Novel bifunctional molecules for targeted protein degradation

Abstract

The present disclosure relates to a novel class of bifunctional molecules useful for the targeted or selective degradation of proteins.

Description

[Technical Field]

[0001] The present disclosure relates to a novel class of bifunctional molecules useful for the targeted or selective degradation of proteins. [Background technology]

[0002] Targeted protein degradation (TPD) is a therapeutic approach that relies on the use of synthetic molecules to repurpose the cellular proteolytic machinery and induce the degradation of specific disease-causing proteins. The TPD approach offers several advantages over other drug modalities (e.g., small molecule inhibitors, antibody- and protein-based drugs, antisense oligonucleotides, and related knockdown approaches), including enhanced pharmacological efficacy through catalytic protein removal from within the cell, the ability to inhibit multiple functions of a specific drug target, including scaffolding function, through targeted knockdown, the opportunity for systemic administration due to favorable biodistribution, potent in vivo efficacy based on catalytic activity and extended duration of action previously limited by de novo protein resynthesis, and ease of chemical synthesis and formulation through the application of small molecule processes.

[0003] Physiological post-translational regulation of intracellular protein levels and the removal of most damaged, misfolded, or excess proteins is mediated by the ubiquitin-proteasome system (UPS). The UPS relies on a complex cascade of protein-protein interactions that allows the polypeptide ubiquitin to be covalently attached to proteins targeted for removal. Ubiquitin on proteins serves as a marker or tag for the proteasome, which then degrades the protein and removes it from the cell.

[0004] The UPS can be repurposed as a therapeutic agent to degrade specific proteins using bifunctional chemical molecules, commonly referred to as bifunctional degradative derivatives. These molecules act by inducing the proximity of desired substrates to UPS proteins, initiating a series of reactions that ultimately lead to the protein's degradation by the proteasome and removal from the cell.

[0005] Proteolytic targeting chimeras (PROTACs) constitute one such bifunctional degradative derivative, which induces the proximity of target proteins to the UPS by recruiting specific ubiquitin E3 ligases. PROTACs consist of two ligands connected by a linker: one ligand engages the desired target protein, and the other ligand recruits the ubiquitin E3 ligase.

[0006] The most frequently used ubiquitin E3 ligases in PROTACs are von Hippel-Lindau (VHL) and cereblon (CRBN). VHL-recruiting PROTACs are typically based on hydroxyproline-containing ligands, while CRBN-recruiting PROTACs are typically characterized by the presence of a glutarimide moiety, such as thalidomide, pomalidomide, and lenalidomide or their close analogs, which acts as a warhead. Other ligases, including mdm2 and the IAP family, have also shown utility in PROTAC design.

[0007] However, these approaches have various limitations that limit their usefulness in treating a wide range of diseases. For example, current PROTAC approaches have limitations including inefficient degradation of some targets, low activity of PROTACs in many specific cell types due to low and heterogeneous expression of E3 ligases and other proteins required for efficient degradation, chemical properties that make it difficult to prepare degradative derivatives with favorable drug-like properties, including favorable drug metabolism and pharmacokinetic profiles, and high susceptibility to induced resistance mechanisms in tumors.

[0008] Due to these limitations, there remains a need to identify novel degradation mechanisms and warheads that can provide new bifunctional degradation-inducing molecules that exhibit efficient degradation across a wide range of targets and cell systems and / or have improved profiles suitable for drug development.

[0009] Further bifunctional degradation-directing molecules are described in WO2019 / 238886, WO2019 / 238817, WO2019 / 238816, and WO2022 / 129925. Summary of the Invention

[0010] The present disclosure is based on the identification of a novel class of bifunctional molecules useful for targeting and / or selective degradation of desired proteins, e.g., "target proteins." Specifically, the present disclosure provides bifunctional molecules that utilize a novel class of warheads to promote proteasomal degradation of selected target protein(s).

[0011] The bifunctional molecules described herein are TBL-LZ where TBL is a target protein binding ligand and L is a linker. The "Z" moiety ("warhead") regulates, promotes, and / or enhances proteasomal degradation of the target protein and is sometimes referred to as a regulator, promoter, and / or enhancer of proteasomal degradation. For example, in use, the TBL portion of the bifunctional molecule binds to a target protein. The Z moiety (which is bound or connected to TBL via the linker) then regulates, promotes, and / or enhances degradation of the target protein by bringing the target protein into proximity with the proteasome and / or targeting the target protein for proteasomal degradation within the cell.

[0012] Accordingly, bifunctional molecules described in this disclosure may hereinafter be considered to comprise a target protein binding ligand (TBL) (i.e., a ligand capable of binding (e.g., specifically binding) to a target protein), a warhead or degradation tag (Z) (e.g., a Z portion that acts to regulate, promote and / or enhance the degradation of the target protein), and a linker (e.g., a chemical linker) that binds, connects, or links the TBL and Z.

[0013] The bifunctional molecules described in this disclosure have been shown to be effective degradative derivatives of a wide range of target proteins. Without being bound by theory, it is hypothesized that the Z moieties of the bifunctional molecules described herein do not bind to the ubiquitin E3 ligases (e.g., CRBN and VHL) that are typically relied upon in conventional PROTAC approaches described above. Thus, it is believed that the bifunctional molecules described herein regulate, promote, and / or enhance proteasomal degradation through an alternative mechanism. Thus, this class of bifunctional molecules of the present invention may be useful for a broader range of diseases, including those that are resistant to many PROTAC degradative derivatives.

[0014] According to a first aspect of the present disclosure, a compound of the general formula: TBL-LZ wherein TBL is a target protein binding ligand; L is a linker, Z is a group represented by the formula (ZI): [ka] wherein: A 2 the ring is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing 1 or 2 heteroatoms selected from N, O, and S as additional ring heteroatoms; R2 is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; where R y is an optionally substituted C 1-6 alkyl or H, R 3 is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S; L represents the linker attachment point, Furthermore, Z is [ka] Instead, nor a pharmaceutically acceptable salt thereof.

[0015] To avoid any misunderstanding, A 2 In embodiments where the ring is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, A 2 The ring is not fused to an aromatic ring. 2In embodiments where the ring is an optionally substituted 7-12 membered bicyclic N-heterocycloalkyl or an optionally substituted 8-18 membered tricyclic N-heterocycloalkyl, the term "heterocycloalkyl" takes its standard meaning in the art, meaning that none of the two or three rings in these systems are aromatic. In other words, Z does not include, for example, tetrahydroquinoline or other fused heterocycloalkyl / aryl or heterocycloalkyl / heteroaryl systems.

[0016] As shown in formula (ZI) above, the linker is R 2 In such an embodiment, the linker may be attached to the Z moiety via an atom on the linker and an R 2 The linker may be attached to the Z moiety by a covalent bond between an atom in the ring system of the aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl of the group. Alternatively, the linker may be NR y or by a covalent bond to the benzylic carbon atom of -CH(aryl)- or -CH(substituted aryl)-, for example by a covalent bond to the benzylic carbon atom of -CH(aryl)- or -CH(substituted aryl)-.

[0017] As noted above, in some embodiments, R 2 In such cases, the linker may be a ring that is connected to an atom on the linker and a heterocycle (e.g., A 2 It may be attached to the Z moiety by a covalent bond between an atom contained in the ring.

[0018] In all instances, the linker may be attached at any suitable position, e.g., with the correct valence and / or chemically suitable. For example, the linker may be R 2 The groups aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y, -CH(aryl)- or -CH(substituted aryl)- at any position, and may substitute a hydrogen atom at any position on the heterocycle shown in formula (ZI).

[0019] As mentioned above, A 2 The ring is an optionally substituted 4-7 membered monocyclic N-heterocycloalkyl, an optionally substituted 7-12 membered bicyclic N-heterocycloalkyl, or an optionally substituted 8-18 membered tricyclic N-heterocycloalkyl, each optionally further containing 1 or 2 heteroatoms selected from N, O and S (e.g., N and O).

[0020] A 2 The ring may be bicyclic or tricyclic and, unless otherwise specified, may include bonded rings, fused rings, bridged rings, and / or rings joined through spiro centers.

[0021] A 2 When a ring is bicyclic, it may be a bridged bicyclic (i.e., it may contain two rings which share three or more atoms) or a spirocyclic bicyclic (i.e., it may contain two rings which share one atom, e.g., the two rings may be joined at a spiro center).

[0022] A 2 When the ring is a bridged bicyclic ring, it may be an optionally substituted 7-12 membered bridged bicyclic N-heterocycloalkyl, optionally further containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, A 2 The ring is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S. In some embodiments, A 2 The ring is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl, optionally further containing one ring atom selected from N.

[0023] A 2When the ring is a spirocyclic bicyclic ring, it may be an optionally substituted 7-12 membered spirocyclic bicyclic N-heterocycloalkyl, optionally further containing 1 or 2 ring heteroatoms selected from N, O, and S. In some embodiments, A 2 The ring is a 7-12 membered spirocyclic bicyclic N-heterocycloalkyl, optionally further containing 1 or 2 ring heteroatoms selected from N, O, and S. In some instances, A 2 The ring is bicyclic and includes a first 5- to 7-membered ring and a second 3- to 7-membered ring. For example, A 2 The ring may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, optionally further comprising one or two ring heteroatoms selected from N, O, and S. In some embodiments, A 2 The ring may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, and optionally further comprising one ring heteroatom selected from N.

[0024] In some embodiments, Z is a group of formula (ZIa): [ka] wherein: R 1 is absent (i.e., when m is 0) or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1 C with an optionally substituted group attached 1-3 Bridged, optionally substituted C 3-5 cycloalkyl or optionally substituted 5- to 7-membered heterocycloalkyl (e.g., 5- to 7-membered N-heterocycloalkyl), optionally 3-5 cycloalkyl or 5- to 7-membered heterocycloalkyl is attached to ring A at a spiro center; R 2 is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; where R y is an optionally substituted C 1-6 alkyl or H, R 3 is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, and substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S; X 1 is CH2, X 2 , X 3 and X 4 are each independently CH, O, or NR; R x is H or C1-C6 alkyl, or one R 1 group and one R x an optionally substituted C 1-3 Forming a crosslink, n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; L indicates the point of attachment of the linker.

[0025] For the avoidance of doubt, in embodiments in which ring A is not an aromatic ring, ring A is not fused to an aromatic ring. In other words, Z does not include, for example, tetrahydroquinoline or other fused heterocycloalkyl / aryl or fused heterocycloalkyl / heteroaryl systems.

[0026] In some embodiments, when n is 1, 2, or 3 (i.e., X 4 When one, two or three groups are present, the X adjacent to (or directly bonded to) the N of the heterocycle of formula (ZIa) 4 The group is CH2.

[0027] In some embodiments, Z is a group of formula (ZIb): [ka] wherein: R 1 is absent (i.e., when m is 0) or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1 an optionally substituted C 1-3 bridged, optionally substituted C 3-5 cycloalkyl, or optionally substituted 5- to 7-membered heterocycloalkyl (e.g., 5- to 7-membered N-heterocycloalkyl), optionally 3-5 cycloalkyl or 5- to 7-membered heterocycloalkyl is attached to ring A at a spiro center; R 2 is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; where R y is an optionally substituted C 1-6 alkyl or H, R 3is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, and substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S; X 1 and X 4 are CH2, respectively, X 2 and X 3 are each independently CH2, O, or NRx, provided that X 2 and X 3 provided that none or only one of is O, R x is H or C1-C6 alkyl, or one R 1 group and one R x C with an optionally substituted group attached 1-3 and forming a crosslink of n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; L indicates the point of attachment of the linker.

[0028] In some embodiments, Z is a group of formula (ZIb'): [ka] wherein: R 1 , R 3 , X 1 , X 2 , X 3 , X 4 , n, m and L are as defined above for formulae (ZIa) and (ZIb).

[0029] In some embodiments, Z is a group of formula (ZIb″): [ka] wherein: R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , n and L are as defined above for formulae (ZIa) and (ZIb).

[0030] As noted above, in some embodiments of formula (ZIa), formula (ZIb), formula (ZIb'), and formula (ZIb'') (and other formulae described herein), two R 1 group, or optionally one R 1 group and one R x C optionally substituted by a group 1-3 A crosslink of C may be formed. 1-3 The bridge may be a C1-C3 alkylene bridging group, such as methylene, ethylene, or propylene. In some embodiments, the C1-C3 bridge may be methylene or ethylene. 1-3 When the bridge is substituted, it may contain 1 to 3 (e.g., 1 or 2) substituents (selected from any suitable substituents described herein). For example, a C1-C3 alkylene bridge may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0031] In a further embodiment, Z is a group of formula (I): [ka] wherein R 1is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; R 2 is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; In the formula, R y is H or C1-C6 alkyl, R 3 is selected from C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x where R is a heteroatom selected from x is H or C1-C6 alkyl, n is 0, 1, 2, or 3; L represents the linker attachment point, Furthermore, Z is [ka] isn't it. In an alternative embodiment of formula (I), R 3 may be replaced by C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and optionally, the C1-C6 alkyl may be substituted with one or more heteroatoms selected from halo, N, O, and S. In some embodiments, R 2may be absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-.

[0032] In some embodiments, R 1 or R 2 At least one of the following is present.

[0033] For example, R 1 If does not exist, R 2 may be present, and may be an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-. For example, R 1 If does not exist, R 2 may be present and is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-.

[0034] Further examples include R 2 If does not exist, R 1 may be present and is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl. 2 If there is no R, then there must be at least one R 1 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl and substituted C1-C6 alkyl, and / or two R 1 The group is bonded to an optionally substituted C 1-3bridged, optionally substituted C 3-6 cycloalkyl, or optionally substituted 5- to 7-membered N-heterocycloalkyl, optionally 3-5 The cycloalkyl or 5- to 7-membered N-heterocycloalkyl is attached to the A ring at a spiro center.

[0035] In some embodiments, R 1 and R 2 For example, in some cases, R 2 exists and at least one R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl and substituted C1-C6 alkyl, and / or two R 1 an optionally substituted C 1-3 bridged, optionally substituted C 3-6 cycloalkyl, or optionally substituted 5- to 7-membered N-heterocycloalkyl.

[0036] In the compounds described herein, R 1 and / or R 2 may be covalently attached to the heterocycle (e.g., the A ring) at any suitable position, e.g., with the correct valence and / or where chemically appropriate. For example, R 1 and / or R 2 may replace a hydrogen atom at any position on the heterocyclic core, for example, at the positions shown in formula (I).

[0037] R 1 and R 2 When both R are present, they may be covalently attached to the same or different positions on the heterocycle (e.g., the A ring). 1 and R 2 may be covalently attached to the heterocyclic core through different carbon atoms. 1 and R 2 may be covalently attached to the heterocyclic core via the same carbon atom.

[0038] As shown in the formulas associated with the Z moiety described herein, there is a double bond in Z. The stereochemistry of this double bond is either E or Z, as indicated by the wavy line in formula (I) (as well as in other formulas and structures disclosed herein). Whether this moiety is designated as E or Z is determined by the R 3 The stereochemistry of the double bond and the moiety attached thereto may be determined by the identity of the group. In some examples, Z may comprise a mixture of E and Z stereoisomers. Thus, the scope of the present disclosure includes the use of either each individual E and Z stereoisomer (e.g., in substantially stereopure form) of the Z moiety according to Formula (I) and other formulae described herein, as well as the use of mixtures of these E and Z isomers. In some cases, the stereochemistry of the double bond and the moiety attached thereto is Z, i.e., the Z stereoisomer. In other examples, the stereochemistry of the double bond and the moiety attached thereto is E, i.e., the E stereoisomer. For the avoidance of doubt, when the vinyl double bond at Z, for example of formula (I), is shown in the structures herein as a particular stereoisomer (E or Z) in any of the specific examples of this disclosure, it is not required to be that particular stereoisomer. In other words, both the E and Z stereoisomers and mixtures of the two are included within the scope of the structures, regardless of whether a specific stereoisomer is shown.

[0039] Further by way of example, Z may be a group represented by formula (Ia) or formula (Ib): [ka] can be expressed as follows: 1 , R 2 , R 3 , X 1 , X 2 , X 3 and n is as defined above and herein.

[0040] It will be understood that the bifunctional molecules of the present disclosure can exist in different stereoisomeric forms. The present disclosure includes within its scope the use of all stereoisomeric forms or mixtures of stereoisomers of the bifunctional molecules. By way of example, if the bifunctional molecule contains one or more chiral centers, the present disclosure encompasses each individual enantiomer of the bifunctional molecule as well as mixtures of enantiomers, including racemic mixtures of such. Further by way of example, if the bifunctional molecule contains two or more chiral centers, the present disclosure encompasses each individual diastereomer of the bifunctional molecule as well as mixtures of various diastereomers.

[0041] Unless otherwise specified, the various structures depicted herein encompass all isomeric (e.g., enantiomeric, diastereomeric, geometric (or conformational) isomeric) forms. For example, the present disclosure encompasses R and S configurations at each asymmetric center, as well as Z and E double bond isomers. Accordingly, single stereoisomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the disclosed compounds are understood to be within the scope of the present disclosure. Additionally, unless otherwise specified, all tautomeric forms of the bifunctional molecules described herein, where they exist, are understood to be included within the scope of the present disclosure.

[0042] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, bifunctional molecules described herein include those in which one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by 13 C or 14 Substitutions with C-enriched carbons are understood to be within the scope of the present disclosure. Such molecules may be useful, for example, as analytical tools, as probes in bioassays, or as therapeutic agents according to the present disclosure. Further by way of example, the bifunctional molecules described herein may be substituted with one or more deuterium atoms.

[0043] As used herein, the expression "bifunctional molecule" may further include pharmaceutically acceptable salts thereof.

[0044] Further by way of example, Z may be represented by the formula (Ic'): [ka] where: R 1 is absent (i.e., when m is 0) or is selected from the group consisting of aryl having 6 to 10 carbon atoms, optionally substituted with 1 to 3 substituents; heteroaryl having 5 to 10 ring atoms, each independently selected from N, O, and S, and having 1 to 3 heteroatoms, optionally substituted with 1 to 3 substituents; C3-C8 cycloalkyl, optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms, each independently containing 1 to 3 ring heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 substituents; C1-C6 alkyl, optionally having 1 to 3 substituents; and / or two R 1 C, to which a group is attached and which optionally has 1 to 3 substituents; 1-3 bridge, optionally having 1 to 3 substituents, C 3-5 cycloalkyl, or 5-7 membered N-heterocycloalkyl optionally having 1 to 3 substituents (e.g., C 3-5 The cycloalkyl or 5-7 membered N-heterocycloalkyl is attached to the A ring at a spiro center; R 2 is absent or optionally substituted with 1 to 3 substituents; aryl having 6 to 10 carbon ring atoms; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents; -NRy and -CH(heteroaryl)-, wherein the aryl has 6 to 10 carbon ring atoms and optionally is substituted with 1 to 3 substituents; and -CH(heteroaryl)-, wherein the heteroaryl has 5 to 10 ring atoms and contains 1 to 3 heteroatoms, each independently selected from N, O, and S, and optionally is substituted with 1 to 3 substituents. In the formula, R y is H or C1-C6 alkyl, R 3 is selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 3 substituents, C3-C8 cycloalkyl optionally substituted with 1 to 3 substituents, heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S and optionally substituted with 1 to 3 substituents, aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents, and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S and optionally substituted with 1 to 3 substituents; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x where R is a heteroatom selected from x is H or C1-C6 alkyl, or one R 1 group and one R x groups are linked to form a C1-C3 bridge, optionally substituted with 1-3 substituents, provided that X 2 and X 3 are not heteroatoms, or only one or two are heteroatoms; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; L indicates the point of attachment of the linker.

[0045] Further by way of example, Z may be represented by formula (Ic): [ka] where: R 1 is absent or selected from the group consisting of aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents, heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, optionally substituted with 1 to 3 substituents, C3-C8 cycloalkyl, and C1-C6 alkyl optionally substituted with 1 to 3 substituents; R 2 is absent or optionally substituted with 1 to 3 substituents; aryl having 6 to 10 carbon ring atoms; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents; -NR y and -CH(heteroaryl)-, wherein the aryl has 6 to 10 carbon ring atoms and optionally is substituted with 1 to 3 substituents; and -CH(heteroaryl)-, wherein the heteroaryl has 5 to 10 ring atoms and contains 1 to 3 heteroatoms, each independently selected from N, O, and S, and optionally is substituted with 1 to 3 substituents. In the formula, R y is H or C1-C6 alkyl, R 3is selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 3 substituents, C3-C8 cycloalkyl optionally substituted with 1 to 3 substituents, heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S and optionally substituted with 1 to 3 substituents, aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents, and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S and optionally substituted with 1 to 3 substituents; X 1 is CH2, X 2 and X 3 are each independently CH or a heteroatom selected from O and NR, and R x is a heteroatom that is H or C1-C6 alkyl, provided that X 2 and X 3 are not heteroatoms, or only one or two are heteroatoms; n is 0, 1, 2, or 3; L indicates the point of attachment of the linker.

[0046] Further by way of example, Z may be represented by formula (Id'): [ka] where: R 1is absent (i.e., when m is 0) or is selected from the group consisting of phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 ring heteroatoms each independently selected from N, O, and S; C3-C8 cycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl; and / or two R's 1 The group is bonded to C 1-3 Crosslinking of C 3-5 cycloalkyl, or 5- to 7-membered N-heterocycloalkyl (e.g., C 3-5 cycloalkyl or 5-7 membered N-heterocycloalkyl is attached to ring A at a spiro center), R 2 is absent or optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; -NR y-CH(phenyl)-, wherein phenyl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and -CH(heteroaryl)-, wherein heteroaryl has 5 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O, and S, and is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; In the formula, R y is H or C1-C6 alkyl, R 3 is selected from the group consisting of C1-C6 alkyl optionally substituted with heterocycloalkyl group; C3-C6 cycloalkyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5 to 6 ring atoms each containing a heteroatom independently selected from N, O, and S, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; X 1 is CH2, X 2 and X 3 are each independently CH2 or O and NR x and R is a heteroatom selected from x is H or C1-C6 alkyl, or one R 1 group and one R x The pieces combine to form C 1-3 where X 2 and X 3 None of the X 2 and X 3is a heteroatom, m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; L indicates the point of attachment of the linker.

[0047] Further by way of example, Z may be represented by formula (Id): [ka] where: R 1 is absent or selected from the group consisting of phenyl optionally substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5-6 ring atoms and containing 1-3 heteroatoms each independently selected from N, O, and S; C3-C8 cycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl optionally substituted with 1-3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; R 2 is absent or optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; -NR y-CH(phenyl)-, wherein phenyl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and -CH(heteroaryl)-, wherein heteroaryl has 5 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O, and S, and is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; In the formula, R y is H or C1-C6 alkyl, R 3 is selected from the group consisting of C1-C6 alkyl optionally substituted with a heterocycloalkyl group, C3-C8 cycloalkyl optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S and optionally substituted with 1 to 3 substituents, phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy, and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x and R is a heteroatom selected from x is H or C1-C6 alkyl, provided that X 2 and X 3 None of X is a heteroatom, or 2 and X 3 provided that only one of the groups is a heteroatom; n is 0, 1, 2, or 3; L indicates the point of attachment of the linker.

[0048] Further by way of example, Z may be represented by formula (Ie'): [ka] where: R 1 is absent (i.e., when m is 0) or is selected from the group consisting of phenyl, heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S, C3-C7 cycloalkyl, heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S, C1-C6 alkyl and C1-C6 haloalkyl, wherein the phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy, and / or two R1 groups are joined to form C 1-3 Crosslinking of C 3-5 Forms a cycloalkyl or 5- to 7-membered N-heterocycloalkyl (e.g., C 3-5 cycloalkyl or 5-7 membered N-heterocycloalkyl is attached to ring A at a spiro center), R 2 is absent, phenyl, heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O, and S, heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O, and S, -NR y-CH(phenyl)- and -CH(heteroaryl) having 5 to 6 ring atoms and each containing 1 or 2 heteroatoms independently selected from N, O and S, wherein phenyl, heteroaryl, heterocycloalkyl, -CH(phenyl)- and -CH(heteroaryl)- are each optionally substituted with one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; In the formula, R y is H or C1-C6 alkyl, R 3 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, and heteroaryl having 5-6 ring atoms and containing 1-3 heteroatoms each independently selected from N, O, and S, optionally substituted with a heterocycloalkyl group having 5-7 ring atoms and containing 1-2 heteroatoms independently selected from N, O, and S, wherein the C3-C6 cycloalkyl, phenyl, and heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, m is 0, 1, 2, or 3; n is 1, 2, or 3; L indicates the point of attachment of the linker.

[0049] Further by way of example, Z may be represented by formula (Ie): [ka] where: R 1is absent or selected from the group consisting of phenyl, heteroaryl having 5-6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S, C3-C7 cycloalkyl, C1-C6 alkyl and C1-C6 haloalkyl, wherein phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; R 2 is absent, phenyl, heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O, and S, heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O, and S, -NR y -CH(phenyl)- and -CH(heteroaryl) having 5 to 6 ring atoms and each containing 1 or 2 heteroatoms independently selected from N, O and S, wherein phenyl, heteroaryl, heterocycloalkyl, -CH(phenyl)- and -CH(heteroaryl)- are each optionally substituted with one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy; In the formula, R y is H or C1-C6 alkyl, R 3 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, and heteroaryl having 5-6 ring atoms and containing 1-3 heteroatoms each independently selected from N, O, and S, optionally substituted with a heterocycloalkyl group having 5-7 ring atoms and containing 1-2 heteroatoms independently selected from N, O, and S, wherein the C3-C6 cycloalkyl, phenyl, and heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; X 1 is CH2, X 2 and X 3are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 1, 2, or 3; L indicates the point of attachment of the linker.

[0050] In a further embodiment, Z has the formula (ZII): [ka] wherein R 2 is absent or as described in any one embodiment disclosed herein; R 3 is as described in any one of the embodiments disclosed herein; X 5 is CR b 2. NR b , O, or 5- to 7-membered heterocycloalkyl (e.g., 5- to 7-membered heterocycloalkyl); Each R 1 are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl and substituted C1-C6 alkyl, and / or two R 1 C with an optionally substituted group attached 1-3 or optionally substituted C 3-5 Cycloalkyl (optionally C 3-5 wherein the cycloalkyl is attached to the heterocycle of formula (ZII) at a spiro center, R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 3; m is 0, 1 or 2; L indicates the point of attachment of the linker.

[0051] In yet another embodiment, Z is a member of formula (ZIIa) to formula (ZIIe): [ka] wherein: R 2 is as described in any one of the embodiments disclosed herein; R 3 is as described in any one of the embodiments disclosed herein; Each R 1 are each independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1 an optionally substituted C 3-5 Cycloalkyl (optionally C 3-5 wherein the cycloalkyl is attached to the heterocycle of formula (ZIIa) at a spiro center, X 5 is C(R b )2, NR b or O, R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 3; n' is 1 or 2; m is 0, 1 or 2; L indicates the point of attachment of the linker.

[0052] For example, Z is a group represented by formula (ZIIIa) to formula (ZIIIh): [ka] wherein: R 2is as described in any one of the embodiments disclosed herein; R 3 is as described in any one of the embodiments disclosed herein; Each R 1 are each independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; X 5 is CH, NRb or O, R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 2; n' is 1 or 2; m is 0, 1 or 2; L indicates the point of attachment of the linker.

[0053] In yet another embodiment, Z is a group represented by formula (ZIVa) to formula (ZIVj): [ka] wherein: R 2 is absent or as described in any one of the embodiments disclosed herein; R 3 is as described in any one of the embodiments disclosed herein; Each R 1 are each independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; n1 is 0, 1, 2 or 2; n' is 1 or 2; m is 0, 1 or 2; L indicates the point of attachment of the linker.

[0054] In yet another embodiment, Z is a group of formula (If): [ka] wherein R 1 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)- and -CH(substituted aryl)-; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted C1-C6 alkyl, substituted aryl, and substituted heteroaryl; where R 1 and R 2 At least one of n is 0, 1, 2, or 3; L indicates the point of attachment of the linker.

[0055] In some embodiments, R of formula (If) 1 , R 2 and R 3 may be selected from any one or more of the group defined above, for example, formula (Ic'), formula (Ic), formula (Id'), formula (Id), formula (Ie') or formula (Ie).

[0056] In some embodiments of the formulae above and described herein, n may be 1, 2, or 3, and / or n1 may be 0, 1, or 2.

[0057] R 1 is not present, Z is a group of formula (II): [ka] where R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 0, 1, 2, or 3; L represents the linker attachment point, Z is [ka] isn't it. R 1 is not present, Z is a group of formula (IIa): [ka] where R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; n is 0, 1, 2, or 3; L represents the linker attachment point, Z is [ka] isn't it.

[0058] As a particular example, in formula (II) or formula (IIa), n may be 1 or 2.

[0059] Further by way of example, Z may be represented by formula (IIb): [ka] where R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 1 or 2, L represents the linker attachment point, Z is [ka] isn't it.

[0060] Further by way of example, Z may be represented by formula (IIc): [ka] where R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 1 or 2, L indicates the point of attachment of the linker.

[0061] In some cases, Z is a group represented by formula (IId): [ka] where R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; n is 1 or 2, L indicates the point of attachment of the linker.

[0062] In another example, Z is a group of formula (IIe): [ka] wherein R 2is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; n is 1 or 2, L indicates the point of attachment of the linker.

[0063] In other embodiments, Z is a group of formula (IIe): [ka] wherein R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker.

[0064] R 2 is not present, Z is a group of formula (III): [ka] wherein R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker. In some embodiments, n may be 1 or 2.

[0065] In some embodiments where n is 2, Z is a group of formula (IIIa): [ka] where R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker.

[0066] In some embodiments where n is 1, Z is a group represented by formula (IIIb): [ka] where R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker.

[0067] As illustrated above, bifunctional molecules of formula (IIIb) contain at least two stereocenters and therefore exist in multiple diastereomeric (and enantiomeric) forms. In some embodiments, R 1The R and L groups can be in a trans relationship (e.g., the groups are held and / or positioned on opposite sides of the heterocyclic core). 1 The L group and the L group can be in a cis relationship (e.g., the groups are held and / or positioned on the same side of the heterocyclic core). By way of further example, a bifunctional molecule of Formula (IIIb) can include at least the following diastereomeric forms: [ka]

[0068] R 1 does not exist and R 2 In embodiments where Z is selected from -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-, Z is a group of formula (IV): [ka] where R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; R4 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; n is 0, 1, 2, or 3; L indicates the point of attachment of the linker.

[0069] In some embodiments, Z is a group represented by formula (IVa): [ka] wherein R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, wherein the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; R 4 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; L indicates the point of attachment of the linker.

[0070] In either formula (IV) or formula (IVa), R 4 may be selected from aryl or substituted aryl.

[0071] R 1 , R 2 , R 3 and R 4 Representative examples of groups are shown below, which are applicable to any one or more of the formulae described herein (unless otherwise indicated).

[0072] With respect to the various structures of Z defined by the formulas herein (and unless otherwise specified), R 1 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0073] In some embodiments, R 1 is optionally substituted aryl or optionally substituted heteroaryl. R 1 When is a substituted aryl or substituted heteroaryl, the aryl or heteroaryl may contain one or more substituents selected from the group consisting of C1-C6 alkyl (e.g., methyl), C1-C6 alkoxy (e.g., methoxy), C1-C6 haloalkyl, and halo.

