506] Representative examples of cancers that may be treated and / or prevented using this method include, but are not limited to breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer. The disclosure also provides treatment of any tumor expressing relevant biomarkers, including but not limited to large tumour suppressor kinase 1 (LATS1 ), LATS2, neurofibromatosis type II (NF2) loss-of-function mutations and YAP / TAZ mutations, for example fusions.

[0507] In this method, the compound of formula (IA) (e.g. wherein R9’ administered in capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc. Furthermore, the the compound of formula (SL) may be administered parenterally, e.g., intravenously, intradermally, subcutaneously, orally, transdermally, topically, transmucosally, vaginally or rectally. The pharmaceutical composition may be formulated to be administered with a pre-loaded syringe.

[0508] In an aspect, the invention provides a method of treating and / or preventing a disease or condition, which is associated with and / or is caused by an abnormal level of TEAD protein activity, which comprises administering a therapeutically effective amount of a compound of formula (I) (e.g. wherein R9isr23

[0509] ) or corresponding subgeneric formulae as described herein to a patient, wherein the compound of formula

[0510] (I) (e.g. wherein R9isr23) or corresponding subgeneric formulae forms in vivo an FBXO22 conjugate wherein the FBXO22 protein is covalently bound (e.g. reversibly covalently bound) to the compound of formula (I) (e.g. wherein R9isr23) or corresponding subgeneric formulae. In embodiments of this method, a monoamine oxidase catalyses the in situ oxidation of the primary amine of the compound of formula (I) (e.g. wherein R9isr23) or corresponding subgeneric formulae, and the resulting aldehyde recruits FBXO22 to a TEAD protein, triggering degradation of the TEAD protein.

[0511] In embodiments, the diseases and / or conditions that may be treated and / or prevented by this method include (but are not limited to) cancer.

[0512] Representative examples of cancers that may be treated and / or prevented using this method include, but are not limited to breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer, and bone cancer. The disclosure also provides treatment of any tumor expressing relevant biomarkers, including but not limited to large tumour suppressor kinase 1 (LATS1 ), LATS2, neurofibromatosis type II (NF2) loss-of-function mutations and YAP / TAZ mutations, for example fusions.

[0513] In this method, the compound of formula (I) (e.g. wherein R9isr23) or corresponding subgeneric formulae may be administered in capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc. Furthermore, the compound of formula (SL) may be administered parenterally, e.g., intravenously, intradermally, subcutaneously, orally, transdermally, topically, transmucosally, vaginally or rectally. The pharmaceutical composition may be formulated to be administered with a pre-loaded syringe.

[0514] As used herein, the term “patient” or “subject” is used to describe an animal, such as a mammal (e.g. a human or a domesticated animal), to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided. For treatment of those infections, conditions or disease states which are specific to a specific animal such as a human patient, the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc. In general, in the present invention, the term patient refers to a human patient unless stated or implied from the context of the use of the term.

[0515] In another aspect, the present invention provides a method of making a compound of formula (SK), a compound of formula (SL), the compounds of formula (SLA), the compounds of formula (IA), formula (I) or corresponding subgeneric formulae (e.g. a method of making a compound of formula (I) or corresponding subgeneric formulae). For example, the present invention provides a method of making a compound as defined herein.

[0516] For example, the method of making a compound of formula (Iz) wherein a, b, c, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R7, R8, and R11are as defined for compounds of formula (I), may comprise the steps of:

[0517] (a) reacting a compound of formula (III) with a compound of formula (IV) to provide a compound of formula (V); and

[0518] (b) converting a compound of formula (V) to provide a compound of formula (Iz). In the compounds of formula (III), (IV), and (V), a, b, c, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R7, R8, and R11are as defined for compounds of formula (I); and RPR0Tis selected from the group consisting of t-butyl carbamate, benzyl, trifluoroacetamide, COMe, benzyl carbamate, 9-fluorenylmethyl carbamate, N- alloxycarbonyl, triphenylmethyl, and 2-(trimethylsilyl)ethoxycarbonyl. Preferably RPR0Tis t-butyl carbamate. Compounds of formula (I) wherein R9is CH2NH2 (e.g. compounds of formula (lz)) may be oxidised to provide compounds of formula (I) wherein R9is CHO.

[0519] In another example, the method of making a compound of formula (Iza) wherein a, b, c, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R7, R8, and R11are as defined for compounds of formula (I), may comprise the steps of:

[0520] (a) reacting a compound of formula (III) with a compound of formula (VI) to provide a compound of formula (VII); and (b) oxidising the compound of formula (VII) (e.g. using Dess-Martin Periodinane) to provide a compound of formula (Iza).

[0521]

[0522] In the compounds of formula (III), (VI), and (VII), a, b, c, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R7, R8, and R11are as defined for compounds of formula (I).

[0523] The disclosure also provides a method for identifying a compound which mediates degradation or reduction of a TEAD protein, the method comprising: providing a compound comprising a moiety which binds to a TEAD ligand and at least one group selected from -OHO, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(CO-CI-C4 alkyl), and N(C1-C4 alkyl)(CO-Ci-C4alkyl); contacting the compound with a cell expressing FBXO22 protein and a TEAD protein; determining whether the level of the TEAD protein is decreased in the cell relative to baseline; and identifying the compound as a compound which mediates degradation or reduction of a TEAD protein.

[0524] The disclosure also provides a library of compounds of formula (SK), compounds of formula (SL), compounds of formula (SLA), compounds of formula (IA), and / or compounds of formula (I) or corresponding subgeneric formulae, the library comprising a plurality of compounds of formula (SK), compounds of formula (SL), compounds of formula (SLA), compounds of formula (IA), and / or compounds of formula (I) or corresponding subgeneric formulae. For example, the disclosure provides a library of compounds of formula (I) or corresponding subgeneric formulae, the library comprising a plurality of compounds of formula (I) or corresponding subgeneric formulae.

[0525] The compounds of formula (I) or corresponding subgeneric formula, may be used in a combination therapy with one or more additional chemotherapeutic agents. Combination therapy includes alternating between administration of the compounds of the invention and the chemotherapeutic agent(s), as well as simultaneously administering the compounds of the invention and the chemotherapeutic agents. In embodiments, the chemotherapeutic agent is docetaxel, an anti-PD-1 therapy or an anti-PDL-1 therapy.

[0526] In the discussion above, reference is made to a number of terms, which are to be understood to have the meanings provided below, unless a context indicates to the contrary. The nomenclature used herein for defining compounds, in particular the compounds described herein, is intended to be in accordance with the rules of the International Union of Pure and Applied Chemistry (IUPAC) for chemical compounds, specifically the “IUPAC Compendium of Chemical Terminology (Gold Book)” (see A. D. Jenkins et al., Pure & Appl. Chem., 68, 2287-2311 (1996)). For the avoidance of doubt, if an IUPAC rule is contrary to a definition provided herein, the definition herein is to prevail.

[0527] As used herein, “heteroaryl” may be a single or fused ring system having one or more aromatic rings containing 1 or more, in some cases 1 to 3, in some cases 1 to 2, in some cases a single O, N and / or S heteroatom(s). The term “heteroaryl” may refer to a mono- or polycyclic heteroaromatic system having 5 to 10 ring atoms. Representative examples of heteroaryl groups may include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl etc. As used herein, “substituted heteroaryl” refers to a heteroaryl group as defined herein which comprises one or more substituents on the heteroaromatic ring.

[0528] As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbyl group. The chain may be saturated or unsaturated, e.g. in some cases the chain may contain one or more double or triple bonds.

[0529] As used herein, “C1-C4 alkyl” refers to a straight or branched chain hydrocarbyl group containing from 1 to 4 carbon atoms. As used herein, a “C1-C3 alkyl” refers to a straight or branched chain hydrocarbyl group containing from 1 to 3 carbon atoms. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl etc. When an alkyl group is substituted, any hydrogen atom(s), CH3, CH2 or CH group(s) may be replaced with the substituent(s), providing valencies are satisfied.

[0530] As used herein, a “cycloalkyl” is a ring containing 3 to 10 carbon atoms, in some cases 3 to 8, or in some cases 5 to 6 carbon atoms. The ring may be saturated or unsaturated, e.g. in some cases the ring may contain one or more double or triple bonds. As used herein, a C3-C6 cycloalkyl is a cycloalkyl containing 3 to 6 carbon atoms in the ring. As used herein, a C3-C5 cycloalkyl is a cycloalkyl containing 3 to 5 carbon atoms in the ring.

[0531] Representative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl etc. When a cycloalkyl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.

[0532] As used herein, “heterocycloalkyl” refers to a monocyclic or polycyclic ring having in one or more rings of the ring system at least one heteroatom selected from 0, N and S (e.g. from one to five ring heteroatoms independently selected from the group consisting of O, N and S). The one or more rings may also contain one or more double bonds provided that the one or more rings are not fully aromaticized. The one or more rings of the heterocycloalkyl may comprise 3 to 10 atoms, in some cases 3 to 8 atoms. The one or more rings may be aliphatic. The one or more rings may be saturated or unsaturated, e.g. in some cases the one or more rings may contain one or more double or triple bonds. Any N heteroatom present in the heterocycloalkyl group may be Ci to Ce alkyl-substituted. In some cases, the heterocycloalkyl is a monocyclic or bicyclic ring, such as a monocyclic ring. Representative examples of heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, dithiolanyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, N- alkylpiperazinyl, morpholinyl, dioxanyl, oxazolidinyl, tetrahydropyranyl, diazaspiroundecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, etc. Where the heterocycloalkyl comprises a divalent radical, this moiety may sometimes be referred to herein as heterocycloalkylene.

[0533] The term “spiro” is used to refer to moieties comprising two or more ring systems, wherein at least two of the ring systems are connected by just one atom (typically a quaternary carbon atom).

[0534] “Bicyclic” is used herein to refer to moieties that feature two joined rings of atoms. Bicyclic systems may comprise a fused ring system (in which at least two rings share a common bond). In other examples, two rings may be joined by a bond between atoms on each of the two or more rings. In other examples, the bicyclic system may comprise a spiro centre (as defined above).

[0535] The term “fused” is used to refer to moieties comprising two or more ring systems, wherein at least two of the ring systems are connected by a [1 ,2] ring junction, i.e. a moiety comprising two or more ring systems wherein two, or more, of the rings present share a bond in each respective ring structure.

[0536] As used herein, an alkoxy refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-. As used herein, a CMalkoxy refers to a Ci-4 alkyl group (as defined above), appended to the parent molecular moiety through a oxy group, -O-. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy etc.

[0537] As used herein, a “halo” or “halogen” group may be F, Cl, Br, or I. In some examples, halo or halogen may be F.

[0538] As used herein, “haloalkyl” may be an alkyl group in which one or more hydrogen atoms thereon have been replaced with a halogen atom, e.g. a Ci-Ce haloalkyl may be a Ci to Ce alkyl in which one or more hydrogen atoms thereon have been replaced with a halogen atom. By way of a representative example, a Ci-Ce haloalkyl may be a fluoroalkyl, such as fluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3) or 1 ,1 -difluoroethyl (-CH2CHF2), and in particular fluoromethyl (-CH2F), difluoromethyl (-CHF2), or trifluoromethyl (-CF3).

[0539] As used herein, a “haloalkoxy” (e.g. CM haloalkoxy) refers to an alkoxy (e.g. C1-C4 alkoxy) as defined above, in which one or more hydrogen atoms thereon have been replaced with a halogen atom.

[0540] As used herein, the terms “aryl”, “heteroaryl”, “cycloalkyl”, “Ci to C4 alkyl”, and “heterocycloalkyl” may refer to either a monovalent radical species or a divalent radical species.

[0541] As used herein, the suffix “anediyl” indicates that a moiety is a divalent radical. For example, C3-C6 cycloalkanediyl is a divalent radical derived from a C3-C6 cycloalkane, e.g. cyclobutanediyl is wherein the wavy lines intersect the bonds between the cyclobutanedienyl and the rest of the compound.

[0542] Likewise, C7-C11 bicyclic cycloalkanediyl is a divalent radical derived from a C7-C11 bicyclic cycloalkane, 3- to 7-membered heterocycloalkanediyl is a divalent radical derived from a 3- to 7-membered heterocycloalkane, and 7- to 12-membered bicyclic heterocycloalkanediyl is a divalent radical derived from a 7- to 12-membered bicyclic heterocycloalkane, as exemplified in the following table:

[0543] It should be understood that throughout this specification, the terms “comprise”, “comprising” and / or

[0544] “comprises” is / are used to denote that aspects, embodiments and examples of this disclosure “comprise” a particular feature or features. It should be understood that this / these terms may also encompass aspects, embodiments and / or examples which “consist essentially of’ or “consist of’ the relevant feature or features.

