Bifunctional molecules for targeted protein degradation

Abstract

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

Description

Technical Field

[0001] The present disclosure relates to a novel class of bifunctional molecules that are useful in the targeted or selective degradation of proteins. Background Art

[0002] Targeted protein degradation (TPD) is a treatment model that relies on the use of synthetic molecules to change the intracellular protein degradation mechanism to induce the degradation of specific pathogenic proteins. Compared with other drug models (e.g., small molecule inhibitors, reagents based on antibodies and proteins, antisense oligonucleotides and related knock-down methods), the TPD method provides some advantages, including: enhanced pharmacology due to catalytic removal of proteins from the cell; the ability to inhibit the multiple functions of specific drug targets, including (e.g.) the backbone function of knocking down by the target; systemic administration opportunities with good biodistribution; effective in vivo efficacy limited only by de novo protein resynthesis due to catalytic efficacy and extended duration of action; and easy chemical synthesis and formulation using small molecule methods.

[0003] Most physiological post-translational regulation of intracellular protein levels and the removal of damaged, misfolded or excess proteins are mediated by the ubiquitin-proteasome system (UPS). The UPS relies on a complex cascade of protein-protein interactions that enables the polypeptide ubiquitin to be covalently attached to the protein to be removed. The ubiquitin on the protein then acts as a marker or tag for the proteasome, which then degrades and removes the protein from the cell.

[0004] The UPS can be repurposed to degrade specific proteins using bifunctional chemical molecules (often called bifunctional degraders) as therapeutic agents. These molecules work by inducing the proximity of desired substrates to UPS proteins, triggering a cascade of events that ultimately leads to degradation and removal of the protein from the cell by the proteasome.

[0005] Proteolysis-targeting chimeras (PROTACs) constitute a class of bifunctional degraders that induce the accessibility of target proteins to the UPS by recruiting specific ubiquitin E3 ligases. PROTACs consist of two ligands connected by a linker—one ligand binds to the desired target protein and the other ligand recruits the ubiquitin E3 ligase.

[0006] The most commonly used ubiquitin E3 ligases in PROTACs are von Hippel-Lindau (VHL) and Cereblon (CRBN). PROTACs that recruit VHL are typically based on ligands containing hydroxyproline, while PROTACs that recruit CRBN are typically characterized by the presence of a glutarimide moiety, such as thalidomide, pomalidomide, and lenalidomide, or similar analogs, to act as a warhead. Other ligases, including the mdm2 and IAP families, have also shown utility in PROTAC design.

[0007] However, these approaches are subject to a series of limitations that restrict their utility for treating a wide range of diseases. For example, limitations of the current PROTAC approach include: inability to efficiently degrade some targets; poor PROTAC activity in a variety of specific cells due to low and variable expression of E3 ligases and other proteins required for efficient degradation; chemical properties that make it more difficult to prepare degraders with suitable drug-like properties (including good drug metabolism and pharmacokinetic profiles); and high sensitivity to inducing resistance mechanisms in tumors.

[0008] Due to these limitations, there remains a need to identify novel degradation mechanisms and warheads capable of delivering new bifunctional degrader molecules that show efficient degradation across a range of targets and cellular systems and / or have improved profiles suitable for drug development.

[0009] Other bifunctional degrader molecules have been described in WO 2019 / 238886, WO 2019 / 238817, WO 2019 / 238816 and WO 2022 / 129925. Summary of the Invention

[0010] The present disclosure is based on the identification of a novel class of bifunctional molecules that are useful in the targeted and / or selective degradation of desired proteins (e.g., "target proteins"). Specifically, the present disclosure provides bifunctional molecules that facilitate proteasomal degradation of selected target proteins using a novel class of warheads.

[0011] The bifunctional molecules described herein comprise the following general structure:

[0012] TBL-LZ

[0013] Wherein, TBL is the target protein binding ligand and L is a linker. The portion "Z" ("warhead") regulates, assists and / or promotes proteasomal degradation of the target protein and, in some cases, can be referred to as a regulator, facilitator and / or promoter of proteasomal degradation. For example, in use, the TBL portion of the bifunctional molecule binds to the target protein. The portion Z (which is connected via a linker or otherwise attached to the TBL) then regulates, assists and / or promotes degradation of the target protein, for example, by acting to bring the target protein into proximity with the proteasome and / or by otherwise marking the target protein for proteasomal degradation within the cell.

[0014] Therefore, the bifunctional molecules described in the present disclosure can be considered to include: 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 portion Z that acts to regulate, assist and / or promote the degradation of the target protein) and a linker (e.g., a chemical linker) that conjugates, connects or links TBL and Z.

[0015] The bifunctional molecules described in this disclosure have been shown to be effective degraders of a wide range of target proteins. Without being bound by theory, it is hypothesized that the Z portion of the bifunctional molecules described herein does not bind to the ubiquitin E3 ligases typically relied upon in the classical PROTAC approaches discussed above (such as CRBN and VHL). Therefore, it is believed that the bifunctional molecules described herein regulate, assist and / or promote proteasomal degradation through alternative mechanisms. Therefore, a class of bifunctional molecules of the present invention can be used to combat a wider range of diseases (including diseases that are resistant to multiple PROTAC degraders).

[0016] According to a first aspect of the present disclosure, there is provided a bifunctional molecule comprising the following general formula:

[0017] TBL-LZ

[0018] Among them, TBL is the target protein binding ligand;

[0019] L is a linker; and

[0020] Z comprises a structure according to formula (ZI):

[0021]

[0022] in:

[0023] Ring A 2 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 of which optionally contains one or two further ring heteroatoms selected from N, O and S;

[0024] R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-;

[0025] Among them, R y is optionally substituted C 1-6 Alkyl or H;

[0026] 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 halogen, N, O and S; and

[0027] L shows the connection point of the linker;

[0028] And further wherein Z is not:

[0029]

[0030] or a pharmaceutically acceptable salt thereof.

[0031] For the avoidance of doubt, in an embodiment, when Ring A 2 is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl group, ring A 2 is not fused to an aromatic ring. In an embodiment, when Ring A 2 When Z is an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, the term "heterocycloalkyl" is intended to have its standard meaning in the art to exclude that any of the two or three rings within these systems is aromatic. In other words, Z does not comprise, for example, tetrahydroquinoline or other fused heterocycloalkyl / aryl or fused heterocycloalkyl / heteroaryl systems.

[0032] As shown in the above formula (ZI), the linker can be connected via R 2 The group is added to the moiety Z. In these examples, the linker can be connected by an atom on the linker and R 2 The linker is attached to the moiety Z by a covalent bond between atoms contained in the ring system of the aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl group. Alternatively, the linker may be attached to the moiety Z by a covalent bond between atoms contained in the ring system of the aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl group. yThe moiety Z is connected to the nitrogen atom of -CH(aryl)- or -CH(substituted aryl)- or to the benzylic carbon atom of the -CH(aryl)- or -CH(substituted aryl)- group, for example, via a covalent bond to the benzylic carbon atom of the -CH(aryl)- or -CH(substituted aryl)- group.

[0033] As described above, in some instances, R 2 In these examples, the linker can be formed by atoms on the linker and the heterocycle (e.g., ring A 2 ) are added to moiety Z.

[0034] In all instances, the linker can 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 can be bonded at R 2 The aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y Any position on -CH(aryl)-, -CH(aryl)- or -CH(substituted aryl)- may replace a hydrogen atom at any position on, for example, the heterocycle shown in formula (ZI).

[0035] As described above, Ring A 2 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 of which optionally contains one or two further ring heteroatoms selected from N, O and S, such as N and O.

[0036] When Ring A 2 When bicyclic or tricyclic, and unless otherwise specified, it may include rings connected by bonds, fused rings, bridged rings, and / or rings connected at spiro centers.

[0037] When Ring A 2 When bicyclic, it may be a bridged bicyclic ring (i.e., it may comprise two rings having three or more atoms in common) or it may be a spirocyclic bicyclic ring (i.e., it may comprise two rings having one atom in common, e.g., the two rings may be joined at a spiro center).

[0038] When Ring A 2 When it is a bridged bicyclic ring, it can be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl group optionally containing one or two additional ring heteroatoms selected from N, O and S. In some embodiments, Ring A 2 is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl group optionally containing one or two additional ring heteroatoms selected from N, O, and S. In some embodiments, Ring A 2 is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl group optionally containing one further ring atom selected from N.

[0039] When Ring A 2 When it is a spiro bicyclic ring, it may be an optionally substituted 7- to 12-membered spiro bicyclic N-heterocycloalkyl group optionally containing one or two other ring heteroatoms selected from N, O and S. In some embodiments, Ring A 2 is a 7- to 12-membered spirobicyclic N-heterocycloalkyl group optionally containing one or two additional ring heteroatoms selected from N, O, and S. In some cases, Ring A 2 is a bicyclic ring and comprises a first 5- to 7-membered ring and a second 3- to 7-membered ring. For example, ring A 2 It may be a spiro bicyclic N-heterocycloalkyl group comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring and optionally containing one or two other ring heteroatoms selected from N, O, and S. In some examples, Ring A 2 It may be a spirobicyclic N-heterocycloalkyl group comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring and optionally containing one further ring heteroatom selected from N.

[0040] In some embodiments, Z comprises a structure according to Formula (ZIa):

[0041]

[0042] in:

[0043] 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 to C6 alkyl, and substituted C1 to C6 alkyl, and / or wherein both R 1 The groups combine to form an optionally substituted C 1-3 Bridged, optionally substituted C 3-5 Cycloalkyl or optionally substituted 5 to 7 membered heterocycloalkyl (eg, 5 to 7 membered N-heterocycloalkyl), optionally wherein the C 3-5 Cycloalkyl or the 5- to 7-membered heterocycloalkyl is attached to ring A at the spiro center;

[0044] R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-;

[0045] Among them, R y is optionally substituted C 1-6 Alkyl or H;

[0046] 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, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halogen, N, O and S;

[0047] X 1 It is CH2;

[0048] X 2 、X 3 and X 4 are independently CH2, O or NR x ;

[0049] R x is H or C1 to C6 alkyl, or wherein one R 1 group and an R x The groups combine to form an optionally substituted C 1-3 bridge;

[0050] n is 0, 1, 2, or 3;

[0051] m is 0, 1, 2, 3, or 4; and

[0052] L shows the point of attachment of the linker.