[0074] Further examples include R 1 may be phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. 1may be heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, which heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0075] Suitable R 1 Representative examples of groups include, but are not limited to, phenyl, substituted phenyl, pyrazolyl, and substituted pyrazolyl.

[0076] In some embodiments, R 1 is cycloalkyl, for example, C3-C7 cycloalkyl or C3-C6 cycloalkyl.

[0077] In some embodiments, R 1 is C1-C6 alkyl, for example, C1-C3 alkyl optionally substituted with 1 to 3 substituents as defined herein.

[0078] Suitable R 1 Further non-limiting examples of groups are shown below. [ka]

[0079] In the above structure, the lines where the wavy lines intersect represent the representative R 1 group and within the parent structure of Z (as illustrated by the various formulas described herein) 1 represents a covalent bond between the carbon atom on the heterocyclic alkyl core that is attached to the group. In the exemplary aryl and heteroaryl structures above, specific substitution patterns are shown, but it will be understood that other substitution patterns are encompassed within the scope of the present disclosure.

[0080] As a further example, with respect to formula (ZII), two R groups may be joined to form a C1-C3 bridge or a C3-C5 cycloalkyl. For example, two R1 The group is bonded to C 3-5 In such cases, C 3-5 A cycloalkyl may be attached to the parent heterocycle at a spiro center.

[0081] For the various structures of Z defined by the formulas herein (unless otherwise specified), R2 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl) and —CH(substituted heteroaryl), where R y is optionally replaced by C 1-6 alkyl (eg methyl) or H.

[0082] In some instances, R 2 is present as a divalent group within Z (and / or the bifunctional molecules described herein). In other words, as shown in Formulas (I) through (IVa) (and unless otherwise specified), R 2 The various groups defined for are covalently bonded to an atom of the heterocyclic core of Z and may also be covalently bonded to an atom of the linker. Thus, these groups can be considered divalent radical species.

[0083] R 2 When is selected from optionally substituted aryl or optionally substituted heteroaryl, R 2 may be selected from aryl having 6 to 10 carbon ring atoms optionally substituted with 1 to 3 substituents, and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, optionally substituted with 1 to 3 substituents. 2may be selected from phenyl optionally substituted with 1-3 substituents selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy, and heteroaryl having 5-6 ring atoms and containing 1 or 2 N atoms, optionally substituted with 1-3 substituents selected from C1-C6 alkyl (e.g., C1-C3 alkyl), halo (e.g., F), C1-C6 haloalkyl (e.g., C1-C3 haloalkyl), and C1-C6 alkoxy (e.g., C1-C3 alkoxy). In some cases, R 2 Suitable examples of include, but are not limited to, optionally substituted phenyl and optionally substituted pyrazolyl.

[0084] R 2 When is selected from optionally substituted heterocycloalkyl, the heterocycloalkyl has 3 to 10 ring atoms and includes 1 to 3 heteroatoms, each independently selected from N, O, and S, and the heterocycloalkyl can be optionally substituted with 1 to 3 substituents. In some examples, the heterocycloalkyl can have 5 to 8 ring atoms (e.g., 6 ring atoms) and can include 1 or 2 N atoms. In some cases, suitable examples include, but are not limited to, optionally substituted piperidinyl and optionally substituted piperazinyl.

[0085] Suitable R 2 Further examples of groups are shown below. [ka] In the structure shown above, R 6 may be selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy. 6 may be selected from H and C1-C6 alkyl.

[0086] In the structure shown above, the lines where the wavy lines intersect are the representative R 2 group and within the parent structure of Z (represented by the various formulas described herein) 2 represents a covalent bond between the carbon atom on the heterocyclic alkyl core that is attached to the group. Although particular substitution patterns are shown in the exemplary structures above, it will be understood that other substitution patterns are also encompassed within the scope of the present disclosure.

[0087] Additionally, the bond to L indicates the point of attachment to the linker. In the exemplary aryl structures above, it will be understood that the linker may replace a hydrogen atom at any suitable position on the aryl ring (e.g., if it is chemically appropriate and has the correct valence).

[0088] With respect to the various structures of Z defined by the formulas described herein, R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted C1-C6 alkyl, substituted aryl, and substituted heteroaryl.

[0089] In some instances, R 3 may be selected from the group consisting of C1-C6 alkyl, aryl having 6-10 carbon ring atoms, and heteroaryl having 5-10 ring atoms and containing 1-3 heteroatoms, each independently selected from N, O, and S, optionally substituted with a heterocycloalkyl group having 5-7 ring atoms and containing 1-2 heteroatoms, each independently selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. By way of further example, in some cases, the aryl and heteroaryl may be optionally substituted with 1 or 2 substituents selected from halo (e.g., F) and C1-C3 alkyl (e.g., methyl).

[0090] Suitable R 3Representative examples of groups include, but are not limited to, thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, oxetanyl, cyclobutanyl, cyclopropanyl, tert-butyl, imidazolyl, oxazolyl, thiophenyl, imidazo(1,2-a)pyridinyl, N-C1-C6 alkylenemorpholine, and 4,5,6,7-tetrahydro-1,3-benzothiazolyl, for example, thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, cyclobutanyl, cyclopropanyl, and tert-butyl.

[0091] In either case, these R 3 Groups can be substituted, for example, substituted thiazolyl, substituted pyridinyl, substituted benzothiazolyl, substituted phenyl, substituted pyrazolyl, substituted isoxazolyl, substituted isothiazolyl, substituted tetrahydropyranyl, substituted tetrahydrofuranyl, substituted oxetanyl, substituted cyclobutanyl, substituted cyclopropanyl, and substituted tert-butyl. R 3 When R is a substituted heteroaryl or aryl group, there may be one or more substituents on the aromatic ring, and it may be, for example, mono-, di-, or tri-substituted. 3 When is an optionally substituted pyrazolyl or imidazolyl, the nitrogen atom of the pyrazolyl or imidazolyl ring may be substituted with, for example, C1-C6 alkyl, such as methyl.

[0092] Suitable R 3 Representative examples of groups include, but are not limited to, optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, tert-butyl, C1-C6 alkyl containing a morpholino substituent, optionally substituted benzothiazolyl, and optionally substituted pyridinyl. 1When is a substituted heteroaryl or aryl group, there may be one or more substituents on the aromatic ring, and it may be, for example, mono-, di-, or tri-substituted.

[0093] Suitable R 3 Further examples of groups are shown below. [ka] In the formula, the dotted lines on the structure represent the respective R 3 indicates the position at which the R group may be attached to the structures depicted in the formulas described herein. When the dotted line is not directly connected to an atom, the R 3 Groups may be attached to the structure shown in the formula via a covalent bond to an atom anywhere on the aromatic ring (provided they have the correct valence and / or are chemically feasible). For example, R 3 A hydrogen at any position on the group may be replaced by a bond to the parent structure shown in the formulas described herein.

[0094] R 5 may be any substituent described herein or may be absent. In some examples, R 5 may be selected from halo (e.g., F, Cl, Br, I), CF, -CHF, -CHF, OCF, -OCHF, -OCHF, C-C alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SOMe, -NH, -NHMe, -NMe, COMe, -NO, CHO, and COMe. As noted above, the aromatic ring may have one or more substituents (e.g., n may be 0 to 5, e.g., 0 to 4, 0 to 3, or 0 to 2). When multiple substituents are present, each substituent may be independently selected from the R groups described above.

[0095] R 6 may be, for example, a C1-C6 alkyl such as methyl.

[0096] G may be selected from CH2, O, and NH.

[0097] Q may be, for example, a C1-C6 alkylene such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0098] In a further embodiment, R 3 is selected from the group consisting of: [ka] In the formula, the dotted lines represent the respective R 3 Indicates the position at which the group is attached to the structure of the formula described herein.

[0099] Further examples include R 5 may be selected from C1-C6 alkyl (e.g., methyl) and halo (e.g., F). As noted above, one or more substituents may be present on the aromatic ring. When two or more substituents are present, each substituent may be selected from the R groups described above. 5 Similarly, when present and unless otherwise indicated, R 5 may be attached to any position of the aryl or heteroaryl ring, provided that it has the correct valence and / or is chemically feasible.

[0100] In the structure shown above, the lines where the wavy lines intersect are the exemplary R 3 represents a covalent bond between a group and a carbon atom of the parent structure of Z (as exemplified by the various formulas described herein). 3 When R is an aryl or heteroaryl group, the covalent bond (as exemplified in the various formulas described herein) may be formed at any position on the aromatic ring (provided it has the correct valence and / or is chemically feasible). For example, 3 A hydrogen at any position on the group may be replaced with a bond to the structure shown in formula (I).

[0101] Further by way of example, suitable R 3 The groups may be selected from the following: [ka] where the dotted lines in these structures represent the respective R 3 indicates the position at which a group may be attached to the structure shown in the formula described herein, R 5 , R 6 , n and G are as defined above.

[0102] In another example, a suitable R 3 The groups may be selected from the following: [ka] where the wavy lines intersect with each other. 3 represents a covalent bond between a group and a carbon atom of the parent structure of Z (as exemplified in the various formulas described herein), R 5 is as defined above.

[0103] Further by way of example, suitable R 3 The groups may be selected from the following: [ka]

[0104] Similarly, in the structure shown above, the dashed crossed lines represent the exemplary R 3 represents a covalent bond between the group and a carbon atom of the parent structure of Z (as exemplified in each formula described herein).

[0105] As mentioned above, R 4 may be selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In some embodiments, R 4may be selected from aryl having 6 to 10 carbon ring atoms; and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. In some embodiments, R 4 may be an optionally substituted phenyl.

[0106] Further by way of example, suitable R 4 The base is: [ka] may be selected from R 7 may be any substituent described herein or may be absent. In some embodiments, R 7 may be selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, or C1-C6 alkoxy. 6 may be C1-C6 alkyl or C1-C3 alkyl (e.g., methyl). As noted above, one or more substituents may be present on the aromatic ring. When two or more substituents are present, each substituent may be a ... 7 Similarly, when present and unless otherwise indicated, R 7 may be covalently attached to any position on the aryl or heteroaryl ring (provided that R 7 has the correct valence and / or is chemically feasible).

[0107] Further, by way of example, representative examples of Z are shown below. [ka] TIFF2025525347000046.tif250170TIFF2025525347000047.tif229170TIFF2025525347000048.tif226170

[0108] In the exemplary structure shown above, R 3 is the R 3 In some embodiments, in the exemplary structures shown above, R 3 may be selected from the group consisting of: [ka] TIFF2025525347000050.tif211170

[0109] As mentioned above, Z is: [ka] isn't it.

[0110] In some embodiments, Z is not (or does not include) a structure selected from one or more of the following: [ka]

[0111] In some embodiments, Z has the structure: [ka] rather than (or does not include) 2’ is selected from H and C1-C6 alkyl; R 3’is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, where the C1-C6 alkyl is optionally substituted with a heterocycloalkyl group; m is 3, 4 or 5; L indicates the point of attachment of the linker.

[0112] In some embodiments, the bifunctional molecule is not: [ka]

[0113] Alternatively, in the various formulas described herein, the linker may be connected to the heterocyclic core (directly or indirectly via R 2 It should be noted that although shown as being linked to the Z moiety (via a linker group), the present disclosure extends to instances where the linker is linked at any other position within the Z moiety (provided it has the correct valence and / or is chemically appropriate). For example, the linker may replace a hydrogen atom at any position within the Z moiety. Thus, in some embodiments, Z is a group of formula (ZV) or formula (V): [ka] In the formula, ring A 2 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , n and L are as defined in any one of the above embodiments.

[0114] The dotted line shown through the square brackets in Formula (ZV) and Formula (V) indicates that the linker may be covalently attached to any atom of the Z moiety, provided that it has the correct valence, is chemically feasible, and / or that attaching the linker at this alternative position does not impair the function of the Z moiety to promote and / or assist in proteasomal degradation.

[0115] According to a further aspect of the present disclosure, there is provided a compound having the general structure: LZ Also provided are compounds comprising: wherein the moiety Z is as defined in any formula described herein (e.g., any one of formulas (I)-(V) and formulas (ZI)-(ZV)); L is a linker as defined herein.

[0116] Such compounds may be useful, for example, in the synthesis described for bifunctional molecules via a modular approach, where each of the TBL, Z, and L moieties is provided as a separate building block. In some examples, L and Z may be combined to produce the compound LZ described above (which may then be further reacted to couple with an appropriate TBL moiety).

[0117] Intermediates / Fragments As noted above, structures comprising the Zi moieties described herein may be considered particularly useful in targeted protein degradation, and therefore intermediates comprising such Zi moieties may be valuable in providing useful intermediates in the synthesis of bifunctional molecules used in targeted protein degradation.

[0118] According to a further aspect, there are provided intermediate compounds or fragments corresponding to any one or more of the formulae of Z described herein, or any of the other exemplary structures described herein, where the LW or W moiety is replaced with a group "G."

[0119] G is attached to the disclosed structure via a covalent bond.

[0120] According to a further embodiment, the compound of formula (VI) or (VIa): [ka] wherein ring A is a compound having a Z moiety according to the formula 2 , R 1 , R 2 , R 3 , n, X 1 , X 2 and X 3 is as defined in any one of the above embodiments.

[0121] As shown in formula (VI) and formula (VIa), G can be attached directly to the heterocyclic core or to R 2 In either case, G is attached to the moiety Z through a covalent bond. G can be attached to any position of the heterocyclic core through a (R 2 provided that it has the correct valence and / or is chemically feasible. For example, G may replace a hydrogen atom at any position on the heterocyclic core.

[0122] The group G in formula (VI) or formula (VIa) is configured to allow the Z moiety to be attached to another chemical structure (e.g., a linker moiety or a linker-target protein binding ligand moiety) via the formation of a new covalent bond, after which the group G can form part of a linker as defined herein.

[0123] In some embodiments, G can include a functional group that can facilitate the formation of a new covalent bond between Z and another moiety, for example, through the formation of an amide, ester, thioester, keto, urethane, amine, or ether bond, or through the formation of a new carbon-carbon or carbon-nitrogen bond.

[0124] For example only, G is: [ka] wherein R G is absent or is C1-C6 alkyl, optionally substituted with one or more heteroatoms selected from N, O and S; X G -COH, -(CO)-N-hydroxysuccinimide, -(CO)-pentafluorophenol ester, -CHO, -COR G1 , -OH, -NH2, -NHR G2 , halo (e.g., iodo and bromo), O-leaving groups (e.g., -OTs (tosylates), -OMs (mesylates), -OTf (triflates)), alkynyl, azido, dienyl, aminooxy, tetrazinyl, (E)-cyclooctenyl, cyclooctynyl, norbornyl, boric acid, borate esters, alkylboranes, or organometallic groups (e.g., organotin, zinc, or other suitable reagents); R G1 and R G2は , each independently selected from C1 to C6 alkyl.

[0125] In this structure, a wavy line is shown over the bond that forms the bond with the heterocyclic core of Z (or the R2 group, if present).

[0126] G is R G a heterocyclic core shown in formula (VI) (directly or via an R 2 bonded via the R group. G If does not exist, X G The group is a heterocyclic core shown in formula (VI) or R 2 is directly bonded to

[0127] Representative examples of suitable G moieties are shown below. [ka]

[0128] It should be noted that the present disclosure also extends to the structure of Z shown in any of the formulae defined herein, e.g., Formulas (I)-(V), Formulas (ZI)-(ZV), or other representative examples of Z, wherein the L group is replaced by the G group defined above with respect to Formula (VI) or (VIa).

[0129] Linker (L) As described herein, TBL is attached or linked to the Z moiety via a linker, L. The linker may be a chemical linker (e.g., a chemical linker moiety), and may be, for example, a covalent linker, meaning that the linker is attached to Z and / or TBL by a covalent bond.

[0130] The linker serves to attach the target protein-binding ligand moiety and the Z moiety to one another while allowing both moieties to bind to their respective targets and / or perform their intended functions. In particular, the linker can attach the target protein-binding ligand to Z while mitigating the possibility that the Z moiety will interfere with, interfere with, or inhibit the binding of the target protein-binding ligand to the target protein. Additionally or alternatively, the linker can attach Z to the target protein-binding ligand while mitigating the possibility that the target protein-binding ligand will interfere with, or inhibit the intracellular interaction of Z (e.g., its function in regulating, promoting, and / or facilitating proteasomal degradation of the target protein).

[0131] In other words, the linker can serve to facilitate target protein degradation by allowing both ends of the bifunctional molecule to bind (or interact in other ways) with various components of the cellular environment. For example, the linker can be configured to allow the target protein-binding ligand to bind to the target protein without interference, hindrance, and / or inhibition from the Z moiety of the bifunctional molecule. Additionally or alternatively, the linker can be configured to allow the Z moiety to interact with various components in the cellular environment to modulate, promote, and / or facilitate proteasomal degradation of the target protein without interference, hindrance, and / or inhibition from the target protein-binding ligand of the bifunctional molecule.

[0132] In many cases, a wide range of linkers are acceptable. The choice of linker can depend on the protein targeted for degradation (target protein) and / or the particular target protein-binding ligand.

[0133] The linker may be selected to provide a particular length and / or flexibility, for example, to hold the target protein-binding ligand and the Z moiety within a particular distance and / or shape. As will be understood by those skilled in the art, the length and / or flexibility of the linker can vary depending on the structure and / or properties of the target protein-binding ligand.

[0134] In some embodiments, TBL is directly linked to the Z moiety by a covalent bond, i.e., the linker is a covalent bond. Such direct bonds are also encompassed by the term "linker" within the context of the present disclosure (unless otherwise specified).

[0135] By way of example only, a linker may comprise any number of atoms between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30, or between 1 and 10. In some embodiments, a linker may comprise any number of atoms in a single linear chain between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30, or between 1 and 10. In some embodiments of the present disclosure, a linker may comprise any number of atoms in a single linear chain between 1 and 25 (e.g., 25), between 1 and 20 (e.g., 3 and 20), or between 1 and 18 (e.g., 3 and 18).

[0136] The degree of flexibility of a linker can depend on the number of rotatable bonds present in the linker. A rotatable bond is defined as a single acyclic bond attached to a non-terminal heavy atom (e.g., an atom other than hydrogen). As described herein, amide (C-N) bonds are not considered rotatable bonds due to their high rotational energy barrier. In some examples, the linker may include one or more moieties selected from a ring, a double bond, and an amide, thereby reducing the flexibility of the linker. In other examples, the linker may include a greater number and / or a higher proportion of single bonds (e.g., may include primarily a single acyclic bond), thereby increasing the flexibility of the linker. It may also be understood that the length of the linker can affect the degree of flexibility. For example, a shorter linker containing fewer bonds may reduce the flexibility of the linker.

[0137] In some embodiments, the number of rotatable bonds present in the linker can be any number between 1 and 20, between 1 and 15, or between 1 and 10. In some embodiments, the number of rotatable bonds present in the linker can be any number between 2 and 9, between 2 and 8, or between 3 and 6.

[0138] In some embodiments, the linker may contain any number of atoms in a single linear chain between 10 and 20, and / or the number of rotatable bonds present in the linker may be any number between 2 and 8.

[0139] The structure of the linker (L) is as follows: (L x ) q wherein each L x represents a subunit of L, q is an integer of 1 or greater.

[0140] For example, q may be any integer between 1 and 30, between 1 and 20, or between 1 and 5.

[0141] For example, when q is 1, the linker is one L x It contains only subunits and can be represented as L1. When q is 2, the linker is made up of two L x The linker comprises subunits, which are covalently bonded to one another and can be represented as L1-L2. As another example, if q is 3, the linker is composed of three L x It contains subunits, which are covalently bonded to each other and can be represented as L1-L2-L3. For higher integer values of q, L can be L1, L2, L3, L4...L q It can contain up to 10 subunits.

[0142] Each L x is CR L1 R L2 , O, C=O, S, S=O, SO2, NR L3 ,SONR L4 ,SONR L5 C=O, CONR L6 , N.R. L7 CO, C(R L8 )=C(R L9), C≡C, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl groups.

[0143] Each R L1 , R L2 , R L3 , R L4 , R L5 , R L6 , R L7 , R L8 , and R L9 can each independently be selected from H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NO2, -CN, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -S(O)OC1-C6 alkyl, -C(O)OC1-C6 alkyl, and -CO(C1-C6 alkyl). In some embodiments, each R L1 , R L2 , R L3 , R L4 , R L5 , R L6 , R L7 , R L8 , and R L9 may each independently be selected from H or C1-C6 alkyl.

[0144] The terms aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl groups are defined above.

[0145] Terminal L x The subunits can link or connect the linker moieties to the TBL and Z moieties of the bifunctional molecule. For example, the terminal L x The subunits are L1 and L q When specified as q can attach a linker to the Z moiety. When q is 1, one Lx A subunit (eg, L1) provides a link between the TBL and Z portions of the bifunctional molecule.

[0146] The TBL and Z moieties can be covalently linked to L through any group that is compatible with the linker chemistry and is stable. By way of example only, the linker may be covalently attached to the TBL moiety through a carbon-carbon bond, a keto, amino, amido, ester, or ether bond. Similarly, the linker may be covalently attached to the Z moiety through a carbon-carbon bond, a carbon-nitrogen bond, a keto, amino, amido, ester, or ether bond.

[0147] In some cases, L at each end x Subunits (e.g., L1 and L q ) is O, C=O, CR L1 R L2 , N.R. L3 ,CONR L6 , N.R. L7 may be independently selected from CO, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl groups.

[0148] In some cases, at least one L x may contain a cyclic structure and be selected from, for example, a heterocycloalkyl group, a heteroaryl group, a cycloalkyl group, or an aryl group.

[0149] In alternative embodiments, the linker is or comprises an alkyl linker, which comprises repeating -CH2- subunits, with the number of repeats ranging from 1 to 50, e.g., 1-50, 1-40, 1-30, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, and 1-2.

[0150] In other embodiments, the linker may be or comprise a polyalkylene glycol. By way of example only, the linker may be or comprise a polyethylene glycol (PEG), where the PEG comprises repeating ethylene glycol (CHO) subunits, e.g., having about 1-50 ethylene glycol subunits, e.g., 1-100 repeat numbers, e.g., 1-50, 1-40, 1-30, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, or 1-5 repeat numbers.

[0151] In some embodiments described herein, the structure of the linker (L) is represented by formula (L1a): [ka] wherein L 1A is absent or is selected from C1-C6 alkylene (e.g., ethylene), C1-C6 alkoxy (e.g., -O(CH2)-, -O(CH2)2-, -O(CH2)5-, -CH2OCH2-), and C1-C6 alkylamino (e.g., -NR L2A (CH2)-, -R L2A (CH2)2-, -R L2A (CH2)5-, -CH2R L2A CH2-), L 2A is -NR L2A C=O- or -C=ONR L2A - and L 3A is C1-C3 alkylene (e.g., ethylene), C1-C6 alkoxy (e.g., —(CH2)O—, —(CH2)2O—, —(CH2)5O—, —CH2OCH2—), and C1-C6 alkylamino (e.g., —(CH2)NR L2A -, -(CH2)2NR L2A -, -(CH2)5NR L2A -, -CH2NR L2A CH2-), where R L2A is H or C1-C6 alkyl (eg, C1-C3 alkyl).

[0152] In a further embodiment, the structure of the linker (L) is represented by formula (L1b): [ka] wherein L 1B is absent or is selected from C1 to C3 alkylene (e.g., ethylene), C1 to C6 alkoxy (e.g., -O(CH2)-, -O(CH2)2-, -O(CH2)5-, -CH2OCH2-), and C1 to C6 alkylamino (e.g., -NR L2A (CH2)-, -NR L2A (CH2)2-, -R L2A (CH2)5-, -CH2R L2A CH2-), L 2B is -NR L2A C=O- or -C=ONR L2A - and L 3B is C1~C 15 Alkylene, -[(CH2)2O] 1-6 (CH2)2-, L 4B is -NR L2A C=O- or -C=ONR L2A - where R L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl), L 5B is C1-C3 alkylene (e.g., ethylene), C1-C6 alkoxy (e.g., —(CH2)O—, —(CH2)2O—, —(CH2)5O—, —CH2OCH2—), and C1-C6 alkylamino (e.g., —(CH2)NR L2A -, -NR L2A (CH2)2-, -(CH2)5NR L2A -, -CH2NR L2A CH2-), where R L2A is H or C1-C6 alkyl (eg, C1-C3 alkyl).

[0153] In some examples described herein, the structure of the linker (L) is represented by formula (L1c): [ka] wherein L 1C is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, any of which may contain one or two additional ring heteroatoms selected from N, O, and S; L 2C is absent or is selected from C1 to C3 alkylene (e.g., ethylene), C1 to C6 alkoxy (e.g., —(CH2)O—, —(CH2)2O—, —(CH2)5O—, —CHOCH2—), and C1 to C6 alkylamino (e.g., —(CH2)NR L2A -, -(CH2)2NR L2A -, -(CH2)5NR L2A -, -CH2NR L2A CH2-), L 3C -R L2B C=O- or -(C=O)R L2B - and L 4C is C1-C3 alkylene (e.g., ethylene), C1-C6 alkoxy (e.g., —(CH2)O—, —(CH2)2O—, —(CH2)5O—, —CH2OCH2—), and C1-C6 alkylamino (e.g., —(CH2)NR L2A -, -(CH2)2NR L2A -, -(CH2)5NR L2A -, -CH2NR L2A CH2-), During the ceremony, R L2Ais H or C1-C6 alkyl (e.g., C1-C3 alkyl), R L2B is NR L2A or an N-linked optionally substituted 4-7 membered monocyclic N-heterocycloalkyl, an optionally substituted 7-12 membered bicyclic N-heterocycloalkyl, or an optionally substituted 8-18 membered tricyclic N-heterocycloalkyl, any of which optionally contain one or two additional ring heteroatoms selected from N, O, and S.

[0154] In an embodiment of the linker (L) represented by formula L1c, L 1C and L 2C In such an embodiment, L 3C R in L2B is an N-linked optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, optionally containing one or two additional ring heteroatoms selected from N, O, and S; and L 3C is R L2B is the terminal subunit of the linker bound to TBL via R L2B The β-glucan is covalently attached to TBL via a suitable β-glucan bond.

[0155] In some embodiments described herein, the structure of the linker (L) is represented by formula (L1d): [ka] wherein L 1D is absent or is selected from C1-C3 alkylene, CO, C1-C3 alkylene (N(C1-C3 alkyl), L 2D is NR L2Aor an optionally substituted 4-7 membered monocyclic N-heterocycloalkyl, an optionally substituted 7-12 membered bicyclic N-heterocycloalkyl, or an optionally substituted 8-18 membered tricyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S; L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl), L 3D is absent or selected from C1-C3 alkylene, —O—, —N(C1-C3 alkyl)-, and CO.

[0156] In a further example, the structure of the linker (L) has the formula (L1e): [ka] wherein L 1E is C1-C3 alkylene (e.g., methylene) or CO, L 2 E is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, either of which optionally contains 1 or 2 additional ring heteroatoms selected from N, O, and S; L 3E is selected from C1 to C3 alkylene (for example, methylene).

[0157] In some embodiments, L 1A , L 1B , L 1C , L 1D , or L 1E is the terminal subunit of the linker structure and is attached (i.e., covalently attached) to the W moiety, and L 3A , L 5B , L 4C , L 3D , L 3E is the terminal subunit of the linker structure and is attached (ie, covalently bound) to the TBL moiety.

[0158] If any of L1A, L1B, or L1D is absent, then L2A, L2B, or L2D is directly (i.e., covalently) attached to the W moiety. If L3D is absent, then L2D is directly (i.e., covalently) attached to the TBL moiety.

[0159] As mentioned above, R L2B L 1C , L 2D , L 2E Linker moieties, such as the example: may be bicyclic or tricyclic, and unless otherwise specified, these moieties may include bonded rings, fused rings, bridged rings, and / or rings joined at spiro centers.

[0160] R L2B L 1C , L 2D , L 2E When any one of the examples is bicyclic, it may be a bridged bicyclic ring (i.e., it may contain two rings that share three or more atoms) or a spirocyclic bicyclic ring (i.e., it may contain two rings that share one atom, e.g., the two rings may be joined at a spiro center).

[0161] L 1C , L 2D , L 2E , or R L2B When any one of the examples of is a bridged bicyclic ring, it may be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl, which may optionally contain one or two additional ring heteroatoms selected from N, O, and S. In some embodiments, L 1C , L 2D , L 2E , or R L2B Examples of L may be 7- or 8-membered bridged bicyclic N-heterocycloalkyl, which may optionally contain one or two additional ring heteroatoms selected from N, O, and S. In some embodiments, L 1C , L 2D , L 2E, or R L2B Examples of may be 7- or 8-membered bridged bicyclic N-heterocycloalkyl optionally containing one additional ring atom selected from N.

[0162] L 1C , L 2D , L 2E , or R L2B When any one of the examples of is a spirocyclic bicyclic ring, it may be an optionally substituted 7-12 membered spirocyclic bicyclic N-heterocycloalkyl, which may optionally contain one or two additional ring heteroatoms selected from N, O, and S. In some cases, L 1C , L 2D , L 2E , or R L2B Examples of L are optionally substituted 7-12 membered spirocyclic bicyclic N-heterocycloalkyls, which may optionally contain one or two additional ring heteroatoms selected from N, O, and S. In some cases, L 1C , L 2D , L 2E , or R L2B Examples of L are bicyclic and include a first 5- to 7-membered ring and a second 3- to 7-membered ring. 1C , L 2D , L 2E , or R L2B Examples of L may be spirocyclic bicyclic N-heterocycloalkyls comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, optionally containing one or two additional ring heteroatoms selected from N, O, and S. In some embodiments, L 1C , L 2D , L 2E , or R L2B An example of may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, which may optionally contain one additional ring heteroatom selected from N.

[0163] In some embodiments, L 1C , L 2D , L 2E , and R L2BThe example structure may be any one selected from the following: [ka] In the formula, L 1A and L 3A is as defined above, X 5 is C(R b )2, NR b or O, R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 3; n' is 1 or 2; m is 0, 1, or 2.

[0164] The dotted lines on the structures above indicate that the linker may be attached at any position in the structure shown (provided it has the correct valence and is chemically compatible).

[0165] In some embodiments, L 1C , L 2D , L 2E , and R L2B An example of is any one selected from the following: [ka]

[0166] The dotted lines on the structures above indicate that the linker may be attached at any position in the structure shown (provided it has the correct valence and is chemically compatible).

[0167] As mentioned above, L 1D is absent or is selected from C1-C3 alkylene, —O—, —N(C1-C3 alkyl)-, and CO. In some embodiments, L 3Dis selected from C1 to C3 alkylene (for example, methylene).

[0168] In some embodiments described herein, the structure of the linker (L) has the formula (Llf), as follows: L 1F (L1f) wherein L 1F is C1-C3 alkylene, CO, and C1-C3 alkylene (NR L1C ), where R L1C is H or C1-C3 alkyl.

[0169] In some embodiments, L 1F is selected from C1 to C3 alkylene (for example, methylene).

[0170] In any of the examples described herein, the linker is or includes one or more of the following: [ka] TIFF2025525347000067.tif199170 In the formula, q1 is an arbitrary integer between 1 and 20, or between 1 and 10 (for example, between 1 and 5).

[0171] Alternatively, in any of the examples described herein, the linker is or includes one or more of the following: [ka] TIFF2025525347000069.tif249170 In the formula, q2 is any integer between 1 and 20, or between 1 and 10 (for example, 3, 4, 5, 6, or 10).