[0545] The present disclosure may also be defined with reference to the following set of clauses:

[0546] Clause 1 . A compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a is 0 to 4; b is 0 or 1 ; c is 0 to 5;

[0547] A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and 0, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;

[0548] G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl, 3- to 7-membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl, wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and O, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy;

[0549] G2is selected from -NR10-, -CO-, -CO2-, -OC(O)O-, -CONR11-, -NR12CO-, -OC(O)NR13-, - NR14C(O)O-, -NR15C(O)NR16-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and O, wherein when G2is - CO2-, -OC(O)O-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;

[0550] G3is C(R19)2; each G4is independently selected from O, NR20or C(R21)2, wherein if c is selected from 2 to 5, then adjacent instances of G4may not both be O and / or NR20;

[0551] R1is selected from halogen and methyl;

[0552] R2is selected from halogen and methyl;

[0553] R3is selected from halogen and methyl;

[0554] R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;

[0555] R5is CN or CON(R22)2;

[0556] R6is selected from H and C1-C3 alkyl;

[0557] R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;

[0558] R9is selected from wherein the wavy line intersects the bond between R9and the rest of the compound;

[0559] R10is selected from H and C1-C4 alkyl;

[0560] R11is selected from H and C1-C4 alkyl;

[0561] R12is selected from H and C1-C4 alkyl;

[0562] R13is selected from H and C1-C4 alkyl;

[0563] R14is selected from H and C1-C4 alkyl;

[0564] R15is selected from H and C1-C4 alkyl;

[0565] R16is selected from H and C1-C4 alkyl;

[0566] R17is selected from H and C1-C4 alkyl;

[0567] R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, -CN, and C1-C4 alkoxy;

[0568] R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, Cs-Ce cycloalkyl, and C1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O; or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and 0, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and 0, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1- C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl;

[0569] R23Is H;

[0570] R24is H; and

[0571] X1is selected from CH and N.

[0572] Clause 1a. or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a is 0 to 4; b is 0 or 1 ; c is 0 to 5;

[0573] A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and O, and is optionally substituted with =0, -OH, or C1- C3 alkoxy;

[0574] G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl, 3- to 7- membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl, wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and 0, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy;

[0575] G2is selected from -NR10-, -CO-, -CO2-, -0C(0)0-, -CONR11-, -NR12CO-, -OC(O)NR13-, - NR14C(O)O-, -NR15C(O)NR16-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and O, wherein when G2is -CO2-, -OC(O)O-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;

[0576] G3is C(R19)2; each G4is independently selected from 0, NR20or C(R21)2, wherein if c is selected from 2 to 6 (e.g. from 2 to 5), then adjacent instances of G4may not both be O and / or NR20;

[0577] R1is selected from halogen and methyl;

[0578] R2is selected from halogen and methyl;

[0579] R3is selected from halogen and methyl;

[0580] R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;

[0581] R5is CN or CON(R22)2;

[0582] R6is selected from H and C1-C3 alkyl;

[0583] R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;

[0584] R9is selected from wherein the wavy line intersects the bond between R9and the rest of the compound;

[0585] R10is selected from H and C1-C4 alkyl;

[0586] R11is selected from H and C1-C4 alkyl;

[0587] R12is selected from H and C1-C4 alkyl;

[0588] R13is selected from H and C1-C4 alkyl;

[0589] R14is selected from H and C1-C4 alkyl;

[0590] R15is selected from H and C1-C4 alkyl;

[0591] R16is selected from H and C1-C4 alkyl;

[0592] R17is selected from H and C1-C4 alkyl;

[0593] R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, - CN, and C1-C4 alkoxy;

[0594] R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N; or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl;

[0595] R23is selected from H, C1-C4 alkyl, and -CO-C1-C4-alkyl;

[0596] R24is selected from H and C1-C4 alkyl; and

[0597] X1is selected from CH and N.

[0598] Clause 2. The compound of clause 1 or 1 a, wherein a is 0.

[0599] Clause 3. The compound of clause 1 , 1 a or 2, wherein b is 1 .

[0600] Clause 4. The compound of any one of clauses 1 to 3, wherein A is phenyl optionally substituted with halogen or C1-C3 haloalkoxy.

[0601] Clause 5. The compound of any one of clauses 1 to 4, wherein A is phenyl.

[0602] Clause 6. The compound of any one of clauses 1 to 5, wherein G1is one of the following groups: wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and R56are each independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; and

[0603] X2is selected from CH or N; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound. Clause 7. The compound of any one of clauses 1 to 6, wherein G1is one of the following groups: wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and R56are each independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0604] Clause 8. The compound of any one of clauses 1 to 7, wherein G1is one of the following groups: wherein R35, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, and R47are each independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0605] Clause 9. The compound of any one of clauses 1 to 6, wherein G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0606] Clause 10. The compound of any one of clauses 1 to 6 or 9, wherein G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0607] Clause 11 . The compound of any one of clauses 1 to 6 or 9, wherein G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0608] Clause 12. The compound of any one of clauses 1 to 6, 9 or 11 , wherein G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0609] Clause 13. The compound of any one of clauses 1 to 11 , wherein G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0610] Clause 14. The compound of any one of clauses 1 to 13, wherein G2is selected from wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0611] Clause 15. The compound of any one of clauses 1 to 14, wherein G2is selected from wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0612] Clause 16. The compound of any one of clauses 1 to 15, wherein G2is selected from

[0613] R11

[0614] ¥ ¥'• o ° wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0615] Clause 17. The compound of any one of clauses 1 to 16, wherein G2is

[0616] ¥ 0 wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0617] Clause 18. The compound of any one of clauses 1 to 16, wherein G2is wherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

[0618] Clause 19. The compound of any one of clauses 1 to 18, wherein each G4is independently selected from 0 and C(R21)z.

[0619] Clause 20. The compound of any one of clauses 1 to 19, wherein one instance of G4is 0.

[0620] Clause 21 . The compound of any one of clauses 1 to 19, wherein one or more instance of G4is CHR21. Clause 22. The compound of any one of clauses 1 to 19 or 21 , wherein each G4is CHR21.

[0621] Clause 23. The compound of any one of clauses 1 to 22, wherein R1is selected from halogen.

[0622] Clause 24. The compound of any one of clauses 1 to 23, wherein R1is F.

[0623] Clause 25. The compound of any one of clauses 1 to 24, wherein R2is selected from halogen.

[0624] Clause 26. The compound of any one of clauses 1 to 25, wherein R2is Cl.

[0625] Clause 27. The compound of any one of clauses 1 to 26, wherein R3is selected from halogen.

[0626] Clause 28. The compound of any one of clauses 1 to 27, wherein R3is F.

[0627] Clause 29. The compound of any one of clauses 1 to 28, wherein R1, R2and R3are each independently selected from halogen (e.g. R1is F, R2is Cl and R3is F).

[0628] Clause 30. The compound of any one of clauses 1 to 29, wherein R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, each optionally substituted by -OH.

[0629] Clause 31. The compound of any one of clauses 1 to 30, wherein R4is selected from C1-C4 alkoxy and C1-C4alkoxy-C1-C4alkoxy, each optionally substituted by -OH.

[0630] Clause 32. The compound of any one of clauses 1 to 31 , wherein R4is selected from C1-C4 alkoxy and C1-C4alkoxy-C1-C4alkoxy, wherein C1-C4 alkoxy is optionally substituted by -OH.

[0631] Clause 33. The compound of any one of clauses 1 to 30, wherein R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy.

[0632] Clause 34. The compound of any one of clauses 1 to 30 or 33, wherein R4is selected from C1-C4 alkoxy and C1-C4 haloalkoxy.

[0633] Clause 35. The compound of any one of clauses 1 to 34 wherein R4is selected from C1-C4 alkoxy.

[0634] Clause 36. The compound of any one of clauses 1 to 35, wherein R4is methoxy.

[0635] Clause 37. The compound of any one of clauses 1 to 33, wherein R4is C1-C4alkoxy-C1-C4alkoxy.

[0636] Clause 38. The compound of any one of clauses 1 to 35 or 37, wherein R4is wherein the wavy line intersects the bond between R4and the rest of the compound. Clause 39. The compound of any one of clauses 1 to 32, wherein R4is wherein the wavy line intersects the bond between R4and the rest of the compound.

[0637] Clause 40. The ligand capable of binding to a TEAD protein or the compound of any one of clauses 1 to 39, wherein the ligand capable of binding to a TEAD protein or the compound is a compound of formula (la), (lb), or (Ic) wherein R57is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; and b, c, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R9, and X1are as defined in any one of clauses 1 or 3 to 25. Clause 41 . The compound of any one of clauses 1 to 40 wherein R6is selected from C1-C3 alkyl.

[0638] Clause 42. The compound of any one of clauses 1 to 41 , wherein R6is methyl.

[0639] Clause 43. The compound of any one of clauses 1 to 39, 41 or 42, wherein

[0640] R7is H; each R8is H.

[0641] Clause 44. The compound of any one of clauses 1 to 43, wherein R9is wherein the wavy line intersects the bond between R9and the rest of the compound.

[0642] Clause 45. The compound of any one of clauses 1 to 43, wherein R9is wherein the wavy line intersects the bond between R9and the rest of the compound.

[0643] Clause 46. The compound of any one of clauses 1 to 43 or 45, wherein R9is

[0644] ■VXNH2wherein the wavy line intersects the bond between R9and the rest of the compound.

[0645] Clause 47. The compound of any of clauses 1 to 46 wherein R10, R12, R13, R14, R15, R16, R17and R18are each H.

[0646] Clause 48. The compound of any of clauses 1 to 47 wherein R10, R11, R12, R13, R14, R15, R16, R17and R18are each H.

[0647] Clause 49. The compound of any one of clauses 1 to 46, wherein

[0648] R11is selected from H and C1-C4 alkyl; each R19is H;

[0649] R20is selected from H and C1-C4 alkyl; each R21is independently selected from H and C1-C4 alkyl; or R11and one instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N; or or one instance of R19and one instance of R21, together with the atoms to which they are connected, form cyclobutanediyl.

[0650] Clause 50. The compound of any one of clauses 1 to 46, wherein

[0651] R11is selected from H and methyl; each R19is H;

[0652] R20is H; each R21is independently selected from H and C1-C4 alkyl; or R11and one instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N; or or one instance of R19and an instance of R21, together with the atoms to which they are connected, form cyclobutanediyl.

[0653] Clause 51. The compound of any one of clauses 1 to 50, wherein the compound is a compound of formula (Id), (le), (lei), (If), (Ifi), (Ig), (Igi) or (Igii)

[0654]

[0655] 10

[0656] wherein a, A, G1, R1, R2, R3, R4, R5, R5, R7, R8, R9, R21, X1and X2are as defined in any one of clauses 1 to 13 or 16 to 35.

[0657] Clause 52. The compound of any one of clauses 1 to 51 , wherein the compound is a compound of formula (Id), (le), (If), or (Ig)

[0658] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, and X1are as defined in any one of clauses 1 to 13 or 16 to 35.

[0659] Clause 53. The compound of any one of clauses 1 to 50, wherein the compound is a compound of formula (Ih), (Ij), (Iji), (Ik), or (Im)

[0660] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined in any one of clauses 1 to 13 or 16 to 35. Clause 54. The compound of any one of clauses 1 to 50 or 53, wherein the compound is a compound of formula (Ih), (Ij), (Ik), or (Im) wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined in any one of clauses 1 to 13 or 16 to 35.

[0661] Clause 55. The compound of any one of clauses 1 to 50, wherein the compound is a compound of formula (In), (Ip), (Ipi), (Ipii), (Iq), (Iqi), (Iqii), (Iqiii), (Iqiv), (Iqv), (Iqvi), (Ir), (Iri), (Irii), or (Is)

[0662] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R21and X1are as defined in any

[0663] 10 one of 1 to 13 or 16 to 35. Clause 56. The compound of any one of clauses 1 to 50 or 55, wherein the compound is a compound of formula (In), (Ip), (Ipi), (Ipii), (Iq), (Iqi), (Iqii), (Iqiii), (Iqiv), (Iqv), (Iqvi), (Ir), or (Is)

[0664] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R21and X1are as defined in any one of 1 to 13 or 16 to 35.

[0665] Clause 57. The compound of any one of clauses 1 to 50, 55 or 56, wherein the compound is a compound of formula (In), (Ip), (Iq), (Ir), or (Is)

[0666] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R1 1and X1are as defined in any one of

[0667] 1 to 13 or 16 to 35. Clause 58 The compound of any one of clauses 51 to 57, wherein a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0668] Clause 59. The compound of any one of clauses 51 to 58, wherein a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0669] Clause 60. The compound of any one of clauses 1 to 50, wherein the compound is a compound of formula (It), (lu), (Iv), (Iw), or (lx)

[0670] wherein A, R1, R2, R3, R4, R5, R6, R7, R9, R11, and X1are as defined in any one of clauses 1 to 13, 16 to 26, or 28 to 35.

[0671] Clause 61. The compound of any one of clauses 1 to 60, wherein one instance of R22is H and the other is selected from H and C1-C4 alkyl.

[0672] Clause 62. The compound of any one of clauses 1 to 61 , wherein each R22is H.

[0673] Clause 63. The compound of any one of clauses 1 to 62, wherein R23is selected from H and C1-C4 alkyl.

[0674] Clause 64. The compound of any one of clauses 1 to 63, wherein R23is H.

[0675] Clause 65. The compound of any one of clauses 1 to 64, wherein R24is H.

[0676] Clause 66. The compound of any one of clauses 1 to 65, wherein R23and R24are both H.

[0677] Clause 67. The compound of any one of clauses 6 to 8 or 14 to 66, wherein R25is H. Clause 68. The compound of any one of clauses 6 to 8 or 14 to 67, wherein one of R26and R27is H, and the other is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0678] Clause 69. The compound of clause 68, wherein both of R26and R27are H.

[0679] Clause 70. The compound of any one of clauses 6 to 8 or 14 to 69, wherein one of R28and R29is H, and the other is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0680] Clause 71 . The compound of clause 70, wherein both of R28and R29are H.

[0681] Clause 72. The compound of any one of clauses 6 to 8 or 14 to 71 , wherein one of R30, R31, and R32is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0682] Clause 73. The compound of clause 72, wherein each of R30, R31, and R32are H.