[0053] For the avoidance of doubt, in an embodiment, Ring A is not an aromatic ring and is not fused to an aromatic ring. In other words, Z does not comprise, for example, tetrahydroquinoline or other fused heterocycloalkyl / aryl or fused heterocycloalkyl / heteroaryl systems.

[0054] In some examples, when n is 1, 2, or 3 (ie, when 1, 2, or 3 X 4 When a group is present), X adjacent to (or directly bonded to) the N of the heterocyclic ring shown in formula (ZIa) is 4 The group is CH2.

[0055] In some examples, Z comprises a structure according to Formula (ZIb):

[0056]

[0057] in:

[0058] 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 to C6 alkyl, and substituted C1 to C6 alkyl, and / or wherein both R 1The groups combine to form an optionally substituted C 1-3 Bridged, optionally substituted C 3-5 Cycloalkyl or optionally substituted 5 to 7 membered heterocycloalkyl (eg, 5 to 7 membered N-heterocycloalkyl), optionally wherein the C 3-5 Cycloalkyl or the 5- to 7-membered heterocycloalkyl is attached to ring A at the spiro center;

[0059] R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-;

[0060] Among them, R y is optionally substituted C 1-6 Alkyl or H;

[0061] 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 halogen, N, O and S;

[0062] X 1 and X 4 They are CH2;

[0063] X 2 and X 3 are independently CH2, O or NR x ; The condition is X 2 and X 3 None or only one of them is O;

[0064] R x is H or C1 to C6 alkyl; or wherein one R 1 group and an R x The groups combine to form an optionally substituted C 1-3 bridge;

[0065] n is 0, 1, 2, or 3;

[0066] m is 0, 1, 2, 3, or 4; and

[0067] L shows the point of attachment of the linker.

[0068] In some examples, Z comprises a structure according to Formula (ZIb'):

[0069]

[0070] in:

[0071] R 1 、R 3 、X 1 、X 2 、X 3 、X 4 , n, m and L are as defined above with respect to formulae (ZIa) and (ZIb).

[0072] In some examples, Z comprises a structure according to Formula (ZIb"):

[0073]

[0074] in:

[0075] R 2 、R 3 、X 1 、X 2 、X 3 、X 4 , n and L are as defined above with respect to formulae (ZIa) and (ZIb).

[0076] As described above, in some embodiments of Formulas (ZIa), (ZIb), (ZIb') and (ZIb") (and other formulae as described herein), two R 1 group, or in some cases, an R 1 group and an R x The group forms an optionally substituted C 1-3 Bridge. The C 1-3 The bridge may be a C1-C3 alkylene bridging group, such as methylene, ethylene or propylene. In some examples, the C1-C3 bridge may be a methylene or ethylene. 1-3 When the bridge is substituted, it may comprise 1 to 3 (e.g., 1 or 2) substituents (selected from any suitable substituents as described herein). For example, the C1 to C3 alkylene bridging group may be optionally substituted with one or two substituents independently selected from halogen, C1 to C3 alkyl, C1 to C3 haloalkyl, and C1 to C3 alkoxy.

[0077] In other embodiments, Z may comprise a structure according to formula (I):

[0078]

[0079] Among them, R 1is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0080] R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-;

[0081] Among them, R y is H or C1 to C6 alkyl;

[0082] R 3 is selected from C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

[0083] X 1 It is CH2;

[0084] X 2 and X 3 are independently CH2, or selected from O and NR x heteroatoms, where R x Is H or

[0085] C1 to C6 alkyl;

[0086] n is 0, 1, 2, or 3; and

[0087] L shows the connection point of the linker;

[0088] And further wherein Z is not:

[0089]

[0090] In alternative embodiments of formula (I), R provided above 3 The select list of can be replaced by the following groups: C1 to C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylheterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with one or more heteroatoms selected from halogen, N, O and S. In some embodiments, R 2 It may 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)-.

[0091] In some instances, R1 or R 2 At least one of exists.

[0092] For example, when R 1 When it does not exist, R 2 may be present and be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-. For example, when R 1 When it does not exist, R 2 may be present and selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-.

[0093] By other examples, when R 2 When it does not exist, R 1 may be present and selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl. By way of even further example, when R 2 When not present, at least one R 1 may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl, and / or wherein two R 1 The groups combine to form an optionally substituted C 1-3 Bridged, optionally substituted C 3-6 Cycloalkyl or optionally substituted 5 to 7 membered N-heterocycloalkyl, optionally wherein the C 3-5 The cycloalkyl group or the 5- to 7-membered N-heterocycloalkyl group is attached to ring A at the spiro center.

[0094] In some instances, R 1 and R 2 Both exist. For example, in some cases, R 2 There is and at least one R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl, and / or wherein two R 1 The groups combine to form an optionally substituted C 1-3 Bridged, optionally substituted C 3-6 cycloalkyl or optionally substituted 5- to 7-membered N-heterocycloalkyl.

[0095] In the compounds described herein, R 1 and / or R 2 The covalent attachment to the heterocycle (e.g., Ring A) can be performed at any suitable position, provided it has the correct valence and / or is chemically suitable. For example, R 1 and / or R 2 A hydrogen atom at any position on the heterocyclic nucleus may be replaced, for example, as shown in formula (I).

[0096] When R 1 and R 2 When both are present, they may be covalently attached to the heterocycle (e.g., Ring A) at the same or different positions. For example, in some cases, R 1 and R 2 Can be covalently linked to the heterocyclic nucleus via different carbon atoms. In other cases, R 1 and R 2 Covalent linkage to the heterocyclic core may be through the same carbon atom.

[0097] As shown in the formulae described herein with respect to the Z moiety, a double bond is present in Z. The stereochemistry of the double bond can be either E or Z, and this is indicated by the wavy bond in formula (I) (and similarly shown in other formulae and structures disclosed herein). The nomenclature of the moiety as either E or Z can be based on the stereochemistry of R 3 The characteristics of the group. In some instances, Z may comprise a mixture of E and Z stereoisomers. Thus, the present disclosure includes within its scope the use of each single E and Z stereoisomer of any Z moiety disclosed according to formula (I) and any other formula described herein (e.g., in substantially stereopure form), 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 bound thereto is Z, i.e., a Z stereoisomer. In other instances, the stereochemistry of the double bond and the moiety bound thereto is E, i.e., an E stereoisomer.

[0098] For the avoidance of doubt, when in any specific example of the present disclosure, in a structure herein, the ethylene double bond of Z, for example, the ethylene double bond of Z of Formula (I) is shown as a specific stereoisomer (E or Z), it need not be that specific stereoisomer. In other words, regardless of the specific stereoisomer shown, both E and Z stereoisomers and mixtures of both are included within the scope of the structure.

[0099] By way of further example, Z may be represented by any of formulas (Ia) or (Ib):

[0100]

[0101] Among them, R 1 、R 2 、R3 、X 1 、X 2 、X 3 and n are as defined above and herein.

[0102] 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 the use of stereoisomers of the bifunctional molecule. For example, when the bifunctional molecule contains one or more chiral centers, the present disclosure covers each single enantiomer of the bifunctional molecule and mixtures of enantiomers including racemic mixtures of these enantiomers. By way of other example, when the bifunctional molecule contains two or more chiral centers, the present disclosure covers each single diastereomer of the bifunctional molecule, as well as mixtures of multiple diastereomers.

[0103] Unless otherwise indicated, the various structures shown herein encompass all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) forms of the structure). For example, the disclosure encompasses both R and S configurations for each asymmetric center, as well as Z and E double bond isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are to be understood to be within the scope of the disclosure. Additionally, unless otherwise indicated, tautomeric forms of the bifunctional molecules described herein, when present, are to be understood to be within the scope of the disclosure.

[0104] 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, wherein one or more hydrogen atoms have been replaced by deuterium or tritium, or wherein one or more carbon atoms have been replaced by 13 C- or 14 C-enriched carbon-substituted bifunctional molecules as described herein are understood to be within the scope of the present disclosure. These molecules may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. By way of further example, bifunctional molecules as described herein may be substituted with one or more deuterium atoms.

[0105] As used herein, reference to a "bifunctional molecule" may also encompass pharmaceutically acceptable salts thereof.

[0106] By way of further example, Z can be represented by formula (Ic'):

[0107]

[0108] in:

[0109] R 1is absent (i.e., m is 0) or is selected from the group consisting of: aryl having 6 to 10 carbon ring atoms, optionally substituted by 1 to 3 substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl being optionally substituted by 1 to 3 substituents; C3 to C8 cycloalkyl optionally substituted by 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 ring heteroatoms independently selected from N, O and S, said heterocycloalkyl being optionally substituted by 1 to 3 substituents; C1 to C6 alkyl optionally substituted by 1 to 3 substituents; and / or wherein, two R 1 The groups are combined to form C optionally substituted with 1 to 3 substituents. 1-3 bridge, C optionally substituted by 1 to 3 substituents 3-5 Cycloalkyl or 5 to 7 membered N-heterocycloalkyl optionally substituted with 1 to 3 substituents (for example, wherein the C 3-5 Cycloalkyl or said 5- to 7-membered N-heterocycloalkyl is attached to ring A at the spiro center);

[0110] R 2 Absent or selected from: aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted by 1 to 3 substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, the heteroaryl being optionally substituted by 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, the heterocycloalkyl being optionally substituted by 1 to 3 substituents; -NR y -CH(aryl)-, wherein the aryl group has 6 to 10 carbon ring atoms and is optionally substituted with 1 to 3 substituents)-; and -CH(heteroaryl)-, wherein the heteroaryl group has 5 to 10 ring atoms and contains 1 to 3 heteroatoms independently selected from N, O and S, and the heteroaryl group is optionally substituted with 1 to 3 substituents;

[0111] Among them, R y is H or C1 to C6 alkyl;

[0112] R 3Selected from the group consisting of: C1 to C6 alkyl optionally substituted with 1 to 3 substituents; C3 to C8 cycloalkyl optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heterocycloalkyl optionally substituted with 1 to 3 substituents; aryl having 6 to 10 carbon ring atoms, said aryl optionally substituted with 1 to 3 substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl optionally substituted with 1 to 3 substituents;

[0113] X 1 It is CH2;

[0114] X 2 and X 3 are independently CH2, or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl, or wherein one R 1 group and an R x The groups are combined to form C optionally substituted with 1 to 3 substituents. 1-3 Bridge; condition is X 2 and X 3 None, only 1 or 2 of them are heteroatoms; and

[0115] m is 0, 1, 2, or 3;

[0116] n is 0, 1, 2, or 3; and

[0117] L shows the point of attachment of the linker.