[0172] Alternatively or additionally, in any of the examples described herein, the linker is or includes one or more of the following: [ka] In the formula, q1 is any integer between 1 and 20, or between 1 and 10 (e.g., between 1 and 5), and q2 is any integer between 1 and 20, or between 1 and 10 (e.g., 3, 4, 5, 6, or 10).

[0173] In certain embodiments, the linker is or includes one or more of the following structures: [ka] TIFF2025525347000072.tif111170

[0174] Alternatively or additionally, in any of the examples described herein, the linker is or includes one or more of the following: [ka] In the formula, q3 is 1 to 8, for example, 1 to 5, and q4 is 1 to 12, for example, 1 to 10. [ka] TIFF2025525347000075.tif190170TIFF2025525347000076.tif164170

[0175] In certain embodiments, the linker is or includes one or more of the following structures: [ka] TIFF2025525347000078.tif194170TIFF2025525347000079.tif198170TIFF2025525347000080.t if141170TIFF2025525347000081.tif207170TIFF2025525347000082.tif196170TIFF20255253470 00083.tif217170TIFF2025525347000084.tif211170TIFF2025525347000085.tif182170TIFF202 5525347000086.tif136122TIFF2025525347000087.tif180170TIFF2025525347000088.tif114170

[0176] In some cases, the structures shown above represent the entire linker. In other examples, the linker of the bifunctional molecule may include multiple structures shown above.

[0177] In these structures, wavy lines are shown on the bond(s) that form the link between each TBL and Z moiety.

[0178] In some embodiments, the bond forming the link between the TBL and / or Z moieties is attached to a cyclic structure. On many of the structures described herein, the bond is shown attached to a specific position on the cyclic structure. However, the present disclosure also encompasses attaching or connecting the TBL and Z moieties at any chemically suitable position on these cyclic structures.

[0179] The present disclosure encompasses the use of any of the linkers disclosed herein in combination with any of the Z and TBL moieties described herein.

[0180] Target protein As used herein, a "target protein" can be any polypeptide or protein that one of skill in the art desires to be selectively degraded within a cell or within a mammal, such as a human or animal subject. In other words, a "target protein" can be a protein or polypeptide selected by one of skill in the art for increased proteolysis within a cell. The term "selected target protein" can be any polypeptide or protein selected as a target for increased proteolysis and / or proteolysis.

[0181] In some examples of the present disclosure, the term "target protein" does not include the androgen receptor. As used herein, "androgen receptor" refers to the protein designated as P10275 (ANDR_HUMAN) in UniProtKB.

[0182] In some examples of the present disclosure, the term "target protein" does not include estrogen receptor. As used herein, "estrogen receptor" refers to the protein designated as P03372 (ESR1_HUMAN) in UniProtKB.

[0183] In other words, in some embodiments, the bifunctional molecules disclosed herein may not be intended for or suitable for use in the targeted degradation of a target protein selected from (i) the estrogen receptor, and (ii) the androgen receptor.

[0184] According to the present disclosure, degradation of a target protein can occur when the target protein is exposed to and / or contacts the bifunctional molecules described herein, for example, when the target protein is exposed to and / or contacts any one of the bifunctional molecules within a cell.

[0185] Selective degradation and / or increased proteolysis of the target protein can result in a decrease in the level of the target protein and therefore a decrease in the action of the target protein in the cell. Control of the levels of a particular protein by the bifunctional molecules described herein can provide treatment for disease states or conditions regulated through or by the target protein by reducing the level of that protein in the cells of a subject.

[0186] Target proteins that can be subject to increased proteolysis and / or selective degradation upon contact with the bifunctional molecules of the present disclosure (and related methods for using such molecules) include any proteins and polypeptides that have a biological function or activity, such as structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transport, and signaling functions or activities.

[0187] By way of example, target proteins may include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integrated function of a cell (including catalytic activity, epigenetic regulation, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signaling molecule activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, biological processes, development, regulation of cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity, permease activity, secretion activity, electron transport activity, virulence, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular tissue assembly and biosynthesis activity, translation regulatory activity).

[0188] Target proteins may include proteins from eukaryotes and prokaryotes, including humans, other animals including livestock, microorganisms, viruses, fungi and parasites, among many other targets of drug therapy.

[0189] In some examples, target proteins may include, but are not limited to: (i) kinases (including serine / threonine kinases and receptor tyrosine kinases), (ii) bromodomain-containing proteins (such as BET family proteins), (iii) epigenetic proteins (including histone or DNA methyltransferases, acetyltransferases, deacetylases, and demethylases); (iv) transcription factors (including STAT3 and Myc), (v) GTPases (including KRAS, NRAS, and HRAS), (vi) phosphatases, and (vii) ubiquitin E3. (viii) nuclear hormone receptors (e.g., thyroid hormone receptor, androgen receptor (AR), and estrogen receptor (ER), although as noted above, in some embodiments, the target proteins may not include androgen receptors and estrogen receptors); (ix) aggregation proteins (including beta-amyloid, tau, Htt, alpha-synuclein, and polyQ-expansion proteins); (x) apoptotic and anti-apoptotic factors (including Bcl2, Bcl-xl, and Mcl-1); and (xi) polymerases (including PARP and POLQ), among many others.

[0190] The target protein may also be selected from targets of human therapeutic drugs, including proteins used to restore function in many diseases (e.g., multifactorial diseases). For example, target proteins may be selected from the following: B7.1 and B7, TNFR1, TNFR2, NADPH oxidase, BclI / Bax and other partners of the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE type V phosphodiesterase, PDE type IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5-HT receptor, dopamine receptor, G protein (i.e., Gq), histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosomal GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAK STAT, RXR and similar, HIV-1 protease, HIV-1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), serine / threonine kinase, tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and their receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / MEK / ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-1) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, endoplasmic reticulum transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin II, glycine receptor, noradrenaline reuptake receptor, endothelial cell membrane protein (ECM) Protein targets include phosphoreceptors, neuropeptide Y and its receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, NGF receptor TrkA, beta-amyloid, tyrosine kinase Flk-II / KDR, vitronectin receptor, integrin receptor, Her-2 / neu, telomerase inhibitor, cytoplasmic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel. Additional target proteins include acetyl-CoA carboxylase, adenylsuccinate synthase, SMARCA2, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[0191] The target protein may be a haloalkane dehalogenase enzyme. For example, a bifunctional molecule according to the present disclosure containing a chloroalkane peptide-binding moiety (a C1-C12, typically about C2-C10 alkylhalo group) can be used to inhibit and / or degrade the haloalkane dehalogenase enzyme used in the fusion proteins or related diagnostic proteins described in PCT / US2012 / 063401, filed December 6, 2011, and published June 14, 2012 as WO2012 / 078559, the contents of which are incorporated herein by reference.

[0192] Target Protein Binding Ligands (TBLs) As used herein, a "target protein-binding ligand" refers to a ligand or moiety that binds to a target protein, e.g., a selected target protein. By way of example, a target protein-binding ligand may be any moiety that selectively and / or specifically binds to a target protein. A bifunctional molecule according to the present disclosure may include a target protein-binding ligand that binds to a target protein with sufficiently high binding affinity that the target protein is more susceptible to degradation or proteolysis than if it were not bound to the bifunctional molecule.

[0193] The target protein binding ligand may bind to the target protein with a binding affinity of about 10 μM or less, about 1 μM or less, about 0.5 μM or less, or about 0.1 μM or less.

[0194] In some examples, the ligand may bind to the target protein with a binding affinity of about 0.01 nM to about 10 μM, eg, about 0.01 nM to about 8 μM, about 0.01 nM to about 5 μM, or about 0.01 nM to about 3 μM.

[0195] To avoid any misunderstanding, binding affinity is a measure showing the tendency of two components bound together to separate (dissociate) into the two components. As used herein, binding affinity refers to a measure showing the tendency of a complex formed by binding a target protein-binding ligand to a target protein to dissociate into its individual components, i.e., the tendency of the target protein-binding ligand to dissociate from the target protein.

[0196] The bond between the target protein and the target protein-binding ligand may comprise one or more bonding interactions, such as one or more of the group consisting of hydrogen bonds, dipole-dipole bonds, ion-dipole bonds, ion-induced dipole bonds, ionic bonds, and covalent bonds. For example, the bond between the target protein and the target protein-binding ligand may comprise a salt bridge (a combination of hydrogen bonds and ionic bonds).

[0197] As noted above, in some embodiments, the target protein binding ligand moiety may not be a target protein binding ligand selected from (i) an estrogen receptor binding ligand and (ii) an androgen receptor binding ligand. In particular, in some embodiments, the target protein ligand included within a bifunctional molecule of the present disclosure is (i) not a ligand that specifically binds to an estrogen receptor, and (ii) not a ligand that specifically binds to an androgen receptor.

[0198] In some examples, the bifunctional molecules disclosed herein do not comprise a target protein binding ligand that binds to the estrogen receptor with a binding affinity of about 10 μM or less, or about 1 μM or less.

[0199] In other words, in some examples, the bifunctional molecules disclosed herein may not comprise a target protein binding ligand that binds to the estrogen receptor with sufficient binding affinity to selectively degrade the estrogen receptor. In particular, when the bifunctional molecules described herein contact the estrogen receptor, the observed DCs 50 The value (for degradation of the estrogen receptor) will be greater than about 10,000 nM, or greater than about 1,000 nM.

[0200] In some examples, the bifunctional molecules disclosed herein may not comprise a target protein binding ligand that binds to the androgen receptor with a binding affinity of about 10 μM or less, or about 1 μM or less.

[0201] Furthermore, in some embodiments, the bifunctional molecules disclosed herein may not contain a target protein binding ligand that binds to the androgen receptor with sufficient binding affinity to selectively degrade the androgen receptor. In particular, when the bifunctional molecules described herein contact the androgen receptor, the observed DCs 50The value (relative to degradation of the androgen receptor) will be greater than about 10,000 nM, or greater than about 1,000 nM.

[0202] A target protein binding ligand may constitute or be derived from a small molecule (or analog or fragment thereof) already known to act as a modulator, promoter, and / or inhibitor of protein function (e.g., any small molecule known to bind to a target protein). By way of example, a target protein binding ligand may constitute or be derived from a small molecule known to inhibit the activity of a particular target protein.

[0203] Non-limiting examples of small molecules that can be included in the target protein-binding ligand portion of the bifunctional molecules described herein include: (i) binders to kinases (serine kinase / threonine kinases (e.g., RAF), receptor tyrosine kinases, and other classes); (ii) compounds that bind to bromodomain-containing proteins (BET family and others); (iii) epigenetic modulating compounds (histone or DNA methyltransferases, acetyltransferases, deacetylases, demethylases, and others, e.g., histone deacetylases (HDACs), lysine acetyltransferases such as P300 (EP300; 300 kDa adenovirus E1A binding protein) and CBP (CREBBP; cyclic-AMP response element binding protein)); and (iv) compounds that bind to transcription factors (STAT3, myc, and others). compounds; (v) conjugates to GTPases (KRAS, NRAS, HRAS, and others), (vi) conjugates to phosphatases, (vii) conjugates to ubiquitin E3 ligases (e.g., MDM2) and deubiquitinating enzymes, (viii) conjugates to nuclear hormone receptors (e.g., thyroid receptor, androgen receptor (AR), and estrogen receptor (ER)) (although in some embodiments, as noted above, the target binding ligand may not include conjugates to androgen receptors), (ix) conjugates to aggregation-prone proteins (including beta-amyloid, tau, Htt, alpha-synuclein, and polyQ-expansion proteins), (x) conjugates to apoptotic and anti-apoptotic factors (including Bcl2, Bcl-xl, and Mcl-1), and (xi) conjugates to polymerases (including PARP and POLQ).

[0204] Other non-limiting examples of small molecules that can be included in the target protein-binding ligand portion of the bifunctional molecules described herein include (i) Hsp90 inhibitors, (ii) human lysine methyltransferase inhibitors, (iii) angiogenesis inhibitors, (iv) compounds that target the aryl hydrocarbon receptor (AHR), (v) compounds that target FKBP, (vi) compounds that target HIV protease, (vii) compounds that target HIV integrase, (viii) compounds that target HCV protease, and (ix) compounds that target acylprotein thioesterase-1 and -2 (APT1 and APT2), among many others.

[0205] BET inhibitors In some examples, the target protein binding ligand is derived from a BET inhibitor (e.g., the BET inhibitor IBET276). In such examples, the target protein binding ligand has the following structure: [ka] where L indicates the attachment position of the linker, and the dotted line in the structure indicates that the linker may be attached to the target protein binding ligand via any position on the aromatic ring (e.g., in some examples, L may be at the 4-position on the aromatic ring). However, the present disclosure also encompasses attaching or connecting to the linker at any chemically suitable position on the target protein binding ligand.

[0206] BRD9 Alternatively, the target protein binding ligand may be derived from a BRD9 inhibitor, for example, the target protein binding ligand has the following structure: [ka] where L indicates the attachment position of the linker. The present disclosure also encompasses attaching or connecting to the linker at any other chemically suitable position on the target protein-binding ligand.

[0207] Kinase inhibitors In other embodiments, the target protein binding ligand is derived from a kinase inhibitor. In such embodiments, the target protein binding ligand has the following structure: [ka] where L indicates the attachment position of the linker. However, the present disclosure also encompasses attaching or connecting to the linker at any chemically suitable position on the target protein-binding ligand.

[0208] The target protein binding ligand may be derived from a kinase inhibitor, such as a CDK9 inhibitor, and has the following structure: [ka] where L indicates the attachment position of the linker. The present disclosure also encompasses attaching or connecting to the linker at any other chemically suitable position on the target protein-binding ligand.

[0209] EGFR Alternatively, the target protein binding ligand may be derived from a kinase inhibitor, such as a mutant EGFR inhibitor, and has the following structure: [ka] where L indicates the attachment position of the linker. Similarly, the present disclosure also encompasses attaching or connecting to the linker at any other chemically suitable position on the target protein-binding ligand.

[0210] In some embodiments, the target protein binding ligand has the formula (EGFR1): [ka] where R 2A is C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, heteroaryl, -O(C1-C6 alkyl), and -NR a1 R b1 wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, and heteroaryl are optionally selected from 1 to 5 R f1 may further have a group, In the formula, each R a1 are each independently H or C1-C6 alkyl, Here, each R b1 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, amino, -(CH2) m1 C(O)NH2, -(CH2) m1 C3-C7 cycloalkyl, -(CH2) m1 C3-C7 heterocycloalkyl, or -(CH2) m1 is heteroaryl, Here, each R f1 are each independently C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, C1-C6 alkylamino, amido, urea, oxo, halo, pyrazolyl, imidazolyl, triazolyl, CN, -NHC(O)(C1-C3 alkyl), acyl, sulfonyl, sulfoxide, sulfonamido, sulfoxyiminyl, -(CH2) m1 C3-C7 heterocycloalkyl and C(O)OR a1 is selected from the group consisting of R 2B is hydrogen and R 2C Ha-NHC(O)R 2D where R 2Dis selected from aryl and heteroaryl, optionally further bearing 1 to 2 substituents independently selected from C1-C6 alkyl, halo, C1-C6 alkoxy, and CN; or R 2B and R 2C taken together form a 5-10 membered aryl or heteroaryl ring, optionally substituted with 1 to 5 substituents independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 alkoxy, CN, amino, C1-C6 alkylamino, -O(C1-C6 haloalkyl), oxo, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl optionally substituted with C1-C3 alkyl, C1-C6 hydroxyalkyl, aryl, and heteroaryl; Each m1 is independently 0, 1, 2, or 3.

[0211] The target protein binding ligand (TBL) of formula (EGFR1) may be attached to the linker L of the bifunctional molecule by a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker may be attached at any suitable position, e.g., as long as it has the correct valence and / or is chemically suitable. For example, the linker of the bifunctional molecule may be attached to the R 2B or R 2C The moiety may be covalently attached at any position (provided it has the correct valence and / or is chemically feasible).

[0212] In some embodiments of Formula (EGFR1), R 2A is a C3-C7 heterocycloalkyl. In particular, R 2A is optionally 1 to 3 R f1 In some embodiments, R may be a C3-C7 heterocycloalkyl containing at least one N ring atom substituted with a group (as defined above). 2A has the following structure: [ka] wherein R f1 is a halo and the wavy line crosses the bond that forms the bond to the pyrimidinyl core of formula (EGFR1).

[0213] In some embodiments, the target protein binding ligand has the formula (EGFR2): [ka] where R A1 is C3-C7 heterocycloalkyl, heteroaryl, -O(C1-C6 alkyl), or -NR a1 R b1 wherein the C3-C7 heterocycloalkyl and heteroaryl are optionally selected from 1 to 5 R f1 may further have a group, R A2 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and C3-C7 heterocycloalkyl; R A3 is absent or is C1-C6 alkyl, C3-C7 heterocycloalkyl, C3-C7 cycloalkyl, -O(C1-C6 alkyl), CN, -NR a1 R a1 , -NHC(O)(C1-C3 alkyl), -C(O)NR a1 R b1 and heteroaryl; Here, each R f1 are each independently C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, C1-C6 alkylamino, amido, urea, oxo, halo, pyrazolyl, imidazolyl, triazolyl, CN, -NHC(O)(C1-C3 alkyl), acyl, sulfonyl, sulfoxide, sulfonamido, sulfoxyiminyl, -(CH2) m1 C3-C7 heterocycloalkyl and C(O)OR a1 is selected from the group consisting of In the formula, each R a1are each independently H or C1-C6 alkyl, Here, each R b1 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, amino, -(CH2) m1 C(O)NH2, -(CH2) m1 C3-C7 cycloalkyl, -(CH2) m1 C3-C7 heterocycloalkyl, or -(CH2) m1 is heteroaryl, Or R a1 and R b1 may be joined together to form a C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, or heteroaryl ring, and the C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, and heteroaryl may each be further substituted with 1 to 3 groups selected from the group consisting of halo, hydroxy, C1-C3 alkyl, amino, oxo, amido, sulfonyl, sulfoxide, sulfoximinyl, sulfonamido, C1-C3 alkoxy, CN, and acyl; X A1 is selected from N and CH; Each m1 is independently 0, 1, 2, or 3.

[0214] In some embodiments of Formula (EGFR2), X A1 is N.

[0215] In some embodiments of Formula (EGFR2), R A1 is C3-C7 heterocycloalkyl, heteroaryl, and NR a1 R b1 is selected from.

[0216] In some embodiments of Formula (EGFR2), R A1 is selected from C3-C7 heterocycloalkyl and heteroaryl, and the C3-C7 heterocycloalkyl and heteroaryl further comprise 1 to 5 R f1 groups, where each R f1 are each independently selected from sulfonyl, alkoxy, and halo; RA3 is absent or -C(O)NR a1 R b1 and;R A2 is C1-C6 alkyl.

[0217] In some embodiments of Formula (EGFR2), R A1 is a C5-C7 heterocycloalkyl containing at least one N heteroatom (eg, piperidinyl) or a heteroaryl containing at least one N heteroatom in the ring (eg, pyrazolyl).

[0218] In some embodiments of Formula (EGFR2), R f1 is selected from -SO2(C3-C7 cycloalkyl) (e.g., -SO2(cyclopropyl)), halo (e.g., F), hydroxy, C1-C6 alkyl, and C1-C6 alkoxy (e.g., methoxy).

[0219] In some embodiments of Formula (EGFR2), R A2 is C1-C6 alkyl or C1-C6 haloalkyl, for example, C1-C4 alkyl or C1-C4 haloalkyl. R A2 Representative examples include, but are not limited to, isopropyl, sec-butyl, and 1,1,1-trifluoropropan-2-yl.

[0220] In some embodiments of Formula (EGFR2), R A3 is C1-C3 alkyl, C3-C7 heterocycloalkyl, heteroaryl, -NR a1 R a1 , and -C(O)NR a1 R b1 is selected from.

[0221] In some embodiments of Formula (EGFR2), R A1is selected from C3-C7 heterocycloalkyl (e.g., piperidinyl) and heteroaryl (e.g., pyrazolyl), wherein the C3-C7 heterocycloalkyl or heteroaryl is selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halo, sulfonyl, and sulfonamido. f1 The group is optionally further substituted.

[0222] In some examples, the target protein binding ligand has the formula (EGFR2a): [ka] where R A2 and R A3 is as defined in equation (2), R f1b is selected from H and C1-C6 alkyl (e.g., C1-C3 alkyl), R f1a is absent or a halo.

[0223] The target protein binding ligands (TBL) of formula (EGFR2) and (EGFR2a) may be attached to the linker L of the bifunctional molecule via a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker may be attached at any suitable position, e.g., as long as it has the correct valence and / or is chemically suitable. For example, the linker of the bifunctional molecule may be attached to the R of formula (EGFR2) or (EGFR2a). A3 R may be covalently attached to the moiety at any position (provided it has the correct valence and / or is chemically compatible). A3 In instances where no linker is present, the linker of the bifunctional molecule may be covalently attached to the heteroaryl ring as shown in formulas (EGFR2) and (EGFR2a).

[0224] In some examples, the target protein binding ligand has the formula (EGFR3): [ka] where R A1 is C3-C7 heterocycloalkyl, heteroaryl, -O(C1-C6 alkyl), or -NR a1 R b1 wherein the C3-C7 heterocycloalkyl and heteroaryl are optionally selected from 1 to 5 R f1 may further have a group, R A2 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and C3-C7 heterocycloalkyl; R A3’ is absent or selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 alkoxy, CN, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, —O(C1-C6 haloalkyl), oxo, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl optionally substituted with C1-C3 alkyl, C1-C6 hydroxyalkyl, aryl, and heteroaryl; Here, each R f1 are each independently C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, C1-C6 alkylamino, amido, urea, oxo, halo, pyrazolyl, imidazolyl, triazolyl, CN, -NHC(O)(C1-C3 alkyl), acyl, sulfonyl, sulfoxide, sulfonamido, sulfoximinyl, -(CH2) m1 C3-C7 heterocycloalkyl, —O(C1-C6 alkyl), and C(O)OR a1 is selected from the group consisting of In the formula, each R a1 are each independently selected from H or C1-C6 alkyl; Here, each R b1 are each independently H, C1-C6 alkyl, C1-C6 alkoxy, amino, -(CH2) m1 C(O)NH2, -(CH2) m1C3-C7 cycloalkyl, -(CH2) m1 C3-C7 heterocycloalkyl, or -(CH2) m1 is heteroaryl, Or R a1 and R b1 may be joined together to form a C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, or heteroaryl ring, and the C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, and heteroaryl may each be further substituted with 1 to 3 groups selected from the group consisting of halo, hydroxy, C1-C3 alkyl, amino, oxo, amido, sulfonyl, sulfoxide, sulfoximinyl, sulfonamido, C1-C3 alkoxy, CN, and acyl; Each m1 is independently 0, 1, 2, or 3; n' is 0, 1, or 2.

[0225] In the example where n' is 2, each R A3’ are each independently selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 alkoxy, CN, amino, C1-C6 alkylamino, —O(C1-C6 haloalkyl), oxo, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl optionally substituted with C1-C3 alkyl, C1-C6 hydroxyalkyl, aryl, and heteroaryl.

[0226] In some embodiments of formula (3), R A1 is selected from C3-C7 heterocycloalkyl and heteroaryl, wherein the C3-C7 heterocycloalkyl and heteroaryl further comprise 1 to 5 R as defined above. f1 Further examples include R A1 may be selected from C5-C7 heterocycloalkyl containing at least one N ring atom (e.g., piperidinyl) and 5-6 membered heteroaryl containing 1, 2 or 3 N ring atoms (e.g., pyrazolyl), both of which may further contain 1-5 R as defined above. f1 The group may be optionally substituted with a group.

[0227] In some examples, the target protein binding ligand has the formula (EGFR3a): [ka] where R A2 , R A3’ and n' are as defined in formula (EGFR3), R f1b is selected from H and C1-C6 alkyl (e.g., C1-C3 alkyl), R f1a is absent or a halo.

[0228] In some embodiments of formula (EGFR3) or (EGFR3a), R A2 may be C1-C6 alkyl (eg, isopropyl).

[0229] In some embodiments of formula (EGFR3) or (EGFR3a), R A3’ may be selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, C3-C7 heterocycloalkyl optionally substituted with C1-C3 alkyl, and —O(C1-C6 haloalkyl).

[0230] In some embodiments of formula (3) or (3a), n' is 2 and the first R A3’ is —O(C1-C6 haloalkyl), and the second R A3’ is a C3-C7 heterocycloalkyl optionally substituted with a C1-C3 alkyl.

[0231] In some embodiments of formula (3) or (3a), n' is 1 and R A3’ is —O(C1-C6 haloalkyl).

[0232] The target protein binding ligands (TBL) of formula (EGFR3) and (EGFR3a) may be attached to the linker L of the bifunctional molecule by a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker may be attached at any suitable position, e.g., as long as it has the correct valence and / or is chemically suitable. For example, the linker of the bifunctional molecule may be attached to the R of formula (EGFR3) or (EGFR3a). A3’ R may be covalently bonded to the moiety at any position (provided it has the correct valence and / or is chemically compatible). A3’ In instances where is not present, the linker of the bifunctional molecule may be covalently attached to the heteroaryl ring, as shown in formulas (EGFR3) and (EGFR3a).

[0233] Representative examples of target protein binding ligands that can be incorporated into the bifunctional molecules of the present disclosure are shown below. [ka] wherein L in the above structure represents the point of attachment of the linker. Similarly, the present disclosure also encompasses attaching or connecting to the linker at any other chemically suitable position on the target protein-binding ligand. [ka] As noted above, the linker may be attached at any suitable position, provided that it has, for example, the correct valency and / or is chemically compatible with the target protein binding ligand.

[0234] As shown in the structure above, the TBL moiety may contain one or more chiral centers. As noted above, the present disclosure encompasses each individual enantiomer of these TBL moieties, as well as mixtures, including racemic mixtures, of such enantiomers. Further by way of example, if the TBL moiety contains more than one chiral center, the present disclosure encompasses each individual diastereomer of the TBL moiety and mixtures of various diastereomers.

[0235] As a specific example, a target protein binding ligand that can be incorporated into a bifunctional molecule of the present disclosure can be represented as follows: [ka]

[0236] KRAS In some cases, the target protein binding ligand can be derived from a GTPase inhibitor, such as a KRAS G12C inhibitor. For example, the target protein binding ligand may have the following structure: [ka] where L indicates the attachment position of the linker. Similarly, the present disclosure also encompasses attaching or connecting to the linker at any other chemically suitable position on the target protein-binding ligand.

[0237] In some cases, the target protein binding ligand can be derived from a GTPase inhibitor, such as a KRAS G12D inhibitor. For example, the target protein binding ligand may have the following structure: [ka] where L indicates the attachment position of the linker. Similarly, the present disclosure also encompasses attaching or connecting to the linker at any other chemically suitable position on the target protein-binding ligand.

[0238] Thus, in some embodiments, the target protein binding ligand has the formula (KRAS1): [ka] where: Ring A 1 represents an optionally substituted saturated or unsaturated 5-10 membered N-containing ring, containing at least one additional heteroatom selected from the group consisting of N, S, and O, and is optionally bridged; Ring B 1 is a 5- to 6-membered unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and O, a 6- to 10-membered (e.g., 6-membered) aromatic hydrocarbon ring, C 3-6 represents an optionally substituted moiety selected from a cycloalkene ring and an 8- to 10-membered spiro ring, wherein ring B1 is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n1 is 0 or 1, X 1 is O or S, Y 1 is an optionally substituted moiety selected from a 6- to 10-membered aromatic hydrocarbon ring and a 6- to 10-membered unsaturated mono- or bicyclic ring containing at least one heteroatom selected from the group consisting of N, S, and O; L 1 is absent or O, optionally substituted C 2-3 Alkynylene and NR c any one moiety selected from the group consisting of Z 1 teeth, (i) cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, optionally substituted C 3-6any moiety selected from cycloalkyl, a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of N, S, and O, and an 8- to 10-membered partially unsaturated ring containing at least one heteroatom selected from the group consisting of N, S, and O; or (ii) hydrogen, -N(R C )2, heterocyclyl, C 1-6 Alkyl, -D-heterocyclyl, -D-aryl, -D-heteroaryl, -D-cycloalkyl, -DN(RC)2, -D-NHC(=NH)NH2, -DC(O)N(RC)2, -DC 1-6 Haloalkyl, -D-ORC, -D-(CH2ORC)(CH2)nOR C , -D-NR C C(O)-aryl, -D-COOH, and -DC(O)OC 1-6 any one moiety selected from alkyl, wherein -D-NR C The heterocyclyl and aryl portions of C(O)-aryl, the heterocyclyl portion of -D-heterocyclyl, and the cycloalkyl portion of -D-cycloalkyl may optionally be joined by one or more R D and the aryl or heteroaryl in -D-aryl and -D-heteroaryl may optionally be substituted with one or more R E may be substituted with a moiety, Each D is independently hydroxy, C 1-4 C optionally substituted with hydroxyalkyl or heteroaryl 1-4 is alkylene, Each R C are each independently hydrogen or C 1-3 is alkyl, Each R D are each independently halo, hydroxy, C 1-3 Hydroxyalkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, cyano, -Q-phenyl, -Q-phenylSOF, -NHC(O)phenyl, -NHC(O)phenylSOF, C 1-3 Alkyl-substituted pyrazolyl, AraC1-3 Alkyl-, tert-butyldimethylsilyloxyCH2-, -N(RC)2, (C 1-3 Alkoxy)C 1-3 Alkyl-, (C 1-3 alkyl)C(O)-, oxo, (C 1-3 haloalkyl)C(O)-, -SO2F, (C 1-3 Alkoxy)C 1-3 Alkoxy, -CH2OC(O)N(R C )2, -CH2NHC(O)OC 1-6 Alkyl, -CH2NHC(O)N(R C )2, -CH2NHC(O)C 1-6 Alkyl, -CH2(pyrazolyl), -CH2NHSO2C 1-6 Alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R C )2, -OC(O)NH(C 1-3 alkyl)O(C 1-3 alkyl), -OC(O)NH(C 1-3 alkyl)O(C 1-3 alkyl)phenyl(C 1-3 alkyl)N(CH3)2, -OC(O)NH(C 1-3 alkyl)O(C 1-3 -C(O)phenyl or -OC(O)heterocyclyl, -CH2heterocyclyl, wherein -NHC(O)phenyl or -OC(O)NH(C 1-3 alkyl)O(C 1-3 the phenyl of the -alkyl)phenyl is optionally substituted with -C(O)H or OH, and the heterocyclyl of the -CHheterocyclyl is optionally substituted with oxo; Q is a bond or O; Each R E are each independently halogen, hydroxy, HC(O)-, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, or -N(R C )2, m is 0 to 3.

[0239] The linker may be attached at any suitable position in the structure of formula (1), for example, where the valence allows for substitution or additional covalent attachment of the linker moiety. 1 The nucleotide sequence is linked to TBL via a suitable substitution on the nucleotide sequence.

[0240] In some embodiments of formula (KRAS1), L 1 C 2-3 When Z is alkynylene, 1 is alkylaminocarbonyl or alkylaminoalkyl, and m1 is 0 or 1. In some embodiments of formula (KRAS1), Z 1 is as defined in (ii), then m1 is 0.

[0241] Y in formula (KRAS1) 1 The optional substituents of are halo, cyano, hydroxy, C 1-4 Alkyl, -SC 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-3 Cyanoalkyl, triazolyl, C 1-3 Haloalkyl, -OC 1-3 Haloalkyl, -SC 1-3 Haloalkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, -CHC(O)N(R C )2, -C 3-4 Alkynyl (NR C )2, -N(R C )2, Deutero C 2-4 Alkynyl, (C 1-3 Alkoxy) Halo C 1-3 Alkyl, and C 3-6 cycloalkyl, where C 3-6 Cycloalkyl is optionally halo or C 1-3 It is substituted with alkyl.