[0683] Clause 74. The compound of any one of clauses 6 to 8 or 14 to 73, wherein one of R33, R34, and R35, is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0684] Clause 75. The compound of clause 74, wherein each of R33, R34, and R35are H.

[0685] Clause 76. The compound of any one of clauses 6 to 8 or 14 to 75, wherein one of R36, R37, R38, and

[0686] R39is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0687] Clause 77. The compound of clause 76, wherein each of R36, R37, R38, and R39are H.

[0688] Clause 78. The compound of any one of clauses 6 to 8 or 14 to 77, wherein one of R40, R41, R42, and

[0689] R43is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0690] Clause 79. The compound of clause 78, wherein each of R40, R41, R42, and R43are H.

[0691] Clause 80. The compound of any one of clauses 6 to 8 or 14 to 79, wherein one of R44, R45, R46, and

[0692] R47is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0693] Clause 81 . The compound of clause 80, wherein each of R44, R45, R46, and R47are H. Clause 82. The compound of any one of clauses 6 to 8 or 14 to 81 , wherein one of R48, R49, R50, and R51is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0694] Clause 83. The compound of clause 82, wherein each of R48, R49, R50, and R51are H.

[0695] Clause 84. The compound of any one of clauses 6 to 8 or 14 to 83, wherein one of R52, R53, R54, R55, and R56is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0696] Clause 85. The compound of clause 84, wherein each of R52, R53, R54, R55, and R56are H.

[0697] Clause 86. The compound of any one of clauses 6 to 8 or 14 to 85, wherein R57is H.

[0698] Clause 87. The compound of any one of clauses 1 to 86, wherein X1is N.

[0699] Clause 88. The compound any one of clauses 1 to 87, wherein X1is N and R4is C1-C4alkoxy-Ci-

[0700] C4alkoxy.

[0701] Clause 89. The compound of any one of clauses 1 to 86, wherein X1is CH.

[0702] Clause 90. The compound of clause 1 , wherein the compound is a compound of formula (laa) wherein any one of clauses 1 to 63.

[0703] Clause 91 . The compound of clause 90, wherein G1is one of the following groups:

[0704] selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; and

[0705] X2is selected from CH or N; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0706] Clause 92. The compound of clause 90 or 91 , wherein G1is one of the following groups: wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and R56are each independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound. Clause 93. The compound of any one of clauses 90 to 92, wherein G1is one of the following groups: wherein R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, and R47are each independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0707] Clause 94. The compound of clause 91 to 93, wherein R25is H.

[0708] Clause 95. The compound of any one of clauses 91 to 94, wherein one of R26and R27is H, and the other is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0709] Clause 96. The compound of clause 95, wherein both of R26and R27are H.

[0710] Clause 97. The compound of any one of clauses 91 to 96, wherein one of R28and R29is H, and the other is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0711] Clause 98. The compound of clause 97, wherein both of R28and R29are H.

[0712] Clause 99. The compound of any one of clauses 91 to 98, wherein one of R30, R31, and R32is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0713] Clause 100. The compound of clause 99, wherein each of R30, R31, and R32are H.

[0714] Clause 101. The compound of any one of clauses 91 to 100, wherein one of R33, R34, and R35, is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0715] Clause 102. The compound of clause 101 , wherein each of R33, R34, and R35are H.

[0716] Clause 103. The compound of any one of clauses 91 to 102, wherein one of R36, R37, R38, and R39is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0717] Clause 104. The compound of clause 103, wherein each of R36, R37, R38, and R39are H.

[0718] Clause 105. The compound of any one of clauses 91 to 104, wherein one of R40, R41, R42, and R43is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0719] Clause 106. The compound of clause 105, wherein each of R40, R41, R42, and R43are H. Clause 107. The compound of any one of clauses 91 to 106, wherein one of R44, R45, R46, and R47is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0720] Clause 108. The compound of clause 107, wherein each of R44, R45, R46, and R47are H.

[0721] Clause 109. The compound of clause 91 to 108, wherein one of R48, R49, R50, and R51is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0722] Clause 110. The compound of clause 109, wherein each of R48, R49, R50, and R51are H.

[0723] Clause 111. The compound of any one of clauses 91 to 110, wherein one of R52, R53, R54, R55, and R56is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy, and the others are H.

[0724] Clause 112. The compound of clause 111 , wherein each of R52, R53, R54, R55, and R56are H.

[0725] Clause 113. The compound of any one of clauses 90 to 112, wherein G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0726] Clause 114. The compound of any one of clauses 90 to 113, wherein G1is one of the following groups: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0727] Clause 115. The compound of any one of clauses 90 to 113, wherein G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0728] Clause 116. The compound of any one of clauses 90 to 115, wherein G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0729] Clause 117. The compound of any one of clauses 90 to 113 or 115, wherein G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0730] Clause 118. The compound of any one of clauses 90 to 117, wherein the compound is a compound of formula (lab), (lac), or (lad)

[0731] wherein R57is selected from H, halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; and b, c, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R9, and X1are as defined in any one of clauses 1 , 3 to 26, or 28 to 38, 40 to 61 or 63.

[0732] Clause 119. The compound of clause 118, wherein R57is H.

[0733] Clause 120. The compound of any one of clauses 90 to 119, wherein the compound is a compound of formula (lae), (laf), (lafi), (lag), (lagi), (lah), or (lahi)

[0734]

[0735] (lahii) wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R21, and X1are as defined in any one of clauses 1 to 13, 16 to 35, or 40 to 63.

[0736] Clause 121 . The compound of any one of clauses 90 to 120, wherein the compound is a compound of formula (lae), (laf), (lag), or (lah)

[0737] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, and X1are as defined in any one of clauses 1 to 13, 16 to 35, or 40 to 63. Clause 122. The compound of any one of clauses 90 to 119, wherein the compound is a compound of formula (laj), (lak), (laki), (lam), or (Ian)

[0738] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined in any one of clauses 1 to 35, or 39 to 62.

[0739] Clause 123. The compound of any one of clauses 90 to 119 or 122, wherein the compound is a compound of formula (laj), (lak), (lam), or (Ian)

[0740] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined in any one of clauses 1 to 35, or 39 to 62.

[0741] Clause 124. The compound of any one of clauses 90 to 119, wherein the compound is a compound of formula (lap), (laq), (laqi), (laqii), (lar), (lari), (larii), (lariii), (lariv), (larv), (larvi), (las), (Iasi),

[0742] (lasii), or (lat)

[0743]

[0744] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined for compounds of formula (I).

[0745] Clause 125. The compound of any one of clauses 90 to 1 19 or 124, wherein the compound is a compound of formula (lap), (laq), (laqi), (laqii), (lar), (lari), (larii), (lariii), (lariv), (larv), (larvi), (las), or (lat)

[0746]

[0747] wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined for compounds of formula (I). Clause 126. The compound of any one of clauses 90 to 119, 124 or 125, wherein the compound is a compound of formula (lap), (laq), (lar), (las), or (lat) wherein a, A, G1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and X1are as defined in any one of clauses 1 to 36, or 40 to 63.

[0748] Clause 127. The compound of any one of clauses 120 to 126, wherein a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound. Clause 128. The compound of any one of clauses 120 to 127, wherein a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0749] Clause 129. The compound of any one of clauses 120 to 127, wherein a is 0 and G1is: wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

[0750] Clause 130. The compound of any one of clauses 90 to 129, wherein the compound is a compound of formula (lau), (lav), (law), (lax), or (lay)

[0751] wherein A, R1, R2, R3, R4, R5, R6, R7, R9, R11, and X1are as defined in any one of clauses 1 to 36, or 40 to 63.

[0752] Clause 131. The compound of any one of clauses 1 to 130, wherein the compound is a compound of formula (III) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; each G4is independently selected from O and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0753] R4is selected from C1-C4 alkoxy and C1-C4alkoxy-C1-C4alkoxy, each optionally substituted by -OH;

[0754] R5is CONH2;

[0755] R9is selected from , wherein the wavy line intersects the bond between R9and the rest of the compound;

[0756] R11is H or methyl; and

[0757] R15is H; each R21is independently selected from H, halogen, and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or R11and an instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O (e.g. R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl;

[0758] X1is selected from CH and N.

[0759] Clause 132. The compound of any one of clauses 1 to 131 , wherein the compound is a compound of formula (Illi) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; each G4is independently selected from 0 and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O; R5is CONH2;

[0760] R9is selected from anc| 'V0, wherein the wavy line intersects the bond between R9and the rest of the compound; and each R21is independently selected from H and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl.

[0761] Clause 133. The compound of formula any one of clauses 1 to 131 wherein the compound is a compound of formula (llavii)

[0762] (llavii) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; each G4is independently selected from O and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0763] R5is CONH2;

[0764] R9is selected from wherein the wavy line intersects the bond between R9and the rest of the compound; and each R21is independently selected from H and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl.

[0765] Clause 134. The compound of formula any one of clauses 1 to 131 , wherein the compound is a compound of formula (I laviii)

[0766]

[0767] (llaviii) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; each G4is independently selected from 0 and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0768] R5is CONHa;

[0769] R9is selected from wherein the wavy line intersects the bond between R9and the rest of the compound; and each R21is independently selected from H and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl.

[0770] Clause 135. The compound of any one of clauses 1 to 131 , wherein the compound is a compound of formula (II) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; each G4is independently selected from O and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0771] R5is CONH2;

[0772] R9is selected from , wherein the wavy line intersects the bond between R9and the rest of the compound;

[0773] R11is H or methyl; and

[0774] R15is H; each R21is independently selected from H, halogen, and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or R11and an instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O (e.g. R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl.

[0775] Clause 136. The compound of any one of clauses 131 to 135, wherein each R21is independently selected from H, and C1-C4 alkyl.

[0776] Clause 137. The compound of any one of clauses 131 to 136, wherein each G4is independently selected from O and C(R21)2.

[0777] Clause 138. The compound of any one of clauses 131 to 137, wherein one instance of G4is O.

[0778] Clause 139. The compound of clause 131 to 137, wherein each G4is CHR21.

[0779] Clause 140. The compound of any one of clauses 131 to 139, wherein

[0780] R11and an instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and 0; or an instance of R19and an instance of R21, together with the atoms to which they are connected, form cyclobutanediyl.

[0781] Clause 141. The compound of any one of clauses 1 to 140, wherein the compound is a compound of formula (llaia), (llaiia) or (llaiiia)

[0782]

[0783] (Ilaiiia) wherein c, G4, R5, R9, R11and R19are as defined in any of clauses 94 to 97.

[0784] Clause 142. The compound any one of clauses 1 to 141 , wherein the compound is a compound of formula (llai), (Hail) or (I laiii)

[0785]

[0786] (llaiii) wherein c, G4, R5, R9, R11and R19are as defined in clauses 94 to 97.

[0787] Clause 143. The compound any one of clauses 1 to 142, wherein the compound is a compound of formula (I Ibi), (llbii) or (llbiii)

[0788] (llbiii) wherein b, G4, R5, R9, R11and R19are as defined in clauses 94 to 98.

[0789] Clause 144. The compound any one of clauses 1 to 140, wherein the compound is a compound of formula (llaiv)

[0790] (llaiv) wherein c, G4, R5, R9, R11and R19are as defined in clauses 94 to 97. Clause 145. The compound any one of clauses 1 to 143, wherein the compound is a compound of formula (llavii)

[0791] (llavii) wherein c, G4, R5, R9, R11and R19are as defined in clauses 94 to 97.

[0792] Clause 146. The compound any one of clauses 1 to 143, wherein the compound is a compound of formula (I laviii)

[0793]

[0794] (Ilaviii) wherein c, G4, R5, R9, R11and R19are as defined in clauses 94 to 97. Clause 147. The compound any one of clauses 1 to140, wherein the compound is a compound of formula (I lav) wherein c, G4, R5, R9, R11and R19are as defined in clauses 94 to 97.

[0795] Clause 148. The compound of clause 1 , wherein the compound is a compound of formula (Ilia)

[0796] or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; d is 0 or 1 ; each G4is independently selected from 0 and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;

[0797] R4is selected from C1-C4 alkoxy and C1-C4alkoxy-C1-C4alkoxy, each optionally substituted by -OH;

[0798] R5is CONH2;

[0799] R9is selected from wherein the wavy line intersects the bond between R9and the rest of the compound;

[0800] R11is H or methyl; and

[0801] R15is H; each R21is independently selected from H, halogen, and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or R11and an instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and O (e.g. R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl;

[0802] X1is selected from CH and N;

[0803] X2is selected from CH and N.

[0804] Clause 149. The compound of clause 148, wherein the compound is a compound of formula (Ilia!)

[0805] or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c, d, G4, R4,

[0806] R5, R9, R1 1, R15, R21, R19, X1, and X2are as defined in clause 148.

[0807] Clause 150. The compound of any one of clauses 15 to 164, wherein the compound is a compound of formula (I Hail) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c, d, G4, R4, R5, R9, R1 1, R15, R21, R19, X1, and X2are as defined in clause 148.

[0808] Clause 151. The compound of any one of clauses 148 to 150, wherein c, d, G4, R4, R5, R9, R1 1, R15, R21, R19, X1, and X2are as defined in any of clauses 1 to 147.

[0809] Clause 152. The compound of any one of clauses 148 to 151 , wherein when X2is CH, d is 1 .