[0118] By way of further example, Z can be represented by Formula (Ic):

[0119]

[0120] in:

[0121] R 1 is absent or selected from: aryl having 6 to 10 carbon ring atoms optionally substituted by 1 to 3 substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl being optionally substituted by 1 to 3 substituents; C3 to C8 cycloalkyl; C1 to C6 alkyl optionally substituted by 1 to 3 substituents;

[0122] R 2is absent or selected from the group consisting of: aryl having 6 to 10 carbon ring atoms, optionally substituted with 1 to 3 substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents; -NR y -CH(aryl)-, wherein the aryl group has 6 to 10 carbon ring atoms and is optionally substituted with 1 to 3 substituents)-; and -CH(heteroaryl)-, wherein the heteroaryl group has 5 to 10 ring atoms and contains 1 to 3 heteroatoms independently selected from N, O and S, and the heteroaryl group is optionally substituted with 1 to 3 substituents;

[0123] Among them, R y is H or C1 to C6 alkyl;

[0124] R 3 Selected from the group consisting of: C1 to C6 alkyl optionally substituted with 1 to 3 substituents; C3 to C8 cycloalkyl optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heterocycloalkyl optionally substituted with 1 to 3 substituents; aryl having 6 to 10 carbon ring atoms, said aryl optionally substituted with 1 to 3 substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl optionally substituted with 1 to 3 substituents;

[0125] X 1 It is CH2;

[0126] X 2 and X 3 are independently CH2, or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl; provided that X 2 and X 3 None, only 1 or 2 of them are heteroatoms; and n is 0, 1, 2 or 3; and

[0127] L shows the point of attachment of the linker.

[0128] By way of further example, Z can be represented by formula (Id'):

[0129]

[0130] in:

[0131] R 1 is absent (i.e., when m is 0) or selected from the group consisting of: phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O, and S, the heteroaryl being optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 ring heteroatoms independently selected from N, O, and S; C3 to C8 cycloalkyl; C1 to C6 alkyl, and C1 to C6 haloalkyl;

[0132] and / or two R 1 Groups combine to form C 1-3 Bridge, C 3-5 Cycloalkyl or 5 to 7 membered N-heterocycloalkyl (for example, wherein the C 3-5 Cycloalkyl or said 5- to 7-membered N-heterocycloalkyl is attached to ring A at the spiro center);

[0133] R 2 -NR is absent or selected from the group consisting of: phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heterocycloalkyl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; y -CH(phenyl)-, wherein the phenyl is optionally substituted by 1 to 3 substituents, each of which is independently selected from the group consisting of: halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; and -CH(heteroaryl), wherein the heteroaryl has 5 to 6 ring atoms and contains 1 to 3 heteroatoms independently selected from N, O, and S, and the heteroaryl is optionally substituted by 1 to 3 substituents, each of which is independently selected from the group consisting of: halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; wherein, Ry is H or C1 to C6 alkyl;

[0134] R 3 is selected from the group consisting of: C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; C3 to C6 cycloalkyl, optionally wherein the C3 to C6 cycloalkyl is substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, the heteroaryl being optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy;

[0135] X 1 It is CH2;

[0136] X 2 and X 3 are independently CH2, or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl, or wherein one R 1 group and an R x Groups combine to form C 1-3 Bridge; condition is X 2 and X 3 None or only one of them is a heteroatom; and

[0137] m is 0, 1, 2, or 3;

[0138] n is 0, 1, 2, or 3; and

[0139] L shows the point of attachment of the linker.

[0140] By way of further example, Z can be represented by Formula (Id):

[0141]

[0142] in:

[0143] R 1is absent or selected from the group consisting of: phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O, and S, said heteroaryl being optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; C3 to C8 cycloalkyl; C1 to C6 alkyl, and C1 to C6 haloalkyl;

[0144] R 2 -NR is absent or selected from the group consisting of: phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heteroaryl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, said heterocycloalkyl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; y -CH(phenyl)-, wherein the phenyl is optionally substituted by 1 to 3 substituents, each of which is independently selected from the group consisting of: halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; and -CH(heteroaryl), wherein the heteroaryl has 5 to 6 ring atoms and contains 1 to 3 heteroatoms independently selected from N, O, and S, and the heteroaryl is optionally substituted by 1 to 3 substituents, each of which is independently selected from the group consisting of: halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; wherein, R y is H or C1 to C6 alkyl;

[0145] R 3selected from the group consisting of: C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; C3 to C8 cycloalkyl optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents; phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0146] X 1 It is CH2;

[0147] X 2 and X 3 are independently CH2, or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl; provided that X 2 and X 3 None or only one of them is a heteroatom; and

[0148] n is 0, 1, 2, or 3; and

[0149] L shows the point of attachment of the linker.

[0150] By way of further example, Z can be represented by Formula (Ie'):

[0151]

[0152] in:

[0153] 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 independently selected from N, O and S; C3 to C7 cycloalkyl; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; C1 to C6 alkyl and C1 to C6 haloalkyl; wherein the phenyl or heteroaryl is optionally substituted with 1 substituent selected from the group consisting of halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy; and / or wherein two R 1 Groups combine to form C 1-3 Bridge, C 3-5Cycloalkyl or 5 to 7 membered N-heterocycloalkyl (for example, wherein the C 3-5 Cycloalkyl or said 5- to 7-membered N-heterocycloalkyl is attached to ring A at the spiro center);

[0154] R 2 is absent or selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; -NR y -CH(phenyl)-; and -CH(heteroaryl), wherein the heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms independently selected from N, O and S; and further wherein the phenyl, heteroaryl, heterocycloalkyl, -CH(phenyl)- and -CH(heteroaryl) are each optionally substituted with 1 substituent selected from the group consisting of halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy;

[0155] Among them, R y is H or C1 to C6 alkyl;

[0156] R 3 selected from the group consisting of: C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted by a heterocycloalkyl group; a heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; a C3 to C6 cycloalkyl; a phenyl; and a heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S; wherein the C3 to C6 cycloalkyl, phenyl and heteroaryl are optionally substituted by one or two substituents selected from the group consisting of halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy;

[0157] X 1 It is CH2;

[0158] X 2 and X 3 are independently CH2 or O; provided that X 2 and X 3 None or only one of them is O;

[0159] m is 0, 1, 2, or 3;

[0160] n is 1, 2, or 3; and

[0161] L shows the point of attachment of the linker.

[0162] By way of further example, Z can be represented by Formula (Ie):

[0163]

[0164] in:

[0165] R 1 is absent or selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; C3 to C7 cycloalkyl; C1 to C6 alkyl and C1 to C6 haloalkyl; wherein the phenyl or heteroaryl is optionally substituted with 1 substituent selected from the group consisting of halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy;

[0166] R 2 is absent or selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; -NR y -CH(phenyl)-; and -CH(heteroaryl), wherein the heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms independently selected from N, O and S; and further wherein the phenyl, heteroaryl, heterocycloalkyl, -CH(phenyl)- and -CH(heteroaryl) are each optionally substituted with 1 substituent selected from the group consisting of halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy;

[0167] Among them, R y is H or C1 to C6 alkyl;

[0168] R 3 selected from the group consisting of: C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted by a heterocycloalkyl group; a heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; a C3 to C6 cycloalkyl; a phenyl; and a heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S; wherein the C3 to C6 cycloalkyl, phenyl and heteroaryl are optionally substituted by one or two substituents selected from the group consisting of halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy;

[0169] X 1 It is CH2;

[0170] X 2 and X 3 are independently CH2 or O; provided that X 2 and X3 None or only one of them is O; and

[0171] n is 1, 2, or 3; and

[0172] L shows the point of attachment of the linker.

[0173] In other embodiments, Z comprises a structure according to Formula (ZII):

[0174]

[0175] Among them, R 2 not present or as described in any of the embodiments disclosed herein;

[0176] R 3 As described in any one of the embodiments disclosed herein;

[0177] X 5 It's 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 to C6 alkyl and substituted C1 to C6 alkyl, and / or wherein two R 1 The groups combine to form an optionally substituted C 1-3 bridge or optionally substituted C 3-5 Cycloalkyl (optionally wherein the C 3-5 The cycloalkyl group is attached to the heterocycle shown in formula (ZII) at the spiro center);

[0178] R b is H or optionally substituted C 1-3 alkyl;

[0179] n1 is 0, 1, 2, or 3;

[0180] m is 0, 1, or 2; and

[0181] L shows the point of attachment of the linker.