[0242] The target protein binding ligand of formula (KRAS1) may be attached to the linker L of the bifunctional molecule by a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker may be attached at any suitable position, e.g., as long as it has the correct valence and / or is chemically suitable. For example, the linker of the bifunctional molecule may be covalently attached to the Z1 moiety of formula (KRAS1) at any position, provided it has the correct valence and / or is chemically compatible.

[0243] In some embodiments, the target protein binding ligand has the formula (KRAS2): [ka] where: Ring A 1 represents an optionally substituted saturated or unsaturated 8-10 membered N-containing bridged ring, which ring contains at least one additional heteroatom selected from the group consisting of N, S and O; Ring B 1 represents a 5- to 6-membered unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and O, a 6-membered aromatic hydrocarbon ring, C 3-6 represents an optionally substituted moiety selected from the group consisting of a cycloalkene ring and an 8- to 10-membered spiro ring, wherein ring B1 is fused with the pyrimidine ring to form a substituted or unsubstituted bicyclic ring; n1 is 0 or 1, X 1 is O or S, Y 1 is an optionally substituted moiety selected from a 6- to 10-membered aromatic hydrocarbon ring and a 6- to 10-membered unsaturated mono- or bicyclic ring containing at least one heteroatom selected from the group consisting of N, S, and O; L 1 is O or optionally substituted C 2-3 is alkynylene, Z 1is cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, optionally substituted C 3-6 any one moiety selected from the group consisting of cycloalkyl, a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of N, S, and O, and an 8- to 10-membered partially unsaturated ring containing at least one heteroatom selected from the group consisting of N, S, and O; m1 is 0 to 3 (for example, m1 is 0 or 1).

[0244] Suitably, L or LZ of the degraded derivative is attached to the Z1 moiety.

[0245] In some embodiments of formula (KRAS2), L 1 C with optional substitution 2-3 When Z is alkynylene, 1 is alkylaminocarbonyl or alkylaminoalkyl.

[0246] In some particular examples, the target protein binding ligand has the formula (KRAS3): [ka] where: L 1 is absent or is any one moiety selected from the group consisting of O and NRC, Z 1 teeth, (ii) hydrogen, -N(R C )2, heterocyclyl, C 1-6 Alkyl, -D-heterocyclyl, -D-aryl, -D-heteroaryl, -D-cycloalkyl, -DN(R C )2, -D-NHC(=NH)NH2, -DC(O)N(R C )2, -DC 1-6 Haloalkyl, -D-OR C , -D-(CH2OR C )(CH2)nORC , -D-NR C C(O)-aryl, -D-COOH, and -DC(O)OC 1-6 alkyl, wherein -D-NR C The heterocyclyl and aryl portions of C(O)-aryl, the heterocyclyl portion of -D-heterocyclyl, and the cycloalkyl portion of -D-cycloalkyl may optionally be joined by one or more R D wherein the aryl or heteroaryl portion of -D-aryl and -D-heteroaryl may optionally be substituted with any one or more R E may be replaced by, where Each D is independently hydroxy, C 1-4 C optionally substituted with hydroxyalkyl or heteroaryl 1-4 is alkylene, Each R C are each independently hydrogen or C 1-3 is alkyl, Each R D are each independently halo, hydroxy, C 1-3 Hydroxyalkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, cyano, -Q-phenyl, -Q-phenylSOF, -NHC(O)phenyl, -NHC(O)phenylSOF, C 1-3 Alkyl-substituted pyrazolyl, AraC 1-3 Alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R C )2, (C 1-3 Alkoxy)C 1-3 Alkyl-, (C 1-3 alkyl)C(O)-, oxo, (C 1-3 haloalkyl)C(O)-, -SO2F, (C 1-3 Alkoxy)C 1-3 Alkoxy, -CH2OC(O)N(R C )2, -CH2NHC(O)OC 1-6 Alkyl, -CH2NHC(O)N(R C )2, -CH2NHC(O)C1-6 Alkyl, -CH2(pyrazolyl), -CH2NHSO2C 1-6 Alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R C )2, -OC(O)NH(C 1-3 alkyl)O(C 1-3 alkyl), -OC(O)NH(C 1-3 alkyl)O(C 1-3 alkyl)phenyl(C 1-3 alkyl)N(CH3)2, -OC(O)NH(C 1-3 alkyl)O(C 1-3 -C(O)phenyl or -OC(O)heterocyclyl, -CH2heterocyclyl, wherein -NHC(O)phenyl or -OC(O)NH(C 1-3 alkyl)O(C 1-3 the phenyl of the -alkyl)phenyl is optionally substituted with -C(O)H or OH, and the heterocyclyl of the -CHheterocyclyl is optionally substituted with oxo; Q is a bond or O; Each R E are each independently halo, hydroxy, HC(O)-, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, or -N(R C )2, R I is aryl or heteroaryl, and the aryl or heteroaryl is halo, cyano, hydroxy, C 1-4 Alkyl, -SC 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-3 Cyanoalkyl, triazolyl, C 1-3 Haloalkyl, -OC 1-3 Haloalkyl, -SC 1-3 Haloalkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, -CHC(O)N(R C )2, -C3-4 Alkynyl (NR C )2, -N(R C )2, Deutero C 2-4 Alkynyl, (C 1-3 Alkoxy) Halo C 1-3 alkyl-, or the C 3-6 Cycloalkyl is optionally halo or C 1-3 Alkyl-substituted C 3-6 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkylaryl; R II is hydrogen, halo, or C 1-3 is alkyl, R III is hydrogen, hydroxy, halo, C 1-3 Alkyl, C 1-3 Cyanoalkyl, C 1-3 Hydroxyalkyl, HC(O)-, -CO2RC, -CO2N(R C ) 2-, or 5-, or 6-membered heteroaryl.

[0247] Ring A of formula (KRAS1) 1 Ring A represented by the formula (KRAS1) 1 represents an optionally substituted, saturated or unsaturated, 5-10 membered N-containing ring containing at least one additional heteroatom selected from the group consisting of N, S, and O, and which is optionally bridged. Ring A 1 is often an optionally substituted, optionally bridged, saturated 6-8 membered N-containing ring. Typically, A 1 contains two heteroatoms independently selected from N or O. Often both heteroatoms are N. In some cases, A 1 is bridged, e.g., by a methylene, ethylene, or propylene (typically methylene or ethylene) bridge, where the bridge is optionally substituted with one or more moieties selected from the group consisting of, e.g., halo and hydroxy groups. 1 is an optionally substituted piperazinyl ring, optionally bridged between two carbon atoms of the ring.

[0248] In some embodiments, A 1 is an optionally substituted piperazinyl ring optionally bridged between two carbon atoms of the ring, and the piperazinyl ring is optionally substituted on the nitrogen with hydroxy and on the carbon with one or more substituents selected from the group consisting of halo, alkoxycarbonyl, cyano, and hydroxyalkyl. In some cases, ring A 1 is the formula (KRAS1a): [ka] wherein: X 2 is NH, N(C 1-6 alkyl), NOH, or O; n2' is 1 or 2, R' is an optional substituent as defined above; n2 is 0 to 8, and when n2 is 2 to 4, two R' may form a bridge between different carbon atoms in the ring. R' is often C 1-6 Alkyl, C 1-6 Alkenyl, halo, alkoxycarbonyl, cyano, or hydroxyalkyl (e.g., C 1-6 n2 is preferably 1 or 2. When n2 is 2, two R' may be joined to form a bridge between two different carbon atoms of the ring.

[0249] In some embodiments, A 1 is the following formula: [ka] wherein: R' is halo, hydroxy, C 1-3 Alkyl, C 1-3 Cyanoalkyl, C 1-3Hydroxyalkyl, HC(=O)-, -CO2RC, or -CO2N(R C ) 2 is one or more substituents selected from the group consisting of n2 is 0 to 6, R C is defined above for formula (KRAS3).

[0250] In some embodiments, A 1 may be any one moiety selected from the group consisting of: [ka]

[0251] In some cases, A 1 is any one ring selected from the following group: [ka]

[0252] For example, A 1 teeth, [ka] may be.

[0253] Ring B of formula (KRAS1) 1 Ring B represented by the formula (KRAS1) 1 is a 5- to 6-membered unsaturated ring having at least one heteroatom selected from the group consisting of N, S, and O, a 6-membered aromatic hydrocarbon ring, C 3-6 represents an optionally substituted moiety selected from the group consisting of cycloalkenes and 8-10 membered spirocycles, wherein ring B1 is fused with a pyrimidine ring to form a substituted or unsubstituted bicyclic ring.

[0254] In many cases, B 1is a 5- to 6-membered saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N and O, a phenyl ring, and C 5-6 is an optionally substituted moiety selected from the group consisting of cycloalkenes. 1 is a six-membered molecule. 1 is optionally aromatic.

[0255] In some embodiments of formula (KRAS1), B 1 is as follows: (i) a 5- to 6-membered saturated or unsaturated ring containing at least one heteroatom selected from the group consisting of N, S, and O (e.g., N or O); (ii) a 6- to 10-membered aromatic hydrocarbon ring, (iii)C 3-6 cycloalkenyl, or (iv) 8- to 10-membered spiro ring, where B 1 is fused to a pyrimidine ring to form a substituted or unsubstituted bicyclic ring, and wherein B within the bicyclic ring 1 Ha, Halo, C 1-6 It may be substituted with one or more substituents selected from the group consisting of alkyl, alkylcarbonyl, and 4- to 6-membered saturated monocyclic heterocyclyl containing one or more heteroatoms selected from N, S, and O.

[0256] In some embodiments, B 1 is selected from the group consisting of benzene, piperidine, pyrrolidine, cyclohexane, cyclohexene, tetrahydro-2H-pyran, 3,4-dihydro-2H-pyran, and spiro[2.5]octane, and optionally halo, C 1-6 It is substituted with one or more substituents selected from the group consisting of alkyl, alkylcarbonyl, and oxetanyl.

[0257] In some embodiments, B 1 is selected from the group consisting of benzene, piperidine, pyrrolidine, tetrahydro-2H-pyran, and 3,4-dihydro-2H-pyran.

[0258] In some cases, B 1 is pyrrolidine, n1 is 1, and X 1 is O or S. B 1 is not pyrrolidine, then n1 is 0.

[0259] Typically, B 1 is an optionally substituted 6-membered N-heteroaromatic ring, for example an optionally substituted pyridine ring.

[0260] In some cases, B 1 is any one ring selected from the group consisting of: [ka] During the ceremony, n3 is 0 to 2, n3' is 0 to 3, R a is an optional substituent as defined above, and in these structures the wavy line indicates the bond(s) that form a bond to the parent structure (as shown in formulas (KRAS1), (KRAS2) and (KRAS3)).

[0261] Typically, B 1 The optional substituents of are halo (such as fluoro or chloro) and C 1-4 alkyl (such as methyl or ethyl). Often, B 1 The optional substituents of B are one or more moieties selected from the group consisting of fluoro, chloro, and ethyl. 1 is unsubstituted or substituted with fluoro.

[0262] In some cases, B 1 is any one ring selected from the group consisting of: [ka]

[0263] For example, B 1 may be something like the following: [ka]

[0264] Similarly, in any of the structures shown above, the wavy lines indicate bonds that form bonds with the parent structure (as shown in formulas (KRAS1), (KRAS2) and (KRAS3)).

[0265] Part L of the formula (KRAS1) 1 -(CH2) m1 -Z 1 L 1 is absent or O, optionally substituted C 2-3 Alkynylene, and NR c where R is any one moiety selected from the group consisting of c is as defined above in formula (KRAS1) or formula (KRAS3).

[0266] m1 is 0 to 3.

[0267] In some cases, L 1 is O and m1 is 1 or 2. In some cases, L 1 is O and m1 is 1.

[0268] Z 1 is as follows: (i) cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, optionally substituted C 3-6 any one selected from a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of cycloalkyl, N, S, and O, and an 8- to 10-membered partially unsaturated ring containing at least one heteroatom selected from the group consisting of N, S, and O; or (ii)-N(R C )2, heterocyclyl, C 1-6 Alkyl, -D-heterocyclyl, -D-aryl, -D-heteroaryl, -D-cycloalkyl, -DN(R C )2, -D-NHC(=NH)NH2, -DC(O)N(R C )2, -DC 1-6 Haloalkyl, -D-OR C , -D-(CH2OR C )(CH2)nOR C , -D-NR C C(O)-aryl, -D-COOH, and -DC(O)OC 1-6 any one moiety selected from the group consisting of alkyl, wherein -D-NR C The heterocyclyl and aryl portions of C(O)-aryl, the heterocyclyl portion of -D-heterocyclyl, and the cycloalkyl portion of -D-cycloalkyl may optionally be joined by one or more R D and the aryl or heteroaryl in -D-aryl and -D-heteroaryl may optionally be substituted with one or more R E The moiety may be substituted with:

[0269] The linker for the degraded derivatives is Z 1 The moiety may be attached at any position (provided it has the correct valence and / or is chemically convenient). For example, Z 1 When contains an aromatic or heteroaromatic ring, the linker can replace a hydrogen atom at any position on that ring.

[0270] Each D is independently optionally hydroxy, C 1-4 Hydroxyalkyl or heteroaryl substituted C 1-4 It is alkylene.

[0271] Each R C are each independently hydrogen or C 1-3 It is alkyl.

[0272] Each R Dare each independently halo, hydroxy, C 1-3 Hydroxyalkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, cyano, -Q-phenyl, -Q-phenylSOF, -NHC(O)phenyl, -NHC(O)phenylSOF, C 1-3 Alkyl-substituted pyrazolyl, araC 1-3 Alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R C )2, (C 1-3 Alkoxy)C 1-3 Alkyl-, (C 1-3 alkyl)C(O)-, oxo, (C 1-3 haloalkyl)C(O)-, -SO2F, (C 1-3 Alkoxy)C 1-3 Alkoxy-, -CH2OC(O)N(R C )2, -CH2NHC(O)OC 1-6 Alkyl, -CH2NHC(O)N(R C )2, -CH2NHC(O)C 1-6 Alkyl, -CH2(pyrazolyl), -CH2NHSO2C 1-6 Alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R C )2, -OC(O)NH(C 1-3 alkyl)O(C 1-3 alkyl), -OC(O)NH(C 1-3 alkyl)O(C 1-3 alkyl)phenyl(C 1-3 alkyl)N(CH3)2, -OC(O)NH(C 1-3 alkyl)O(C 1-3 alkyl)phenyl or -OC(O)heterocyclyl, -CH2heterocyclyl, where -NHC(O)phenyl or -OC(O)NH(C 1-3 alkyl)O(C 1-3 The phenyl of the -alkyl)phenyl is optionally substituted with -C(O)H or OH, and the heterocyclyl of the -CH2heterocyclyl is optionally substituted with oxo.

[0273] Q is a bond or O.

[0274] Each R E are each independently halogen, hydroxy, HC(O)-, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, or -N(R C )2.

[0275] In some embodiments, Z 1 is as defined in (i).

[0276] In some embodiments, L 1 is O or substituted or unsubstituted C 2-3 is alkynyl, Z 1 is cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, C 3-6 cycloalkyl, a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of N, S, and O, or an 8- to 10-membered partially unsaturated ring containing at least one heteroatom selected from the group consisting of N, S, and O, Z 1 The ring is halo, hydroxy, C 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 It may be substituted by a substituted or unsubstituted 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of methoxyalkyl, N, S, and O, and further, the substituted or unsubstituted 5- to 6-membered saturated ring is selected from the group consisting of C 1-3 It may be substituted by alkyl, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, or cyanoalkyl.

[0277] In some cases, L 1 When is O, m1 is 0 or 1, and L 1 C 2-3In the case of alkynyl, m1 is 1 and Z 1 is dimethylaminocarbonyl or dimethylaminomethyl.

[0278] In some embodiments, L 1 is O, m1 is 0 or 1, Z 1 is C 3-6 cycloalkyl, a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of N, S, and O, an 8- to 10-membered partially saturated ring containing at least one heteroatom selected from the group consisting of N, S, and O, wherein Z 1 The ring is halo, hydroxy, C 1-6 Alkyl, C 1-3 Alkoxy, C 2-3 C substituted with an alkynyl, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, or a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of N, S, and O and optionally further substituted with halo. 1-6 It may be substituted with alkyl.

[0279] In some embodiments, L 1 is O, m1 is 1, Z 1 is C 3-6 cycloalkyl or a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of N, S, and O, wherein Z 1 The rings are halo, hydroxy, cyano, C 1-6 Alkyl, C 1-3It may be substituted with alkoxy, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, or C1-6 alkyl substituted with a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of N, S, and O and optionally further substituted with halo.

[0280] In some embodiments, Z 1 teeth, (i) cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline, or 1,2,3,4-tetrahydroisoquinoline, and is not a halo, hydroxy, cyano, or C 1-6 Alkyl or C 1-3 optionally substituted with alkoxy, or (ii) alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl, or C substituted with a 5- to 6-membered saturated ring containing at least one heteroatom selected from the group consisting of N and O and optionally further substituted with halo 1-6 Alkyl.

[0281] In some embodiments, Z 1 are halo, hydroxy, C 1-3 Cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline, or 1,2,3,4-tetrahydroisoquinoline, optionally substituted with alkoxy, methyl, ethyl, isopropanyl, ethylcarbonylmethyl, hydroxyethyl, dimethylamino, dimethylaminomethyl, methoxyethyl, cyanomethyl, morpholylmethyl, or 3-fluoropyrrolidinylmethyl.

[0282] In some embodiments, Z 1 is as defined in (ii).

[0283] In some cases, L 1 is O, m1 is 0, and Z 1 is C 1-6alkyl (such as methyl, ethyl, isopropyl, or isobutyl) or one or more R (as defined above with respect to formulae (KRAS1) and (KRAS3)) D is -D-heterocyclyl optionally substituted by

[0284] In some cases, D is methylene and heterocyclyl is hexahydro-1H-pyrrolidinyl, hexahydro-3H-pyrrolidin-3-one, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, hexahydropyrrolidine 4(1H)-oxide, azetidinyl, pyrrolidinyl, pyrrolidin-2-one, oxetanyl, piperidinyl, 1-azabicyclo[2.2.1]heptanyl, morpholinyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, thiopyranyl, 6-oxa-2-2λ 2 -Azaspiro[3.4]octanyl, 7-oxa-2λ 2 -azaspiro[3.5]nonanyl, 2',3'-dihydrospiro[cyclopropane-1,1'-indenyl], (2S)-1-azabicyclo[2.2.1]heptan-2-yl, and tetrahydrofuranyl, each of which is selected from the group consisting of one or more R D is optionally replaced by

[0285] Optionally, D is methylene and the heterocyclyl is selected from one or more R D and hexahydro-1H-pyrrolidinyl optionally substituted with

[0286] In some cases, heterocyclyl can be substituted with halo (such as fluoro), hydroxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Alkyl, C 1-3 one or more R independently selected from the group consisting of alkoxy, phenyl, or pyrazolyl; D and hexahydro-1H-pyrrolidinyl substituted with

[0287] In some cases, a heterocyclyl may be a heterocyclic group having three RD Hexahydro-1H-pyrrolidinyl substituted with groups, one of which is halo (e.g., fluoro), hydroxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Alkyl, C 1-3 alkoxy, phenyl, or pyrazolyl, two of which are independently C 1-3 It is alkyl.

[0288] In some cases, heterocyclyl is C 1-3 It is an alkyl-substituted azetidinyl.

[0289] In some cases, the heterocyclyl is selected from hydroxyalkyl, haloalkyl, C 1-3 Alkyl, alkoxy, ara C 1-3 pyrrolidinyl substituted with any one moiety selected from the group consisting of alkyl, -Q-phenyl, and -NHC(O)phenyl, wherein the ar-C of -Q-phenyl and -NHC(O)phenyl is 1-3 The aryl portion of the alkyl or the phenyl portion of the -NHC(O)phenyl each optionally contains one or more R D is replaced by

[0290] The heterocyclyl may be pyrrolidinyl substituted with two groups, where the first is C 1-3 alkyl and the second is C 1-3 It is alkoxy or halo.

[0291] In some cases, heterocyclyl is C 1-3 It is an alkyl-substituted pyrrolidin-2-one.

[0292] In some cases, heterocyclyl is acetyl, (C 1-3 Alkoxy)C 1-3 alkoxy, or piperidinyl substituted with any one of the group consisting of -C(O)CH2Cl.

[0293] In many cases, L 1is O, m1 is 0, D is ethylene or propylene, and heterocyclyl is morpholinyl or oxa-5-azabicyclo[2.2.1]heptan-5-yl.

[0294] In some cases, L 1 is O, m1 is 0, and Z 1 is -D-heteroaryl, where the heteroaryl moiety is one or more R E D can be methylene or ethylene, and heteroaryl can be pyridyl, pyrazolyl, imidazolyl, triazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, or pyrimidinyl, each of which can be optionally substituted with one or more RE. R E Ha, Halo, C 1-4 Alkyl, -N(R C )2, or C 1-4 For example, heteroaryl may be independently one or more selected from the group consisting of C 1-4 Alkyl or -N(R C Alternatively, the heteroaryl may be a pyrazolyl substituted with C 1-4 Alkyl, C 1-4 Haloalkyl, and C 1-4 Alternatively, the heteroaryl may be imidazolyl substituted with any one moiety selected from the group consisting of hydroxyalkyl. 1-4 It is an alkyl-substituted triazolyl.

[0295] In some cases, L 1 is O, m1 is 0, and Z 1 is -D-aryl, where the aryl moiety is R E (as defined above for formulae (KRAS1) and (KRAS3)) may optionally be substituted with one or more of:

[0296] In other cases, L 1 is O, m1 is 0, and Z 1is -D-cycloalkyl, where the cycloalkyl moiety is optionally substituted with one or more RE (defined above for formulae (KRAS1) and (KRAS3)).

[0297] In some cases, L 1 is O, m1 is 0 and Z 1 -DN(R C For example, D may be ethylene, and each R C may independently be C 1-3 It may be selected from alkyl.

[0298] In some cases, L 1 is O, m1 is 0 and Z 1 is -D-NC(=NH)-NH2. For example, D can be ethylene or propylene.

[0299] In other cases, L 1 is O, m1 is 0 and Z 1 Ha-DC 1-6 haloalkyl; or L 1 is O, m1 is 0 and Z 1 HA-D-OR C Alternatively, L 1 is O, m1 is 0 and Z 1 HA-D-(CH2OR C )(CH2)nOR C Otherwise, L 1 is O, m1 is 0 and R 2 Ha-D-NR C It may be C(O)-aryl.

[0300] Substructure of formula (KRAS1) -(C(X 1 )) n1 Y 1 In some cases, X 1 is O. In some cases, n1 is 0.

[0301] Y 1is an optionally substituted moiety selected from the group consisting of 6- to 10-membered aromatic hydrocarbon rings and 6- to 10-membered unsaturated monocyclic or bicyclic rings containing at least one heteroatom selected from the group consisting of N, S, and O. For example, Y 1 may be an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, such as an optionally substituted moiety selected from the group consisting of naphthyl, phenyl, 1,2,3,4-tetrahydronaphthalene, and 2,3-dihydro-1H-indenyl. 1 is a substituted naphthyl, for example, hydroxy, ethynyl, halo (e.g., chloro or fluoro), C 1-4 Alkyl, C 1-4 and naphthyl substituted with one or more substituents selected from the group consisting of alkoxy.

[0302] In some embodiments, Y 1 is an 8- to 10-membered unsaturated bicyclic ring containing at least one heteroatom selected from the group consisting of N and S, or a 6- to 10-membered aromatic hydrocarbon ring, wherein the ring is not substituted with any of halo, hydroxy, amino, C 1-6 Alkyl, C 2-3 Alkenyl, C 2-3 It may be substituted with one or more substituents selected from the group consisting of alkynyl and a 5- to 6-membered unsaturated monocyclic heterocyclyl containing one or more heteroatoms selected from the group consisting of N, S, and O.

[0303] In some embodiments, Y 1 is selected from the group consisting of benzene, naphthalene, benzo[b]thiophene, thieno[3,2-b]pyridine, isoquinoline, indole, and indazole, each of which is selected from the group consisting of halo, hydroxy, amino, C 1-6 Alkyl, C 2-3 Alkenyl, C 2-3 It is optionally substituted with one or more substituents selected from the group consisting of alkynyl and thiophenyl.

[0304] In some cases, Y 1is an optionally substituted heteroaryl, such as an optionally substituted moiety selected from the group consisting of isoquinolinyl, indazolyl, or benzo[d][1,3]dioxolyl. For example, Y 1 is halo or C 2-4 It may be isoquinolinyl substituted with alkynyl. 1 is chloro or C 1-3 In a further alternative, Y may be an indazolyl substituted with alkyl. 1 may be benzo[d][1,3]dioxolyl substituted with two halo.

[0305] In some cases, Y 1 is the following formula (KRAS1b): [ka] wherein: X 3 , CH, CR b and N, n4 is 0 to 4, and R b is an optional substituent as described above. The wavy lines on formula (1b) are shown on bonds that form bonds with the parent structure (as shown in formula (1)).

[0306] In many cases, n4 is 2 or 1 (e.g., 2). Typically, X 3 is CH or CR b is.

[0307] R b is hydroxy, C 2-4 alkynyl (e.g., ethynyl), halo (e.g., chloro or fluoro), C 1-4 Alkoxy (e.g., methoxy), C 1-4 Alkyl, C 2-4 haloalkynyl (e.g., haloethynyl), C 1-4 Haloalkyl, C 2-4alkenyl (e.g., ethenyl), C 2-4 Haloalkenyl, C 1-4 haloalkoxy (e.g., halomethoxy), C 3-4 cycloalkyl (e.g., cyclopropyl), C 1-4 The substituents may be any one or more selected from the group consisting of alkenylol and amino. For example, R b is hydroxy, C 2-4 alkynyl (e.g., ethynyl), halo (e.g., chloro or fluoro), C 1-4 Alkoxy (e.g., methoxy), C 1-4 Alkyl, C 2-4 Haloalkynyl (e.g., haloethynyl), and C 1-4 It may be any one or more substituents selected from the group consisting of haloalkyl.

[0308] In some embodiments, R b (or optional substituents) are halo, cyano, hydroxy, C 1-4 Alkyl, -SC 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-3 Cyanoalkyl, triazolyl, C 1-3 Haloalkyl, -OC 1-3 Haloalkyl, -SC 1-3 Haloalkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, -CHC(O)N(R 5 )2, -C 3-4 Alkynyl (NR 5 )2, -N(R 5 )2, Deutero C 2-4 Alkynyl, (C 1-3 Alkoxy) Halo C 1-3 Alkyl- and C 3-6 any one or more substituents selected from the group consisting of cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally halo or C 1-3 It may be substituted with alkyl.

[0309] In some embodiments, A 1 is the following formula: [ka] B 1 is benzene, piperidine, or pyrrolidine, each optionally containing halo or C 1-6 substituted with alkyl, wherein B 1 is pyrrolidine, n1 is 1, and X 1 is O and B 1 is not pyrrolidine, then n1 is 0; Y 1 is naphthalinyl, halo, hydroxy, C 1-6 Alkyl, C 2-3 Alkenyl, or C 2-3 optionally substituted with alkynyl; L 1 is O, m1 is 1, Z 1 is cyclobutanyl, cyclopropanyl, piperidinyl, morpholinyl, piperazinyl, isoindolinyl, or 1,2,3,4-tetrahydroisoquinolinyl, each optionally containing halo, hydroxy, C 1-3 It is substituted with alkoxy, methyl, ethyl, isopropanyl, ethylcarbonylmethyl, hydroxyethyl, dimethylamino, dimethylaminomethyl, alkoxyalkyl, cyanomethyl, morpholinylmethyl, or 3-fluoropyrrolidinemethyl.

[0310] CBP and / or p300 inhibitors In some cases, the target protein binding ligand may be derived from a CBP and / or p300 inhibitor. For example, the target protein binding ligand may have the following structure: [ka] where L indicates the attachment position of the linker. Similarly, the present specification also encompasses attachment or connection to the linker at any other chemically suitable position on the target protein-binding ligand.

[0311] In some embodiments, the target protein binding ligand has the formula (C1): [ka] wherein: The linker portion of the bivalent compound is R B or R A is bound to X A and X C are each independently selected from C or N, and X A and X C At least one of is C and X A and X C provided that at most one of is N, X B is CR XB1 , O, and NR XB2 where R XB1 is H, optionally substituted C 1-8 any one of the substituents selected from the group consisting of alkyl, and optionally substituted 3- to 10-membered carbocyclyl, XB2 is absent or H, optionally substituted C 1-8 any one substituent selected from the group consisting of alkyl and optionally substituted 3- to 10-membered carbocyclyl; A A does not exist or is AA1 R AA2 , CO, O, S, SO, SO2, and NR AA1 wherein each R is selected from the group consisting of AA1 and R AA2 are each independently hydrogen, halo, hydroxy, cyano, nitro, optionally substituted C 1-8Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8 Alkylamino, optionally substituted C 1-8 Alkylamino C 1-8 selected from the group consisting of alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 10-membered carbocyclylamino, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; A B and R AA1 , A B and R AA2 , and / or R AA1 and R AA2 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring (e.g., a 4- to 20-membered heterocyclyl ring); A B is any one substituent selected from the group consisting of aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, wherein each substituent is substituted with R A and optionally is selected from hydrogen, halo, oxo, CN, NO, OR AB1 , S.R. AB1 , N.R. AB1 R AB2 ,OCOR AB1 , OCO2R AB1 , OCONR AB1 R AB2 , C.O.R. AB1 , CO2R AB1 ,CONR AB1 R AB2 , SOR AB1 , SO2R AB1 , SO2NR AB1 R AB2 , N.R. AB3 CO2RAB1 , N.R. AB3 COR AB1 , N.R. AB3 C(O)NR AB1 R AB2 , N.R. AB3 SOR AB1 , N.R. AB3 SO2R AB1 , N.R. AB3 SO2NR AB1 R AB2 , optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8 Alkylamino, optionally substituted C 1-8 Alkylamino C 1-8 substituted by one or more substituents independently selected from the group consisting of alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 10-membered carbocyclylamino, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R AB1 , R AB2 and R AB3 are each independently hydrogen, optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8 Alkylamino C 1-8 selected from alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R AB1and R AB2 , or R AB1 and R AB3 together with the atoms to which they are attached form a 4- to 20-membered heterocyclyl ring, R A is absent or is hydrogen, halo, CN, NO2, OR A1 , S.R. A1 , N.R. A1 R A2 ,OCOR A1 , OCO2R A1 , OCONR A1 R A2 , C.O.R. A1 , CO2R A1 ,CONR A1 R A2 , SOR A1 , SO2R A1 , SO2NR A1 R A2 , N.R. A3 CO2R A1 , N.R. A3 COR A1 , N.R. A3 C(O)NR A1 R A2 , N.R. A3 SOR A1 , N.R. A3 SO2R A1 , N.R. A3 SO2NR A1 R A2 , optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Alkoxy, optionally substituted C 1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8 Alkylamino, optionally substituted C 1-8 Alkylamino C 1-8selected from alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 10-membered carbocyclylamino, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R A1 , R A2 and R A3 are independently hydrogen, optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8 Alkylamino C 1-8 selected from alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R A1 and R A2 , or R A1 and R A3 together with the atom to which they are attached form a 3- to 20-membered cycloalkyl ring or a 4- to 20-membered heterocyclyl ring; R B does not exist or R B1 O, R B1 S, R B1 NR B2 , R B1 OC(O), R B1 OC(O)O, R B1 OCONR B2 , R B1 C(O), R B1 C(O)O, R B1 CONR B2 , R B1 S(O), R B1 SO2, R B1 SO2NR B2 , R B1 NR B3 C(O)O, R B1 NRB3 C(O), R B1 NR B3 C(O)NR B2 , R B1 NR B3 S(O), R B1 NR B3 SO2, R B1 NR B3 SO2NR B2 , optionally substituted C 1-8 Alkylene, optionally substituted C 2-8 Alkenylene, optionally substituted C 2-8 Alkynylene, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C 3-13 Fused cycloalkyl, optionally substituted C 3-13 Fused heterocyclyl, optionally substituted C 3-13 Bridged cycloalkyl, optionally substituted C 3-13 Bridged heterocyclyl, optionally substituted C 3-13 Spirocycloalkyl, optionally substituted C 3-13 is selected from the group consisting of spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, R B1 is absent or optionally replaced by C 1-8 Alkylene, optionally substituted C 2-8 Alkenylene, optionally substituted C 2-8 Alkynylene, optionally substituted C 1-8 Alkoxy C 1-8 Alkylene, optionally substituted C 1-8 Haloalkylene, optionally substituted C 1-8 hydroxyalkylene, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C 3-13 Fused cycloalkyl, optionally substituted C 3-13 Fused heterocyclyl, optionally substituted C 3-13 Bridged cycloalkyl, optionally substituted C 3-13Bridged heterocyclyl, optionally substituted C 3-13 Spirocycloalkyl, optionally substituted C 3-13 is a divalent moiety selected from the group consisting of spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R B2 and R B3 each independently represents an optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8 Alkylamino C 1-8 selected from the group consisting of alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R B2 and R B3 together with the atoms to which they are attached form a 3- to 20-membered cycloalkyl ring or a 4- to 20-membered heterocyclyl ring; R C is hydrogen, COR C1 , CO2R C1 ,CONR C1 R C2 , SOR C1 , SO2R C1 , SO2NR C1 R C2 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R C1 and R C2 are each independently hydrogen, optionally substituted C 1-6Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R C1 and R C2 together with the atoms to which they are attached form a 4- to 20-membered heterocyclyl ring.