[0810] Clause 153. The compound of any one of clauses 148 to 152, wherein when X2is N, d is 0. Clause 154. The compound any one of clauses 131 to 153, wherein the compound is a compound of formula (I Ibv) wherein b, G4, R5, R9, R11and R19are as defined in clauses 94 to 98.

[0811] Clause 155. The compound any one of clauses 131 to 153, wherein the compound is a compound of formula (llavi)

[0812] (llavi) wherein c, G4, R5, R9, R11and R19are as defined in clauses 94 to 97.

[0813] Clause 156. The compound any one of clauses 131 to 153 or 155, wherein the compound is a compound of formula (llbvi)

[0814]

[0815] (Ilbvi) wherein b, G4, R5, R9, R11and R19are as defined in clauses 94 to 98. Clause 157. The compound any one of clauses 131 to 154, wherein the compound is a compound of formula (Ila) wherein c, G4, R5, R9, R11and R19are as defined in clauses 94 to 97.

[0816] Clause 158. The compound any one of clauses 131 to 154 or 157, wherein the compound is a compound of formula (lib) wherein b, G4, R5, R9, R11and R19are as defined in clauses 94 to 98.

[0817] Clause 159. The compound of clause 1 , wherein the compound is selected from compounds 1 to 26 and 30 to 34 shown in Table 1 (e.g. from compounds 1 to 24 and 30 to 34).

[0818] Clause 160. The compound of clause 1 , wherein the compound is selected from compounds 1 to 17 shown in Table 1 (e.g. from compounds 1 to 10).

[0819] Clause 161. A compound capable of binding (e.g., covalently, for example reversibly covalently) to F- box only protein 22 (FBXO22), and capable of binding to a transcriptional enhanced associate domain (TEAD) protein.

[0820] Clause 162. The compound of clause 161 , wherein the compound is a compound of formula (SK): wherein Lcis a linker,

[0821] TB is a moiety that is capable of binding to a TEAD protein, and

[0822] FBX is a moiety that is capable of binding (e.g., covalently, for example reversibly covalently) to FBXO22.

[0823] Clause 163. The compound of clause 161 or 162, wherein the compound is a compound of formula (Ixx)

[0824] or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein A, R1-R7, R22and X1are as defined in any of clauses 1 to 158;

[0825] Lcis a linker; and

[0826] FBX is a moiety that is capable of binding to FBXO22.

[0827] Clause 164. The compound of any one of clauses 161 to 163, wherein the compound is a compound of formula (Ixy): or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein A, R1-R7, R22and X1are as defined in any of clauses 1 to 158;

[0828] Lcis a linker; and

[0829] FBX is a moiety that is capable of binding to FBXO22.

[0830] Clause 165. The compound of any one of clauses 161 to 162, wherein the compound is a compound of formula (SL): wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

[0831] Clause 166. The compound of any of clauses 161 to 165, wherein the compound is a compound according to any one of clauses 1 to 160, wherein R9 is

[0832] Clause 167. A compound of formula (IA):

[0833]

[0834] A, R1-R7, R9’, R22and X1are as defined in any of clauses 1 to 158; and Lcis a linker.

[0835] Clause 168. The compound of any one of clauses 162 to 158, wherein Lcis represented by formula (LI) wherein a, b, c, R8, G1, G2, G3and G4are as defined in any of clauses 1 to 167, and wherein * indicates the position that is attached to FBX, , , or R9, and the wavy line intersects the bond between (CHR8)aand the rest of the compound.

[0836] Clause 169. A compound according to formula (SLA):

[0837] TB'LC-NH2

[0838] (SLA) wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

[0839] Clause 170. An F-box only protein 22 (FBXO22) conjugate comprising an FBXO22 protein covalently (e.g. reversibly covalently) bound to a ligand capable of binding to a transcriptional enhanced associate domain (TEAD) protein.

[0840] Clause 171. The FBXO22 conjugate of clause 170, wherein the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein at a cysteine residue.

[0841] Clause 172. The FBXO22 conjugate of clause 170 or 171 , wherein the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein via the reaction of an electrophilic group (e.g acrylamide, cyanoacrylamide, chloroacetamide, iodoacetamide, aldehyde, ketone, epoxide, nitrile, alkyne, alkene, aryl / heteroaryl halide, aryl / heteroaryl vinyl, aryl / heteroaryl acetylene, cyanoacrylamide and sulfonyl fluoride ) on the ligand capable of binding to a TEAD protein with the thiol group of a cysteine residue in the FBXO22 protein.

[0842] Clause 173. The FBXO22 conjugate of any one of clauses 170 to 172, wherein the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein via the reaction of an aldehyde on the ligand capable of binding to a TEAD protein with the thiol group of a cysteine residue in the FBXO22 protein.

[0843] Clause 174. The FBXO22 conjugate of any one of clauses 170 to 173, wherein the cysteine residue is at a position corresponding to residue 117, 226, 227, 326, 365, or 378 of SEQ ID NO: 1.

[0844] Clause 175. The FBXO22 conjugate of any one of clauses 170 to 174, wherein the cysteine residue is at a position corresponding to residue 326 of SEQ ID NO: 1 .

[0845] Clause 176. The FBXO22 conjugate of any one of clauses 170 to 175, wherein the ligand capable of binding to a TEAD protein is a synthetic ligand.

[0846] Clause 177. The FBXO22 conjugate of any one of clauses 170 to 176, wherein the ligand capable of binding to a TEAD protein comprises a structure represented by formula (SL): wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

[0847] Clause 178. The FBXO22 conjugate of any one of clauses 170 to 177, wherein the ligand capable of binding to a TEAD protein is a compound as defined in any one of claims 1 to 158 wherein R9is'V0, 159, 160, or 161 to 168 wherein FBX or R9are ,

[0848] Clause 179. The FBXO22 conjugate of any one of clauses 170 to 177, wherein the ligand is a compound of formula (I A) as defined in clause 167 or a compound of formula (I) as defined in any one of clauses 1 to 160 (e.g. a compound of formula (I) as defined in any one of clauses 1 to

[0849] 160), wherein wherein the wavy line intersects the bond between R9and the rest of the compound.

[0850] Clause 180. The FBXO22 conjugate of any one of clauses 177 to 179or the compound of any of clauses 162 or 165, wherein TB is a moiety that is capable of binding to the S site of a TEAD protein.

[0851] Clause 181. The FBXO22 conjugate of any one of clauses 177 to 179 or the compound of any of clauses162 to 165, wherein TB is a moiety that is capable of binding to the palmitoylation site of a TEAD protein. Clause 182. A pharmaceutical composition comprising the compound of any one of clauses 1 to 169, together with a pharmaceutically acceptable carrier, optionally wherein the compound is present in the composition as a pharmaceutically acceptable salt, solvate or derivative.

[0852] Clause 183. A compound of any one of clauses 1 to 169, a conjugate of any one of clauses 170 to 181 , or the pharmaceutical composition of claim 182, for use in medicine.

[0853] Clause 184. The compound, conjugate or pharmaceutical composition for use of clause 183, wherein the disease or condition is cancer.

[0854] Clause 185. The compound, conjugate or pharmaceutical composition for use of clause 185, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer and bone cancer.

[0855] Clause 186. The compound, conjugate or pharmaceutical composition for use of any one of clauses 183 to 185, wherein the disease or condition is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction.

[0856] Clause 187. A compound of any one of clauses 1 to 169 or the pharmaceutical composition of clause 182, for use in medicine.

[0857] Clause 188. The compound or pharmaceutical composition for use of clause 187, wherein the disease or condition is cancer.

[0858] Clause 189. The compound or pharmaceutical composition for use of clause 188, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer and bone cancer.

[0859] Clause 190. The compound or pharmaceutical composition for use of any one of clauses 187 to 189, wherein the disease or condition is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction.

[0860] Clause 191. A method of making a compound as defined in any one of clauses 1 to 169.

[0861] Clause 192. A method for identifying a compound which mediates degradation or reduction of a TEAD protein, the method comprising: providing a compound comprising a moiety which binds to a TEAD ligand and at least one group selected from -CHO, NHz, NH(CI-C4 alkyl), N(CI-C4 alkyl)z, NH(CO- C1-C4 alkyl), and N(C1-C4 alkyl)(CO-C1-C4 alkyl); contacting the compound with a cell expressing FBXO22 protein and a TEAD protein; determining whether the level of the TEAD protein is decreased in the cell relative to baseline; and identifying the compound as a compound which mediates degradation or reduction of a TEAD protein.

[0862] The present invention will now be described in detail with reference to the following non-limiting examples.

[0863] EXAMPLES

[0864] List of Abbreviations: pL = Microliter HPLC = high performance liquid chromatography pM = Micromolar LCMS = liquid chromatography mass pm = Micrometer spectrometry

[0865] ACN = acetonitrile 25 M = Molar

[0866] Boc = tert-butyloxycarbonyl M+H+= parent mass spectrum peak plus H+

[0867] °C = degrees Celsius mg = Milligram DCM = Dichloromethane min = minutes

[0868] DIPEA = N, N-Diisopropylethylamine, or Hunig's mL = Milliliter base 30 mM = Millimolar

[0869] DMF = N,N-dimethylformamide mmol = Millimole

[0870] DMSO = Dimethylsulfoxide MS = mass spectrum FA = formic acid nM = nanomolar g or G = gram RT or r.t. = room temperature h or H = Hour(s) 35 TFA = trifluoroacetic acid

[0871] HATU = 1-[Bis(dimethylamino)methylene]-1 H- THF = tetrahydrofuran

[0872] 1 ,2 ,3-triazolo[4, 5-b]pyridi ni u m 3-oxide TLC = thin layer chromatography hexafluorophosphate Chemistry - Materials and Methods

[0873] All chemicals, unless otherwise stated were commercially available or synthetised as previously described in the literature and used without further purification. Solvents were anhydrous and reactions preformed under positive pressure of nitrogen or argon, as required.

[0874] LCMS

[0875] Method D: Column: CORTECS C18 (1.6um; 3.0x30mm), Mobile Phase A :0.05% FA in Water, Mobile Phase B : 0.05% FA in ACN, (Time / B%): 0_3,0.1_3,1.4_97,2_97,2.05_3,2.5_3; Flow rate: 0.85ml / min(Gradient), Column Oven Temp:45 °C.

[0876] Method E: Column: Poroshell 120 EC-C18(3X100mm, 2.7pm), Mobile Phase: A: 0.05% TFA in water, Mobile Phase B: 0.05% TFA in ACN, T / B%: 0.01 / 10,0.2 / 10,6 / 90,8 / 90,8.1 / 10,10 / 10, Flow rate:0.7 ml / min (Gradient) Column Oven Temp:40 °C.

[0877] Method G: Column: Poroshell 120 EC-C18(3X50mm, 1.9pm), Mobile Phase: A: 0.05% TFA in water, Mobile Phase B: 0.05% TFA in ACN, T / B%: 0.01 / 5,2.0 / 5,9.5 / 60,12.0 / 95,15.0 / 95,17.5 / 5,18.0 / 5 Flow rate:1.0 ml / min (Gradient) Column Oven Temp: 40 °C.

[0878] Method H: Column: BAKERBOND Q2100 C18(2.1X50mm,1 ,8pm), Mobile Phase: C: 0.05% FA in water, Mobile Phase D: 0.05% FA in ACN, T / D%: 0.0 / 2_0.3 / 2_2.0 / 98_2.8 / 98_3.0 / 2_3.7 / 2, Flow rate:0.6 ml / min (Gradient) Column Oven Temp:40 °C.

[0879] Method I: Column: AQUITY UPLC BEH C18 (2.1 X 50 mm, 1.7 pm), Mobile Phase: A: 0.05% FA in water, Mobile Phase B: 0.05% FA in ACN, T / D%: 0.0 / 3_0.3 / 3_2.0 / 97_2.8 / 97_3.0 / 3_3.7 / 3, Flow rate:0.6 ml / min (Gradient) Column Oven Temp: 40 °C. Method J: Column: Poroshell 120 EC-C18(3X100mm, 2.7|jm), Mobile Phase: A: 0.05% TFA in water, Mobile Phase B: 0.05% TFA in ACN, T / B%: 0.01 / 10,0.2 / 10,6 / 90,8 / 90,8.1 / 10,10 / 10, Flow rate:0.7 ml / min (Gradient) Column Oven Temp:40 °C.

[0880] HPLC

[0881] Method D: Column: X-Bridge CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B - Acetonitrile Inj Volume; 5.0|jL, Flow Rate: 1 .2. ml_ / minute Gradient program: Time(min) / B Cone.: 0.01 / 5, 1.0 / 5, 8.0 / 100, 12.0 / 100, 14.0 / 5, 18.0 / 5.

[0882] Method E: Column: BAKERBOND (1.8um C18,100 mm X 2.1 mm), Mobile Phase-A: 0.05% FA in Water, Mobile Phase-B: 0.05% FA in Acetonitrile, Column Temperature: 50°C, Flow Rate: 0.5 mU min, Gradient: 0 / 5, 1 / 5, 6 / 90, 8.5 / 90, 8.8 / 5, 11 / 5, Diluent: ACN: Water.

[0883] Method G: Column: BAKERBOND (1.8um C18,100 mm X 2.1 mm), Mobile Phase-A: 0.05% FA in Water, Mobile Phase-B: 0.05% FA in Acetonitrile, Column Temperature: 50°C, Flow Rate: 0.5 mU min, Gradient: 0 / 5, 1 / 5, 6 / 90, 10 / 90, 10.5 / 5, 13 / 5, Diluent: ACN: Water (80: 20).