[0182] In other embodiments, Z comprises a structure according to any one of Formulas (ZIIa) to (ZIIe):

[0183]

[0184] in:

[0185] R 2 As described in any one of the embodiments disclosed herein;

[0186] R 3 As described in any one of the embodiments disclosed herein;

[0187] Each R 1 are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl, and / or wherein two R 1 The groups combine to form an optionally substituted C 3-5 Cycloalkyl (optionally wherein the C 3-5 A cycloalkyl group is attached to the heterocycle shown in formula (ZIIa) at the spiro center); X 5 It is C(R b )2、NR b or O;

[0188] R b is H or optionally substituted C 1-3 alkyl;

[0189] n1 is 0, 1, 2, or 3;

[0190] n' is 1 or 2;

[0191] m is 0, 1, or 2; and

[0192] L shows the point of attachment of the linker.

[0193] For example, Z may comprise a structure according to formula (ZIIIa) to (ZIIIh):

[0194]

[0195] in:

[0196] R 2 As described in any one of the embodiments disclosed herein;

[0197] R 3 As described in any one of the embodiments disclosed herein;

[0198] Each R 1 independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0199] X 5 It is CH2, NR b or O;

[0200] R b is H or optionally substituted C 1-3 alkyl;

[0201] n1 is 0, 1, or 2;

[0202] n' is 1 or 2;

[0203] m is 0, 1, or 2; and

[0204] L shows the point of attachment of the linker.

[0205] In even other embodiments, Z comprises a structure according to Formulas (ZIVa) to (ZIVj):

[0206]

[0207] in:

[0208] R 2 not present or as described in any of the embodiments disclosed herein;

[0209] R 3 As described in any one of the embodiments disclosed herein;

[0210] Each R 1 independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0211] n1 is 0, 1, or 2;

[0212] n' is 1 or 2;

[0213] m is 0, 1, or 2; and

[0214] L shows the point of attachment of the linker.

[0215] In other examples, Z comprises a structure according to Formula (If):

[0216]

[0217] Among them, R 1 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0218] R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, and -CH(substituted aryl)-;

[0219] R 3 is selected from the group consisting of C1 to C6 alkyl, aryl, heteroaryl, substituted C1 to C6 alkyl, substituted aryl, and substituted heteroaryl; and

[0220] Among them, R 1 and R 2 At least one of them exists;

[0221] n is 0, 1, 2, or 3; and

[0222] L shows the point of attachment of the linker.

[0223] In some examples, R shown in formula (If) 1 、R 2 and R 3 It may be selected from those defined above, for example, those defined for any one or more of formula (Ic'), (Ic), (Id'), (Id), (Ie') or (Ie).

[0224] In some examples of the formulae described above and herein, n can be 1, 2, or 3 and / or n1 can be 0, 1, or 2.

[0225] In R 1 In those cases where it is absent, Z may be represented by formula (II):

[0226]

[0227] Among them, R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl);

[0228] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl;

[0229] X 1 It is CH2;

[0230] X 2 and X 3 are independently CH2 or O; provided that X 2 and X 3 None or only one of them is O; and

[0231] n is 0, 1, 2, or 3; and

[0232] L shows the connection point of the linker;

[0233] And wherein Z is not:

[0234]

[0235] In R 1In those cases where it is absent, Z may be represented by formula (IIa):

[0236]

[0237] Among them, R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl);

[0238] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and

[0239] n is 0, 1, 2, or 3; and

[0240] L shows the connection point of the linker;

[0241] And wherein Z is not:

[0242]

[0243] By way of specific example, in formula (II) or (IIa), n may be 1 or 2.

[0244] By way of further example, Z may be represented by formula (IIb):

[0245]

[0246] Among them, R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl;

[0247] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl;

[0248] X 1 It is CH2;

[0249] X 2 and X 3 are independently CH2 or O; provided that X 2 and X 3 None or only one of them is O;

[0250] n is 1 or 2; and

[0251] L shows the connection point of the linker;

[0252] And wherein Z is not:

[0253]

[0254] By way of further example, Z may be represented by formula (IIc):

[0255]

[0256] Among them, R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl;

[0257] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl;

[0258] X 1 It is CH2;

[0259] X 2 and X 3 are independently CH2 or O; provided that X 2 and X 3 None or only one of them is O;

[0260] n is 1 or 2; and

[0261] L shows the point of attachment of the linker.

[0262] In some cases, Z can be represented by formula (IId):

[0263]

[0264] Among them, R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl;

[0265] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl;

[0266] n is 1 or 2; and

[0267] L shows the point of attachment of the linker.

[0268] In other examples, Z can comprise a structure according to Formula (IIe):

[0269]

[0270] Among them, R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl;

[0271] R3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl;

[0272] n is 1 or 2; and

[0273] L shows the point of attachment of the linker.

[0274] In other examples, Z can comprise a structure according to Formula (IIf):

[0275]

[0276] Among them, R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl;

[0277] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and

[0278] L shows the point of attachment of the linker.

[0279] In R 2 In those cases where it is absent, Z may comprise a structure according to formula (III):

[0280]

[0281] Among them, R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl;

[0282] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and

[0283] n is 0, 1, 2, or 3; and

[0284] L shows the point of attachment of the linker.

[0285] In some examples, n can be 1 or 2.

[0286] In some instances where n is 2, Z can be represented by formula (IIIa):

[0287]

[0288] Among them, R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl;

[0289] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and

[0290] L shows the point of attachment of the linker.

[0291] In some instances where n is 1, Z can be represented by formula (IIIb):

[0292]

[0293] Among them, R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C1-C6 alkyl;

[0294] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and

[0295] L shows the point of attachment of the linker.

[0296] As mentioned above, the bifunctional molecules of formula (IIIb) contain at least two stereocenters and therefore exist in several diastereomeric (and enantiomeric) forms. In some embodiments, the group R 1 and L can exist in a trans relationship (eg, these groups are held and / or positioned on opposite sides of the heterocyclic core). In other examples, the group R 1 and L can exist in a cis relationship (e.g., these groups remain and / or are positioned on the same side of the heterocyclic core). By way of further example, the bifunctional molecule represented by formula (IIIb) can encompass at least the following diastereomeric forms:

[0297]

[0298] In R 1 does not exist and R 2 In those examples selected from -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-, Z may be represented by formula (IV):

[0299]

[0300] Among them, R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl;

[0301] R 4is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

[0302] n is 0, 1, 2, or 3; and

[0303] L shows the point of attachment of the linker.

[0304] In some examples, Z can comprise a structure according to Formula (IVa):

[0305]

[0306] Among them, R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl;

[0307] R 4 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

[0308] L shows the point of attachment of the linker.

[0309] In either of Formulas (IV) or (IVa), R 4 It may be selected from an aryl group or a substituted aryl group.

[0310] Now, the following provides the group R 1 、R 2 、R 3 and R 4 Representative examples of which apply to any one or more of the formulae described herein (unless otherwise stated).

[0311] For the various structures of Z defined herein by formula (and unless otherwise specified), R 1 It may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl.

[0312] In some instances, R 1 is optionally substituted aryl or optionally substituted heteroaryl. 1 When it is a substituted aryl or substituted heteroaryl, the aryl or heteroaryl may contain one or more substituents selected from C1 to C6 alkyl (e.g., methyl), C1 to C6 alkoxy (e.g., methoxy), C1 to C6 haloalkyl and halogen.

[0313] By other examples, R 1It may be phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy. By yet another example, R 1 It may be a heteroaryl group having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; C3 to C8 cycloalkyl.

[0314] Suitable R 1 Representative examples of groups include, but are not limited to, phenyl, substituted phenyl, pyrazolyl, and substituted pyrazolyl.

[0315] In some instances, R 1 is a cycloalkyl group, such as a C3 to C7 cycloalkyl group or a C3 to C6 cycloalkyl group.

[0316] In some instances, R 1 is C1 to C6 alkyl, such as C1 to C3 alkyl optionally substituted with 1 to 3 substituents as defined herein.

[0317] Suitable R 1 Other non-limiting examples of groups are shown below:

[0318]

[0319] In the structure shown above, the lines intersecting the wavy lines represent the exemplary R shown above. 1 The group is connected to the R in the parent structure of Z 1 Covalent bonds between carbon atoms on the heterocycloalkyl core of the group (as shown in the various formulae described herein). Although specific substitution patterns are shown in the exemplary aryl and heteroaryl structures above, it is understood that other substitution patterns are also contemplated within the scope of this disclosure.

[0320] In other examples, such as with respect to formula (ZII), two R 1 Groups can be combined to form C 1-3 Bridge or C 3-5 Cycloalkyl. For example, two R 1 Groups can be combined to form C 3-5 In these examples, C 3-5 The cycloalkyl group can be attached to the parent heterocyclic structure at a spiro center.

[0321] For the various structures of Z defined herein by formula (and unless otherwise specified), R 2It can be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl) and -CH(substituted heteroaryl); wherein R y is optionally substituted C 1-6 Alkyl (such as methyl) or H.

[0322] In some instances, R 2 is present in Z (and / or the bifunctional molecules described herein) as a divalent group. In other words, as shown in formulas (I) to (IVa) (and unless otherwise specified), for R 2 The various groups defined are covalently bonded to atoms of the heterocyclic core of Z and may also be covalently bonded to atoms of the linker. Thus, these groups may be considered as divalent groups.

[0323] When R 2 When R is selected from optionally substituted aryl and optionally substituted heteroaryl, 2 can be selected from aryl groups having 6 to 10 carbon ring atoms, which are optionally substituted with 1 to 3 substituents; and heteroaryl groups having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, which are optionally substituted with 1 to 3 substituents. By way of further example, R 2 Can be selected from phenyl optionally substituted with 1 to 3 substituents selected from H, C1 to C6 alkyl, halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy; and heteroaryl having 5 to 6 ring atoms and containing 1 or 2 N atoms, optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl (e.g., C1 to C3 alkyl), halogen (e.g., F), C1-C6 haloalkyl (e.g., C1 to C3 haloalkyl) and C1 to C6 alkoxy (e.g., C1 to C3 alkoxy). In some cases, R 2 Suitable examples of include, but are not limited to, optionally substituted phenyl and optionally substituted pyrazolyl.