[0312] The target protein binding ligand represented by formula (C1) may be attached to the linker L of the bifunctional molecule by a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker may be attached at any suitable position, for example, as long as it has the correct valence and / or is chemically suitable.

[0313] For example, the linker of a bifunctional molecule may be R A or R B The linker may be covalently attached to TBL as shown in formula (C1) via a group. For example, the linker may be R A or R B It may be covalently bonded to an atom on any of the groups at any position (provided it has the correct valence and / or is chemically feasible) (e.g., by replacing a hydrogen atom).

[0314] In some embodiments, the linker is R A In other embodiments, the linker is R B is bonded to.

[0315] To avoid any misunderstanding, the linker is R A is specified as being bound to R A is not present and defined, the linker will instead use A B Similarly, if the linker is R Bis specified as being bound to R B is not present and defined, the linker will instead use X C is bound (e.g., covalently bound) to

[0316] In a more specific embodiment, X A is C, and furthermore, X B and X C are each N, that is, the compound has the following formula (C2): [ka] wherein the linker portion of the bifunctional compound is R B or R A is bonded to A A , A B , R A , R B and R C is as defined above for formula (C1).

[0317] A in formula (C1 and C2) A -A B -R A portion In some embodiments, A A -A B -R A The part has formula (C3): [ka] wherein: A A and R A is as defined above for formula (C1), X 4 is CR X41 and N, where R X41 is hydrogen, halo, hydroxy, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6Alkynyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 1-6 selected from alkylamino, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkoxy, optionally substituted 3- to 6-membered cycloalkylamino, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R AB4 is not present or optionally A A or form a ring with hydrogen, halo, R AB5 NR AB6 , R AB5 OR AB6 , R AB5 SR AB6 , R AB5 NR AB6 R AB7 , R AB5 OCOR AB6 , R AB5 OCO2R AB6 , R AB5 OCONR AB6 R AB7 , R AB5 COR AB6 , R AB5 CO2R AB6 , R AB5 CONR AB6 R AB7 , R AB5 SOR AB6 , R AB5 SO2R AB6 , R AB5 SO2NR AB6 R AB7 , R AB5 NR AB8 CO2R AB6 , R AB5 NR AB8 COR AB6 , R AB5 NR AB8 C(O)NR AB6 R AB7 , R AB5 NR AB8 SOR AB6 , R AB5 NR AB8 SO2R AB6 , RAB5 NR AB8 SO2NR AB6 R AB7 , optionally substituted C 1-8 Alkyl, optionally substituted C 1-8 Alkylene, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkenylene, optionally substituted C 2-8 Alkynyl, optionally substituted C 2-8 any one moiety selected from the group consisting of alkynylene, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R AB5 is absent or optionally replaced by C 1-8 Alkylene, optionally substituted C 2-8 Alkenylene, optionally substituted C 2-8 Alkynylene, optionally substituted C 1-8 Alkoxy C 1-8 Alkylene, optionally substituted C 1-8 Alkylamino C 1-8 Alkylene, optionally substituted C 1-8 Haloalkylene, optionally substituted C 1-8 a divalent or trivalent moiety selected from hydroxyalkylene, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R AB6 , R AB7 and R AB8 are each independently absent, hydrogen, or optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8Alkylamino C 1-8 selected from the group consisting of alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R AB6 and R AB7 , or R AB6 and R AB8 together with the atoms to which they are attached form a 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0318] In some cases, A A does not exist.

[0319] In some embodiments, A B -R A is represented by formula (C4) or formula (C5): [ka] where R A is as defined above. To avoid any misunderstanding, A A When A is not present, the bond crossed by the wavy line is attached to the central ring motif of formula (C1) or formula (C2). A If there is a bond, the bond that the wavy line crosses is A A is bonded to.

[0320] In some cases, A A is NR AA1 where R AA1 is hydrogen, optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8 Alkylamino C 1-8selected from the group consisting of alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 10-membered carbocyclylamino, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0321] In some embodiments, A A -A B -R A are expressed as equations (C4) to (C8): [ka] wherein R A is as defined above.

[0322] In some embodiments, A A -A B -R A is represented by any one of formulas (C6), (C7), and (C8), where R A is as defined above for formula (C1).

[0323] In some embodiments, R A is selected from the group consisting of optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. A is aromatic. For example, R A may be selected from optionally substituted aryl (e.g., phenyl) and optionally substituted heteroaryl (e.g., pyrazolyl or pyridinyl). A is an optionally substituted heteroaryl. For example, R A may be selected from optionally substituted pyrazolyl (eg, N-methylpyrazolyl) and optionally substituted pyridinyl.

[0324] In a more specific embodiment, A A -A B -R A are expressed as equations (C9) to (C12): [ka] It is represented by one of the following:

[0325] In a more specific embodiment, A A -A B -R A is represented by any one of formulas (C9).

[0326] Any one of R of formula (C1) to formula (C12) B portion As mentioned above, R B does not exist or R B1 O, R B1 S, R B1 NR B2 , R B1 OC(O), R B1 OC(O)O, R B1 OCONR B2 , R B1 C(O), R B1 C(O)O, R B1 CONR B2 , R B1 S(O), R B1 SO2, R B1 SO2NR B2 , R B1 NR B3 C(O)O, R B1 NR B3 C(O), R B1 NR B3 C(O)NR B2 , R B1 NR B3 S(O), R B1 NR B3 SO2, R B1 NR B3 SO2NR B2 , optionally substituted C 1-8 Alkylene, optionally substituted C 2-8Alkenylene, optionally substituted C 2-8 Alkynylene, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C 3-13 Fused cycloalkyl, optionally substituted C 3-13 Fused heterocyclyl, optionally substituted C 3-13 Bridged cycloalkyl, optionally substituted C 3-13 Bridged heterocyclyl, optionally substituted C 3-13 Spirocycloalkyl, optionally substituted C 3-13 As noted above, in some embodiments, R is selected from the group consisting of spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. B is connected to the "linker" portion of the bifunctional molecule.

[0327] In some embodiments, R B is an optionally substituted C 1-8 In some cases, R is selected from alkylene, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. B is an optionally substituted 4- to 8-membered heterocyclyl. B can also be an optionally substituted 4- to 8-membered N-heterocyclyl, for example, an optionally substituted 5- to 7-membered N-heterocyclyl. In certain embodiments, R B is, for example, an optionally substituted 6-membered N-heterocyclyl, such as optionally substituted piperidinyl. B is piperidinyl, where the piperidinyl is attached to the linker via the nitrogen atom.

[0328] Any one of R of formula (C1) to formula (C12) C portion As mentioned above, R C is hydrogen, COR C1 , CO2RC1 ,CONR C1 R C2 , SOR C1 , SO2R C1 , SO2NR C1 R C2 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 It is selected from alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0329] R C1 and R C2 are each independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R C1 and R C2 together with the atoms to which they are attached form a 4- to 20-membered heterocyclyl ring.

[0330] In some embodiments, R C is COR C1 and CONR C1 R C2 wherein R C1 and R C2 is as defined above. In some cases, R C1 and R C2 are each independently hydrogen and optionally substituted C 1-6 For example, R C1 and R C2 are each independently hydrogen and unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-3alkyl). In some cases, R C1 is C 1-6 Alkyl (C 1-3 alkyl, for example, methyl), and R C2 is hydrogen. In some embodiments, R C is selected from COMe and CONHMe.

[0331] PARP In other cases, the target protein binding ligand may be derived from a polymerase inhibitor, such as a PARP1 inhibitor. For example, the target protein binding ligand may have the following structure: [ka] where L indicates the attachment position of the linker. The present disclosure also encompasses attaching or connecting the linker at any other chemically suitable position on the target protein-binding ligand.

[0332] In other cases, the target protein binding ligand may be derived from a polymerase inhibitor, such as a POLQ inhibitor. For example, the target protein binding ligand may have the following structure: [ka] where L indicates the attachment position of the linker. The present disclosure also encompasses attaching or connecting the linker at any other chemically suitable position on the target protein-binding ligand.

[0333] In other cases, the target protein binding ligand may be derived from a deubiquitinase inhibitor, such as a USP1 inhibitor. For example, the target protein binding ligand may have the following structure: [ka] where L indicates the attachment position of the linker. The present disclosure also encompasses attaching or connecting the linker at any other chemically suitable position on the target protein-binding ligand.

[0334] Representative examples of possible target protein-binding ligand moieties for various classes of target protein-binding ligands are described below.

[0335] SMARCA2 / SMARCA4 In some cases, the target protein binding ligand may be derived from a SMARCA2 inhibitor. For example, the target protein binding ligand may be represented by Formula 1T: [ka] wherein the wavy line crosses the bond between the SMARCA2 / SMARCA4 conjugate and the linker; During the ceremony, R 1T is hydrogen, halo, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxy, -COOR at , -CON(R at )2, C6~C 10 aryl or C5-C9 heteroaryl, wherein alkyl, alkenyl, alkoxy, aryl and heteroaryl are each independently hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and -OCOR at and optionally substituted with one or more groups selected from at are independently selected from hydrogen and C1-C4 alkyl; R 2T is -NR 3T R 4T -OR 3T and A T Does not exist or is OCR 5T R 6T, one or more R 7T C6 to C optionally substituted with 10 Aryl, one or more R 7T and 3- to 8-membered heteroaryl optionally substituted with one or more R8T; Each R 3T , R 4T , R 5T , R 6T and R 7T are each independently selected from hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; Each R 8T are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or aryl; R 3T and R 5T together with the atom to which they are attached form a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, wherein the heterocycloalkyl and heteroaryl are selected from the group consisting of hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and -OCOR at and optionally substituted with one or more groups selected from at are independently selected from hydrogen and C1-C4 alkyl, or R 3T and one R 8T together with the atom to which they are attached form a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, wherein the heterocycloalkyl and heteroaryl are selected from the group consisting of hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and -OCOR at wherein each R at are independently selected from hydrogen and C1-C4 alkyl.

[0336] In some embodiments, R 1T is C6~C 10 Aryl, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and -OCOR at and optionally substituted with one or more groups selected from at are independently selected from hydrogen and C1-C4 alkyl.

[0337] In some embodiments, R 1T is C6~C 10 It is aryl and is substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, and amino.

[0338] In some embodiments, R 1T has the following structure: [ka] is a group of the formula mt is 0, 1, 2, 3, or 4; R 9T is hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at , and -OCOR at where each R at are independently selected from hydrogen and C1-C4 alkyl; Each R 10T are each independently hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at , and -OCOR at where each R at are each independently selected from hydrogen and C1-C4 alkyl; In the formula, the wavy line represents R1T and the rest of the molecule.

[0339] In some embodiments, R 1T has the following structure: [ka] is a group of the formula R 9T is hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at , and -OCOR at where each R at are independently selected from hydrogen and C1-C4 alkyl; Each R 11T are each independently hydrogen, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at , and -OCOR at where each R at are each independently selected from hydrogen and C1-C4 alkyl; In the formula, the wavy line represents R 1T and the rest of the molecule.

[0340] In some embodiments, R 1T has the following structure: [ka] where the wavy line represents R 1T and the rest of the molecule.

[0341] In some embodiments, R 2T is -NR 3T R 4T is.

[0342] In some embodiments, A T is CR 5T R 6T , one or more R 7T and one or more R 8T and 3- to 8-membered heterocycloalkyl optionally substituted with

[0343] In some embodiments, A 1T is selected from 3- to 8-membered heteroaryl and 3- to 8-membered heterocycloalkyl.

[0344] In some embodiments, A 1T is selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyrrolidinyl, pyrryl, pyrazolidinyl, pyrazolyl, imidazolyl, imidazolidinyl, and diazabicyclo[3.2.1]octanyl.

[0345] In some embodiments, A 1T is selected from piperidinyl, pyrazolyl, and diazabicyclo[3.2.1]octanyl.

[0346] In some embodiments, mt is 0, 1, or 2.

[0347] In some embodiments, R 3T is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0348] In some embodiments, R 3T is selected from hydrogen and C1-C4 alkyl.

[0349] In some embodiments, R 3T is hydrogen.

[0350] In some embodiments, R 4T is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0351] In some embodiments, R 4T is selected from hydrogen and C1-C4 alkyl.

[0352] In some embodiments, R 4T is hydrogen.

[0353] In some embodiments, R 5T is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0354] In some embodiments, R 5T is selected from hydrogen and C1-C4 alkyl.

[0355] In some embodiments, R 5T is hydrogen.

[0356] In some embodiments, R 3T and R 5T together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl ring.

[0357] In some embodiments, R 6T is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0358] In some embodiments, R 6T is selected from hydrogen and C1-C4 alkyl.

[0359] In some embodiments, R 6T is hydrogen.

[0360] In some embodiments, R 7T is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0361] In some embodiments, R 7T is selected from hydrogen and C1-C4 alkyl.

[0362] In some embodiments, R 7T is hydrogen.

[0363] In some embodiments, R 8T is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0364] In some embodiments, R 8T is selected from hydrogen and C1-C4 alkyl.

[0365] In some embodiments, R 8T is hydrogen.

[0366] In some embodiments, R 3T and R 8T together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl ring.

[0367] In some embodiments, R 9T is selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and amino.

[0368] In some embodiments, R 9T is selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, and amino.

[0369] In some embodiments, R 9T is selected from hydroxy and amino.

[0370] In some embodiments, R 9T is hydroxy.

[0371] In some embodiments, each R 10Tare each independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, and amino.

[0372] In some embodiments, each R 10T are each independently selected from halo, C1-C4 alkyl, and C1-C4 haloalkyl.

[0373] In some embodiments, each R 10T are each independently selected from halo.

[0374] In some embodiments, each R 11T are each independently selected from hydrogen, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, and amino.

[0375] In some embodiments, each R 11T are each independently selected from hydrogen, halo, C1-C4 alkyl, and C1-C4 haloalkyl.

[0376] In some embodiments, each R 11T are each independently selected from hydrogen, halo, and C1-C4 alkyl.

[0377] In some embodiments, each R 11T are each independently selected from hydrogen and halo.

[0378] In some embodiments, the SMARCA conjugate has formula 2T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker; During the ceremony, mt is 0, 1, 2, 3, or 4; A1T is selected from 3- to 8-membered heteroaryl optionally substituted with one or more R7T, or 3- to 8-membered heterocycloalkyl optionally substituted with one or more R8T; Each R 3T , R 4T , R 7T and R 8T are each independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 9T is selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, and amino; Each R 10T are each independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, C1-C4 haloalkyl, and amino.

[0379] In some embodiments of the SMARCA conjugate of formula 2T, mt is 0, 1, or 2; A 1T is selected from 3- to 8-membered heteroaryl and 3- to 8-membered heterocycloalkyl; R 3T and R 4T are both hydrogen, R 9T is hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, and amino; Each R 10T are each independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, and C1-C4 haloalkyl.

[0380] In some embodiments of the SMARCA conjugate of formula 2T, mt is 0, 1, or 2; A 1T is selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, pyrazolyl, imidazolyl, imidazolidinyl, and diazabicyclo[3.2.1]octanyl; R 3T and R 4T are both hydrogen, R 9T is hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, and amino; Each R 10T are each independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, and C1-C4 haloalkyl.

[0381] In some embodiments of the SMARCA conjugate of formula 2T, mt is 0, 1, or 2; A 1T is selected from piperidinyl, pyrazolyl, and diazabicyclo[3.2.1]octanyl; R 3T and R 4T are both hydrogen, R 9T is hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, and amino; Each R 10T are each independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl, and C1-C4 haloalkyl.

[0382] In some embodiments, the SMARCA conjugate has formula 3T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker; wherein: R 9T is hydroxy or amino, Each R 11T are each independently selected from H and halo.

[0383] In some embodiments, the SMARCA2 conjugate has the following formula 4T: [ka] where the wavy line crosses the bond between the SMARCA2 binder and the linker.

[0384] In some embodiments, the SMARCA2 conjugate has formula 5T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker, R 9T is hydroxy or amino, Each R 11T are each independently selected from H and halo.

[0385] In some embodiments, the SMARCA2 conjugate has the following formula 6T: [ka] where the wavy line crosses the bond between the SMARCA2 binder and the linker.

[0386] In some embodiments, the SMARCA2 conjugate has formula 7T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker, R 9T is hydroxy or amino, Each R 11T are each independently selected from H and halo.

[0387] In some embodiments, the SMARCA2 conjugate has formula 8T: [ka] where the wavy line crosses the bond between the SMARCA2 binder and the linker.

[0388] In some embodiments, the SMARCA2 conjugate has the following formula 9T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker, m is 0, 1, 2, 3, or 4; R 4T is selected from hydrogen and C1-C4 alkyl; R 9T is selected from hydroxy, C1-C4 alkoxy, and amino; Each R 10T are each independently selected from hydroxy, C1-C4 alkoxy, halo, C1-C4 alkyl, and amino.

[0389] In some embodiments of the SMARCA conjugate of formula 9T, mt is 0, 1, or 2; R 4T is hydrogen, R 9T is selected from hydroxy, C1-C4 alkoxy, and amino; Each R 10T are each independently selected from hydroxy, C1-C4 alkoxy, halo, and C1-C4 alkyl.

[0390] In some embodiments, the SMARCA2 conjugate has formula 10T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker, R 9T is hydroxy or amino, Each R 11T are each independently selected from H and halo.

[0391] In some embodiments, the SMARCA2 conjugate has formula 11T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker, In some embodiments, the SMARCA2 conjugate has formula 12T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker, m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; Each R 4T , R 7T and R 8T are each independently selected from hydrogen and C1-C4 alkyl; R 9T is selected from hydroxy, C1-C4 alkoxy, and amino; Each R 10T are each independently selected from hydroxy, C1-C4 alkoxy, halo, C1-C4 alkyl, and amino.

[0392] In some embodiments of the SMARCA conjugate of formula 12T, mt is 0, 1, or 2; n is 0, R 4T is hydrogen, R 9T is selected from hydroxy, C1-C4 alkoxy, and amino; Each R 10T are each independently selected from hydroxy, C1-C4 alkoxy, halo, and C1-C4 alkyl.

[0393] In some embodiments, the SMARCA2 conjugate has formula 13T: [ka] wherein the wavy line crosses the bond between the SMARCA2 binder and the linker, R 9 is hydroxy or amino, Each R 11 are each independently selected from H and halo.

[0394] In some embodiments, the SMARCA2 conjugate has the following formula 14T: [ka] where the wavy line crosses the bond between the SMARCA2 binder and the linker.

[0395] I. Kinase and Phosphatase Inhibitors Examples of kinase inhibitors are described in Jones et al. Small-Molecule Kinase Downregulators (2017, Cell Chem. Biol., 25:30-35). Additional kinase inhibitors that may be used according to some examples of the present disclosure include, but are not limited to, the following: 1. Erlotinib derivative tyrosine kinase inhibitor. [ka] where R is a linker attached, for example, via an ether group. 2. Kinase inhibitor sunitinib (derivatized). [ka] (derivatized so that R is, for example, a linker attached to the pyrrole moiety) 3. Kinase inhibitor sorafenib (derivatized). [ka] (derivatized such that R is, for example, a linker attached to the amide moiety) 4. Kinase inhibitor dasatinib (derivatized). [ka] (derivatized so that R is, for example, a linker attached to a pyrimidine) 5. Kinase inhibitor lapatinib (derivatized). [ka] (The linker is derivatized to attach, for example, via the terminal methyl of the sulfonylmethyl group) 6. Kinase inhibitor U09-CX-5279 (derivatized). [ka] The linker is derivatized to bond to the cyclopropyl group or cyclopropyl group via, for example, an amine (aniline), a carboxylic acid, or an amine alpha. 7. Kinase inhibitors described in Millan, et al., Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease (2011, J. Med. Chem., 54:7797), including derivatized kinase inhibitors Y1W and Y1X having the following structures: [ka] (l-ethyl-3-[2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl]urea The linker is derivatized to attach, for example, via an isopropyl group. [ka] 1-(3-t-[tert-]butyl-1-phenyl-1H-pyrazol-5-yl)-3-[2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl]urea For example, the linker is preferably derivatized to attach via either an isopropyl group or a tert-butyl group. 8. Kinase inhibitors described in Schenkel, et al., Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors (2011, J. Med. Chem., 54(24):8440-8450), including the (derivatized) compounds 6TP and OTP having the following structures: [ka] 4-Amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamidothienopyridine 19 The linker is derivatized to attach, for example, via a terminal methyl group attached to an amide moiety. [ka] 4-Amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamidothienopyridine 8 The linker is derivatized to attach, for example, via a terminal methyl group attached to an amide moiety. 9. Kinase inhibitors described in Van Eis, et al., "2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes" (2011 December, Biorg. Med. Chem. Lett., 15, 21(24):7367-72), including the kinase inhibitor 07U having the following structure: [ka] 2-Methyl-N-1-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine The linker is derivatized to attach, for example, through a secondary amine or terminal amino group. 10. Kinase inhibitors described in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy" (2011, J. Struct. Biol., 176:292), including the kinase inhibitor YCF having the following structure: [ka] The linker is derivatized, for example, to attach via any of the terminal hydroxyl groups. 11. Kinase inhibitors described in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy" (2011, J. Struct. Biol., 176:292), including (derivatized) kinase inhibitors XK9 and NXP having the following structures: [ka] N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide [ka] N-{4-[(1E)-N-carbamimidoylethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide The linker is derivatized to attach, for example, via a terminal hydroxyl group (XK9) or a hydrazone group (NXP). 12. The kinase inhibitor afatinib (derivatized) (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide) (the linker is derivatized to attach, for example, via an aliphatic amine group). 13. The kinase inhibitor fostamatinib (derivatized) ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyl disodium phosphate hexahydrate) (derivatized to allow linker attachment, e.g., via a methoxy group). 14. Kinase inhibitor gefitinib (derivatized) (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine). [ka] (The linker is derivatized to attach, for example, via a methoxy group or an ether group) 15. The kinase inhibitor afatinib (derivatized) (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide) (the linker is derivatized to attach, for example, via an aliphatic amine group). 16. The kinase inhibitor vandetanib (derivatized) (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (the linker is derivatized to attach, for example, via a methoxy group or a hydroxyl group). 17. Kinase inhibitor Gleevec (also known as imatinib) (derivatized). [ka] where R is derivatized to be a linker attached, for example, via an amide group or via an aniline amine group. 18. Kinase inhibitor pazopanib (derivatized) (VEGFR3 inhibitor). [ka] (where R is derivatized to be a linker attached, for example, to the phenyl moiety or via the aniline amine group). 19. Kinase inhibitor AT-9283 (derivatized) Aurora kinase inhibitor. [ka] (wherein R is a linker attached to, for example, the phenyl moiety). 20. Kinase inhibitor TAE684 (derivatized) ALK inhibitor). [ka] (wherein R is a linker attached to, for example, the phenyl moiety). 21. Kinase inhibitor Nilotinib (derivatized) Abl inhibitor. [ka] where R is derivatized to be, for example, a phenyl moiety or a linker attached to an aniline amine group. 22. Kinase inhibitor NVP-BSK805 (derivatized) JAK2 inhibitor). [ka] where R is derivatized to be, for example, a phenyl moiety or a linker attached to a diazole group. 23. Kinase inhibitor Crizotinib-derivatized ALK inhibitor. [ka] where R is derivatized to be, for example, a phenyl moiety or a linker attached to a diazole group. 24. Kinase inhibitor JNJ FMS (derivatized) inhibitor. [ka] where R is derivatized to be a linker attached to, for example, the phenyl moiety. 25. Kinase inhibitor Foretinib (derivatized) Met inhibitor. [ka] where R is derivatized to be a linker attached to, for example, a hydroxyl or ether group on the phenyl moiety or quinoline moiety. 26. Allosteric protein tyrosine phosphatase inhibitor PTP1B. (derivatization) [ka] As shown, the linker is derivatized to allow attachment at, for example, R. 27. Inhibitors of the SPH-2 domain of tyrosine phosphatases (derivatized). [ka] The linker is derivatized to attach, for example, at R. 28. Inhibitors (derivatized) of BRAF (wt and mutant). [ka] The linker group is derivatized, e.g., to attach at R (e.g., the kinase inhibitor vemurafenib (PLX4032) (derivatized) (propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-amide), e.g., the linker is derivatized to attach via a sulfonylpropyl group). 29. Inhibitor of tyrosine kinase ABL (derivatized). [ka] The linker is derivatized to allow attachment at, for example, R. 30. Kinase inhibitor OSI-027 (derivatized) mTORCl / 2 inhibitor. [ka] The linker is derivatized to allow attachment at, for example, R. 31. Kinase inhibitor OSI-930 (derivatized) c-Kit / KDR inhibitor. [ka] The linker is derivatized to attach, for example, at R, and 32. Kinase inhibitor OSI-906 (derivatized) IGF1R / IR inhibitor. [ka] The linker is derivatized to allow attachment at, for example, R. (derivatized so that "R" indicates the attachment site of the linker on the piperazine moiety).

[0396] II. Compounds targeting human BET bromodomain-containing proteins Compounds that target human BET bromodomain-containing proteins include, but are not limited to, compounds that associate with the targets described below, where "R" represents a linker attachment site, such as the following: JQl,Filippakopoulos et al.Selective inhibition of BET bromodomains.Nature (2010). [ka] 2.I-BET,Nicodeme et al.Supression of Inflammation by a Synthetic Histone Mimic.Nature (2010):Chung et al.Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains.J.Med Chem.(2011). [ka] 3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. (2011, J. Med. Chem. 54:6761-6770). [ka] 4.I-BET151, Dawson et al.Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia.Nature(2011). [ka] (R in each case indicates the attachment site of the linker.)

[0397] BRD9 Representative examples of BRD9 targeting have been developed over the years and include those described in the following literature: WO 2014 / 114721, WO 2016 / 077375, WO 2016 / 077378, WO 2016 / 139361, WO 2019 / 152440, the article by Martin LJ et al., "Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor" (Journal of Medicinal Chemistry, 2016, 59, 4462-4475), the article by Theodoulou NH et al., "Discovery of I-BRD9, a selective Cell Active Chemical Probe for Bromodomain-Containing Protein 9 Inhibition" (Journal of Medicinal Chemistry, 2015, 59, 1425-1439), and the article by Clack P. et al. (Angewandte Chemie, 2015, 127, 6315-6319).

[0398] Such BRD9 binding molecules (mentioned in the paragraph above) can be incorporated into the bifunctional molecules of the present disclosure as target protein binding ligands (TBLs).

[0399] The BRD9 binder has the formula BRD91a: [ka] wherein: Z 1 is N or CR A and Z 2 is N or CR B and Z 3 is N or CR D and Z 4 is N or CR E and In the formula, Z 1 , Z 2 , Z 3 and Z 4 Not more than three of these are N, R A and R E are each independently -H, -OC 1-3 Alkyl, and -C 1-3 is selected from the group consisting of alkyl, R B and R D are each independently -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, 4- to 7-membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2, -N(C 1-3 alkyl)2, -NH-R F selected from the group consisting of R F is -SO2-C 1-3 Alkyl and -C 1-3 alkyl, wherein -C 1-3 The alkyl is optionally substituted with a 5- to 6-membered heteroaryl; Alternatively, R A and R B together to form a benzene ring, Alternatively, R C and Z 2 , or R C and Z 3 together (for example, R C and R B , or R Cand R D together with the carbon atom to which they are attached) optionally -C 1-3 forming a 5- to 7-membered heterocycloalkyl substituted with alkyl; R C -H, -YR G , -NH2, -C 1-3 is selected from the group consisting of alkyl, and 4- to 7-membered heterocycloalkyl; Y is absent or -CR H R I -, -SO2- and -CO-; R H and R I are each independently -H or -C 1-3 alkyl, or R H and R I together form -C3-4 cycloalkyl, R G are -NH2, -OH, -C 1-3 and is selected from the group consisting of alkyl, -N(RJRK), -O-RL, aryl, and 5- to 6-membered heteroaryl, wherein the aryl and heteroaryl are optionally independently substituted with one or more halogens, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, which monocyclic or bicyclic heterocycloalkyl may optionally contain suitable substituents, such as halogen, -OH, -NH, -C, or -C. 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl, and -CH2-R M1 and optionally substituted with one or more groups independently selected from R M1 -NH2, -OH, halogen, -CN, -C 1-3 Alkyl or -OC 1-3 selected from 5-10 membered mono- or bicyclic aryl or heteroaryl optionally substituted with alkyl; R J is -H or -C1-3 is alkyl, R K -C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 alkyl)2, -C 2-3 Alkyl-NHC 1-3 alkyl, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is optionally selected from the group consisting of -C 1-3 substituted with suitable substituents such as alkyl; R L -C 1-3 alkyl or 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally C 1-3 is substituted with alkyl, where R C YR G If R B and R D are each independently -H, -OH, halogen, -NH2, -CN, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, and -C 1-3 Alkyl-OC 1-3 alkyl, where R A ~R E at least one of the substituents is not hydrogen; A 2 is represented by formula 1b or formula 1c: [ka] wherein the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom located ortho to R M is an optionally substituted C 1-6 Alkyl, optionally substituted C2-6 Alkenyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, C 2-6 selected from the group consisting of alkynyl, and H; Z 5 is N or CR O and Z 6 is N or CR P and Z 7 is N or CR N and where Z 5 , Z 6 and Z 7 and exactly one of them is N, Z 8 is CR W or N, R N is a halogen, optionally substituted -C 1-6 Alkyl, -H, C(O)C 1-5 Alkyl, -NH2, optionally substituted amino, -OH, cyano, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, and thiol; R O is H, halogen, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino; R P is H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl and optionally substituted C 6-10 aryl; Alternatively, R N and Z 5 are bonded together and optionally substituted C 6-10 arene or optionally substituted C 2-9 Forming a heteroarene, R N and R O are bonded together with the carbon atom to which they are attached, and optionally substituted C 6-10 arene or optionally substituted C 2-9 forming a heteroarene, R S is H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl and optionally substituted C 3-10 carbocyclyl; R T is H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 or R is selected from the group consisting of heteroalkenyl, optionally substituted sulfone, and optionally substituted sulfonamide. T and R Ueach together with the atom to which it is attached, optionally substituted C 2-9 forming a heterocyclyl, R U and R V are each independently H, halogen, hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, thiol, optionally substituted sulfone, and optionally substituted amino; Alternatively, R T and R U are optionally substituted C, along with the atoms to which they are attached. 2-9 forming a heterocyclyl, R W is H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 aryl or optionally substituted C 2-9 heteroaryl; Here, the BRD9 conjugate is attached to the linker at any suitable position.