[0884] Method H: Column: BAKERBOND (1.8um C18,100 mm X 2.1 mm), Mobile Phase-A: 0.05% TFA in Water, Mobile Phase-B: 0.05% TFA in Acetonitrile, Column Temperature: 50°C, Flow Rate: 0.5 ml / min, Gradient: 0 / 5, 1 / 5, 6 / 90, 8.5 / 90, 8.8 / 5, 11 / 5, Diluent: ACN: Water.

[0885] Method I: Column: BAKERBOND (1 ,8um C18.100 mm X 2.1 mm), Mobile Phase-A: 0.05% TFA in Water, Mobile Phase-B: 0.05% TFA in Acetonitrile, Column Temperature: 50°C, Flow Rate: 0.5 ml / min, Gradient: 0 / 5, 1 / 5, 6 / 90, 10 / 90, 10.5 / 5, 13 / 5., Diluent: ACN: Water.

[0886] Prep-HPLC

[0887] Method A: Column: X-SELECT CSH C18(250*30mm),5um; Mobile Phase A: 10mM Ammonium bicarbonate in Water; Mobile Phase B: Acetonitrile; Flow rate: 25 ml / min; Gradient (Time / %B): 0 / 2,3 / 2,10 / 10,40 / 50; Sample diluent: ACN+H2O+DMSO.

[0888] Method B: Column: X-TIMATE C18 (19*250 mm), 5um; Mobile Phase A: 0.1% Formic Acid in Water; Mobile Phase B: Acetonitrile; Flow rate: 18 ml / min; Gradient (Time / %B): 0 / 10,3 / 10,10 / 25,22 / 30,30 / 35; Sample diluent: ACN+ H2O.

[0889] Method C: Column: YMC C18 (250*20) *5U; Mobile Phase A: 0.1% TFA in Water; Mobile Phase B: Acetonitrile; Flow rate: 15 ml / min; Gradient (Time / %B): 0 / 10,3 / 1010 / 30,40 / 45; Sample diluent: ACN+H2O+THF+DMSO.

[0890] Method D: Column: X-BRIDGE C18 (150*19 mm); 5um; Mobile Phase A: 0.1% TFA in Water; Mobile Phase B: Acetonitrile; Flow rate: 16 ml / min; Gradient (Time / %B): 0 / 10,3 / 10,10 / 25,20 / 30,30 / 40,31 / 98,35 / 98,36 / 10,40 / 10; Sample diluent: ACN+H2O.

[0891] Example 1 : 2-((2S.3S.4S)-2-((((1R.4S)-4-((2-aminoethv0carbamovncvclohexyl)amino) methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihvdrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide (Compound 1)

[0892] Step 1 : tert-Butyl (2-((1S,4R)-4-((((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5- chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-1- carboxamido)ethyl)carbamate (Compound 1a)

[0893] To a stirred solution of (1 S,4R)-4-((((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5- chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-1 -carboxylic acid (prepared as disclosed in W02023031801 A1 ; 200 mg, 0.34 mmol) in DMF (2 mL) was added DIPEA

[0894] (0.15 mL, 0.85 mmol) followed by HATU (0.2 g, 0.51 mmol) at 0 °C. After 5 min, tert-butyl (2- aminoethyl)carbamate (0.06 g, 0.4 mmol) was added and stirring at RT was continued for 16 h. The reaction progress was monitored by TLC. After completion, to the reaction mixture was added cold water and the resultant solid was filtered and dried under vacuum to afford the title compound (200 mg, 80.4%) as an off white solid.

[0895] LCMS: 727.4 [M+H]+; 98% at RT = 1.23 min (method D).

[0896] Step 2: 2-((2S,3S,4S)-2-((((1 R,4S)-4-((2-aminoethyl)carbamoyl)cyclohexyl)amino)methyl) -5- chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy benzamide

[0897] (Compound 1)

[0898] To a stirred solution of tert-butyl (2-((1S,4r)-4-((((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3- methoxyphenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-1 -carboxamido)ethyl)carbamate (180 mg, 0.25 mmol) in DCM (3 ml) was added 4 M HCI in dioxane (2.0 mL, 8 mmol) at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 12 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford HCI salt of compound 1 (150 mg, 96.6%) as an off white solid.

[0899] 1H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.53 (m, 1 H), 8.24 - 7.94 (m, 5H), 7.84 - 7.71 (m, 1 H), 7.64 - 7.48 (m, 3H), 7.46 - 7.34 (m, 3H), 7.32 - 7.22 (m, 1 H), 7.19 - 7.04 (m, 2H), 3.97 - 3.77 (m, 3H), 3.66 - 3.46 (m, 1 H), 3.27 - 3.18 (m, 2H), 3.04 - 2.75 (m, 2H), 2.15 - 1.97 (m, 2H), 1.81 (d, J = 3.1 Hz, 2H), 1.44 - 1.19 (m, 6H), 0.94 (d, J= 7.1 Hz, 3H). LCMS: 627.4 [M+H]+; 96.87% at RT = 1.75 min (Method E).

[0900] HPLC: 95.44% at RT = 4.06 min (Method H).

[0901] The compounds shown in Tables 2 and 4 were synthesized using analogous procedures starting from (1S,4R)-4-((((2S,3S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-methyl-2- phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-1 -carboxylic acid or (1S,4R)-4- ((((2S,3S,4R)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-1 -carboxylic acid, as appropriate.

[0902] Table 2: Compounds 2a to 16a, 18a to 26a, 27, 28a, 29, 30a to 33a

[0903] Table 3: Yields and analytical data for compounds 2a to 16a, 18a to 26a, 27, 28a, 29, and 30a toa

[0904] Table 4: Compounds 2 to 16, 18 to 26

[0905] Table 5: Yields and analytical data for compounds 2 to 16, 18 to 26 and 28

[0906] Table 6: Additional analytical data for compounds 2, 15, 21 to 23 and 26

[0907] Example 2: (S)-2-((2S.3SH5-chloro-6-fluoro-3-methyl-2-((((1 r.4S)-4-((4-oxobutyl)carbamovh cvclohexyl)amino)methyl)-2-phenyl-2,3-dihvdrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide

[0908] (Compound 17)

[0909] To a stirred solution of (S)-2-((2S,3S)-5-chloro-6-fluoro-2-((((1r,4S)-4-((4- hydroxybutyl)carbamoyl)cyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-methoxybenzamide (Compound 29; 25 mg, 0.038 mmol) in DCM (5 mL) was added Dess-Martin Periodinane (0.32 g, 0.76 mmol) at 0°C. The reaction mixture was slowly allowed to warm to room temperature and stirred for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with aq. NaHCOs and extracted with DCM (2 x 20 mL). Combined organic layer was washed with brine, dried over anhydrous NazSCU, filtered and the filtrate was concentrated under reduced pressure. The crude compound was further purified by prep HPLC (Method D) to afford TFA salt of (S)-2-((2S,3S)-5-chloro-6-fluoro-3-methyl-2-((((1r,4S)-4-((4- oxobutyl)carbamoyl)cyclohexyl)amino) methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide (Compound 17; 3.0 mg, 12%) as a pale brown solid. LCMS: 654.0 [M+H]+; 80.69% at RT = 3.37 min (Method J).

[0910] HPLC: 76.57% at RT = 4.04 min (Method G).

[0911] Example 3: 2-((2S,3S)-5-chloro-6-fluoro-2-((((1RS,4SR)-4-((RS)-3-formylpyrrolidine-1- carbonyl)cvclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihvdrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide (Compound 30)

[0912] 2-((2S,3S)-5-chloro-2-((((1 SR,4SR)-4-(3-(dimethoxymethyl)pyrrolidine-1- carbonyl)cyclohexyl)amino)methyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide (Compound 30a, 8 mg, 0.011 mmol) was dissolved in formic acid (1 mL) and the resulting mixture was heated at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure. Purification by prep-HPLC (Method A, FA buffer) to afford 2-((2S,3S)-5-chloro-6-fluoro-2- ((((1 RS,4SR)-4-((RS)-3-formylpyrrolidine-1 -carbonyl)cyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (2.87 mg, 38.4% yield) as a pale yellow sticky solid.

[0913] LCMS: 666.0 [M+H]+& 684.0 [M+H+18]+; 87.1% at RT = 3.33 min (Method-E).

[0914] HPLC: 86.4% at RT = 4.34 min (Method-F).

[0915] The compounds shown in Tables 7 and 8 were synthesized using analogous procedures from the starting material listed in the tables.

[0916] Table 7: Compounds 31 to 33

[0917] Table 8: Yields and analytical data for compounds 31 to 33

[0918] Table 9: Additional analytical data for compound 33

[0919] Example _ 4: _ (S)-2-((2S.3S)-2-(((1-(5-amino-4.4-difluorooentanoyl)piperidin-4- yl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2.3-dihvdrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide (Compound 34)

[0920]

[0921] Step-1 : (S)-2-((2S,3S)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3-dihydrobenzofuran-

[0922] 4-yl)-3-fluoro-4-methoxybenzonitrile

[0923] To a stirred solution of oxalyl chloride (0.05 mL, 0.6088 mmol) in DCM (2 mL) at -78 °C was added DMSO (0.09 mL, 1.22 mmol) and the resulting mixture was stirred for 5 min. A solution of 2-[(2S,3S)-5- chloro-6-fluoro-2-(hydroxymethyl)-3-methyl-2-phenyl-3H-benzofuran-4-yl]-3-fluoro-4-methoxy- benzamide (prepared as disclosed in W02023031801 A1 ; 70.0 mg, 0.15 mmol) in DCM (2 mL) was added at the same temperature. After 30 min, triethylamine (0.25 mL, 1 .83 mmol) was added, and the reaction was continued at -78 °C for another 1 h and at 0 °C for 30 min. Ice-cold water (5 mL) was added, and the reaction mixture was extracted with DCM (2 x 5 mL). The combined organic layers were dried over NazSCU, filtered and concentrated to afford (S)-2-((2S,3S)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzonitrile (65 mg, 93%) as an off-white solid. The aldehyde was taken to the next step without further purification.

[0924] Step-2: tert-butyl (5-(4-((((2S,3S)-5-chloro-4-((S)-6-cyano-2-fluoro-3-methoxyphenyl)-6- fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)piperidin-1-yl)-2,2-difluoro-5- oxopentyl)carbamate

[0925] To a stirred solution of (S)-2-((2S,3S)-5-chloro-6-fluoro-2-formyl-3-methyl-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzonitrile (65 mg, 0.14 mmol) in 1 ,2-DCE (1 mL) at room temperature was added tert-butyl (5-(4-aminopiperidin-1-yl)-2,2-difluoro-5-oxopentyl)carbamate (Compd A, 99 mg, 0.29 mmol), acetic acid (2 drops), and 4 A molecular sieves (100 mg) and the resulting suspension was stirred for 16 h. Sodium triacetoxyborohydride (65 mg, 0.29 mmol) was added, and the reaction was continued for another 16 h at room temperature. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over NazSCU, filtered and concentrated. Purification by silica gel chromatography (EtOAc as eluent) afforded tert-butyl (5-(4- ((((2S,3S)-5-chloro-4-((S)-6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-yl)methyl)amino)piperidin-1-yl)-2,2-difluoro-5-oxopentyl)carbamate (60 mg, 53%) as an off-white solid.

[0926] LCMS: 759.35 [M+H]+, 99.5% at RT = 1.52 min (Method-D). Step-3: tert-butyl (5-(4-((((2S,3S)-4-((S)-6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6- fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)piperidin-1-yl)-2,2-difluoro-5- oxopentyl)carbamate

[0927] To a stirred solution of tert-butyl (5-(4-((((2S,3S)-5-chloro-4-((S)-6-cyano-2-fluoro-3- methoxyphenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)piperidin-1 -yl)- 2,2-difluoro-5-oxopentyl)carbamate (60 mg, 0.08 mmol) in 4:1 EtOH and water (6 mL) was added hydrido(dimethylphosphinous acid-kp)[hydrogen bis(dimethylphosphinito-kp)]platinum(ll) (3.5 mg, 0.008 mmol) at room temperature and the reaction mixture was heated to 80°C for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with EtOAc (10 mL). The organic layer was washed successively with saturated aqueous NaHCCh (3 mL) and saturated aqueous NaCI (3 mL). The organic layer was dried over NaaSCU, filtered and concentrated to afford tert-butyl (5- (4-((((2S,3S)-4-((S)-6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-yl)methyl)amino)piperidin-1-yl)-2,2-difluoro-5-oxopentyl)carbamate (50 mg, 72%).

[0928] LCMS: 777.38 [M+H]+, 88% at RT = 1.26 min (Method-D).

[0929] Step-4: (S)-2-((2S,3S)-2-(((1-(5-amino-4,4-difluoropentanoyl)piperidin-4-yl)amino)methyl)-5- chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound 34)

[0930] To a stirred solution of tert-butyl (5-(4-((((2S,3S)-4-((S)-6-carbamoyl-2-fluoro-3-methoxyphenyl)-5- chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)piperidin-1-yl)-2,2-difluoro- 5-oxopentyl)carbamate (50 mg, 0.064 mmol) in EtOAc (1 mL) at 0 °C was added HCI (0.64 mL, 0.64 mmol, 1 M in EtOAc) and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene. The resulting residue was washed with n-pentane (3 x 10 mL) and lyophilized to afford (S)-2-((2S,3S)-2-(((1-(5-amino-4,4- difluoropentanoyl)piperidin-4-yl)amino)methyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (30 mg, 64%) as a pale-yellow solid and as an HCI salt.