[0324] When R 2 When selected from optionally substituted heterocycloalkyl, the heterocycloalkyl may have 3 to 10 ring atoms and contain 1 to 3 heteroatoms independently selected from N, O and S, and the heterocycloalkyl may be optionally substituted with 1 to 3 substituents. In some examples, the heterocycloalkyl may have 5 to 8 ring atoms (e.g., 6 ring atoms) and may contain 1 or 2 N atoms. In some cases, suitable examples include, but are not limited to, optionally substituted piperidinyl and optionally substituted piperazinyl.

[0325] Suitable R2 Other examples of groups are shown below:

[0326]

[0327] Among them, in the structure shown above, R 6 Can be selected from H, C1-C6 alkyl, halogen, C1-C6 haloalkyl and C1-C6 alkoxy. 6 It can be selected from H and C1-C6 alkyl.

[0328] In the structure shown above, the lines intersecting the wavy lines represent the exemplary R shown above. 2 The group is connected to the R in the parent structure of Z 2 Covalent bonds between carbon atoms on the heterocycloalkyl core of the group (as shown in the various formulae described herein). Although specific substitution patterns are shown in the exemplary structures above, it is understood that other substitution patterns are also contemplated within the scope of this disclosure.

[0329] Additionally, the bond to L illustrates the point of attachment to the linker. In the exemplary aryl structures above, it is understood that the linker can replace a hydrogen atom at any suitable position on the aryl ring (e.g., so long as it is chemically suitable and has the correct valence).

[0330] For the various structures of Z defined by the formulae herein, R 3 is selected from the group consisting of C1-C6 alkyl, aryl, heteroaryl, substituted C1-C6 alkyl, substituted aryl and substituted heteroaryl.

[0331] In some instances, R 3 Can be selected from the group consisting of the following: C1 to C6 alkyl optionally substituted by a heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatomic groups independently selected from N, O and S; aryl with 6 to 10 carbon ring atoms; and heteroaryl with 5 to 10 ring atoms and containing 1 to 3 heteroatomic groups independently selected from N, O and S; wherein, the aryl and heteroaryl are optionally substituted by one or two substituents selected from the group consisting of the following: halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy. By other examples, in some cases, the aryl and heteroaryl can be optionally substituted by one or two substituents selected from halogen (e.g., F) and C1-C3 alkyl (e.g., methyl).

[0332] Suitable R 3Representative examples of radicals include, but are not limited to, thiazolyl, pyridyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, oxetanyl, cyclobutyl, cyclopropenyl, tert-butyl, imidazolyl, oxazolyl, thiophenyl, imidazo(1,2-a)pyridyl, N-C1 to C6 alkylenemorpholine, and 4,5,6,7-tetrahydro-1,3-benzothiazolyl, such as thiazolyl, pyridyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, cyclobutanyl, cyclopropanyl, and tert-butyl.

[0333] In each case, these R 3 The group may be substituted, such as substituted thiazolyl, substituted pyridyl, substituted benzothiazolyl, substituted phenyl, substituted pyrazolyl, substituted isoxazolyl, substituted isothiazolyl, substituted tetrahydropyranyl, substituted tetrahydrofuranyl, substituted oxetanyl, substituted cyclobutane, substituted cyclopropane and substituted tert-butyl. 3 When R is a substituted heteroaryl or aryl, one or more substituents may be present on the aromatic ring, for example, it may be monosubstituted, disubstituted or trisubstituted. 3 When it is an optionally substituted pyrazolyl or imidazolyl group, the nitrogen atom of the pyrazolyl or imidazolyl ring may be substituted by a C1-C6 alkyl group, such as a methyl group.

[0334] 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. 3 When it is a substituted aryl or heteroaryl group, one or more substituents may be present on the aromatic ring, for example, it may be monosubstituted, disubstituted or trisubstituted.

[0335] Suitable R 3 Other examples of groups are shown below:

[0336]

[0337] The dotted lines on the structure represent the R 3 Each of the groups can be attached to the positions of the structures shown in the formulae described herein. 3 The group may be attached to the structure shown in the formula by a covalent bond to an atom at any position on the aromatic ring (as long as it has the correct valence and / or is chemically suitable). 3A hydrogen at any position on the group may be replaced by a bond to the parent structure as shown in the formula as described herein.

[0338] R 5 can be any substituent as described herein or can be absent. In some instances, R 5 Can be selected from halogen (for example, F, Cl, Br, I), CF , -CH F, -CHF , OCF , -OCH F, -OCHF , C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO Me, -NH , -NHMe, -NMe , CO Me, -NO , CHO and COMe. As mentioned above, one or more substituents can be present on the aromatic ring (for example, n can be 0 to 5, such as 0 to 4, 0 to 3 or 0 to 2). When there is more than one substituent, each substituent can be independently selected from R described above. 5 group.

[0339] R 6 It may be a C1 to C6 alkyl group, such as a methyl group.

[0340] G may be selected from CH2, O and NH.

[0341] Q may be a C1 to C6 alkylene group, such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0342] In other embodiments, R 3 Select from the group consisting of:

[0343]

[0344] The dotted lines represent the R 3 Each of the groups is attached to a position in the structure of the formulae described herein.

[0345] By other examples, R 5 Can be selected from C1-C6 alkyl (for example, methyl) and halogen (for example, F). As mentioned above, there can be one or more substituents on the aromatic ring. When there are two or more substituents, each substituent can be independently selected from the R 5 Again, when present and unless otherwise indicated, R 5 Addition can be made at any position to the aryl or heteroaryl ring (provided it has the correct valence and / or is chemically suitable).

[0346] In the structure shown above, the lines intersecting the wavy lines represent the exemplary R shown above. 3A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in the various formulae described herein). 3 In those cases where R is an aryl or heteroaryl group, the covalent bond (as shown in the various formulae described herein) can be formed at any position on the aromatic ring (as long as it has the correct valence and / or is chemically suitable). For example, R shown above 3 A hydrogen at any position on the group may be replaced by a bond to the structure represented by formula (I).

[0347] By way of further example, suitable R 3 The group may be selected from the following:

[0348]

[0349]

[0350] The dotted lines on the structure represent the R 3 Each of the groups may be attached to a position of the structure represented by the formula described herein, and R 5 、R 6 , n and G are as defined above.

[0351] In other examples, suitable R 3 The group may be selected from the following:

[0352]

[0353] The lines intersecting the wavy lines represent the exemplary R shown above. 3 A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in the various formulae described herein), and R 5 As defined above.

[0354] By way of further example, suitable R 3 The group may be selected from the following:

[0355]

[0356] Again, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R shown above. 3 A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in the various formulae described herein).

[0357] As mentioned above, R 4 can be selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl. In some examples, R 4Can be selected from aryl groups having 6 to 10 carbon ring atoms; and heteroaryl groups having 5 to 10 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S; wherein the aryl and heteroaryl groups are optionally substituted with one or two substituents selected from halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy. In some examples, R 4 Phenyl may be optionally substituted.

[0358] By way of further example, suitable R 4 The group may be selected from the following:

[0359]

[0360] R 7 can be any substituent as described herein or can be absent. In some instances, R 7 can be selected from C1 to C6 alkyl, halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy. 6 It can be a C1 to C6 alkyl group or a C1 to C3 alkyl group (e.g., methyl group). As mentioned above, one or more substituents can be present on the aromatic ring. When there are two or more substituents, each substituent can be independently selected from the R 7 Again, when present and unless otherwise indicated, R 7 Covalent bonding to the aryl or heteroaryl ring can be at any position (provided it has the correct valence and / or is chemically suitable).

[0361] By way of further example, representative examples of Z are shown below:

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368] In the exemplary structure shown above, R 3 R can be selected from those disclosed herein 3 In some cases, in the exemplary structures shown above, R 3 You can select from the group consisting of:

[0369]

[0370]

[0371] As mentioned above, Z is not:

[0372]

[0373] In some examples, Z is not (or does not include) a structure selected from one or more of the following:

[0374]

[0375] In some instances, Z is not (or does not include) the following structure:

[0376]

[0377] Among them, R 2 'Selected from H and C1 to C6 alkyl;

[0378] R 3 ' is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted by heterocycloalkyl;

[0379] m is 3, 4, or 5; and

[0380] L shows the point of attachment of the linker.

[0381] In some instances, the bifunctional molecule is not:

[0382]

[0383] Alternatively, it has been noted that although the various formulae described herein show the linker being connected via the heterocyclic nucleus (directly or indirectly via R 2 In some embodiments, the linker is connected to the Z portion, but the disclosure also extends to instances in which the linker is connected at any other position in the Z portion (so long as it has the correct valence and / or is chemically suitable). For example, the linker can replace a hydrogen atom at any position in the Z portion.

[0384] Thus, in some examples, Z can be represented as shown in formula (ZV) or (V):

[0385]

[0386] Among them, ring A 2 、R 1 、R 2 、R 3 、X 1 、X 2 、X3 , n and L are as defined in any of the embodiments disclosed above.

[0387] The dashed lines indicated by the square brackets in formulas (ZV) and (V) indicate that the linker can be attached via a covalent bond to any atom on the Z moiety, provided it has the correct valence, is chemically suitable, and / or provided that attachment of the linker at that alternative position does not disrupt the function of the Z moiety in promoting and / or assisting proteasomal degradation.

[0388] According to other aspects of the present disclosure, there is also provided a compound comprising the following general structure:

[0389] LZ

[0390] wherein the moiety Z is as defined in any of the formulae described herein (e.g., any of formulae (I) to (V) and (ZI) to (ZV)); and

[0391] L is a linker as defined herein.

[0392] These compounds can be useful in the synthesis of the described bifunctional molecules, for example, via a modular approach in which each of the moieties TBL, Z, and L is provided as a separate building block. In some examples, L and Z can be linked to provide the compound LZ as described above (which can then be further reacted to link to the appropriate TBL moiety).

[0393] Intermediates / fragments

[0394] As described above, structures comprising a Z moiety as described herein may find particular utility in targeted protein degradation. As such, intermediates comprising these Z moieties may be valuable in providing useful intermediates for the synthesis of bifunctional molecules for targeted protein degradation.