[0400] In some embodiments, Z of formula BRD91a 1 , Z 2 , Z 3 and Z 4 One or less of the groups may be N. In some cases, Z 1 is CR A , Z 2 is CRB , Z 3 is N or CR D , Z 4 is CR E That is, Z 3 may be N. In such embodiments, the BRD9 conjugate has the formula BRD91a': [ka] wherein: R A , R B , R C , R E , Z 3 and A 2 is as defined above and herein.

[0401] A 2 is of formula BRD91b or formula BRD91c: [ka] wherein the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom ortho to Z 5 , Z 6 , Z 7 , Z 8 , R M , R S , R T , R U and R V is as defined above and herein.

[0402] Z 7 is N or CR N and Z 5 is N or CR O In some embodiments, R N (together with the carbon to which it is attached) and Z 5 are bonded together and optionally substituted C 6-10arene or optionally substituted C 2-9 For the avoidance of doubt, Z 5 is N and R N (together with the carbon to which it is attached) and Z 5 are bonded together and optionally substituted C 6-10 arene or optionally substituted C 2-9 When forming a heteroarene, R N (together with the carbon to which it is attached) and Z 5 together with optional substitution NC 2-4 Forms heteroarenes. For example, Z 5 If N, then R N and N combine to give: [ka] As shown in 2-4 A heteroaryl may be formed, wherein the wavy line represents A 2 and R A and R E The bond between the carbon atom ortho to the Z 6 and R M is as defined above, and 1B is an optionally substituted N-C 2-4 It is a heteroarene, for example, an optionally substituted 5-membered heteroarene, such as any one selected from the group consisting of optionally substituted pyrrole, imidazole, pyrazole, and triazole (including 1,2,3-triazole and 1,2,4-triazole).

[0403] In some embodiments, Z 5 is CR O and Z 7 is CR N If R N and R O are bonded together with the carbon to which they are attached, as follows: [ka] As shown in the 6-10 arene or optionally substituted C 2-9 In the formula, the wavy line represents A 2 and R A and R E The bond between the carbon atom ortho to Z 6 and R M is as defined above, and as previously mentioned, Ring 1C is an optionally substituted C 6-10 arene or optionally substituted C 2-9 For example, ring 1C may be an optionally substituted benzene or a 5- or 6-membered heteroarene, such as any one selected from the group consisting of optionally substituted benzene, pyridine, pyrrole, imidazole, pyrimidine, thiophene, and pyrazole.

[0404] In some embodiments, R N (together with the carbon atom to which it is attached) and Z 5 may be joined together to form a benzene ring or a 5- to 6-membered heteroarene ring (e.g., Ring 1C may be a benzene ring or a 5- to 6-membered heteroarene ring), and these rings may each optionally independently be selected from the group consisting of halogen, —OH, —NH, —NH—C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, 1d, C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, where -C 1-5 The alkyl group can be optionally substituted with a 5- to 6-membered heteroaryl or phenyl, where 1d is [ka] where Y 2 is NR R or O, Y 1 is S(O) a or NR R and Each R R are each independently H or C 1-4 is alkyl, Each R Q is C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and -C(O)C 1-3 independently selected from the group consisting of alkyl, a is 0 to 2; r is 0 to 3.

[0405] In some embodiments, Z 7 is CR N That is, A 2 is the formula BRD91b': [ka] wherein the wavy line represents A 2 and R A and R E The bond between the carbon atom ortho to the Z 5 , Z 6 , R M and R N is as defined above and herein.

[0406] R M is an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, C 2-6In some embodiments, RM is selected from the group consisting of optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, and H. For example, R M is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl, and H. In some embodiments, R M For example, C 1-5 -C such as alkyl 1-5 Alkyl, cyclopropyl, -C 1-4 haloalkyl, and H. In some embodiments, R M is C 1-3 It is alkyl.

[0407] R N is a halogen, optionally substituted -C 1-6 Alkyl, -H, C(O)C 1-5 Alkyl, -NH2, optionally substituted amino, -OH, cyano, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 In some embodiments, R N is a halogen, optionally substituted C 1-6 Alkyl, H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 In some embodiments, R N is a halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C1-5 Alkyl, -NH2, -NHC 1-3 alkyl, and —OH. For example, R N is C 1-5 It may be alkyl or halogen.

[0408] Z 5 is N or CR O where R O is H, halogen, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 For example, R is selected from the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino. O is H or C 1-3 Optionally substituted C such as alkyl 1-6 In some embodiments, R O is H or -C 1-3 It may also be alkyl.

[0409] In some embodiments, R N -C 1-5 alkyl or halogen, or R N and Z 5are taken together to form an optionally substituted 5- to 6-membered heteroarene or benzene ring. In some embodiments, the optionally substituted 5- to 6-membered heteroarene ring can contain one or more heteroatoms selected from the group consisting of N, S, and O, such as N and S, i.e., the optionally substituted 5- to 6-membered heteroarene ring can be an N-heteroarene or an S-heteroarene. In some embodiments, the optionally substituted 5- to 6-membered heteroarene ring is any one selected from the optionally substituted group consisting of pyridine, pyrrole, imidazole, pyrimidine, thiophene, and pyrazole.

[0410] For the avoidance of doubt, the optional substituents are halogen, -OH, -NH, -NH-C 1-3 Alkyl, -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, 1d, C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, where -C 1-5 The alkyl group can be optionally substituted with a 5- to 6-membered heteroaryl or phenyl, where 1d is [ka] and in the formula Y 2 is NR R or O, Y 1 is S(O) a or NR R and Each R R are each independently H or C 1-4 is alkyl, Each R Q is C 1-4 Alkyl, C 1-4Haloalkyl, halogen, and -C(O)C 1-3 independently selected from the group consisting of alkyl, a is 0 to 2; r is 0 to 3.

[0411] For example, optional substituents include halogen, —OH, —NH, —NH—C 1-3 Alkyl, -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, and C 1-4 In some cases, the optional substituents may be independently selected from the group consisting of C1-C4 alkyl, allyl, crotyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Haloalkyl, C 3-5 In some embodiments, R N and Z 5 are bonded together to form an optionally substituted C 6-10 Aryl or optionally substituted C 2-9 When forming a heteroaryl, the C 6-10 Aryl or C 2-9 The heteroaryl is unsubstituted.

[0412] Z 6 is N or CR P where R P is H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl and optionally substituted C 6-10 aryl. For example, R P is H or C 1-6 H or optionally substituted C, such as alkyl 1-6 In some embodiments, R P is H or -C 1-3Alkyl, i.e., Z 6 is N, CH, or CC 1-3 It is an alkyl group. For example, Z 6 is CH or CC 1-3 It may also be alkyl.

[0413] In some particular embodiments, A 2 is selected from formula BRD91b', where formula BRD91b' is [ka] and Here, the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom located in the ortho position to R M -C 1-5 Alkyl, -cyclopropyl, -C 1-4 selected from the group consisting of haloalkyl, and H; R N is a halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 is selected from the group consisting of alkyl, and -OH; Z 5 is N or CR O and Z 6 is N or CR P and Z 5 and Z 6 Only one of may be N, R O is H or -C 1-3 is alkyl, R P is H or -C 1-3 is alkyl, where R O and R P Only one of them is -C 1-3 may be alkyl, Alternatively, RN and Z 5 are taken together to form a benzene ring or a 5- or 6-membered heteroaryl ring, each of which may be selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, 1d, C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, where -C 1-5 The alkyl group can be optionally substituted with a 5- to 6-membered heteroaryl or phenyl; Here, 1d is [ka] and in the formula Y 2 is NR R or O, Y 1 is S(O) a or NR R and Each R R are each independently H or C 1-4 is alkyl, Each R Q is C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and -C(O)C 1-3 independently selected from the group consisting of alkyl, a is 0 to 2; r is 0 to 3.

[0414] The BRD9 conjugate may have the linker attached at any suitable position (provided it has the correct valence and / or is chemically suitable). For example, the linker may be attached at any suitable position between an atom on the linker and R C , R A , RB , R D or R E Alternatively, the linker may be attached to the BRD9 conjugate by a covalent bond between an atom that is part of R C , R A , R B , R D and / or R E may be directly attached to the ring to which R is attached, i.e., the linker C , R A , R B , R D or R E In some embodiments, the linker may be substituted with an atom on the linker and R C or by a covalent bond between atoms that form part of R C is attached to the BRD9 conjugate by a covalent bond between an atom on the linker and the atom to which it would otherwise be attached, i.e., the linker is R C Replace with.

[0415] Alternatively, R C and Z 2 , or R C and Z 3 together (for example, R C and R B or R C and R D together with the carbon atom to which they are attached) optionally -C 1-3 When forming a 5- to 7-membered heterocycloalkyl substituted with alkyl, the linker may be attached to the BRD9 conjugate by a covalent bond between an atom on the linker and an atom forming part of the 5- to 7-membered heterocycloalkyl.

[0416] In some embodiments, the BRD9 conjugates are represented by the formula BRD91a1, BRD91a2, and BRD91a3, as follows: [ka] wherein the wavy line crosses the bond between the BRD9 binder and the linker; A 2 , Z 1 , Z 2 , Z 3 and Z 4 is as defined above and herein; R C is absent or is as defined above and herein; Ring 1A optionally contains -C 1-3 It is a 5- to 7-membered heterocycloalkane substituted with alkyl.

[0417] Ring 1A may contain one or two heteroatoms independently selected from the list consisting of N, S, and O. For example, ring 1A may be selected from the list consisting of pyrrolidine, piperidine, piperazine, morpholine, oxolane, oxane, tetrahydrothiophene, and thiane. In some cases, ring 1A may be an N-heterocycloalkane such as pyrrolidine, piperidine, or piperazine. In a particular example, ring 1A is pyrrolidine.

[0418] For the avoidance of doubt, it should be noted that the linker is a linker that is connected to an atom on the linker and a feature on the BRD9 binder (e.g., R C When attached to a BRD9 conjugate by a covalent bond between an atom forming part of a BRD9 conjugate, the linker replaces a chemical group or feature with a valence of one (e.g., a hydrogen atom) to satisfy the valence. For example, if the feature on the BRD9 conjugate is dimethylamide (-C(O)N(CH)) or dimethylaminomethylene (-CHN(CH)), the linker can replace a methyl group or a hydrogen atom on that feature.

[0419] Alternatively, the linker can be a bond between the atoms on the linker and A 2 Atoms that form part of, for example, R M , R N , R O , R P , R S , R T , R U , R V or R Wor the linker may be attached to the BRD9 conjugate by a covalent bond between R M , R N , R O , R P , R S , R T , R U , R V or R W Alternatively, R N and Z 5 are bonded together to form an optionally substituted C 6-10 arene or optionally substituted C 2-9 When forming a heteroarene, optionally R N and R O together with the carbon atom to which they are attached, an optionally substituted C 6-10 arene or optionally substituted C 2-9 When forming a heteroarene, the linker may be an atom on the linker and an optionally substituted C 6-10 arene or optionally substituted C 2-9 It may be attached to the BRD9 binder by a covalent bond between atoms that form part of the heteroarene.

[0420] R N and Z 5 are linked together to form an optionally substituted thiophene, the linker has the following structure: [ka] wherein the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom located ortho to R M and Z 6 is as defined above and herein.

[0421] The linker may be attached to an atom that forms part of a substituent attached at the same position as shown above. For example, the linker may be attached to an atom that forms part of substituent 1d that is attached at the same position as shown above. This is because R N and Z 5 are bonded together to form an optionally substituted thiophene, as exemplified in the following structure, where the wavy line represents A 2 and R A and R E and crosses the bond between the carbon atom located in the ortho position to Y. 2 is O and Y 1 is N and R R is H and R Q and r is as defined above. [ka]

[0422] As defined above, Z of the BRD9 binder 1 , Z 2 , Z 3 , Z 4 and R C can be defined as follows: Z 1 is N or CR A and Z 2 is N or CR B and Z 3 is N or CR D and Z 4 is N or CR E and In the formula, Z 1 , Z 2 , Z 3 and Z 4 Not more than three of these are N, R A and R E are each independently -H, -OC 1-3 Alkyl, and -C 1-3 is selected from the group consisting of alkyl, RB and R D are each independently -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, 4- to 7-membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2, -N(C 1-3 alkyl)2, -NH-R F selected from the group consisting of R F is -SO2-C 1-3 Alkyl and -C 1-3 alkyl, wherein -C 1-3 The alkyl is optionally substituted with a 5- to 6-membered heteroaryl; Alternatively, R A and R B together form a benzene ring; or R C and Z 2 , or R C and Z 3 together (for example, R C and R B or R C and R D together with the carbon atom to which they are attached) optionally -C 1-3 forming a 5- to 7-membered heterocycloalkyl substituted with alkyl; R C -H, -YR G , -NH2, -C 1-3 is selected from the group consisting of alkyl, and 4- to 7-membered heterocycloalkyl; Y is absent or -CR H R I -, -SO2- and -CO-; R H and R Iare each independently -H or -C 1-3 alkyl, or R H and R I together form -C3-4 cycloalkyl, R G -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ), -OR L , aryl, and 5- to 6-membered heteroaryl, wherein the aryl and heteroaryl are optionally independently substituted with one or more halogen, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is optionally substituted with, for example, halogen, —OH, —NH, —C 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl and -CH2-R M1 and is substituted with any suitable substituent, such as one or more groups independently selected from R M1 -NH2, -OH, halogen, -CN, -C 1-3 Alkyl or -OC 1-3 selected from 5-10 membered mono- or bicyclic aryl or heteroaryl optionally substituted with alkyl; R J is -H or -C 1-3 is alkyl, R K -C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 alkyl)2, -C 2-3 Alkyl-NHC 1-3 and optionally substituted 4- to 7-membered heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is optionally selected from the group consisting of -C 1-3 substituted with any suitable substituent, such as alkyl; R L -C 1-3 alkyl or 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally C 1-3 is substituted with alkyl, where R C YR G If R B and R D are each independently -H, -OH, halogen, -NH2, -CN, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl and -C 1-3 Alkyl-OC 1-3 alkyl, wherein the substituent R A ~R E At least one of them is not hydrogen.

[0423] In some embodiments of the BRD9 binding ligands described herein (unless otherwise specified), (i)R A , R B , R D and R E are each independently -OC 1-3 Alkyl, -H, halogen, -OC 1-3 Haloalkyl, -OH, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2 and -N(C 1-3 alkyl)2; or (ii)R A , R D and R E are each independently -OC 1-3 Alkyl, -H, halogen, -OC 1-3 Haloalkyl, -OH, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3alkyl)2 and -N(C 1-3 alkyl)2, and R B and R C together with optional -C 1-3 Forms a 5- to 7-membered heterocycloalkyl substituted with alkyl.

[0424] In such embodiments, the 5- to 7-membered heterocycloalkyl may be as defined above for Ring 1A.

[0425] In some embodiments, R A , R B , R D and R E independently, -OC 1-3 Alkyl, -H, halogen, -OC 1-3 Haloalkyl, -OH, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2 and -N(C 1-3 For example, R A , R B , R D and R E independently, -OC 1-3 Alkyl, -H, halogen and -OC 1-3 It may be selected from the group consisting of haloalkyl.

[0426] In some cases, R A , R B , R D and R E At least one of R may be -H. For example, A and R B At least one of R may be -H. A , R B , R D and R E At least two of the are -H.

[0427] In some embodiments, RA , R B , R D and R E At least one of them is -OC 1-3 Alkyl, halogen, -OC 1-3 haloalkyl. B and R E -OC 1-3 Alkyl, halogen and -OC 1-3 haloalkyl.

[0428] In some embodiments, R C is -H or -YR G Y is -CR H R I - or -CO-, where R H and R I is as defined above. R H and R I may each be -H, or R H and R I Together -C 3-4 It may also form a cycloalkyl.

[0429] R G may be as defined above, or may be —NH, —OH, —C 1-3 Alkyl, -N(R J R K ), -OR L , optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein R J , R K , R L and the optional substituents of the 4- to 7-membered monocyclic heterocycloalkyl and the 7- to 12-membered bicyclic heterocycloalkyl are as defined above. R J is -H or -C 1-3 alkyl, and R K Ha-C 1-3R may be selected from alkyl, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl. L -C 1-3 It may also be alkyl.

[0430] R G or R K is an optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, the optionally substituted 4- to 7-membered monocyclic heterocycloalkyl can be a 5- to 7-membered monocyclic heterocycloalkyl containing 1 to 3 ring heteroatoms selected from N, O, and S. In some embodiments, the optionally substituted 4- to 7-membered monocyclic heterocycloalkyl can be a 5- to 7-membered monocyclic heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N. In some embodiments, the optionally substituted 4- to 7-membered monocyclic heterocycloalkyl can be piperazinyl, piperidinyl, or diazepanyl (each of which can optionally contain 1 to 3 substituents as described herein).

[0431] R G or R KWhen is an optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may be a bridged bicyclic ring or a spirocyclic bicyclic ring (i.e., it may contain two rings joined at a spiro center). By way of example only, the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may be a bridged piperazinyl or a bridged piperidinyl. In other examples, the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may contain 1 to 3 ring heteroatoms selected from N, O, and S (e.g., 1 to 2 ring heteroatoms selected from N), and may be an optionally substituted spirocyclic bicyclic heterocycloalkyl. In some examples, the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl is spirocyclic and includes a 5- or 6-membered first ring and a 3- to 6-membered second ring.

[0432] In some embodiments, R C may be any one selected from the following: [ka] In the formula, Y is CR H R I (e.g. CH2), R G1 and R G2 are each independently selected from H or C1-C3 alkyl; R J is as defined above and herein; L indicates the point of attachment of the linker.

[0433] In the above structure, the Y and L groups may both be attached to the heterocycle(s) via covalent bonds between atoms on the Y and L groups and atoms of the heterocycle. These groups may be attached at any chemically suitable position as long as valences are satisfied (e.g., by each replacing an H atom).

[0434] Further by way of example only, R C may be any one selected from the following: [ka] In the formula, Y is CR H R I (e.g., CH2), L indicates the point of attachment of the linker.

[0435] In certain embodiments, R is [ka] CH2N(C 1-3 alkyl)2, -C(O)N(C 1-3 alkyl)2, -C(CH2CH2)N(C 1-3 alkyl)2, and CH2OCH3, wherein the wavy line represents R C and the rest of the BRD9 conjugate, and R C and the linker.

[0436] In some embodiments, the BRD9 conjugate has formula BRD91e, formula BRD91f, or formula BRD91g, as follows: [ka] wherein the wavy line crosses the bond between the BRD9 binder and the linker; R A , R B , R E , R M , R N , Z 3 , Z 5 and Z 6 is as defined above, R C is not present or is not R C is as defined for Ring 1A optionally contains -C 1-3 a 5- to 7-membered heterocycloalkane substituted with alkyl; Ring 1D is an optionally substituted C 6-10 arene or optionally substituted C 2-9 It is a heteroarene. In some embodiments, Ring 1D is an optionally substituted benzene or an optionally substituted 5- to 6-membered heteroarene. The 5- to 6-membered heteroarene is selected from the group consisting of S, N, and O. It may contain one or more heteroatoms, such as S. In some examples, Ring 1D is a 5- to 6-membered N-heteroarene or S-heteroarene, such as any one selected from the group consisting of thiophene, pyrazole, imidazole, pyrrole, pyrimidine, and pyridine. In particular examples, Ring 1D is a thiophene fused to the remainder of the BRD9 conjugate at the 2' and 3' positions, and in more particular examples, is attached by a covalent bond between an atom on the linker and the carbon atom at the 5' position of the thiophene. In certain such examples, the BRD9 conjugate has the formula BRD91g': [ka] where the wavy line crosses the bond between the BRD9 binder and the linker, and R A , R B , R C , R E , R M , Z 3 , and Z 6 is as defined above.

[0437] In some embodiments, Ring 1A is pyrrolidine. In particular examples, Ring 1A is pyrrolidine and is fused to the remainder of the BRD9 conjugate at the 3' and 4' positions, and in more particular embodiments, is attached to the linker by a covalent bond between an atom on the linker and the nitrogen atom of the pyrrolidine. In certain such embodiments, the BRD9 conjugate has the formula BRD91f': [ka] where the wavy line crosses the bond between the BRD9 binder and the linker, and where R A , R E , R M , R N , Z 3 , Z 5 and Z 6 is as defined above and herein.

[0438] In some embodiments, the BRD9 conjugate is of formula BRD91e, BRD91f', or BRD91g'.

[0439] In certain embodiments, the BRD9 conjugates have the formulas BRD91ea-BRD91eh, BRD91fa-BRD91fh, and BRD91ga: [ka] wherein the wavy line crosses the bond between the BRD9 binder and the linker; R A , R B , R E , R M , Z 3 and Z 6 is as defined above and herein; R C is absent or is as defined above and herein; R Nis as defined above and herein, for example, halogen, —C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 selected from the group consisting of alkyl and —OH; R O is as defined above and herein, for example, —H or —C 1-3 is alkyl, Each R X is R N and Z 5 Optionally substituted C 6-10 Aryl or optionally substituted C 2-9 as defined as optional substituents of heteroaryl, e.g., each R X are each independently a halogen, -OH, -NH2, or -NH-C 1-3 Alkyl, -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy and C 1-4 haloalkoxy; n is 0 to 3 (e.g., 0), o is 0 to 2 (e.g., 0), p is 0 or 1 (e.g., 0), q is 0 to 4 (for example, 0).

[0440] Each of n, o, p, and q may be 0.

[0441] In some embodiments, the BRD9 conjugate has the formula BRD91ea': [ka] wherein the wavy line crosses the bond between the BRD9 binder and the linker; R A and R Eare as defined above and herein, for example, each independently H or —OC 1-3 alkyl, R B and R D are as defined above and herein, for example, each independently represents -OC 1-3 Alkyl, -H, -halo, -C 1-3 Alkyl or -OC 1-3 haloalkyl; R C does not exist or -YR G and Y is -CR H R I - and -CO-, R H and R I are each independently -H or -C 1-3 alkyl, or R H and R I Together -C 3-4 forming a cycloalkyl, R G is -N(R J R K ) (e.g. -N(C 1-3 alkyl)-, -N(C 1-3 alkyl)(optionally substituted 4- to 7-membered monocyclic heterocycloalkylene)-, or -N(C 1-3 alkyl)(optionally substituted 7- to 12-membered bicyclic heterocycloalkylene), -O-, optionally substituted 4- to 7-membered monocyclic heterocycloalkylene, and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene; R J and R K is as defined above and herein; R M is as defined above and herein, for example, -C 1-3 is alkyl, R N , R O and R Pare each as defined above and herein, for example, each independently -halo, -C 1-3 Alkyl, and -C 1-3 haloalkyl.

[0442] In more specific embodiments, the BRD9 conjugates are of formula BRD91h to BRD91z and BRD92a to BRD92g: [ka] TIFF2025525347000203.tif195170 wherein R C is not present or -YR G and Y is -CR H R I - and -CO-, R H and R I are each -H; or R H and R I Together -C 3-4 forming a cycloalkyl, R G is -N(R J R K ) (e.g., -N(C 1-3 alkyl)-, -N(C 1-3 alkyl)(optionally substituted 4- to 7-membered monocyclic heterocycloalkylene), or —N(C 1-3 alkyl) (optionally substituted 7- to 12-membered bicyclic heterocycloalkylene), -O-, optionally substituted 4- to 7-membered monocyclic heterocycloalkylene containing 1 or 2 N ring atoms, and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing 1 or 2 N ring atoms; R J and R K is as defined above and herein; where the wavy line crosses the bond between the BRD9 binder and the linker.

[0443] In certain embodiments of any of the above formulas (e.g., any one of formulas BRD91e, BR91g, BRD91g', BRD91ea-BRD91eh, BRD91ea', BRD91h-BRD91z, and BRD92a-BRD92g, unless otherwise specified), R G is -N(C 1-3 alkyl)-, -O- or [ka] is.

[0444] In some embodiments of any of the above formulas (e.g., any one of formulas BRD91e, BRD91g, BRD91g', BRD91ea-BRD91eh, BRD91ea', BRD91h-BRD91z, and BRD92a-BRD92g, unless otherwise specified), R C is the following: [ka] wherein Y is any one selected from CR H R I (e.g., CH2) or -CO-, R H and R I is as defined above and herein; L indicates the point of attachment of the linker.

[0445] In particular, in each of the structures shown above, Y may be CH2.

[0446] In some cases, the BRD9 binder comprises: [ka] where the wavy line crosses the bond between the BRD9 binder and the linker.

[0447] III. Heat Shock Protein 90 (HSP90) Inhibitors HSP90 inhibitors useful according to the present disclosure include, but are not limited to: 1. HSP90 inhibitors identified in Vallee et al., "Tricyclic Series of Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90 Molecular Chaperone" (2011, J. Med. Chem., 54:7206), including YKB (N-[4-(3H-imidazo[4,5-C]Pyridin-2-yl)-9H-Fluoren-9-yl]-succinamide). [ka] The linker is derivatized to allow attachment, for example, through a terminal amide group. 2. HSP90 inhibitor p54(modified)(8-[(2,4-dimethylphenyl)sulfanyl]-3[pent-4-yn-1-yl]-3H-purin-6-amine). [ka] The linker is attached, for example, via a terminal acetylene group. 3. HSP90 inhibitors (modifications) identified in Broough, et al., “4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer” (2008), J. Med. Chem., 51:196), including compound 2GJ (5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide). [ka] The linker is derivatized to attach, for example, through an amide group (at an amine or an alkyl group on an amine). 4. Structure: [ka] HSP90 inhibitors (modifications) identified in Wright, et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, (June 2004, Chem Biol. 11(6):775-85), including the HSP90 inhibitor PU3 having the formula: 5. The HSP90 inhibitor geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1](derivatized)) or a derivative thereof (e.g., 17-alkylamino-17-desmethoxygeldanamycin (“17-AAG”) or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin (“17-DMAG”)), where a is derivatized to attach, for example, via an amide group.

[0448] IV. HDM2 / MDM2 inhibitors HDM2 / MDM2 inhibitors of the present invention include, but are not limited to: 1. HDM2 / MDM2 inhibitors including (or additionally including) the compounds Nutlin-3, Nutlin-2, and Nutlin-1 (derivatized), as described below, and all derivatives and analogs thereof, as identified in Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 (2004, Science, 303:844-848) and Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: An route to chemical proteomics (2008, Biorg. Med. Chem. Lett., 18:5904-5908). [ka] (The linker is derivatized to attach, for example, at a methoxy group or as a hydroxyl group). [ka] (The linker is derivatized to attach at, for example, a methoxy or hydroxyl group). [ka] (wherein the linker is derivatized to attach, for example, via a methoxy group or as a hydroxyl group); and

[0449] V. HDAC Inhibitors HDAC inhibitors (derivatized) useful in some embodiments of the present disclosure include, but are not limited to: 1. Finnin, MS et al. Structures of Histone Deacetylase Homologue Bound to the TSA and SAHA Inhibitors. (1999, Nature, 40:188-193). [ka] (where "R" is derivatized to indicate the site of attachment of the linker, for example). 2. Compounds defined by formula (I) of PCT WO0222577 (the entire text of which is incorporated herein by reference) ("DEACETYLASE INHIBITORS"), where the linker has been derivatized to attach, for example, via a hydroxyl group.

[0450] VI. Human Lysine Methyltransferase Inhibitors Human lysine methyltransferase inhibitors useful in some examples of the present disclosure include, but are not limited to: 1. Chang et al. Structural Basis for G9a-Like protein Lysine Methyltransferase Inhibition by BIX-1294 (2009, Nat. Struct. Biol., 16(3):312). [ka] (where "R" is derivatized to indicate the site of attachment of, for example, a linker). 2. Liu, F. et al Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Methyltransferase G9a. (2009, J.Med.Chem., 52(24):7950). [ka] (derivatized so that "R" indicates a potential attachment site for the linker). 3. Azacitidine (derivatized) (4-amino-1-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (the linker is derivatized to attach, for example, via a hydroxy or amino group); and 4. Decitabine (derivatized) (4-amino-1-(2-deoxy-bD-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) (the linker is derivatized to attach, for example, via one of the hydroxy groups or at the amino group).

[0451] VII. Angiogenesis Inhibitors Angiogenesis inhibitors useful in some embodiments of the present disclosure include, but are not limited to: 1. GA-1 (derivatized) and its derivatives and analogs having the structure(s) described in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, (2003 December, Mol. Cell Proteomics, 2(12):1350-1358) and linked to a linker. 2. Estradiol (derivatized), which can be attached to a linker as outlined in Rodriguez-Gonzalez, et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, (2008, Oncogene 27:7201-7211). 3. Estradiol, testosterone (derivatized), and related derivatives, including but not limited to DHT and its derivatives and analogs, having the structure(s) outlined in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, (2003 December, Mol. Cell Proteomics, 2(12):1350-1358), and attached to a linker. 4. Ovalicin, fumagillin (derivatized), and derivatives and analogs thereof, having the structure(s) outlined in Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skp1- Cullin-F box complex for ubiquitination and degradation (2001 Jul., Proc. Natl. Acad. Sci. USA, 98(15):8554-8559) and U.S. Patent No. 7,208,157, the entire contents of which are incorporated herein by reference, and attached to a linker.

[0452] VIII. Immunosuppressive compounds Immunosuppressant compounds useful in some examples of the present disclosure include, but are not limited to: 1. AP21998 (derivatized) having structure(s) as outlined in Schneekloth, et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation (2004, J. Am. Chem. Soc., 126:3748-3754) and attached to a linker. 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (where the linker is derivatized to attach, e.g., to one of the hydroxyls) and beclomethasone dipropionate (where the linker is derivatized to attach, e.g., to the propionate salt). 3. Methotrexate (derivatized so that a linker can be attached, for example, to either of the terminal hydroxyls). 4. Cyclosporin (derivatized so that the linker can be attached at a, for example, the butyl group). 5. Tacrolimus (FK-506) and rapamycin (derivatized so that a linker group can be attached, for example, at one of the methoxy groups); and 6. Actinomycin (derivatized so that the linker can be attached at one of the isopropyl groups, for example).