[0931] LCMS: 677.0 [M+H]+, 96% at RT = 1.89 min (Method-E).

[0932] HPLC: 97.8% at RT = 4.37 min (Method-C).

[0933] 1H NMR: (400 MHz, DMSO-d6) δ 7.63-7.55 (m, 2H), 7.44-7.39 (m, 2H), 7.35-7.22 (m, 4H), 7.10 (br s, 1 H), 7.06 (d, J = 8.8 Hz, 1 H), 4.04-3.90 (m, 1 H), 3.88 (s, 3H), 3.66-3.58 (m, 1 H), 3.24 (q, J = 7.2 Hz, 1 H), 3.18-3.10 (m, 2H), 3.00-2.75 (m, 4H), 2.42-2.35 (m, 2H), 2.15-2.02 (m, 2H), 1.72-1 .55 (m, 3 H), 1.12- 1 .02 (m, 2H), 0.93 (d, J = 7.2 Hz, 3H).

[0934] Example s: tert-butyl (5-(4-aminoDiDeridin-1-yl)-2,2-difluoro-5-oxoDentyl)carbamate (Compd A)

[0935]

[0936] Step-h Synthesis of tert-butyl 3, 3-difluoropiperidine-1 -carboxylate

[0937] To a stirred solution of tert-butyl 3-oxopiperidine-1 -carboxylate (1 .00 g, 5.02 mmol) in DCM (10 mL) at -78 °C was added diethylaminosulfur trifluoride (1 .40 mL, 10.04 mmol) dropwise and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was cooled to 0 °C and ice-cold water (5 mL) was added. Both the layers were separated, and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over NazSCU, filtered and concentrated. Purification by silica gel chromatography (using 50% EtOAc in heptane as eluent) afforded tert-butyl 3,3- difluoropiperidine-1 -carboxylate (700 mg, 63% yield) as a colourless oil.

[0938] 1H NMR: (CDCI3, 400 MHz) <53.62 (t, J = 11 .6 Hz, 2H), 3.41 (t, J = 5.2 Hz, 2H), 2.03-1 .92 (m, 2H), 1.77-1.70 (m, 2H), 1.46 (s, 9H).

[0939] Step-2\ Synthesis of tert-butyl 5, 5-difluoro-2-oxopiperidine-1 -carboxylate

[0940] To a stirred solution of sodium periodate (3.39 g, 15.8 mmol) in water (28 mL) was added ruthenium (IV) oxide (160 mg, 1.17 mmol). To this solution was then added a solution of tert-butyl 3,3- difluoropiperidine-1 -carboxylate (700 mg, 3.16 mmol) in EtOAc (49 mL) and the biphasic mixture was stirred vigorously at room temperature for 16 h. The reaction mixture was filtered through a pad of Celite by washing with EtOAc. The two layers were separated, and the organic layer was dried over NazSO4, filtered and concentrated. Purification by silica gel chromatography (using 40% EtOAc in heptane as eluent) afforded tert-butyl 5,5-difluoro-2-oxopiperidine-1 -carboxylate (660 mg, 89% yield).1H NMR: (CDCI3, 400 MHz) <53.98 (t, J = 12.4 Hz, 2H), 2.66 (t, J = 7.2 Hz, 2H), 2.39-2.27 (m, 2H), 1.53 (s, 9H).

[0941] Step-3: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-4,4-difluoropentanoate

[0942] To a stirred solution of tert-butyl 5,5-difluoro-2-oxopiperidine-1-carboxylate (660 mg, 2.80 mmol) in MeOH (7 mL) at 0 °C was added sodium methoxide (1 .04 mL, 5.61 mmol, 5.4 M in MeOH) and the resulting mixture was stirred at room temperature for 1 h. All the volatiles were evaporated under reduced pressure and the resulting crude residue was dissolved in EtOAc (10 mL). The organic layer was washed with aqueous HCI (5 mL, 1 M), brine (5 mL), dried over NazSCU, filtered and concentrated. Purification by silica gel chromatography (using 40% EtOAc in heptane as eluent) afforded methyl 5-((tert- butoxycarbonyl)amino)-4,4-difluoropentanoate (580 mg, 77% yield) as a colourless gummy oil.

[0943] 1H NMR: (CDCI3, 400 MHz) 54.85-4.67 (br s, 1 H), 3.69 (s, 3H), 3.58-3.45 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.30-2.12 (m, 2H), 1 .45 (s, 9H).

[0944] Step-4: Synthesis of 5-((tert-butoxycarbonyl)amino)-4,4-difluoropentanoic acid

[0945] To stirred solution of methyl 5-((tert-butoxycarbonyl)amino)-4,4-difluoropentanoate (500 mg, 1.87 mmol) in THF (10 mL) at room temperature was added solution of LiOH (137 mg, 5.61 mmol) in water (2 mL) and the reaction was continued for 3 h. THF was evaporated under reduced pressure and the resulting residue was diluted with water ( 10 mL) and acidified with aqueous HCI (1 M). The aqueous layer was repeatedly extracted with 5% MeOH in DCM (5 x 10 mL). The combined organic layers were dried over NasSO4, filtered and concentrated to afford 5-((tert-butoxycarbonyl)amino)-4,4-difluoropentanoic acid (350 mg, 74% yield) as a thick colourless oil.

[0946] LCMS: 254.13 [M+H]+; 99.4% at RT = 1.14 min (Method-D).

[0947] 1H NMR: (DMSO, 400 MHz) 6 12.25 (br s, 1 H), 7.29 (br s, 1 H), 3.40-3.29 (m, 2H), 2.38 (t, J = 7.6 Hz, 2H), 2.12-1.97 (m, 2H), 1 .36 (s, 9H).

[0948] Step-5: Synthesis of tert-butyl (2,2-difluoro-5-(4-((4-nitrophenyl)sulfonamido)piperidin-1-yl)- 5-oxopentyl)carbamate

[0949] To a solution of 5-((tert-butoxycarbonyl)amino)-4,4-difluoropentanoic acid (500 mg, 1.97 mmol) in DMF (10 mL) at room temperature was added HATU (1.18 g, 2.96 mmol), / V, / V-diisopropylethylamine (0.83 mL, 5.92 mmol) and the resulting mixture was stirred for 15 min. 4-Nitro-A / -(piperidin-4- yl)benzenesulfonamide (845 mg, 2.96 mmol) was added and the reaction mixture was stirred at the same temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH in DCM (2 x 30 mL). The combined organic layers were dried over anhydrous NazSO4, filtered and concentrated. Purification by silica gel chromatography (EtOAc as the eluent) afforded tert-butyl (2,2- difluoro-5-(4-((4-nitrophenyl)sulfonamido)piperidin-1 -yl)-5-oxopentyl)carbamate (650 mg, 63% yield) as a brown semi-solid.

[0950] LCMS: 521 .26 [M+H]+; 82% at RT = 1 .44 min (Method-D).

[0951] Step-6: Synthesis of tert-butyl (5-(4-aminopiperidin-1-yl)-2,2-difluoro-5- oxopentyl)carbamate

[0952] To a solution of tert-butyl (2,2-difluoro-5-(4-((4-nitrophenyl)sulfonamido)piperidin-1 -yl)-5- oxopentyl)carbamate (200 mg, 0.38 mmol) in DMF (3.00 mL) at room temperature were added potassium carbonate (80 mg, 0.57 mmol) and thiophenol (0.05 mL, 0.46 mmol) successively and the resulting mixture was stirred at the same temperature for 16 h. The reaction mixture was diluted with ice-cold water (5 mL) and filtered through a pad of Celite. The aqueous layer was washed with heptane (3 x 5 mL) to remove the non-polar impurities. The aqueous layer was extracted with EtOAc (3 x 10 mL), washed with brine (5 mL), dried over anhydrous NazSCH, filtered and concentrated to afford tert-butyl (5-(4-aminopiperidin-1-yl)-2,2- difluoro-5-oxopentyl)carbamate (70 mg, 54%) as a pale-yellow gummy oil. This compound was used as such in the next step without further purification.

[0953] LCMS: 336.35 [M+H]+; 96.8% at RT = 0.97 min (Method-D).

[0954] Synthesis of 4-nitro-M-(piperidin-4-yl)benzenesulfonamide:

[0955] Step-1 A: Synthesis of tert-butyl 4-((4-nitrophenyl)sulfonamido)piperidine-1-carboxylate

[0956] To a solution of tert-butyl 4-aminopiperidine-1 -carboxylate (2 g, 9.98 mmol) in DCM (20 mL) at room temperature was added A / ,A / -diisopropylethylamine (5.23 mL, 29.9 mmol) and 4-nitrobenzenesulfonyl chloride (3.32 g, 14.9 mmol) and the resulting mixture was stirred for 4 h. The reaction mixture was diluted with ice-cold water (10 mL), and both the layers were separated. The organic layer was dried over anhydrous NazSCL, filtered and concentrated. Purification by silica gel chromatography (using 30% EtOAc in heptane as eluent) afforded tert-butyl 4-((4-nitrophenyl)sulfonamido)piperidine-1 -carboxylate (3.85 g, 65%) as a pale-yellow gummy liquid.

[0957] LCMS: 330.22 [(M-56)+H]+; 93.9% at RT = 1.41 min (Method-D).

[0958] Step-2A: Synthesis of 4-nitro-A / -(piperidin-4-yl)benzenesulfonamide

[0959] To a solution of tert-butyl 4-((4-nitrophenyl)sulfonamido)piperidine-1-carboxylate (1 .00 g, 2.6 mmol) in DCM (20 mL) at room temperature was added HCI (5.2 mL, 20.8 mmol, 4 M in dioxane) and the resulting mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford 4- nitro-A / -(piperidin-4-yl)benzenesulfonamide (600 mg, 81%) as a HCI salt.

[0960] LCMS: 286.52 [M+H]+; 97.5% at RT = 0.69 min (Method-D).

[0961] Example 6: Degradation of TEAD

[0962] Compound dilutions

[0963] Stock solutions of compounds were prepared at a concentration of 10 mM in DMSO and stored at -20°C. Stock solutions were pre-diluted in DMSO to 1000-fold the desired top start concentration, as required. Dilution series were prepared in DMSO from this top concentration for a 10-point dose response. Compounds were dispensed directly into cell assay plates using the FlexDrop iQ Non-contact Dispenser (Revvity). The final concentration of DMSO was 0.1% in all wells.

[0964] Cell Culture

[0965] NCI-H226 cells were maintained in RPMI (Gibco, #12027599) containing 10% FBS (Gibco, #17479633). For immunofluorescence assays, cells were seeded in phenol-red free RPMI (Gibco, #11835030) containing 10% FBS (Gibco, #17479633), unless otherwise stated. Parental and FBXO22 KO HeLa cells were maintained in DMEM (Gibco, #12077549) containing 10% FBS (Gibco, #17479633). For immunofluorescence assays, cells were seeded in phenol-red free DMEM (PAN Biotech, #P04-03591 ) containing 10% FBS (Gibco, #17479633), unless otherwise stated.

[0966] Immunofluorescence assay

[0967] TEAD1 degradation was assessed using NCI-H226 cells (as described above) by quantifying TEAD1 protein levels via an immunofluorescence assay. Briefly, NCI-H226 cells were seeded at 2,000 cells / 50 pil / well in sterile black-walled, optically clear bottom 384-well PhenoPlates (Perkin Elmer, Cat#6057300) and incubated overnight at 37°C and 5% CO2 prior to addition of compounds the following day, as described above. After compound dosing, cell plates were incubated for 24 hours at 37°C and 5% CO2. To stain for TEAD1 , cells were fixed with 4% paraformaldehyde v / v then blocked prior to incubation with anti-TEAD1 primary antibody (BD, Cat#610923) at 4°C overnight. The following day, secondary antibody (Invitrogen, Cat#A-11001) and Hoechst 33342 (Abeam, Cat#ab228551 ) were incubated for 1 hour. To measure TEAD1 protein levels, plates were imaged with the Operetta CLS High-Content Analysis System (Revvity). Image analysis was based on cellular fluorescent TEAD1 signal in individual cell nuclei, as identified by the Hoechst stain. TEAD1 protein levels were determined by mean fluorescent intensity. The effect of compounds on TEAD1 protein levels was normalised to cells treated with vehicle only (0.1% DMSO) and stained with the TEAD1 primary antibody (set at 100%) and TEAD1 protein levels in cells that were not stained with the TEAD1 primary antibody (set at 0%). DMAX was determined by calculating 100 - YMIN, and DC50 values were determined using a standard four parameter curve fitting.

[0968] TEAD degradation results

[0969] The degradation of TEAD was detected according to the procedure outlined above for a number of exemplary compounds of the invention. The results are shown in Table 10. In particular, the table shows the DMAX and DC50 of indicated example compound at 24 h of treatment.