[0395] According to other aspects, intermediate compounds or fragments corresponding to any one or more of the formulas for Z described herein or any other example structures described herein are provided, wherein the LW or W moiety has been replaced by a group "G."

[0396] G is covalently linked to the disclosed structure.

[0397] According to other aspects, there is provided a compound comprising a Z moiety according to formula (VI) or (VIa):

[0398]

[0399] Among them, ring A 2 、R 1 、R 2 、R3 ,n,X 1 、X 2 and X 3 As defined in any one of the embodiments disclosed above.

[0400] As shown in formula (VI) and (VIa), G is directly or through R 2 In either case, G is covalently linked to the moiety Z. G may be linked (directly or via R 2 Indirectly) to any position of the heterocyclic core (as long as it has the correct valence and / or is chemically suitable). For example, G can replace a hydrogen atom at any position on the heterocyclic core.

[0401] The group G in formula (VI) or (VIa) is configured so that the Z portion can be connected to another chemical structure (such as a linker portion or a linker-target protein binding ligand portion) via the formation of a new covalent bond. After the new covalent bond is formed, the group G can form a part of a linker as defined herein.

[0402] In some examples, G can comprise a functional group that can facilitate the formation of a new covalent bond between Z and another moiety, for example, via the formation of an amide, ester, thioester, ketone, carbamate, amine, or ether bond, or via the formation of a new carbon-carbon bond or a new carbon-nitrogen bond.

[0403] By way of example only, G may be represented as follows:

[0404]

[0405] Among them, R G C1-C6 alkyl is absent or optionally substituted by one or more heteroatoms selected from N, O and S;

[0406] X G is a group selected from the group consisting of: -CO2H, -(CO)-N-hydroxysuccinimide and -(CO)-pentafluorophenol ester, -CHO, -COR G1 、-OH、-NH2、-NHR G2 , halogen (e.g., iodo and bromo), O-leaving group (e.g., -OTs (tosylate), OMs (mesylate), -OTf (triflate)), alkynyl, azide, diene group, aminooxy group, tetrazinyl, (E)-cyclooctenyl, cyclooctynyl, norbornyl, boronic acid, boronate, alkylborane or organometallic group (e.g., organotin, zinc or other suitable reagent); and R G1 and R G2 are independently selected from C1-C6 alkyl.

[0407] In this structure, the heterocyclic nucleus with Z (or, if present, R 2 Wavy lines are shown over the bonds forming connections (groups).

[0408] G through R G The group is attached to the heterocyclic core shown in formula (VI) (directly or via R 2 Group). In R G In those cases where the group X is not present G Directly connected to the heterocyclic core or R 2 superior.

[0409] Representative examples of suitable G moieties are shown below:

[0410]

[0411] It should be noted that the present disclosure further extends to any structure of Z shown in the formulae defined herein, such as formulae (I) to (V) and (ZI) to (ZV) or other representative examples of Z, wherein the group L on these structures has been replaced by a group G as defined above with respect to formula (VI) or (VIa).

[0412] Connector (L)

[0413] As described herein, TBL is connected or coupled to moiety Z via a linker L. The linker can be a chemical linker (e.g., a chemical linker moiety), and can be, for example, a covalent linker, which means that the linker is coupled to Z and / or TBL via a covalent bond.

[0414] The linker plays the effect that target protein binding ligand and Z part are connected to each other, and also allows these two parts to be combined with their respective targets and / or bring into play their predetermined function.Specifically, the linker can play the effect that target protein binding ligand is connected to Z, and also alleviates the possibility that Z part destroys, interferes and / or suppresses target protein binding ligand and target protein is combined.In addition or as an alternative, the linker can work to connect Z to target protein binding ligand, and also alleviates the possibility that target protein binding ligand destroys, interferes and / or suppresses the cellular interaction (for example, its function in regulating, helping and / or promoting the proteasome degradation of target protein) of Z.

[0415] In other words, by allowing each end of the bifunctional molecule to be used for binding to multiple components of the cellular environment (or another type of interaction), the linker can play a role in helping the targeted protein degradation. For example, the linker can be configured to allow the target protein binding partner to bind to the target protein without interference, destruction and / or inhibition by the Z part of the bifunctional molecule. Additionally or alternatively, the linker can be configured to allow the Z part to interact with multiple components in the cellular environment, thereby regulating, helping and / or promoting the proteasome degradation of the target protein without interference, destruction and / or inhibition by the target protein binding partner of the bifunctional molecule.

[0416] In many cases, a wide range of linkers will be tolerated. The choice of linker may depend on the protein being targeted for degradation (target protein) and / or the specific target protein binding partner.

[0417] The linker can be selected to provide a specific length and / or flexibility, for example, so that the target protein binding ligand and the Z portion are maintained within a specific distance and / or geometric structure. As will be appreciated by those skilled in the art, the length and / or flexibility of the linker can be varied based on the structure and / or properties of the target protein binding ligand.

[0418] In some examples, TBL is directly linked to moiety Z via a covalent bond, ie the linker is a covalent bond. Such direct linkage is also encompassed by the term "linker" in the context of this disclosure (unless otherwise specified).

[0419] By way of example only, a linker can comprise any number of atoms between 1 to 200, 1 to 100, 1 to 50, 1 to 30, or 1 to 10. In some cases, a linker can comprise any number of atoms in a single linear chain between 1 to 200, 1 to 100, 1 to 50, 1 to 30, or 1 to 10. In some examples of the present disclosure, a linker can comprise any number of atoms in a single linear chain between 1 to 25, such as 25, or 1 to 20, such as 3 and 20, or 1 to 18, such as 3 and 18.

[0420] The flexibility degree of a joint can depend on the number of rotatable bonds present in the joint. A rotatable bond is defined as a single non-cyclic bond combined with a non-terminal heavy atom (e.g., a non-hydrogen atom). As described herein, an amide (CN) bond is considered to be non-rotatable due to a high rotational energy barrier. In some cases, the joint can include one or more parts selected from rings, double bonds, and amides to reduce the flexibility of the joint. In other cases, the joint can include a single bond (e.g., mainly including a single non-cyclic bond) of a larger number and / or ratio to increase the flexibility of the joint. It can also be understood that the length of the joint can affect the flexibility degree. For example, a shorter joint comprising fewer keys can also reduce the flexibility of the joint.

[0421] In some examples, the number of rotatable bonds present in the linker can be any number between 1 and 20, 1 and 15, or 1 and 10. In some examples, the number of rotatable bonds present in the linker can be any number between 2 and 9, 2 and 8, or 3 and 6.

[0422] In some examples, the linker can comprise any number between 10 and 20 atoms in a single linear chain; and / or the number of rotatable bonds present in the linker can be any number between 2 and 8.

[0423] The structure of the linker (L) can be represented as follows:

[0424] (L x ) q

[0425] Among them, each L x represents a subunit of L; and

[0426] q is an integer greater than or equal to 1.

[0427] For example, q can be any integer between 1 and 30, between 1 and 20, or between 1 and 5.

[0428] For example, when q is 1, the linker contains only one L x In the case where q is 2, the linker comprises two L subunits covalently linked to each other and can be represented as L1-L2. x In another example, when q is 3, the linker comprises three L covalently linked to each other and can be represented as L1-L2-L3 x For integer values ​​of q or even higher, L can contain the following subunits L1, L2, L3, L 4…… Until L q .

[0429] L x Each of which can be independently selected from CR L1 R L2 ,O,C=O,S,S=O,SO2,NR L3 ,SONR L4 ,SONR L5 C=O、CONR L6 NR L7 CO、C(R L8 )=C(R L9 ), C≡C, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.

[0430] R L1 、R L2 、RL3 、R L4 、R L5 、R L6 、R L7 、R L8 and R L9 Each of can be independently selected from H, halogen, C1 to C6 alkyl, C1 to C6, haloalkyl, -OH, -O(C1 to C6 alkyl), -NH2, -NH(C1 to C6 alkyl), -NO2, -CN, -CONH2, -CONH(C1 to C6 alkyl), -CON(C1 to C6 alkyl)2, -S(O)OC1 to C6 alkyl, -C(O)OC1 to C6 alkyl and -CO(C1 to C6 alkyl). In some examples, R L1 、R L2 、R L3 、R L4 、R L5 、R L6 、R L7 、R L8 and R L9 Each of may be independently selected from H and C1 to C6 alkyl.

[0431] The terms aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl are as defined above.

[0432] Terminal L x The subunit can connect or couple the linker moiety to the TBL and Z moieties of the bifunctional molecule. For example, if the terminal L x The subunits are denoted as L1 and L q , then L1 can connect the connector to the TBL part, and L q A linker may be attached to the Z moiety. In those cases where q is 1, one L x The subunit (eg, L1) provides the link between the TBL and Z portions of the bifunctional molecule.

[0433] The TBL and Z moieties can be covalently linked to L via any group that is suitable and stable for the chemical nature of the linker. By way of example only, the linker can be covalently bonded to the TBL moiety via a carbon-carbon bond, a keto group, an amino group, an amide, an ester, or an ether bond. Similarly, the linker can be covalently bonded to the Z moiety via a carbon-carbon bond, a carbon-nitrogen bond, a keto group, an amino group, an amide, an ester, or an ether bond.

[0434] In some cases, each terminal L x Subunits (e.g., L1 and L q ) are independently selected from O, C=O, CR L1 R L2 NR L3 、CONRL6 NR L7 CO, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.

[0435] In some instances, L x At least one of comprises a ring structure and is, for example, selected from heterocycloalkyl, heteroaryl, cycloalkyl, or aryl.

[0436] In alternative examples, the linker can be or comprise an alkyl linker comprising repeating subunits of -CH2-; wherein the number of repeats is 1 to 50, for example, 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.

[0437] In other examples, the linker can be or comprise a polyalkylene glycol. By way of example only, the linker can be or comprise polyethylene glycol (PEG), which comprises repeating subunits of ethylene glycol (C2H4O), for example, having about 1-50 ethylene glycol subunits, for example, wherein the number of repeats is 1 to 100, for example, 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 repeats.