[0453] IX. Compounds targeting the aryl hydrocarbon receptor (AHR) Compounds that target the aryl hydrocarbon receptor (AHR) according to some examples of the present disclosure include, but are not limited to: 1. Apigenin (derivatized in a manner that allows it to be attached to a linker as outlined in Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages 2058-2062, November 23, 2007); and 2. SR1 and LGC006 (derivatized to allow a linker to be attached) described in Boitano, et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells (2010 September, Science, 329(5997):1345-1348).

[0454] XI. Compounds targeting FKBP [ka] (derivatized so that "R" indicates the linker attachment site).

[0455] XIV. Compounds Targeting Thyroid Hormone Receptors (TRs) 1. Thyroid hormone receptor ligands (derivatized) [ka] (derivatized so that "R" indicates the linker attachment site and MOMO indicates a methoxymethoxy group).

[0456] XV. Compounds that target HIV protease 1. HIV protease inhibitors (derivatized) [ka] (Derivatized so that "R" indicates the linker attachment site.) See 2010, J. Med. Chem, 53:521-538. 2. HIV protease inhibitors [ka] ("R" is derivatized to indicate a potential site for linker attachment). See 2010, J. Med. Chem., 53:521-538.

[0457] XVI. Compounds that target HIV integrase 1. HIV integrase inhibitors (derivatized) [ka] (Derivatized so that "R" indicates the linker attachment site.) See 2010, J. Med. Chem., 53:6466. 2. HIV integrase inhibitors (derivatized) [ka] 3. HIV integrase inhibitor Isentress (derivatized) [ka] (Derivatized so that "R" indicates the linker attachment site.) See 2010, J. Med. Chem., 53:6466.

[0458] XVII. Compounds targeting HCV protease 1.HCV protease inhibitors (derivatized) [ka] (derivatized so that "R" indicates the linker attachment site).

[0459] XVIII. Compounds Targeting Acyl-Protein Thioesterase-1 and -2 (APT1 and APT2) 1. APT1 and APT2 inhibitors (derivatized) [ka] (where "R" is derivatized to indicate the linker attachment site). See 2011, Angew. Chem. Int. Ed., 50:9838-9842.

[0460] XIX. Compounds targeting ubiquitin-specific protease 1 (Usp1) Examples of additional USP1 binding ligands are shown below. A compound of formula USP1A, USP2A or USP3A. [ka] During the ceremony, A is aryl or heteroaryl, each of which is optionally C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-7 Cyclohaloalkyl, C 1-4 substituted with one or more substituents selected from the group consisting of haloalkoxy, halo, hydroxyl, and amino; B is heteroaryl containing at least one N ring atom and optionally C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C1-4 substituted with one or more substituents selected from the group consisting of haloalkoxy, halo, hydroxyl, and amino; R 1 and R 1’ are each independently H and C 1-2 alkyl, n is 1 to 3; Y is aryl or heteroaryl, each of which is optionally C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-7 Cyclohaloalkyl, C 1-4 substituted with one or more selected from the group consisting of haloalkoxy, halo, hydroxyl, and amino; R 2 and R 4 are each independently H and C 1-4 is selected from the group consisting of alkyl, R 3 is LZ or C 1-4 alkyl-LZ; X 1 and X 2 are each independently N, CLZ, and CR 5 where R 5 is H and C 1-4 alkyl, and wherein X 1 and X 2 One of the two is CLZ, where: [ka] indicates that the bond is a single bond or a double bond, where X if the bond is a double bond 3 and X 4 are independently CLZ and CR 6 wherein X is selected from the group consisting of 3and X 4 is CLZ, and Here, if the bond is a single bond, X 3 and X 4 are each independently 6 LZ and CR 6 2, and X 3 and X 4 Either one of the two is CR 6 LZ, Here, each R 6 are independently H, C 1-4 selected from the group consisting of alkyl, NH, NHMe, and NMe; X 5 is N or CH, X 6 is C=O, CR 7 2, NH, and NMe, wherein each R 7 are each independently H and C 1-4 is selected from the group consisting of alkyl, X 7 is N or CH, L is a linker (defined above); Z is as defined above and herein.

[0461] In some cases, compounds that target Usp1 have the formula USP1, USP2, or USP3, as follows: [ka] is a compound of the formula A is aryl or heteroaryl, each of which is optionally C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-7 Cyclohaloalkyl, C 1-4 substituted with one or more selected from the group consisting of haloalkoxy, halo, hydroxyl, and amino; B is heteroaryl containing at least one N ring atom and optionally C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4 substituted with one or more selected from the group consisting of haloalkoxy, halo, hydroxyl, and amino; R 1 and R 1’ are each independently H and C 1-2 alkyl, n is 1 to 3; R 2 and R 4 are each independently H and C 1-4 alkyl, R 3 is LZ or C 1-4 alkyl-LZ; X 1 and X 2 are each independently N, CLZ, and CR 5 where R 5 is H and C 1-4 alkyl, and wherein X 1 and X 2 One of the two is CLZ, X 3 and X 4 are each independently 6 LZ and CR 6 2, wherein each R 6 are each independently H and C 1-4 alkyl; and X 3 and X 4 Either one of the two is CR 6 LZ, X 7 is N or CH, L is a linker (as defined above and herein); Z is as defined above and herein.

[0462] As a further example, compounds that target Usp1 may have the formula USP1a, USP2a, or USP3a: [ka] wherein A, B, R 3 , X 1 , X 2 , R 6 , L and Z are as defined above for formulas USP1A, USP2A, USP3A, USP1, USP2 and USP3.

[0463] A, B, Y, X 1 , X 2 , X 3 , X 4 , R 1 , R 1’ , R 2 , R 3 , R 4 , R 5 and R 6 Representative examples of each group are shown below and are applicable to any one or more of the formulae described herein in connection with compounds targeting Usp1 (formulae USP1A, USP2A, USP3A, USP1, USP2, USP3, USP1a, USP2a and USP3a) (unless otherwise noted).

[0464] As noted above, A may be aryl or heteroaryl, each of which is optionally C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-7 Cyclohaloalkyl, C 1-4and optionally substituted by any one or more selected from the group consisting of haloalkoxy, halo, hydroxyl, and amino. For the avoidance of doubt, when A is heteroaryl, it is optionally substituted at one or more carbon atoms or heteroatoms.

[0465] When A is heteroaryl, it may contain one or more nitrogen atoms, for example, two nitrogen atoms. Optionally, the heteroaryl is monocyclic. Optionally, the heteroaryl is N-heteroaryl.

[0466] In some embodiments, A is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, and optionally C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-7 Cyclohaloalkyl, C 1-4 It is substituted with any one or more substituents selected from the group consisting of haloalkoxy, halo, hydroxyl and amino.

[0467] By way of further example, A may be selected from the group consisting of phenyl, pyrimidinyl, and pyrazolyl, and optionally C 1-4 Alkyl (e.g., isopropyl or methyl), C 3-7 cycloalkyl (e.g., cyclopropyl), C 1-4 Alkoxy (e.g., methoxy), C 1-4 Haloalkyl (e.g., C such as trifluoromethyl) 1-4 Fluoroalkyl), C 3-7 Cyclohaloalkyl (e.g., C 3-7 cyclofluoroalkyl), C 1-4 Haloalkoxy (e.g., C such as difluoromethoxy) 1-4By way of further example, A may be selected from the group consisting of phenyl, pyrimidinyl, and pyrazolyl, and may optionally be substituted with any one or more substituents ... 1-4 Alkyl (e.g., isopropyl or methyl), C 3-7 cycloalkyl (e.g., cyclopropyl), C 1-4 Alkoxy (e.g., methoxy), C 1-4 Optionally, A is selected from the group consisting of phenyl and pyrimidinyl, and optionally, C 1-4 Alkyl (e.g., isopropyl), C 3-7 Cycloalkyl (e.g., cyclopropyl) and C 1-4 In some embodiments, A is substituted with any one or two substituents selected from the group consisting of alkoxy (e.g., methoxy). In some embodiments, A is N-alkyl-4-alkylpyrazolyl, 4,6-dialkylpyrimidinyl, and 2,4-dialkylpyridinyl (wherein each alkyl group is C 1-4 alkyl).

[0468] Representative examples of suitable A groups include, but are not limited to, the following: [ka] In the formula, R C is selected from the group consisting of methoxy, cyclopropyl and difluoromethoxy. [ka] In the formula, R A is methyl, ethyl, fluoro or difluorotrifluoroethyl.

[0469] In the structures shown above, the wavy intersecting lines represent the covalent bond between the A group illustrated above and the carbon atom on the heteroaryl core that is bonded to the A group (as illustrated in the various formulas described herein). In the exemplary aryl and heteroaryl structures above, specific substitution patterns are shown, but it will be understood that other substitution patterns are encompassed within the scope of the present disclosure.

[0470] As noted above, B is heteroaryl containing at least one N ring atom, and optionally C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4 and is substituted by any one or more selected from the group consisting of haloalkoxy, halo, hydroxyl, and amino. For the avoidance of doubt, B is optionally substituted by one or more carbon or heteroatoms.

[0471] In some embodiments, B is a monocyclic 5- to 6-membered heteroaryl containing at least one N ring atom (e.g., containing 1, 2, or 3 N ring atoms). By way of further example, B may be selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, and oxadiazolyl, and optionally, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4 and optionally substituted with any one or more substituents selected from the group consisting of haloalkoxy, halo, hydroxyl, and amino. Often, B is a monocyclic 5-membered heteroaryl. Optionally, B contains at least two nitrogen atoms. Further by way of example, B may be selected from the group consisting of imidazolyl, pyrazolyl, and triazolyl (e.g., 1,2,3-triazolyl), and optionally, C 1-4 Alkyl, C1-4 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4 In some embodiments, B may be selected from the group consisting of imidazolyl, pyrazolyl, and triazolyl (e.g., 1,2,3-triazolyl), and optionally, C 1-4 alkyl (e.g., isopropyl, methyl, or ethyl), C 1-4 haloalkyl (e.g., trifluoromethyl or fluoroethyl), and C 1-4 It may be substituted with one or more substituents selected from the group consisting of alkoxy (such as methoxy).

[0472] Representative examples of suitable A groups include, but are not limited to, the following: [ka] In the formula, Q A is selected from methyl, isopropyl, ethyl, fluoroethyl and methoxy. [ka] In the formula, Q E is selected from isopropyl, methyl, ethyl and fluoroethyl.

[0473] In the structures shown above, the wavy intersecting lines represent the covalent bond between the B group shown above and the carbon atom on the aryl core that is bonded to the B group (as exemplified in the various formulas described herein). While particular substitution patterns are shown in the exemplary heteroaryl structures above, it will be understood that other substitution patterns are encompassed within the scope of the present disclosure.

[0474] As noted above, Y may be aryl or heteroaryl, each of which is optionally C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-7 It may be optionally substituted with one or more selected from the group consisting of cyclohaloalkyl, C1-4 haloalkoxy, halo, hydroxyl and amino.

[0475] To avoid any misunderstanding, Y is 1 R 1’ A reference to a monovalent radical species associated with Y is B and CR. 1 R 1’ For example, a reference to phenyl refers to a divalent radical species to which B can be attached. 1 R 1’ means a divalent benzene group bonded to

[0476] In many cases, when Y is phenyl, B and CR 1 R 1’ are in parallel positions with each other.

[0477] Often, when Y is heteroaryl, it is a monocyclic 6-membered heteroaryl. The heteroaryl is typically an N-heteroaryl containing at least one nitrogen atom. Often, the N-heteroaryl contains two nitrogen atoms.

[0478] By way of example, Y may be phenyl, pyrimidinyl (e.g., pyrimidine-1,5-diyl), or pyridinyl, optionally including halo and C 1-4 It may be substituted with one or more substituents selected from the group consisting of alkoxy.

[0479] Representative examples of Y include, but are not limited to, the following: [ka] In the formula, Z A is selected from H and halo (e.g., F); Z C is selected from H and methoxy; and [ka] As mentioned above, R 1 and R 1’ are each independently H and C 1-2 alkyl (e.g., methyl). For example, R 1 and R 1’ may each be H.

[0480] As noted above, n can be 1 to 3. In some embodiments, n is 1.

[0481] As mentioned above, R 2 and R 4 are each independently H and C 1-4 alkyl (e.g., methyl). By way of example, R2 and R4 may both be H.

[0482] In these examples, n is 1 and R 1 , R 1’ , R 2 and R 4 are each H, the bifunctional molecule has the formula USP1a, USP2a, or USP3a: [ka] wherein A, B, R 3 , X 1 , X 2 and X 4 is as defined above (and herein) for Formula USP1, Formula USP2 and Formula USP3.

[0483] In relation to formula USP2 (and also formula (USP2a) as mentioned above), X 1 and X 2 are each independently N, CLZ, and CR 5 where R 5 is selected from the group consisting of H and C1-C4 alkyl, and X 1 and X 2 One of them is CLZ.

[0484] X 1 If is CLZ, then X 2 is N or CR 5 where R may be 5 is selected from the group consisting of H and C1-C4 alkyl (e.g., methyl). 1 If is CLZ, then X 2 may be CH.

[0485] X 2 If is CLZ, then X 1 is N or CR 5 where R may be 5 is selected from the group consisting of H and C1-C4 alkyl (e.g., methyl). 2 If is CLZ, then X 2 may be CH.

[0486] In some examples of the present disclosure, the bifunctional molecule has the formula USP2b, USP2c, USP2d, or USP2e: [ka] where A, B, L and Z are as defined above and herein for Usp target binding ligands.

[0487] With respect to formula USP3, X 3 and X 4 are each independently 6 LZ and CR6 2, wherein each R 6 are each independently H and C 1-4 alkyl, wherein X 3 and X 4 One of them is CR 6 It is LZ.

[0488] X 3 is CR 6 In an embodiment where LZ is 4 is CR 6 2, where each R 6 are each independently H and C 1-4 alkyl (e.g., methyl). 3 may be CH-LZ, and X 4 may be CH2.

[0489] X 4 is CR 6 In an embodiment where LZ is 3 is CR 6 2, where each R 6 are each independently H and C 1-4 alkyl (e.g., methyl). 4 may be CH-LZ, and X 3 may be CH2.

[0490] In some embodiments of the present disclosure, the compound targeting Usp1 has formula USP3b, formula USP3c, formula USP3d, or formula USP3e: [ka] wherein A, B, X 6 , [ka] L and Z are as defined above and herein.

[0491] In particular, in some embodiments, X6 in any of formulas USP3b-USP3e is C=O.

[0492] Further representative examples of compounds that target Usp1 according to the present disclosure are provided below. [ka] wherein L and Z are as defined above and herein.

[0493] XX. Compounds targeting aggregating proteins (including synuclein-binding agents) [ka] In the formula, L represents the attachment position of the linker. The present disclosure also encompasses binding or connecting the linker at any other chemically suitable position on the target protein-binding ligand.

[0494] XXI. Compounds Targeting Apoptotic and Anti-Apoptotic Factors (Including Bcl-2 and Bcl-XL) [ka] In the formula, L represents the attachment position of the linker. The present disclosure also encompasses binding or connecting the linker at any other chemically suitable position on the target protein-binding ligand.

[0495] isotope labeled compounds The present disclosure also provides various deuterated forms of the compounds disclosed herein, or compounds of formula (ZI), (ZII), (ZIIIa-ZIIIf), (ZIVa-ZIVj), (I), (II), (III), (IV), (IVa), (ZV), (V), (VI), and (VIa); (EGFR1), (EGFR2), and (EGFR3); (KRAS1), (KRAS2), and (KRAS3); (C1)-(C12), respectively. (BRD91), 1T, 2T, 3T, 4T, 5T, 6T, 7T, 8T, 9T, 10T, 11T, 12T, 13T, 14T or (USP 1A), (USP 2A) and (USP 3A)) (including the corresponding subgeneric formulas defined herein), or a pharmaceutically acceptable salt thereof of the present disclosure and / or the corresponding tautomeric form (including the subgeneric formulas defined above). Each available hydrogen atom bonded to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art will recognize that the compounds of formula (ZI), (ZII), (ZIIIa to ZIIIf), (ZIVa to ZIVj), (I), (II), (III), (IV), (IVa), (ZV), (V), (VI) and (VIa); (EGFR1), (EGFR2) and (EGFR3); (KRAS1), (KRAS2) and (KRAS3); (C1) to (C12); (BRD91), 1T, 2T, 3T, 4T, 5T , 6T, 7T, 8T, 9T, 10T, 11T, 12T, 13T, 14T; or (USP 1A), (USP 2A) and (USP 3A)) (including the corresponding subgeneric formulas defined herein), or pharmaceutically acceptable salts of the present disclosure and / or the corresponding tautomeric forms (including the subgeneric formulas defined above). For example, deuterated materials such as alkyl groups can be prepared using conventional techniques (see, for example, methyl-d3-amine (Cat. No. 489,689-2) available from Aldrich Chemical Co., Milwaukee, Wis.).

[0496] The present disclosure also includes any of the formulae disclosed herein, for example, formulas (ZI), (ZII), (ZIIIa-ZIIIf), (ZIVa-ZIVj), (I), (II), (III), (IV), (IVa), (ZV), (V), (VI) and (VIa); (EGFR1), (EGFR2) and (EGFR3); (KRAS1), (KRAS2) and (KRAS3); (C1) to (C12); (BRD91), 1T, 2T, 3T, 4T, 5T, 6T, 7T, 8T, 9T, Also included are isotopically labeled compounds that are identical to those set forth in USP 1A, USP 2A, and USP 3A (including the corresponding subgeneric formulas defined herein), or pharmaceutically acceptable salts and / or corresponding tautomeric forms of the present disclosure (including the subgeneric formulas defined above), except for the replacement of one or more atoms 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 the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, e.g., 3 H, 11 C. 14 C. 18 F, 123 I or 125 I. Compounds of the present disclosure and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and / or isotopes of other atoms are included within the scope of the present disclosure. Isotopically labeled compounds of the present disclosure, such as 3 H and 14 Compounds incorporating radioactive isotopes such as C may be tritiated, i.e., useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).

[0497] Degradation activity Degradation can be determined by measuring the amount of target protein in the presence of a bifunctional molecule described herein and / or comparing this amount to the amount of target protein in the absence of the bifunctional molecule. For example, the amount of target protein in cells contacted and / or treated with a bifunctional molecule described herein can be determined. This amount can be compared to the amount of target protein in cells not contacted and / or treated with the bifunctional molecule (as a control). If the amount of target protein decreases when contacted and / or treated in cells with the bifunctional molecule, the bifunctional molecule can be considered to promote and / or facilitate target protein degradation and / or proteolysis.

[0498] The amount of target protein can be determined using methods known in the art, for example, by performing immunoblotting assays, Western blot analysis and / or ELISA using cells contacted or treated with the bifunctional molecule.

[0499] Selective degradation and / or increased proteolysis can be considered to have occurred if, after administration of the bifunctional molecule to cells, the amount of the target protein is reduced by at least 10% compared to a control, e.g., by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0500] For example, selective degradation and / or increased proteolysis can be considered to have occurred if at least a 10% decrease (e.g., at least a 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease) in the amount of the target protein is observed within 4 hours or more (e.g., 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) after administration of the bifunctional molecule to the cells. The bifunctional molecule can be administered at any concentration, for example, from 0.01 nM to 10 mM, such as 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 mM, and 10 mM. In some cases, an increase in target protein degradation of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or approximately 100% is observed following administration of the bifunctional molecule at a concentration of approximately 100 nM (e.g., after an incubation period of approximately 8 hours).

[0501] One measure of the degradative activity of a bifunctional molecule is the DC 50 As used herein, DC 50 is the concentration required to achieve 50% of maximal degradation of the target protein. The bifunctional molecules described herein can include a DC50 of 10,000 nM or less, 1,000 nM or less, 500 nM or less, 100 nM or less, or 75 nM or less. In some cases, the bifunctional molecules can have a DC50 of 50 nM or less, 25 nM or less, or 10 nM or less. 50 Includes:

[0502] Another measure of the degradative activity of a bifunctional molecule is the D max As used herein, D max represents the maximum percentage of target protein degradation. The bifunctional molecules described herein may achieve a D of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or about 100%. max may include:

[0503] Yet another measure of the effectiveness of the described bifunctional molecules is cell viability and / or their IC 50 For example, the antiproliferative effects of the bifunctional molecules described herein can be assessed in cell viability assays to determine IC 50 As used herein, IC 50 Values represent the concentration at which 50% cell viability was observed in a cell viability assay (following administration of the bifunctional molecules described herein). In terms of cell viability, the bifunctional molecules described herein have an IC of less than 1000 nM, less than 500 nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 20 nM, or less than 10 nM. 50 In some cases, the bifunctional molecules described herein may have an IC of less than 5 nM. 50 It may contain a value.

[0504] Pharmaceutical Compositions The present disclosure provides compositions comprising the bifunctional molecules described herein, which can be suitably formulated so that they can be introduced into the environment of a cell by means that allow a sufficient portion of the molecule to enter the cell and induce degradation of the target protein.

[0505] Accordingly, provided is a pharmaceutical composition comprising a bifunctional molecule described herein together with a pharmaceutically acceptable carrier.

[0506] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, phosphate buffer 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 solution, or fixed oils. Preservatives and other additives may also be present, such as antibacterial agents, antioxidants, chelating agents, and inert gases.

[0507] In addition to the aforementioned carrier components, the pharmaceutical compositions may alternatively or additionally include one or more suitable additional carrier components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), as well as substances included to render the formulation isotonic with the blood of the intended recipient.

[0508] The pharmaceutical composition may be present in any formulation that is typical for administering pharmaceutical compounds 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.

[0509] A pharmaceutical composition is formulated to be compatible with its intended route of administration, which includes parenteral (e.g., intravenous), intradermal, subcutaneous, oral, transdermal, topical, transmucosal, vaginal, and rectal administration.

[0510] Pharmaceutical compositions can include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), topical (including cutaneous, buccal, and sublingual), rectal, nasal, and pulmonary administration, for example, by inhalation. The compositions may, where appropriate, be conveniently presented in individual unit dosage forms and may be prepared by any of the methods well known to those skilled in the art of pharmacy. Methods typically include the step of bringing the active compound into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0511] Pharmaceutical compositions suitable for oral administration in which the carrier is solid are most preferably presented as unit dose formulations such as boluses, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active compound in a free-flowing form, such as a powder or granules, mixed with an optional binder, lubricant, inert diluent, glidant, surfactant, or dispersant in a suitable machine. Molded tablets can be made by molding the active compound with an inert liquid diluent. Tablets may be optionally coated, or, if uncoated, may optionally be scored. Capsules can be prepared by filling the active ingredient, alone or in admixture with one or more accessory ingredients, into capsule shells, which are then sealed in the usual manner. Cachets are similar to capsules, in that the active compound, along with any accessory ingredient(s), is sealed in a rice paper envelope. Bifunctional molecules can also be formulated as dispersible granules, which can be, for example, suspended in water before administration or sprinkled on food.Granules can also be packaged, for example, in sachets.Compositions suitable for oral administration where the carrier is a liquid can be presented as a solution or 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, for example, tablets where the active compound is formulated in a suitable release-controlling matrix or coated with a suitable release-controlling film.

[0512] Pharmaceutical compositions suitable for parenteral administration include sterile solutions or suspensions of active compounds in aqueous or oily vehicles.Injectable preparations can be adapted for bolus injection or continuous infusion.Such preparations are conveniently presented in unit-dose or multi-dose containers, and are sealed after the introduction of the preparation until required for use.Alternatively, bifunctional molecules can be in powder form, which is combined with a suitable vehicle such as sterile pyrogen-free water before use.

[0513] The pharmaceutical compositions may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implant, for example, subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion exchange resins.

[0514] Pharmaceutical compositions suitable for topical formulation may be provided, for example, as a gel, cream, or ointment.

[0515] The bifunctional molecules described herein can be present in the pharmaceutical composition as pharmaceutically and / or physiologically acceptable salts, solvates, or derivatives.

[0516] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is generally considered suitable for use in medicine (including veterinary context). For example, a pharmaceutically acceptable salt is one that can be contacted with the tissues of a mammalian subject (e.g., human) without undue toxicity, irritation, allergic reaction, etc. As further examples 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.

[0517] Representative examples of pharmaceutically and / or physiologically acceptable salts of the bifunctional molecules of the present disclosure include, but are not limited to, acid addition salts formed with organic carboxylic acids such as acetic acid, lactic acid, tartaric acid, maleic acid, citric acid, pyruvic acid, oxalic acid, fumaric acid, oxaloacetic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, as well as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, and sulfamic acid. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like.

[0518] In some embodiments, salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharmaceutically acceptable salts may include amine cations formed, where appropriate, with non-toxic ammonium, quaternary ammonium, and amine counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0519] Pharmaceutically and / or physiologically functional derivatives of the compounds of the present invention are derivatives that can be converted into the parent compound in the body. Such pharmaceutical and / or physiologically functional derivatives may also be referred to as "prodrugs" or "bioprecursors." Pharmaceutically and / or physiologically functional derivatives of the compounds of the present disclosure may include in vivo hydrolyzable esters or amides, particularly esters.

[0520] It may be convenient or desirable to prepare, purify, and / or handle corresponding pharmaceutically and / or physiologically acceptable solvates of the bifunctional molecules described herein, which can be used in any one of the described uses / methods. The term solvate is used herein to refer to a complex of a solute and a solvent, such as a compound or a salt of the compound. When the solvent is water, the solvate may be referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, etc., depending on the number of water molecules present per molecule of substrate.

[0521] Use of Z part As described herein, the Z moiety may form part of a bifunctional molecule intended for use in methods of targeted protein degradation, where the group Z serves to regulate, promote and / or facilitate the proteasomal degradation of the target protein.

[0522] Thus, a further aspect of the disclosure provides the use of a Z moiety or a compound comprising a Z moiety described herein (e.g., as defined in any one of Formulas (I)-(V)) in a method of targeted protein degradation (e.g., a method of targeted protein degradation in vitro or in vivo). For example, the Z moiety may find particular use as a promoter or facilitator of targeted protein degradation.

[0523] Also provided is the use of moiety Z or a compound comprising moiety Z (e.g., as defined by any one of formulas (I) to (V)) in the manufacture of a bifunctional molecule suitable for targeted protein degradation.

[0524] Treatment methods and uses The bifunctional molecules of the present disclosure can regulate, facilitate, and / or promote the proteasomal degradation of a target protein. Thus, provided are methods for selectively degrading a target protein in a cell and / or increasing proteolytic hydrolysis of a target protein in a cell, comprising contacting and / or treating a cell with a bifunctional molecule described herein. The methods can be performed in vivo or in vitro.

[0525] Specifically, provided is a method of selectively degrading a target protein and / or increasing proteolysis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bifunctional molecule of the present disclosure.

[0526] Thus, the bifunctional molecules of the present disclosure can find applications in medicine and / or therapy. Specifically, the bifunctional molecules of the present disclosure can find use in the treatment and / or prevention of any disease or condition regulated through a target protein. For example, the bifunctional molecules of the present disclosure can be useful in treating any disease that is regulated by reducing the level of the target protein in a cell, e.g., in a subject's cell. It should be understood that if, after administration of a degradation derivative of the present invention, the level of the target protein in the cell is reduced and the activity of the selected protein is involved in a disease state or disorder, the degradation derivative is useful in treating the disease.

[0527] Further provided is the use of the bifunctional molecules described herein in the manufacture of a medicament for the treatment and / or prevention of any disease or condition modulated through a target protein. Further provided is the use of a Z moiety (e.g., as defined in any one of formulas (I)-(V)) in the manufacture of a medicament for the treatment and / or prevention of any disease or condition modulated through a target protein.

[0528] Diseases and / or conditions that may be treated and / or prevented by the molecules of the present disclosure include any disease associated with and / or caused by abnormal levels of protein activity.

[0529] Such diseases and conditions include those whose pathology is associated, at least in part, with abnormal (e.g., elevated) protein levels and / or protein overexpression. For example, the bifunctional molecules may find use in the treatment and / or prevention of diseases in which elevated protein levels are observed in afflicted subjects. In other examples, diseases and / or conditions may be those whose pathology is associated, at least in part, with inappropriate protein expression (e.g., expression at the wrong time and / or in the wrong cells), excessive protein expression, or expression of a mutant protein. In one example, a mutant protein disease occurs when a mutant protein interferes with the normal biological activity of a cell, tissue, or organ.

[0530] Accordingly, provided are methods for treating and / or preventing diseases or conditions associated with and / or caused by abnormal levels of protein activity, comprising administering a therapeutically effective amount of a bifunctional compound described herein.

[0531] Representative examples of diseases and / or conditions that can be treated and / or prevented by the use of the described bifunctional molecules include (but are not limited to) cancer, asthma, multiple sclerosis, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0532] Further examples include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, and vasculitis.

[0533] Still further examples include aceruloplasminemia, type II achondroplasia, achondrogenesis imperfecta, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous multiple colonic polyps, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria, alpha 1-antitrypsin deficiency, alpha 1 proteinase inhibitors, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, Androgen insensitivity syndrome, Anemia, Diffuse truncal angiokeratoma, Retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, Arachnodactyly (Marfan syndrome), Stickler syndrome, Congenital multiple arthrochalasia (Ehlers-Danlos syndrome arthrochalasia type), Ataxia-telangiectasia, Rett syndrome, Primary pulmonary hypertension, Sandhoff disease, Neurofibromatosis type II, Bear-Stevenson dermatogynous syndrome, Mediterranean fever, Familial, Benji Symptoms include: cerebellar syndrome, beta-thalassemia, acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bonneville disease (tuberculous sclerosis), prion diseases, Birt-Hogg-Dupé syndrome, osteoporosis (osteogenesis imperfecta), deviated thenar-Hallux syndrome (Rubinstein-Taybi syndrome), bronzing diabetes mellitus / bronzing cirrhosis (hemochromatosis), spinal-bulbar muscular atrophy (Kennedy disease), Berger-Grubb syndrome Zucker's syndrome (lipoprotein deficiency), CGD chronic granulomatous disease, ankle-ankle dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri-the-cat syndrome, CAVD (congenital absence of the vas deferens), Cayler cardio-facial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (achondroplasia), otospondylomegaly epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal skeletal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis)Congenital erythroblastic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, congenital tissue disorders, conotruncal dysfacial syndrome, Cooley anemia (beta-thalassemia), copper storage disorders (Wilson's disease), copper transport disorders (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint disorders (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, myotonic dystrophy, Bear-Stevenson cutaneous gyriform syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher syndrome, de Degenerative neurological disorders including Grouchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, diffuse globoid cell sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythroblastic protoporphyria, irithroid 5-aminolevulinic acid synthetase deficiency, erythroblastic porphyria, erythroblastic protoporphyria, porphyria cutanea erythroblastica, Friedreich's ataxia, familial polyserositis, porphyria cutanea tarda, hereditary pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), cystic fibrosis, fragile X syndrome, galactosemia, hereditary encephalopathy, giant cell hepatitis (new Hemochromatosis), Glenn-Blood-Strandberg syndrome (pseudoxanthoma elasticum), Gunter's disease (congenital erythroblastic porphyria cutanea), hemochromatosis, Hallgren's syndrome, sickle cell disease, hemophilia, hepatic erythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford syndrome (progeria), immune system syndromes including hyperandrogenism, hypochondroplasia, hypochromic anemia, X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter's syndrome, Kniest dysplasia, dementia mottledis,Metabolic disorders including Langer-Saldino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromas, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendeus disease, Peutz-Jeghers syndrome, polycystic kidney disease, multiple fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Willi syndrome, hemochromatosis, primary hyperuria Acidemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disease, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia (SAD) including developmental delay and acanthosis nigricans AN), Li-Fraumeni syndrome, sarcoma, breast cancer, leukemia, adrenal tumor (SBLA) syndrome, tuberous sclerosis complex (tuberous sclerosis), SDAT, SED congenital (spondyloepiphyseal dysplasia), SED Strudwick type (spondyloepiphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal dysplasia), SEMD, Strudwick type (spondyloepiphyseal dysplasia, Strudwick type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-O Pitts syndrome, South African hereditary porphyria (variegate porphyria), infantile ascending hereditary spastic paraplegia, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar degeneration, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, neuropathy with liability to pressure palsies (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome,These include triple X syndrome (triplex syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome, (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frohlich disease, Waardenburg syndrome, Warburg-Shaw-Fredelius syndrome, Weissenbach-Zweimüller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weissenbach-Zweimüller syndrome, and xeroderma pigmentosum.