[0970] Table 10: Degradation of TEAD

[0971] Example 7: Degradation of TEAD

[0972] Pan-TEAD Western blot

[0973] NCI-H226 cells were seeded at 250,000 cells per well (2 ml) in transparent 6-well plates (Greiner BioOne, #657160) and incubated overnight at 37°C and 5% COa. The next day, compounds were prepared as described in Example 8 below at 1000x concentration then cells were treated with 2 pl compound / well and incubated for 24 hours at 37°C and 5% CO2. To detect TEAD1 , cells were lysed in RIPA buffer containing protease inhibitor. Proteins were resolved by SDS-PAGE then transferred onto nitrocellulose membrane. Following blocking in 5% BSA, membranes were incubated with anti-pan-TEAD primary antibody (CST, Cat#13295) at 4°C overnight. The following day, secondary antibody (BioRad, Cat#12004162) and hFAB GAPDH loading control antibody (BioRad, Cat#1200416) were incubated for 1 hour. To measure pan-TEAD and loading control protein levels, membranes were imaged with the ChemiDoc Imaging System. Data were normalised to the loading control and relative to DMSO.

[0974] The resulting Western blot is shown in Figure 1 .

[0975] Example 8: Various methods for Examples 9 to 12

[0976] A series of experiments were conducted to establish the mechanism of degradation facilitated by compounds of formula (I), as described in Examples 9 to 12 below. Many of the Examples 9 to 12 provide data comparing the activity of certain compounds of the invention to compounds 25 to 29. Compounds 25 to 29 are provided in Table 11 below.

[0977] Table 11 : Compounds 25, 26 and 27 to 29

[0978] Many of Examples 9 to 12 also use the same or similar methods. Therefore, general methods for various aspects are provided below and referenced in subsequent Examples 9 to 12. Cell culture

[0979] NCI-H226 cells were grown in RPMI containing 10% FBS while HeLa (parental and FBXO22 KO) were grown in DMEM containing 10% FBS. For experiments completed in the absence of serum, NCI-H226 were cultured in RPMI containing 10% FBS prior to experimental set-up. Upon experimental set-up, cells were detached and diluted in DMEM without serum (-). NCI-H226 were then centrifuged, media removed and re-suspended in DMEM (-).

[0980] Compound management

[0981] Stock solutions of compounds of formula (I) were prepared at a concentration of 10 mM in DMSO and stored at -20°C. Stock solutions were pre-diluted in DMSO to 1000-fold the desired top start concentration, as required. Amino guanidine hydrochloride (Sigma, Cat#396494) was prepared fresh for each use by re-suspending at a concentration of 15 mM in RPMI containing 10% FBS.

[0982] For immunofluorescence, compounds of formula (I) were prepared in a dilution series in DMSO from a top concentration for a 10-point dose response. Compounds were then dispensed directly into cell assay plates using the FlexDrop iQ Non-contact Dispenser (Revvity), and incubated for 24 hours prior to completion of the immunofluorescence protocol. The final concentration of DMSO was 0.1% in all wells.

[0983] For Western blotting, compounds of formula (I) were prepared in DMSO while aminoguanidine was prepared in media in a serial dilution. Compounds of formula (I) were dispensed into cell assay plates manually for co-treatment with aminoguanidine, and incubated for 24 hours prior to completion of the Western blotting protocol. The final concentration of DMSO was 0.1% in all wells.

[0984] Cell seeding, treatment and transfection

[0985] To assess TEAD1 degradation in the presence or absence of FBXO22 or serum, TEAD1 levels were assessed by quantifying protein levels via an immunofluorescence or Western blot assay. Cells were seeded according to Table 12 for immunofluorescence, in black-walled optically clear bottom 384-well PhenoPlates (PerkinElmer, Cat#6057300) or for Western blotting in 6-well plates. Following incubation overnight at 37°C and 5% CO2, compound addition was undertaken. After compound dosing, cell plates were incubated at 37°C and 5% COsfor 6 hours when assessing activity in the presence or absence of serum, or 24 hours for all other experiments.

[0986] To confirm whether cysteine (Cys) 326 is involved in FBXO22 interaction, FBXO22 KO HeLa cells were seeded in 10 cm dishes, then the day after seeding, the transfection mix with plasmids in Table 13 was set up in Opti-MEM (Life Technologies, Cat#11058021 ) using Lipofectamine 3000 (Invitrogen, Cat#L3000015) and incubated with the cells. The next day, cells were re-seeded at 2,000 or 4,000 cells / 50 pl / well, for mock or DNA-transfected cells, in black-walled optically clear bottom 384-well PhenoPlates (PerkinElmer, Cat#6057300). Cells were treated with compounds 24 hours after re-seeding. Cell plates were then incubated at 37°C and 5% CO2 for 24 hours.

[0987] Table 12: cell seeding densities

[0988] Table 13: plasmids used for transfections

[0989] TEAD1 immunofluorescence assay

[0990] To stain for TEADI , cells were fixed with 4% paraformaldehyde v / v then blocked prior to incubation with TEAD1 primary antibody (BD, Cat#610923) at 4°C overnight. The following day, secondary antibody (Invitrogen, Cat#A-11001) and Hoechst 33342 (Abeam, Cat#ab228551 ) were incubated for 1 hour. To measure TEAD1 protein levels, plates were imaged with the Operetta CLS High-Content Analysis System (Revvity). Image analysis was based on cellular fluorescent TEAD1 signal in individual cell nuclei, as identified by the Hoechst stain. TEAD1 protein levels were determined by mean fluorescent intensity. The effect of compounds on TEAD1 protein levels was normalised to cells treated with vehicle only (0.1% DMSO) and stained with the TEAD1 primary antibody (set at 100%) and TEAD1 protein levels in cells that were not stained with the TEAD1 primary antibody (set at 0%). DMAX was determined by calculating 100 - YMIN, and DCso values were determined using a standard four parameter curve fitting.

[0991] TEAD1 and FBXO22 immunofluorescence assay

[0992] For experiments to confirm which cysteine residue is involved in the FBXO22 interaction, the anti- TEAD1 antibody above was multiplexed with the primary rabbit anti-FLAG antibody (Cell Signalling Technology, Cat#14793). The following day, secondary antibodies (Invitrogen, Cat#A-11001 and (Invitrogen, Cat#A-21244) and Hoechst 33342 (Abeam, Cat#ab228551 ) were incubated for 1 hour. To measure TEAD1 protein levels in cells transfected with FBXO22 constructs, image analysis was based on cellular fluorescent TEAD1 signal in individual cell nuclei, identified by the Hoechst stain, where also the fluorescent signal for FLAG-FBOX22 was present. Degradation was considered rescued when a doseresponse curve could be visualised in FBXO22 KO HeLa cells transfected with FLAG-FBXO22 or FLAG- FBXO22-C326A. The activity of the degrader was considered not-rescued when no dose-response curve could be visualised.

[0993] Example 9: Binding to TEAD1

[0994] In vitro biochemical FRET assay

[0995] His-human TEAD1 (209-426) (6nM) and GST-YAP1 (50-171 ) (6mM) were pre-incubated with an 11 -point serial dilution of compound (highest concentration 10 pM, 3-fold dilution, final DMSO concentration of 1%) in 1X PBS, pH 7.4, 0.1% BSA, 5mM DTT in white 384-well microplates (PerkinElmer) for 30 minutes at room temperature. An equal volume of pre-mixed Anti-his Tb Gold (Cisbio) and anti-GST-d2 (Cisbio) in PPI terbium detection buffer (Cisbio) was then added to above-described mixture and incubated for 2 hours at room temperature. Fluorescence was measured on a PerkinElmer EnVision 2104 Multilabel Reader. The IC50 values were estimated by fitting the data by nonlinear fit regression (GraphPad Prism).

[0996] Table 14: TEAD1 binding results for various compounds

[0997] Example 10: Determination of amine oxidation to drive degradation

[0998] To determine that the active compound is that wherein R9is an aldehyde, and that the oxidation of R9from the amine to the aldehyde occurs outside of the cell by an amine oxidase was established by treatment with a pan amine oxidase inhibitor, amino guanidine (AG). In the presence of this inhibitor degradation was markedly reduced (Table 15).

[0999] To assess whether TEAD1 was degraded in the presence of amino guanidine, NCI-H226 cells were seeded at 300,000 cells per well (2 ml) in transparent 6-well plates (Greiner BioOne, #657160) and incubated overnight at 37°C and 5% CO2. Amino guanidine hydrochloride (Sigma, Oat#396494) was prepared fresh for each use by re-suspending at a stock concentration of 15 mM in RPMI containing 10% FBS, while remaining compounds were prepared as above in Example 8 at 10OOx concentration. NCI-H226 cells were co-treated with amino guanidine for the appropriate concentration and 2 pl compound 2 then incubated for 24 hours at 37°C and 5% CO2. Cell lysis and Western blotting was completed as above in Example 8 for pan-TEAD (Example 9) however, here an anti-TEAD1 primary antibody (CST Cat#12292S) was used in the manner previously described for Western blotting. Data were normalised to the loading control and relative to a no aminoguanidine control enabling DMAX (%) to be calculated.

[1000] Table 15: TEAD1 degradation in the NCI-H226 in the presence of amino guanidine following compound addition

[1001] Extra-cellular degradation was established by running an assay in the absence of serum. Although run at a shorter timepoint (6 hrs), degradation was not observed when compounds of formula (I) wherein R9is an amine were used to facilitate degradation, but was observed when compounds of formula (I) wherein R9is an aldehyde were used to facilitate degradation. This indicates that degradation is mediated by an extra-cellular amine oxidase present in the serum, and that oxidation of the amine to an amine is required to form the active species (Table 16).

[1002] To determine TEAD1 degradation in the presence or absence of serum, NCI-H226 cells were prepared in RPMI media + or - 10% fetal bovine serum (FBS). NCI-H226 prepared + / - FBS were then seeded at 2,000 cells per well (50 pl) in sterile black transparent bottom 384-well plates (PerkinElmer #6057300) and incubated overnight at 37°C and 5% CO2. The next day, compounds were prepared as above in Example 8 at 1000x concentration then cells were treated using the FlexDrop iQ non-contact dispenser (PerkinElmer). Cells were incubated with compounds for 6 hours at 37°C and 5% CO2. Fixation and staining was completed as described in the TEAD1 immunofluorescence assay outlined above.

[1003] Table 16: TEAD1 degradation in the NCI-H226 in the presence (+) or absence (-) of serum following compound addition (6h)

[1004] Example 11 : Determination of FBXO22 mediated degradation

[1005] FBXO22 dependence was established by screening compounds in HeLa cells. Using HeLa parental FBXO22 wild-type (WT) and HeLa FBXO22 knockout (KO) cells, it was shown that a series of amines and aldehydes facilitate degradation of TEAD in the FBXO22 WT cell line but not in the FBXO22 KO cell lines (Table 17). This establishes that FBXO22 is indeed the E3 ligase that is recruited by the compounds of formula (I) resulting in the degradation of TEAD for compounds of formula (I). Where R9was modified in a way which falls outside of the present claims, and would prevent oxidation to an aldehyde, degradation of TEAD was prevented.

[1006] FBXO22 KO HeLa

[1007] Parental and FBXO22 KO HeLa cells were seeded at 1 ,500 and 2,000 cells / 50 pl / well respectively (50 pl) in sterile black transparent bottom 384-well plates (PerkinElmer #6057300) and incubated overnight at 37°C and 5% CO2. The next day, compounds were prepared as above in Example 8 at 1000x concentration then cells were treated using the FlexDrop iQ non-contact dispenser (PerkinElmer). Cells were incubated with compounds for 24 hours at 37°C and 5% CO2. TEAD1 staining was then carried out as described in the TEAD1 immunofluorescence assay section above. When a dose response was observed in the parental cells but no dose-response curve could be measured in the FBXO22 KO cells, the activity of the compound was determined to be mediated by FBXO22 E3 ligase.

[1008] Table 17: TEAD1 degradation in the parental HeLa and FBXO22 KO HeLa cell lines following compound addition (24h)

[1009] Example 12: Determination of interacting cysteine residue

[1010] It was confirmed the FBXO22 cysteine that interacts with the compounds of formula (I) is the cysteine residue at a position corresponding to residue 326 of SEQ ID NO: 1 . This was done by a rescue experiment in the HeLa FBXO22 KO cells. When FBXO22 WT was re-expressed in the HeLa cells degradation was rescued. When attempts to rescue degradation were made using a C326A FBXO22 mutant, however, degradation was not rescued. This indicates that cysteine residue at a position corresponding to residue 326 of SEQ ID NO: 1 is the key cysteine involved in the interaction of FBXO22 and the compounds of formula (I) (Table 18).

[1011] FBXO22 KO HeLa cells were seeded at 2,500,000 cells in a 10 cm dish (ThermoFisher Scientific, Cat#734-2043) and incubated overnight at 37°C and 5% CO2. Cells were transfected by addition of 1 ml mixture of optiMEM containing 15 pg FLAG-FBXO22 constructs (WT or C326A) and lipofectamine 3000 and P3000 reagent (Invitrogen, Cat# L3000015) or lipofectamine and P3000 reagent only (mock transfection). The next day, mock transfected and DNA-transfected FBXO22 KO HeLa cells were seeded at 2,000 and 4,000 cells per well respectively (50 pl) in sterile poly-D-lysine black transparent bottom 384- well plates (PerkinElmer #6057500) and incubated overnight at 37°C and 5% CO2.

[1012] The next day, compounds were prepared as above at 1000x concentration then cells were treated using the FlexDrop IQ non-contact dispenser (PerkinElmer). Cells were incubated with compounds for 24 hours at 37°C and 5% CO2. Cells were then fixed with 4% paraformaldehyde v / v then blocked prior to incubation with anti-TEAD1 primary antibody (BD, Cat#610923) and anti-FLAG antibody (Cell Signaling Technology, Cat#14793) at 4°C overnight.