[0438] In some examples described herein, the structure of the linker (L) can be or include a structure as shown in formula (L1a):

[0439] L 1A -L 2A -L 3A (L1a)

[0440] Among them, L 1A There is no 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-);

[0441] L 2A Yes-NR L2A C=O- or -C=ONR L2A -;as well as

[0442] L 3A selected from 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-);

[0443] Among them, R L2A is H or a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0444] In other examples, the structure of the linker (L) can be or include a structure as shown in formula (L1b):

[0445] L 1B —L 2B —L 3B -L 4B —L 5B (L1b)

[0446] Among them, L 1B There is no or is selected from C1-C3 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)-、-NR L2A (CH2)2-、-R L2A (CH2)5-、-CH2R L2A CH2-);

[0447] L 2B Yes-NR L2A C=O- or -C=ONR L2A -;

[0448] L 3B Selected from C1-C 15 Alkylene, -[(CH2)2O] 1-6 (CH2)2-;

[0449] L 4B Yes-NR L2A C=O- or -C=ONR L2A -, where R L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl);

[0450] L 5Bselected from 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-);

[0451] Among them, R L2A is H or a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0452] In some examples described herein, the structure of the linker (L) can be or include a structure as shown in formula (L1c):

[0453] L 1C —L 2C —L 3C —L 4C (L1c)

[0454] Among them, 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, each of which optionally contains one or two further ring heteroatoms selected from N, O and S;

[0455] L 2C There is no or is selected from 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-);

[0456] L 3C Yes-R L2B C=O- or -(C=O)R L2B -;as well as

[0457] L 4C selected from 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)2NRL2A -、-(CH2)5NR L2A -、-CH2NR L2A CH2-);

[0458] in:

[0459] R L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl); and

[0460] R L2B It is NR L2A or an N-attached 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 one or two additional ring heteroatoms selected from N, O and S.

[0461] In the example of the linker (L) represented by formula L1c, L 1C and L 2C Both may not exist. In these instances, L 3C R in L2B is an N-linked optionally substituted 4 to 7 membered monocyclic N-heterocycloalkyl group optionally containing one or two further ring heteroatoms selected from N, O and S, and L 3C It is through R L2B The terminal subunit of the linker is linked (suitably covalently linked) to the TBL.

[0462] In some examples described herein, the structure of the linker (L) can be or include a structure as shown in formula (L1d):

[0463] L 1D —L 2D —L 3D (L1d)

[0464] Among them, L 1D Not present or selected from C1-C3 alkylene, CO, C1-C3 alkylene (N (C1-C3 alkyl); L 2D It is NR L2A or 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 one or two additional ring heteroatoms selected from N, O, and S; wherein R L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl); and

[0465] L 3D It is absent or selected from C1-C3 alkylene, -O-, -N(C1-C3 alkyl)- and CO.

[0466] In other examples, the structure of the linker (L) can be or include a structure as shown in formula (L1e):

[0467] L 1E -L 2E -L 3E (L1e);

[0468] Among them, L 1E is C1-C3 alkylene (e.g., methylene) or CO;

[0469] L 2E is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each of which optionally contains one or two further ring heteroatoms selected from N, O and S; and

[0470] L 3E is selected from C1-C3 alkylene (eg, methylene).

[0471] In some instances, L 1A , L 1B , L 1C , L 1D or L 1E is the terminal subunit of the linker moiety connected (ie, covalently bonded) to the W moiety, and L 3A , L 5B , L 4C , L 3D , L 3E It is the terminal subunit of the linker moiety that is connected (ie, covalently bonded) to the TBL moiety.

[0472] When L 1A , L 1B or L 1D When any one of them does not exist, L 2A , L 2B or L 2D Directly attached (ie, covalently bonded) to the W moiety. 3D When L does not exist, 2D Directly attached (ie, covalently bonded) to the TBL moiety.

[0473] As mentioned above, some linker moieties, such as R L2B L 1C , L 2D , L 2E Examples may be bicyclic or tricyclic, and unless otherwise specified, these moieties may contain rings connected by bonds, fused rings, bridged rings, and / or rings connected at spiro centers.

[0474] When R L2B L 1C , L2D , L 2E Where any of the examples is a bicyclic ring, it may be a bridged bicyclic ring (i.e., it may comprise two rings that have three or more atoms in common) or it may be a spirocyclic bicyclic ring (i.e., it may comprise two rings that have one atom in common, e.g., the two rings may be joined at a spiro center).

[0475] When R L2B L 1C , L 2D , L 2E When any of the examples is a bridged bicyclic ring, it may be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl group optionally containing one or two additional ring heteroatoms selected from N, O, and S. In some examples, L 1C , L 2D , L 2E and R L2B Examples of L can be 7 or 8 membered bridged bicyclic N-heterocycloalkyl groups optionally containing one or two additional ring heteroatoms selected from N, O and S. In some examples, L 1C , L 2D , L 2E and R L2B Examples of can be 7 or 8 membered bridged bicyclic N-heterocycloalkyl optionally containing one further ring atom selected from N.

[0476] When L 1C , L 2D , L 2E and R L2B When any of the examples of is a spirobicyclic ring, it may be an optionally substituted 7- to 12-membered spirobicyclic N-heterocycloalkyl group optionally containing one or two other ring heteroatoms selected from N, O and S. In some examples, L 1C , L 2D , L 2E and R L2B Examples of can be 7 to 12 membered spirobicyclic N-heterocycloalkyl groups optionally containing one or two additional ring heteroatoms selected from N, O and S. In some cases, L 1C , L 2D , L 2E and R L2B Examples of L may be bicyclic and include a first 5- to 7-membered ring and a second 3- to 7-membered ring. 1C , L 2D , L 2E and R L2B Examples of can be spirobicyclic N-heterocycloalkyl groups comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring and optionally containing one or two additional ring heteroatoms selected from N, O, and S. In some examples, L 1C , L 2D, L 2E and R L2B Examples of may be spirobicyclic N-heterocycloalkyl groups comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring and optionally containing one further ring heteroatom selected from N.

[0477] In some instances, L 1C , L 2D , L 2E and R L2B The structure of an example can be any one selected from the following:

[0478]

[0479] Among them, L 1A and L 3A As defined above;

[0480] X 5 It is C(R b )2、NR b or O;

[0481] R b is H or optionally substituted C 1-3 alkyl;

[0482] n1 is 0, 1, 2, or 3;

[0483] n' is 1 or 2;

[0484] m is 0, 1, or 2.

[0485] The dashed lines on the above structures indicate that a linker can be attached to the shown structure at any position shown (as long as it has the correct valence and / or is chemically suitable).

[0486] In some instances, L 1C , L 2D , L 2E and R L2B Examples of are any one selected from the following:

[0487]

[0488] The dashed lines on the above structures indicate that a linker can be attached to the shown structure at any position shown (as long as it has the correct valence and / or is chemically suitable).

[0489] As mentioned above, L 1D is absent or selected from C1-C3 alkylene, -O-, -N(C1-C3 alkyl)- and CO. In some examples, L 3D is selected from C1-C3 alkylene (eg, methylene).

[0490] In some examples described herein, the linker (L) can be or comprise a structure represented by formula (L1f):

[0491] L 1F (L1f)

[0492] Among them, L 1F Selected from C1-C3 alkylene, CO and C1-C3 alkylene (NR L1C ); where R L1C is H or C1-C3 alkyl.

[0493] In some instances, L 1F Selected from C1-C3 alkylene (such as methylene).

[0494] In any of the examples described herein, the linker is or comprises one or more of:

[0495]

[0496]

[0497] Here, q1 is any integer between 1 and 20 or between 1 and 10 (eg, between 1 and 5).

[0498] Alternatively, in any example described herein, the linker is or comprises one or more of:

[0499]

[0500]

[0501]

[0502] Here, q2 is any integer between 1 and 20 or between 1 and 10 (eg, 3, 4, 5, 6, or 10).

[0503] As a further alternative, in any example described herein, the linker is or comprises one or more of the following:

[0504]

[0505]

[0506] wherein 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).

[0507] In particular embodiments, the linker is or comprises one or more of the following structures:

[0508]

[0509]

[0510]

[0511] In yet other alternatives, in any example described herein, the linker is or comprises one or more of:

[0512]

[0513]

[0514] wherein q3 is 1 to 8, such as 1 to 5, and q4 is 1 to 12, such as 1 to 10.

[0515]

[0516]

[0517]

[0518] In particular embodiments, the linker is or comprises one or more of the following structures:

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531] In some cases, the structure shown above represents the entire linker. In other examples, the linker of the bifunctional molecule can comprise multiple structures shown above.

[0532] In these structures, wavy lines are shown over the bonds forming connections to the TBL and Z moieties, respectively.

[0533] In some instances, the bond forming the connection to the TBL and / or Z moiety is attached to the ring structure. In the various structures described herein, the bond is shown attached to a specific position on the ring structure. However, the present disclosure also encompasses attachment or coupling to the TBL and Z moieties at any chemically suitable position on these ring structures.

[0534] The present disclosure encompasses the use of any linker disclosed herein in combination with any Z moiety and TBL moiety described herein.

[0535] Target protein

[0536] As used herein, a "target protein" can be any polypeptide or protein that one wishes to selectively degrade in a cell or mammal (e.g., a human or animal subject). In other words, a "target protein" can be a protein or polypeptide that one selects for increased proteolysis in a cell. The term "selected target protein" can be any polypeptide or protein that has been selected for targeted protein degradation and / or increased proteolysis.

[0537] In some examples of the present disclosure, the term "target protein" does not include androgen receptor. As used herein, "androgen receptor" refers to the protein designated as P10275 by UniProtKB (ANDR_HUMAN).

[0538] 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 P03372 by UniProtKB (ESR1_HUMAN).