[0534] Representative examples of cancers that can be treated and / or prevented using the described bifunctional molecules include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas (particularly Burkitt's lymphoma and non-Hodgkin's lymphoma); benign and malignant melanoma, myeloproliferative disorders, multiple myeloma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma. sarcomas, including synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, neuronal glioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma cancer. Further examples include T-cell acute lymphoblastic leukemia (T-ALL), T-lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell acute lymphoblastic leukemia, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell acute lymphoblastic leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, and Philadelphia chromosome-positive CML.

[0535] As used herein, the terms "patient" or "subject" are used to refer to an animal, e.g., a mammal (e.g., a human or livestock), receiving treatment, including prophylactic treatment, with a composition according to the present disclosure. When the treatment of these infections, conditions, or disease states is specific to a particular animal, e.g., a human patient, including domestic animals such as dogs and cats, or farm animals such as horses, cows, and sheep, the term "patient" refers to that particular animal. Generally, in the present invention, the term patient refers to a human patient, unless otherwise specified or suggested by context.

[0536] Assay The present disclosure also encompasses methods for screening bifunctional molecules to identify target protein binding ligands and linkers suitable for use in the bifunctional molecules described herein, e.g., bifunctional molecules that can effectively modulate, facilitate, and / or promote proteolysis of a target protein. This method can be useful for identifying linkers suitable for particular target protein binding partners so that levels of degradation can be further optimized.

[0537] The method may include: a. (i) a first ligand having a structure according to Z (as defined in any formula of Z disclosed herein); (ii) a second ligand that binds to the target protein (target protein-binding ligand); (iii) a linker that covalently bonds the first and second ligands; b. contacting the cell with a bifunctional molecule; and c. Detecting the degradation of a target protein within a cell.

[0538] The method may further include the following steps: d. detecting degradation of the target protein in the cell in the absence of the bifunctional molecule; and e. Comparing the level of degradation of said target protein in cells contacted with the bifunctional molecule to the level of degradation of the target protein in the absence of the bifunctional molecule.

[0539] Here, an increase in the level of degradation of the target protein in cells contacted with the bifunctional molecule indicates that the bifunctional molecule facilitates and / or promotes the degradation of the target protein.

[0540] In such methods, detecting degradation of the target protein may include detecting a change in the level of the target protein in the cell. For example, a decrease in the level of the target protein indicates degradation of the target protein. An increased decrease in the level of the target protein in cells contacted with the bifunctional molecule (compared to any decrease in the level of the target protein observed in the cells in the absence of the bifunctional molecule) indicates that the bifunctional molecule facilitated and / or promoted degradation of the target protein.

[0541] The method may further include providing a plurality of linkers, each used to covalently link a first and a second ligand together to form a plurality of bifunctional molecules. The level of degradation provided by each of the plurality of bifunctional molecules can be detected and compared. Those bifunctional molecules that exhibit higher levels of target protein degradation indicate preferred and / or optimal linkers for use with the selected target protein binding partner.

[0542] The method can be carried out in vivo or in vitro.

[0543] Compound Library The present disclosure also provides a library of bifunctional molecules, the library comprising a plurality of bifunctional molecules, the plurality of bifunctional molecules comprising a plurality of Zi moieties that are covalently linked to selected target protein partners.

[0544] Thus, the target protein binding partner may be pre-selected and the Z moiety may not be predetermined. The library can be used to determine the activity of candidate Z moieties of bifunctional molecules in modulating, facilitating, and / or promoting selective proteolysis of the target protein.

[0545] The present disclosure also includes a library of bifunctional molecules, the library comprising a plurality of bifunctional molecules, the plurality of bifunctional molecules comprising a plurality of target protein-binding ligands and selected Z moieties. Thus, the Z moieties of the bifunctional molecules may be pre-selected and the target protein may not be predetermined. The library can be used to determine the activity of the putative target protein-binding ligands and their value as binders of the target protein to promote targeted protein degradation.

[0546] Manufacturing method According to a further aspect of the present disclosure, there is provided a method of making the bifunctional molecules described herein.

[0547] A method for making a bifunctional molecule can include the following steps. (a) providing a first ligand or moiety having a structure according to Z (defined according to any one of the formulas for Z disclosed herein); (b) providing a second ligand or moiety that binds to the target protein (e.g., a target protein-binding ligand as defined herein); and (c) linking (e.g., covalently linking) the first and second ligands or moieties using a linker as defined herein.

[0548] In another embodiment, the method for making the bifunctional molecule can include the following steps. (a) providing a target protein-binding ligand (as defined herein); (b) attaching (e.g., covalently attaching) a linker (as defined herein) to the target protein binding ligand to provide a target protein binding ligand-linker conjugate (TBL-L); (c) further reacting the linker portion of the conjugate to add and / or form a structure according to Z (as defined in any of formulas (I)-(III)) onto the linker to provide a bifunctional molecule having the general formula TBL-LZ.

[0549] It should be understood that throughout this specification, the terms "comprise," "comprising," and / or "comprises" are used to indicate that aspects, embodiments, and examples of the present disclosure "comprise" specified feature(s). It should be understood that this / these terms may also encompass aspects, embodiments, and / or examples that "consist essentially of" or "consist of" the associated feature(s).

[0550] Disclaimer Bifunctional molecules of the present invention may be free of one or more structures. By way of example, bifunctional molecules of the present invention do not include bifunctional molecules having the structures of disclaimer Z defined below.

[0551] Aryl / Heteroaryl Cyanoacrylamides In an embodiment of the present invention, the bifunctional molecule of the first aspect does not include a bifunctional molecule having the structure of Disclaimer 2 or Z as defined below.

[0552] In an embodiment, the bifunctional molecule of the first aspect has the general formula (DII) as follows: [ka] or Z, wherein R D1ais selected from C1-C6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from halo, N, O and S, and / or substituted with a carbocyclyl or heterocyclic group; A does not exist or CR D2a R D2a’ and Ring E is selected from aryl, heteroaryl, substituted aryl, and substituted heteroaryl; R D2a and R D2a’ are each independently selected from H and C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from N, O or S, or R 2 and R 2’ together form a 3-, 4-, 5- or 6-membered carbocyclic or heterocyclic ring, R D3a is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, carbocycle, substituted carbocycle, heterocyclyl and substituted heterocyclyl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S, and / or the heterocycle group is substituted with a heterocyclyl group; R D4a is H or C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from N, O or S; Or R D1a and R D4a together form a 5-, 6- or 7-membered heterocyclic ring, Or A is CR D2a R D2a’’ If R D1a and R D2a taken together form a 5-, 6-, or 7-membered heterocyclic ring; or R D2a and R D4a together form a 5-, 6- or 7-membered heterocyclic or carbocyclic ring, LII indicates the attachment point of the linker. 【0553...

Claims

1. General formula: TBL-L-Z A difunctional molecule containing, During the ceremony, TBL is a target protein-binding ligand, L is a linker, Z is given by equation (ZI): 【Chemistry 1】 The structure includes the following, in the formula, Ring A ２ This is a optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl or an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each containing one or two optionally selected additional ring heteroatoms from N, O, and S. R ２ It is either absent, or aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR ｙ Selected from -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl), Here, R ｙ C is replaced by an optional substitution. １－６ Alkyl or H, R ３ C １－６ Selected from alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylheterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and optionally, the above C １－６ The alkyl group is substituted with one or more heteroatoms selected from halogens, N, O, and S. L indicates the linking point of the linker, Furthermore, Z is, 【Chemistry 2】 Instead, Or, it is not a pharmaceutically acceptable salt. Bifunctional molecules.

2. Ring A ２ is a 5- to 7-membered monocyclic N-heterocycloalkyl optionally substituted, a 7- or 8-membered bridged bicyclic N-heterocycloalkyl optionally substituted, or a 7- to 12-membered spirobicyclic N-heterocycloalkyl optionally substituted, each containing one or two additional ring heteroatoms optionally selected from N, O and S, the bifunctional molecule according to claim 1.

3. The bifunctional molecule according to claim 2, wherein the optionally substituted 7- to 12-membered spirodicyclic N-heterocycloalkyl group comprises a first 5- to 7-membered ring and a second 3- to 7-membered ring.

4. Z is given by equation (ZIa): 【Transformation 3】 The structure includes the following, in the formula, R １ It is either absent, or aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C １ ~C ６ Alkyl and substituted C １ ~C ６ Selected from alkyl and / or two R １ A group is bonded and optionally substituted C １－３ Bridged, optionally replaced C ３－５ A cycloalkyl or optionally substituted 5- to 7-membered heterocycloalkyl (e.g., a 5- to 7-membered N-heterocycloalkyl) is formed, where the C ３－５ Cycloalkyl groups or 5- to 7-membered heterocycloalkyl groups are optionally bonded to ring A at a spirocenter. R ２ It is either absent, or aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR ｙ Selected from -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl), Here, R ｙ C is replaced by an optional substitution. １－６ Alkyl or H, R ３ C １－６ Selected from alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylheterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and optionally C １－６ Alkyl is substituted with one or more heteroatoms selected from halogens, N, O, and S. X １ CH ２ And, X ２ , X ３ and X ４ Each is independently CH ２ , O or NR ｘ And, R ｘ is H or C １ ~C ６ Alkyl or one R １ Base and one R ｘ The group is bonded to C １－３ It forms a bridge, n is 0, 1, 2, or 3. m is 0, 1, 2, 3 or 4, The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

5. Z is given by equation (ZIb): 【Chemistry 4】 The structure includes the following, in the formula, R １ It is either absent, or aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C １ ~C ６ Alkyl and substituted C １ ~C ６ Selected from alkyl and / or two R １ A group is bonded and optionally substituted C １－３ Bridged, optionally replaced C ３－５ A cycloalkyl or optionally substituted 5- to 7-membered heterocycloalkyl (for example, a 5- to 7-membered heterocycloalkyl) is formed, where the C ３－５ Cycloalkyl or 5- to 7-membered heterocycloalkyl groups are optionally bonded to ring A at a spirocenter. R ２ It is either absent, or aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR ｙ Selected from -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl), Here, R ｙ C is replaced by an optional substitution. １－６ Alkyl or H, R ３ C １－６ Selected from alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylheterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and optionally C １－６ Alkyl is substituted with one or more heteroatoms selected from halogens, N, O, and S. X １ and X ４ These are CH ２ And, X ２ and X ３ Each is independently CH ２ , O or NR ｘ And, however, X ２ and X ３ The condition is that none of them are O, or only one is O. R ｘ is H or C １ ~C ６ Alkyl or one R １ Base and one R ｘ The group is bonded to C １－３ Forming a crosslink n is 0, 1, 2, or 3. m is 0, 1, 2, 3 or 4, The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

6. Z is given by equation (ZII): 【Transformation 5】 The structure includes the following, in the formula, R ２ It is either absent, or aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR ｙ Selected from -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl), Here, R ｙ C is replaced by an optional substitution. １－６ Alkyl or H, R ３ C １ ~C ６ Selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. X ５ CR ｂ ２ , NR ｂ , O or 5- to 7-membered heterocycloalkyl (for example, 5- to 7-membered N-heterocycloalkyl), Each R １ is independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C １ to C ６ alkyl and substituted C １ to C ６ alkyl, and / or two R １ groups are bonded to form an optionally substituted C １－３ bridge or an optionally substituted C ３－５ cycloalkyl (optionally, the C ３－５ cycloalkyl is bonded to the heterocyclic ring represented by formula (ZII) at a spiro center), R ｂ is C, which is replaced by H or of any choice. １－３ It is alkyl, n1 is 0, 1, 2, or 3. m is 0, 1, or 2. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

7. Z is obtained from equation (ZIIa) to (ZIIe): 【Transformation 6】 Includes a structure by In the formula, R ２ It is either absent, or aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR ｙ Selected from -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl), Here, R ｙ is optionally substituted C １－６ alkyl or H, and R ３ C １ ~C ６ Selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally, C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. Each R １ These are independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C １ ~C ６ Alkyl, substituted C １ ~C ６ Selected from alkyl and / or two R １ A group is bonded and optionally substituted C ３－５ A cycloalkyl group is formed, and optionally the C ３－５ The cycloalkyl group is bonded to the heterocycle shown in formula (ZIIa) via a spirocenter. X ５ is C(R ｂ ) ２ , NR ｂ or O, R ｂ is C, which is replaced by H or of any choice. １－３ It is alkyl, n1 is 0, 1, 2, or 3. n' is either 1 or 2. m is 0, 1, or 2. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

8. Z is (ZIVj) from equation (ZIVa): 【Transformation 7】 Includes a structure by In the formula, R ２ It is either absent, or aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR ｙ Selected from -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl), Here, R ｙ C is replaced by an optional substitution. １－６ Alkyl or H, R ３ C １ ~C ６ Selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally, C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. Each R １ These are, independently, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, and C. １ ~C ６ Alkyl and substituted C １ ~C ６ Selected from alkyl groups, n1 is 0, 1, or 2. n' is either 1 or 2. m is 0, 1, or 2. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

9. Z is given by the following equation (IIa): 【Transformation 8】 Includes a structure by In the formula, R ２ This is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-. R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. n is 0, 1, 2, or 3. L indicates the linking point of the linker, Z is, 【Chemistry 9】 The bifunctional molecule described in claim 1, not the one described in claim 1.

10. Z is given by equation (IIb): 【Chemistry 10】 Includes a structure by In the formula, R ２ It is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. X １ CH ２ And, X ２ and X ３ Each is independently CH ２ or O, however X ２ and X ３ The condition is that none of them are O, or only one is O. n is either 1 or 2. L indicates the linking point of the linker, Z is, 【Chemistry 11】 The bifunctional molecule described in claim 1, not the one described in claim 1.

11. Z is given by equation (IIc): 【Chemistry 12】 The structure includes the formula, where R ２ The heterocycloalkyl and substituted heterocycloalkyl are selected from, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. X １ CH ２ And, X ２ and X ３ Each is independently CH2 or O, where X ２ and X ３ The condition is that none of them are O, or only one is O. n is either 1 or 2. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

12. Z is given by equation (IId): 【Chemistry 13】 Includes a structure by In the formula, R ２ The heterocycloalkyl and substituted heterocycloalkyl are selected from, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. n is either 1 or 2. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

13. Z is given by equation (IIe): 【Chemistry 14】 Includes a structure by In the formula, R ２ It is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. n is either 1 or 2. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

14. Z is given by equation (IIf): 【Chemistry 15】 Includes a structure by In the formula, R ２ It is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl, R ３ The C1-C6 alkyl group is selected from C1-C6 alkyl groups, aryl groups, heteroaryl groups, substituted aryl groups, and substituted heteroaryl groups, and optionally the C1-C6 alkyl group is substituted with a heterocycloalkyl group. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

15. Z is given by equation (III): 【Chemistry 16】 Includes a structure by In the formula, R １ These include aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C １ ~C ６ Selected from alkyl groups, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. n is 0, 1, 2, or 3. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

16. Z is given by equation (IIIa): 【Chemistry 17】 Includes a structure by In the formula, R １ These include aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C １ ~C ６ Selected from alkyl groups, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

17. Z is given by equation (IIIb): [Chemistry 18] Includes a structure by In the formula, R １ These include aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C １ ~C ６ Selected from alkyl groups, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

18. Z is given by equation (IV): 【Chemistry 19】 Includes a structure by In the formula, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. R ４ It is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, n is 0, 1, 2, or 3. The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

19. Z is given by equation (IVa): 【Chemistry 20】 The structure includes the following, in the formula, R ３ C １ ~C ６ Selected from alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, and optionally C １ ~C ６ The alkyl group is substituted with a heterocycloalkyl group. R ４ It is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, The bifunctional molecule according to claim 1, wherein L indicates the linkage point of the linker.

20. A bifunctional molecule according to any one of claims 4 to 13, 15, and 18, wherein n is 1, 2, or 3, and n1 is 0, 1, or 2.

21. Each R １ They became independent, (i) Hello, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl and C １ ~C ６ A heteroaryl having 5 to 6 ring atoms, each containing a phenyl molecule optionally substituted with 1 to 3 substituents selected from alkoxys, and 1 to 3 heteroatoms independently selected from N, O, and S, wherein the phenyl molecule is optionally substituted with 1 to 3 substituents selected from alkoxys, and the heteroaryl molecule is independently substituted with 1 to 3 heteroatoms selected from N, O, and S, and the phenyl molecule is optionally substituted with 1 to 3 substituents selected from alkoxys. １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl and C １ ~C ６ Heteroaryl compounds optionally substituted with one to three substituents selected from alkoxy compounds; C ３ ~C ８ Selected from the group consisting of cycloalkyls, (ii) A bifunctional molecule according to any one of claims 6 to 8, 15, 16, and 17, selected from the group consisting of phenyl, substituted phenyl, pyrazolyl, and substituted pyrazolyl.

22. Two R's １ The group is bonded to C ３－５ A bifunctional molecule according to claim 6 or claim 7, which forms a cycloalkyl group.

23. R １ C ３ ~C ７ Cycloalkyl or C １ ~C ３ A difunctional molecule according to any one of claims 6 to 8, 15, 16, and 17, wherein the molecule is alkyl.

24. R １ The structure is as follows: 【Chemistry 21】 A bifunctional molecule according to any one of claims 6 to 8, 15, 16, and 17, selected from one of the above.

25. R ２ but, (i) H, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Haloalkyl and C １ ~C ６ Phenyls optionally substituted with one to three substituents selected from alkoxys, and heteroaryls having five to six ring atoms and containing one or two N atoms, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Haloalkyl and C １ ~C ６ Selected from the heteroaryls, which are optionally substituted with one to three substituents selected from alkoxys. (ii) Selected from optionally substituted phenyl and optionally substituted pyrazolyl (iii) The following structure: 【Chemistry 22】 One of the following is selected, and in the formula, R ６ H, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Haloalkyl and C １ ~C ６ Selected from alkoxy, or (iv) The bifunctional molecule according to any one of claims 1 to 14, which does not exist.

26. R ２ but, (i) A heterocycloalkyl which is optionally substituted, wherein the heterocycloalkyl has 3 to 10 ring atoms and contains 1 to 3 heteroatoms which are independently selected from N, O, and S. (ii) Selected from piperidinil substituted by choice and piperazinil substituted by choice, (iii) The following structure: 【Chemistry 23】 One of the following is selected, and in the formula, R ６ H, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Haloalkyl and C １ ~C ６ Selected from alkoxy, or (iv) The bifunctional molecule according to any one of claims 1 to 14, which does not exist.

27. R ３ but, (i) C having a heterocycloalkyl group having 5 to 7 ring atoms that are optionally substituted and containing one or two heteroatoms independently selected from N, O, and S. １ ~C ６ Selected from alkyl, aryl having 6 to 10 carbocyclic atoms, and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O, and S, where the aryl and heteroaryl are halo, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl and C １ ~C ３ It is optionally substituted with one or two substituents selected from the group consisting of alkoxys, or (ii) C containing optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted oxazoyl, tert-butyl, or morpholino substituents. １ ~C ６ A bifunctional molecule according to claim 1, selected from alkyl, optionally substituted benzothiazolyl, and optionally substituted pyridinyl.

28. R ３ The structure is as follows: 【Chemistry 24】 One of the following is selected, and in the formula, R ５ is a halo (e.g., F, Cl, Br, I), CF ３ ien-CH ２ F, -CHF ２ , C １ ~C ６ Alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO ２ Me, -NH ２ , -NHMe, -NMe ２ CO ２ Me, -NO ２ A bifunctional molecule according to claim 1, selected from -CHO and -COMe.

29. R ３ The structure is as follows: 【Chemistry 25】 A bifunctional molecule according to claim 1, selected from one of the following.

30. Z has the following structure: 【Chemistry 26-1】 【Chemistry 26-2】 【Chemistry 26-3】 【Chemistry 26-4】 【Chemistry 26-5】 It includes one of the above, and in the formula, R ３ The following: 【Chemistry 27】 One of them is the bifunctional molecule described in claim 1.

31. The bifunctional molecule according to claim 1, wherein the linker contains 1 to 25 or 1 to 18 atoms in a single linear chain.

32. The bifunctional molecule according to claim 1, wherein the linker comprises 1 to 10 or 1 to 8 rotatable bonds.

33. The linker (L) is covalent, or the structure of the linker (L) is (L ｘ ) ｑ And in the formula, each Lx is CR Ｌ１ R Ｌ２ ,O,C=O,S,SO,SO ２ , NR Ｌ３ , SONR Ｌ４ , SONR Ｌ５ C=O, CONR Ｌ６ , NR Ｌ７ CO, C(R Ｌ８ ) = C(R Ｌ９ ), represents a subunit of L independently selected from C≡C, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl, R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ５ , R Ｌ６ , R Ｌ７ , R Ｌ８ and R Ｌ９ These are H, Halo, and C, respectively, and are independent of each other. １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -OH, -O(C) １ ~C ６ Alkyl), -NH ２ ,-NH(C １ ~C ６ Alkyl), -NO ２ , -CN, -CONH ２ , -CONH(C １ ~C ６ Alkyl), -CON(C １ ~C ６ Alkyl) ２ , -SO ２ (C １ ~C ６ Alkyl), -CO ２ (C １ ~C ６ Alkyl), and -CO(C １ ~C ６ Selected from alkyl, The bifunctional molecule according to claim 1, wherein q is an integer from 1 to 30.

34. The linker (L) is given by formula (L1a): 【Chemistry 28】 It can be expressed as shown, In the ceremony, L １Ａ It does not exist, or C １ -C ６ Alkylene, C １ -C ６ Alkoxy (e.g., -O(CH)) ２ )-,-O(CH ２ ) ２ -, -O(CH ２ ) ５ -ien-CH ２ OCH ２ -) and C １ -C ６ Alkylamino (e.g., -NR Ｌ２Ａ (CH ２ )-,-R Ｌ２Ａ (CH ２ ) ２ -, -R Ｌ２Ａ (CH ２ ) ５ -ien-CH ２ R Ｌ２Ａ CH ２ Selected from -) L ２Ａ -NR Ｌ２Ａ C=O- or -C=ONR Ｌ２Ａ - and L ３Ａ C １ -C ３ Alkylene (e.g., ethylene), C １ -C ６ Alkoxy and C １ -C ６ Selected from alkylaminos, Here, R Ｌ２Ａ is H or C １ -C ６ Alkyl (for example, C １ -C ３ It is alkyl. Alternatively, the structure of the linker (L) is given by formula (L1b): 【Chemistry 29】 It can be expressed as shown, In the ceremony, L １Ｂ It does not exist, or C １ -C ３ Alkylene, C １ -C ６ Alkoxy and C １ -C ６ Selected from alkylaminos, L ２Ｂ -NR Ｌ２Ａ C=O- or -C=ONR Ｌ２Ａ - and L ３Ｂ C １ ~C １５ Alkylene, -[(CH ２ ) ２ O] １－６ (CH ２ ) ２ - Selected from, L ４Ｂ -NR Ｌ２Ａ C=O- or -C=ONR Ｌ２Ａ - and here R Ｌ２Ａ is H or C １ ~C ６ It is alkyl, L ５Ｂ C １ ~C ３ Alkylene (e.g., ethylene), C １ ~C ６ Alkoxy and C １ ~C ６ Selected from alkylaminos, Here, R Ｌ２Ａ is H or C １ -C ６ Alkyl (for example, C １ -C ３ It is alkyl. Alternatively, the structure of the linker (L) is given by formula (L1c): 【Transformation 30】 It can be expressed as shown, In the ceremony, L １Ｃ These are optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl groups, optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl groups, or optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl groups, each containing optionally one or two additional ring heteroatoms selected from N, O, and S. L ２Ｃ It does not exist, or C １ ~C ３ Alkylene (e.g., ethylene), C １ ~C ６ Alkoxy (e.g., -(CH) ２ ) O-, -(CH ２ ) ２ O-,-(CH ２ ) ５ O-, -CH ２ OCH ２ -), and C １ ~C ６ Alkylamino (e.g., -(CH) ２ ) NR Ｌ２Ａ -, - (CH ２ ) ２ NR Ｌ２Ａ -, - (CH ２ ) ５ NR Ｌ２Ａ -ien-CH ２ NR Ｌ２Ａ CH ２ Selected from -) L ３Ｃ is, -R Ｌ２Ｂ C=O- or -(C=O)R Ｌ２Ｂ - and L ４Ｃ C １ ~C ３ Alkylene (e.g., ethylene), C １ ~C ６ Alkoxy (e.g., -(CH) ２ ) O-, -(CH ２ ) ２ O-,-(CH ２ ) ５ O-, -CH ２ OCH ２ -), and C １ ~C ６ Alkylamino (e.g., -(CH) ２ ) NR Ｌ２Ａ -, - (CH ２ ) ２ NR Ｌ２Ａ -, - (CH ２ ) ５ NR Ｌ２Ａ -ien-CH ２ NR Ｌ２Ａ CH ２ Selected from -) During the ceremony, R Ｌ２Ａ is H or C １ -C ６ It is alkyl, R Ｌ２Ｂ NR Ｌ２Ａ or an N-bonded, optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each containing one or two additional ring heteroatoms optionally selected from N, O, and S. Alternatively, the structure of the linker (L) is given by formula (L1d): 【Chemistry 31】 It can be expressed as shown, In the ceremony, L １Ｄ It does not exist, or C １ ~C ３ Alkylene, CO, C １ ~C ３ Alkylene (N(C) １ ~C ３ Selected from alkyl, L ２Ｄ NR Ｌ２Ａ Alternatively, a 4- to 7-membered monocyclic N-heterocycloalkyl group optionally substituted, a 7- to 12-membered bicyclic N-heterocycloalkyl group optionally substituted, or a 8- to 18-membered tricyclic N-heterocycloalkyl group optionally substituted, each comprising one or two additional ring heteroatoms optionally selected from N, O, and S, where R Ｌ２Ａ is H or C １ -C ６ It is alkyl, L ３Ｄ It does not exist, or C １ -C ３ Alkylene, -O-, -N(C) １ ~C ３ Selected from alkyl) and CO, Alternatively, the structure of the linker (L) is given by formula (L1e): 【Chemistry 32】 It can be expressed as shown, In the ceremony, L １Ｅ C １ ~C ３ It is alkylene or CO, L ２Ｅ These are optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyls and optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyls, each containing one or two optionally selected additional ring heteroatoms from N, O, and S. L ３Ｅ is C １ ~C ３ Selected from alkylenes, Alternatively, the linker (L) is given by formula (L1f): L １Ｆ (L1f) It can be expressed as shown, where L １Ｆ is C １ ~C ３ Alkylene, CO, and C １ ~C ３ Alkylene (NR) Ｌ１Ｃ ) is selected, and here, R Ｌ１Ｃ is H or C １ ~C ３ It is alkyl. The bifunctional molecule according to claim 1.

35. The bifunctional molecule according to claim 1, wherein the target protein-binding ligand (TBL) is selected from the group consisting of (i) a conjugate to a kinase, (ii) a conjugate to a bromodomain-containing protein, (iii) an epigenetic regulatory compound, (iv) a conjugate to a transcription factor, (vi) a conjugate to a phosphatase, (vii) a conjugate to a ubiquitin E3 ligase and / or deubiquitinase, (viiii) a conjugate to a nuclear hormone receptor, (ix) a conjugate to a highly aggregated protein, (x) a conjugate to an apoptotic factor and an anti-apoptotic factor, and (xi) a conjugate to a polymerase.

36. A pharmaceutical composition comprising a bifunctional molecule according to claim 1 and a pharmaceutically acceptable carrier, wherein optionally, the bifunctional molecule is present in the composition as a pharmaceutically acceptable salt, solvate, or derivative.

37. A bifunctional molecule according to claim 1 for use in pharmaceuticals, or the pharmaceutical composition according to claim 36.

38. A bifunctional molecule or pharmaceutical composition for use according to claim 37, wherein the use comprises the treatment and / or prevention of a disease or condition related to and / or caused by an abnormal level of protein activity.

39. A bifunctional molecule or pharmaceutical composition for use according to claim 37, for use in the treatment and / or prevention of cancer.

40. A method for treating and / or preventing a disease or condition associated with and / or caused by abnormal levels of protein activity, comprising administering a therapeutically effective amount of the bifunctional molecule described in claim 1 or the pharmaceutically active composition described in claim 36 to a subject in need thereof.

41. The method according to claim 40, wherein the disease or condition is cancer.

42. A method for selectively degrading and / or increasing the proteolysis of a target protein within a cell, comprising contacting the cell with the bifunctional molecule described in claim 1 or the pharmaceutical product described in claim 36 and / or treating the cell with it.

43. A method for selectively degrading and / or increasing the proteolysis of a target protein in a subject where such degradation is necessary, the method comprising administering to the subject a therapeutically effective amount of the bifunctional molecule described in claim 1 or the pharmaceutical composition described in claim 36.

44. Use of the Z portion as defined in claim 1 in a method for degrading a target protein.

45. Use of the Z portion according to claim 1 in the production of a bifunctional molecule suitable for target protein degradation.

46. Equation (VI): 【Transformation 33】 A compound containing a Z portion by the formula, where A ２ , R ２ , R ３ This is as defined in claim 1, A compound in which G is configured to allow the Z portion to bond to another chemical structure through the formation of a new covalent bond.

47. structure: L-Z A compound comprising, where Z is as defined in claim 1, A compound in which L is the linker.

48. The compound according to claim 47, wherein L is defined in any one of claims 31 to 34.

49. A method for producing a bifunctional molecule as defined in claim 1.

50. A method for screening a bifunctional molecule as defined in claim 1, a. (i) A first ligand comprising the structure of Z as defined in claim 1, (ii) A second ligand that binds to the target protein, (iii) To provide a bifunctional molecule comprising a linker that covalently binds the first and second ligands, b. Bringing the bifunctional molecule into contact with the cell, c. To detect the degradation of the target protein within the cell, d. Detecting the degradation of the target protein within cells in the absence of the bifunctional molecule, and e. Comparing the degradation level of the target protein in the cell in which the bifunctional molecule has been contacted with the degradation level of the target protein in the absence of the bifunctional molecule, The increase in the degradation level of the target protein within the cell upon contact with the bifunctional molecule indicates that the bifunctional molecule facilitated and / or promoted the degradation of the target protein. Optionally, detecting the degradation of the target protein includes detecting changes in the level of the target protein within the cell. method.

51. The method according to claim 50, wherein the linker is as defined in any one of claims 31 to 34.

52. A compound library comprising a plurality of bifunctional molecules as described in claim 1.

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