[1013] The following day, secondary antibodies (Invitrogen, Cat#A-11001 and Invitrogen, Cat#A-21244) and Hoechst 33342 (Abeam, Cat#ab228551 ) were incubated for 1 hour. Plates were imaged with the Operetta CLS High-Content Analysis System (Revvity). Image analysis was based on cellular fluorescent TEAD1 signal in FLAG-positive cells, as identified by the 647 AlexaFluor stain. TEAD1 protein levels were determined by mean fluorescent intensity. The effect of compounds on TEAD1 protein levels was normalised to cells treated with vehicle only (0.1% DMSO) and stained with the TEAD1 primary antibody (set at 100%) and TEAD1 protein levels in cells that were not stained with the TEAD1 primary antibody (set at 0%).

[1014] Degradation was considered rescued when a dose-response curve could be visualised in transfected cells while the activity of the degrader was considered not to be rescued if this dose response was not observed.

[1015] Table 18: TEAD degradation in presence of FBXO22 WT, FBXO22 KO and FBXO22 C326A transfection

[1016] Ternary complex formation

[1017] 10 pM recombinant human TEAD1 (209-426) was incubated in 50mM Tris pH 7.5, 200mM NaCI, 1 mM TCEP in the presence or absence of 20 pM 33 at 4°C for 2 hours, followed by addition of 10 pM recombinant SKP1 (1 -163) / FBXO22 (13- 403) and incubation at 4°C overnight. Protein complexes were fractionated and detected at UV 280nm by HPLC on a Superdex 200 increase 5 / 150 GL (GE) column (on Agilent 1260 Infinity) and. Representative fractions were collected and visualised by SDS_PAGE (A) in the absence of compound and (B) in the presence of 33. The resulting SDS-PAGE is shown in Figure 2.

[1018] Example 13: FBXO22 Sequence The protein sequence of human F-box only protein 22 (FBXO22) as described herein is provided in Table 19.

[1019] Table 19: Protein sequence of human F-box only protein 22 (FBXO22)

Claims

CLAIMS1. A compound of formula (I),or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a is 0 to 4; b is 0 or 1 ; c is 0 to 5;A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and O, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl, 3- to 7-membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl, wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and 0, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy;G2is selected from -NR10-, -CO-, -CO2-, -00(0)0-, -CONR11-, -NR12CO-, -OC(O)NR13-, - NR14C(O)O-, -NR15C(O)NR15-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and 0, wherein when G2is - CO2-, -0C(0)0-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;G3is C(R19)2; each G4is independently selected from O, NR20or C(R21)z, wherein if c is selected from 2 to 5, then adjacent instances of G4may not both be O and / or NR20;R1is selected from halogen and methyl;R2is selected from halogen and methyl;R3is selected from halogen and methyl;R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;R5is CN or CON(R22)2;R6is selected from H and C1-C3 alkyl;R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;R9is selected from, wherein the wavy line intersects the bond between R9and the rest of the compound;R10is selected from H and C1-C4 alkyl;R11is selected from H and C1-C4 alkyl;R12is selected from H and C1-C4 alkyl;R13is selected from H and C1-C4 alkyl;R14is selected from H and C1-C4 alkyl;R15is selected from H and C1-C4 alkyl;R16is selected from H and C1-C4 alkyl;R17is selected from H and C1-C4 alkyl;R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, -CN, and C1-C4 alkoxy;R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, andC1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and 0; or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1- C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl;R23Is H;R24is H; andX1is selected from CH and N.

2. A compound of formula (I),or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a is 0 to 4; b is 0 or 1 ; c is 0 to 5;A is selected from phenyl and 5- or 6-membered heteroaryl, wherein said phenyl is optionally substituted with halogen or C1-C3 haloalkoxy, and wherein said heteroaryl comprises one or more heteroatoms selected from N, S and O, and is optionally substituted with =0, -OH, or C1-C3 alkoxy;G1is selected from C3-C6 cycloalkanediyl, C7-C11 bicyclic cycloalkanediyl (including spiro- and fused bicyclic cycloalkanediyls), 3- to 7-membered heterocycloalkanediyl and 7- to 12-membered bicyclic heterocycloalkanediyl (including spiro- and fused bicyclic heterocycloalkanediyls), wherein said heterocycloalkanediyl and bicyclic heterocycloalkanediyl comprises one or more heteroatoms selected from the group consisting of N, S and O, and wherein said cycloalkanediyl, heterocycloalkanediyl, bicycloalkanediyl and bicyclic heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy;G2is selected from -NR10-, -CO-, -CO2-, -0C(0)0-, -CONR11-, -NR12CO-, -OC(O)NR13-, - NR14C(O)O-, -NR15C(O)NR15-, -SO2-, -NR17S(O)2-, -S(O)2NR18-, and 5-membered heteroarylene, wherein the hetereoarylene comprises one or more heteroatoms selected from N, S and O, wherein when G2is - CO2-, -0C(0)0-, -NR14C(O)O-, or -NR17S(O)2-, then b is 1 ;G3is C(R19)2; each G4is independently selected from O, NR20or C(R21)p, wherein if c is selected from 2 to 6 (e.g. from 2 to 5), then adjacent instances of G4may not both be 0 and / or NR20;;R1is selected from halogen and methyl;R2is selected from halogen and methyl;R3is selected from halogen and methyl;R4is selected from C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4alkoxy-C1-C4alkoxy, wherein the alkoxy is optionally substituted by -OH;R5is CN or CON(R22)2;R6is selected from H and C1-C3 alkyl;R7is selected from H and C1-C4 alkyl; each R8is independently selected from H and C1-C4 alkyl;R9is selected from, wherein the wavy line intersects the bond between R9and the rest of the compound;R10is selected from H and C1-C4 alkyl;R11is selected from H and C1-C4 alkyl;R12is selected from H and C1-C4 alkyl;R13is selected from H and C1-C4 alkyl;R14is selected from H and C1-C4 alkyl;R15is selected from H and C1-C4 alkyl;R16is selected from H and C1-C4 alkyl;R17is selected from H and C1-C4 alkyl;R18is selected from H and C1-C4 alkyl; each R19is independently selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and alkoxy is optionally substituted with one or more groups selected from halogen, -OH, -CN, and C1-C4 alkoxy;R20is selected from H and C1-C4 alkyl; each R21is independently selected from H, halogen, -OH, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or R11and one instance of R19or R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N; or one instance of R19and one instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 alkoxy; or two R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl or a 3- to 7-membered heterocycloalkanediyl comprising one or more heteroatoms selected from the group consisting of N, S and O, wherein said cycloalkanediyl and heterocycloalkanediyl are each optionally substituted with one or more groups independently selected from halogen, -OH, -CN, C1-C4 alkyl, and C1- C4 alkoxy; each R22is independently selected from H and C1-C4 alkyl;R23is selected from H, C1-C4 alkyl, and -CO-C1-C4-alkyl;R24is selected from H and C1-C4 alkyl; andX1is selected from CH and N.

3. The compound of claim 1 or 2, wherein a is 0.

4. The compound of any one of claims 1 to 3, wherein b is 1 .

5. The compound of any one of claims 1 to 4, wherein A is phenyl optionally substituted with halogen or C1-C3 haloalkoxy.

6. The compound of any one of claims 1 to 5, wherein G1is:wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

7. The compound of any one of claims 1 to 6, wherein G1is:wherein * indicates the position that is attached to G2, and the wavy line intersects the bond between G1and the rest of the compound.

8. The compound of any one of claims 1 to 7, wherein G2iswherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

9. The compound of any one of claims 1 to 8, wherein G2iswherein the wavy line intersects the bond between G1and G2, and * indicates the position that is attached to G3.

10. The compound of any one of claims 1 to 9, wherein each G4is independently selected from O and C(R21)2.11 . The compound of any one of claims 1 to 10, wherein R1, R2and R3are each independently selected from halogen.

12. The compound of any one of claims 1 to 11 , wherein R4is selected from C1-C4 alkoxy and C1- C+alkoxy-Ci-C+alkoxy, each optionally substituted by -OH.

13. The compound of any one of claims 1 to 12, wherein R4is selected from C1-C4 alkoxy.

14. The compound of any one of claims 1 to 13 wherein R6is selected from C1-C3 alkyl.

15. The compound of any one of claims 1 to 14, whereinR7is H; and each R8is H.

16. The compound of any of claims 1 to 15 wherein R10, R12, R13, R14, R15, R16, R17and R18are each H.

17. The compound of any one of claims 1 or 3 to 16, whereinR1 1is selected from H and C1-C4 alkyl; each R19is H or halogen;R20is selected from H, halogen, and C1-C4 alkyl ; each R21is independently selected from H and C1-C4 alkyl; or R11and one instance of R21, together with the atoms to which they are connected, form a 4- to 6-membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and 0; or or one instance of R19and one instance of R21, together with the atoms to which they are connected, form cyclobutanediyl.

18. The compound of any one of claims 1 to 17, wherein one instance of R22is H and the other is selected from H and C1-C4 alkyl.

19. The compound of any one of claims 1 to 18, wherein X1is CH.

20. The compound of claim 1 or 2, wherein the compound is a compound of formula (laa)wherein a, b, A, G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R7, R8, R9, and X1are as defined in any one of claims 1 to 19.21 . The compound of claim 1 or 2, wherein the compound is a compound of formula (Ilia)or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein c is 0 to 4; d is 0 or 1 ; each G4is independently selected from O and CHR21, wherein if c is selected from 2 to 4, then adjacent instances of G4may not both be O;R4is selected from C1-C4 alkoxy and C1-C4alkoxy-C1-C4alkoxy, each optionally substituted by -OH;R5is CONHs;R9is selected from, wherein the wavy line intersects the bond between R9and the rest of the compound;R11is H or methyl; andR15is H; each R21is independently selected from H, halogen, and C1-C4 alkyl; each R19is independently selected from H and C1-C4 alkyl; or R11and an instance of R21, together with the atoms to which they are connected, form a 4- to 6- membered heterocycloalkanediyl which comprises one N and optionally one or more additional heteroatoms selected from the group consisting of N, S and 0 (e.g. R11and one instance of R21, together with the atoms to which they are connected, form a 3- to 6-membered heterocycloalkanediyl which comprises one N); or an instance of R19and an instance of R21, together with the atoms to which they are connected, form a C3-C6 cycloalkanediyl;X1is selected from CH and N;X2is selected from CH and N.

22. The compound of claim 1 , wherein the compound is selected from compounds 1 to 26 and 30 to 34 shown in Table 1 .

23. A compound capable of binding to F-box only protein 22 (FBXO22) (e.g., covalently, for example reversibly covalently) and capable of binding to a transcriptional enhanced associate domain (TEAD) protein.

24. The compound of claim 23, wherein the compound is a compound of formula (SK):wherein Lcis a linker,TB is a moiety that is capable of binding to a TEAD protein, and FBX is a moiety that is capable of binding to FBXO22.

25. The compound of claim 23 or 24, wherein the compound is a compound of formula (Ixx)or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein A, R1-R7, R22and X1are as defined for compounds of formula (I) in any of claims 1 to 22;Lcis a linker; andFBX is a moiety that is capable of binding to FBXO22.

26. The compound of any one of claims 23 to 25, wherein the compound is a compound of formula (Ixy):or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein a, b, c, A, G1-G4, R1-R8, R10-R24and X1are as defined for compounds of formula (I) in any of claims 1 to 22; andFBX is a moiety that is capable of binding to FBXO22.

27. The compound of any one of claims 23 to 25, wherein the compound is a compound of formula (SL):wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

28. The compound of any of claims 23 to 27, wherein the compound is a compound according to any one of claims 1 to 22, wherein29. A compound according to formula (SLA):wherein Lcis a linker and TB is a moiety that is capable of binding to a TEAD protein.

30. An F-box only protein 22 (FBXO22) conjugate comprising an FBXO22 protein covalently (e.g. reversibly covalently) bound to a ligand capable of binding to a transcriptional enhanced associate domain (TEAD) protein.

31. The FBXO22 conjugate of claim 30, wherein the FBXO22 protein is covalently (e.g. reversibly covalently) bound to the ligand capable of binding to a TEAD protein at a cysteine residue.

32. The FBXO22 conjugate of claim 31 , wherein the cysteine residue is a cysteine residue at a position corresponding to residue 117, 226, 227, 326, 365, or 378 of SEQ ID NO: 1.

33. A pharmaceutical composition comprising the compound of any one of claims 1 to 29, together with a pharmaceutically acceptable carrier, optionally wherein the compound is present in the composition as a pharmaceutically acceptable salt, solvate or derivative.

34. A compound of any one of claims 1 to 29, a conjugate of any one of claims 30 to 32, or the pharmaceutical composition of claim 33 (e.g. a compound of any one of claims 1 to 29 or the pharmaceutical composition of claim 33), for use in medicine.

35. The compound, conjugate or pharmaceutical composition (e.g. the compound or pharmaceutical composition) for use of claim 34, wherein the disease or condition is cancer.

36. The compound, conjugate or pharmaceutical composition (e.g. the compound or pharmaceutical composition) for use of claim 35, wherein the cancer is selected from breast cancer, lung cancer,ovarian cancer, colorectal cancer, malignant pleural mesothelioma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer and bone cancer.

36. The compound, conjugate or pharmaceutical composition (e.g. the compound or pharmaceutical composition) for use of any one of claims 34 to 36, wherein the disease or condition is mediated by YAP overexpression and / or YAP amplification and / or YAP / TAZ-TEAD interaction.

37. A method of making a compound as defined in any one of claims 1 to 29.

Images