[0539] In other words, in some instances, the bifunctional molecules disclosed herein may not be intended or may not be suitable for the targeted degradation of a target protein selected from: (i) an estrogen receptor; and (ii) an androgen receptor.

[0540] According to the present disclosure, degradation of the target protein can occur when the target protein is subjected to and / or contacts a bifunctional molecule as described herein, for example, when the target protein is subjected to and / or contacts any of the bifunctional molecules in a cell.

[0541] Selective degradation and / or increased proteolysis of a target protein will reduce the level of the target protein and, therefore, can reduce the effect of the target protein in the cell. The control of the levels of a specific protein provided by the bifunctional molecules described herein can provide treatment for a disease state or condition that is modulated by or by the target protein by reducing the level of that protein in the subject's cells.

[0542] Target proteins that may undergo enhanced proteolysis and / or selective degradation when contacted with the bifunctional molecules of the present disclosure (and related methods of using these molecules) include any proteins and polypeptides. Target proteins include proteins and polypeptides that have biological functions or activities, such as structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction functions and activities.

[0543] For example, target proteins can include structural proteins, receptors, enzymes, cell surface proteins, proteins involved in the integral functions of the cell, including those involved in catalytic activity, epigenetic regulation, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthetic proteins, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction protein activity, structural molecule activity, binding activity (protein, lipid, carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulatory protein activity, nucleic acid binding activity, transcriptional regulatory protein activity, extracellular organization and biogenesis activity, and translational regulatory protein activity.

[0544] Target proteins can include proteins from eukaryotic and prokaryotic organisms, including humans, other animals (including domesticated animals), microorganisms, viruses, fungi, and parasites, as well as a variety of other targets for drug therapy.

[0545] In some examples, target proteins may include, but are not limited to: (i) kinases (such as 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; (vii) ubiquitin E3 ligases and demethylases. Ubiquitinating enzymes; (viii) nuclear hormone receptors (including, for example, thyroid hormone receptors, androgen receptors (AR) and estrogen receptors (ER), but as described above, in some instances, the target protein does not include androgen receptors and estrogen receptors); (ix) aggregation-prone proteins (including β-amyloid protein, Tau, Htt, α-synuclein and polyQ-extended proteins); (x) apoptotic and anti-apoptotic factors (including Bcl2, Bcl-xl and Mcl-1); and (xi) polymerases (including PARP and POLQ), etc.

[0546] The target protein can also be selected from targets for human therapeutic drugs. These include proteins that can be used to restore function in a variety of diseases, such as polygenic diseases, including, for example, target proteins selected from the group consisting of B7.1 and B7, TNFR1, TNFR2, NADPH oxidase, BclI / Bax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (i.e., Gq), histamine receptor, 5-lipoxygenase, tryptase-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAK STAT, RXR and analogs, 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 p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / MEK / ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide nucleotide 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, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptors, norepinephrine reuptake receptors, endothelin receptors, neuropeptide Y and receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA (NGF receptor), beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytoplasmic phospholipase A2, and EGF receptor tyrosine kinase.Other protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channels, and chloride channels. Other target proteins include acetyl-CoA carboxylase, adenylate succinate synthetase, SMARCA2; protoporphyrinogen oxidase and enolpyruvylshikimate-phosphate synthase.

[0547] The target protein can also be a haloalkane dehalogenase. For example, bifunctional molecules according to the present disclosure containing a chloroalkane peptide binding portion (C1-C12, typically about C2-C10 alkyl halide) can be used to inhibit and / or degrade haloalkane dehalogenase, which is used in fusion proteins or related diagnostic proteins, such as those described in PCT / US2012 / 063401, filed December 6, 2011, and WO 2012 / 078559, published June 14, 2012, the contents of which are incorporated herein by reference.

[0548] Target Binding Ligand (TBL)

[0549] 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). For example, a target protein binding ligand can be any moiety that selectively and / or specifically binds to a target protein. A bifunctional molecule according to the present disclosure can include a target protein binding ligand that binds to the target protein with sufficient binding affinity such that the target protein is more susceptible to degradation or proteolysis than a target protein not bound by the bifunctional molecule.

[0550] The target protein binding ligand can bind to the target protein with a binding affinity of less than or equal to about 10 μM, less than or equal to about 1 μM, less than or equal to about 0.5 μM, or less than or equal to about 0.1 μM.

[0551] In some examples, the ligand can bind to the target protein with a binding affinity of about 0.01 nM to about 10 μM, such as about 0.01 nM to about 8 μM, about 0.01 nM to about 5 μM, about 0.01 nM to about 3 μM.

[0552] For the avoidance of doubt, binding affinity is a measure of the tendency of an object comprising two components bound together to separate (dissociate) into the two components. As used herein, binding affinity is a measure of the tendency of the complex formed when a target protein binding ligand binds to a target protein to dissociate into separate components, i.e., the tendency of the target protein binding ligand to dissociate from the target protein.

[0553] The binding between the target protein and the target protein binding partner can include one or more binding interactions, such as one or more of hydrogen bonds, dipole-dipole bonds, ion-dipole bonds, ion-induced dipole bonds, ionic bonds, and covalent bonds. For example, the binding between the target protein and the target protein binding partner can include a salt bridge (a combination of hydrogen bonds and ionic bonds).

[0554] As described above, in some examples, the target protein binding ligand portion may not be a target protein binding ligand selected from the following: (i) estrogen receptor binding ligand; and (ii) androgen receptor binding ligand. Specifically, in some examples, the target protein ligand contained in the bifunctional molecule of the present disclosure: (i) is not a ligand that specifically binds to the estrogen receptor; and (ii) is not a ligand that specifically binds to the androgen receptor.

[0555] In some examples, the bifunctional molecules disclosed herein do not comprise a target protein binding ligand that binds to an estrogen receptor with a binding affinity of less than or equal to about 10 μM or less than or equal to about 1 μM.

[0556] In other words, in some instances, the bifunctional molecules disclosed herein may not contain a target protein binding ligand that binds to an estrogen receptor with sufficient binding affinity to cause selective degradation of the estrogen receptor. Specifically, if the bifunctional molecules described herein are contacted with an estrogen receptor, the DC 50 The values ​​(for degradation of the estrogen receptor) will be greater than about 10,000 nM or greater than about 1,000 nM.

[0557] 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 less than or equal to about 10 μM or less than or equal to about 1 μM.

[0558] Additionally, in some instances, the bifunctional molecules disclosed herein may not contain a target protein binding ligand that binds to the androgen receptor with sufficient binding affinity to allow selective degradation of the androgen receptor. Specifically, if the bifunctional molecules described herein are contacted with the androgen receptor, the observed DC 50 The value (for degradation of the androgen receptor) will be greater than about 10,000 nM or greater than about 1,000 nM.

[0559] The target protein binding ligand may comprise or be derived from a small molecule (or an analog or fragment thereof) 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). For example, the target protein binding ligand may comprise or be derived from a small molecule known to inhibit the activity of a given target protein.

[0560] 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 (including serine / threonine kinases such as RAF, receptor tyrosine kinases, and others), (ii) compounds that bind to bromodomain-containing proteins (including the BET family, etc.), (iii) epigenetic regulator compounds (including binders to histone or DNA methyltransferases, acetyltransferases, deacetylases, and demethylases, such as histone deacetylases (HDACs), lysine acetyltransferases, such as P300 (EP300; 300 kDa adenovirus E1A binding protein) and CBP (CREBBP; cyclic AMP response element binding protein)), (iv) binding agents for transcription factors, including STAT3, myc, etc., (v) G The present invention also includes binding agents for TPases (including KRAS, NRAS, HRAS, etc.), (vi) binding agents for phosphatases, (vii) binding agents for ubiquitin E3 ligases (e.g., MDM2) and deubiquitinating enzymes; (viii) binding agents for nuclear hormone receptors (including, for example, thyroid receptor, androgen receptor (AR) and estrogen receptor (ER), although in some instances, as described above, the target binding ligand does not include binding agents for androgen receptor and estrogen receptor); (ix) binding agents for aggregation-prone proteins (including β-amyloid, Tau, Htt, α-synuclein and polyQ-extended proteins); (x) binding agents for apoptotic and anti-apoptotic factors (including Bcl2, Bcl-xL and Mcl-1) and (xi) binding agents for polymerases (including PARP and POLQ), as well as numerous others.

[0561] 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 targeting the aryl hydrocarbon receptor (AHR), (v) compounds targeting FKBP, (vi) compounds targeting HIV protease, (vii) compounds targeting HIV integrase, (viii) compounds targeting HCV protease, (ix) compounds targeting acyl protein thioesterase-1 and -2 (APT1 and APT2), and many others.

[0562] BET inhibitors

[0563] In some cases, the target protein binding ligand is derived from a BET inhibitor (e.g., BET inhibitor IBET276). In these examples, the target protein binding ligand can comprise the following structure:

[0564]

[0565] Wherein, L shows the connection position of the linker, and the dotted line on the above structure indicates that the linker can be connected to the target protein binding ligand via any position on the aromatic ring (for example, in some examples, L can be present at the 4-position on the aromatic ring). However, the present disclosure also covers the connection or coupling to the linker at any chemically suitable position on the target protein binding ligand.

[0566] BRD9

[0567] Alternatively, the target protein binding ligand may be derived from a BRD9 inhibitor. For example, the target protein binding ligand may comprise the following structure:

[0568]

[0569] Wherein, L shows the connection position of the linker. The present disclosure also covers the connection or coupling to the linker at any other chemically suitable position on the target protein binding ligand.

[0570] Kinase inhibitors

[0571] In other examples, the target protein binding ligand is derived from a kinase inhibitor. In these examples, the target protein binding ligand may comprise the following structure:

[0572]

[0573] Wherein, L shows the connection position of the linker. However, again, the present disclosure also covers the connection or coupling to the linker at any chemically suitable position on the target protein binding ligand.

[0574] Target protein binding ligands can be derived from kinase inhibitors, such as CDK9 inhibitors, and can contain the following structures:

[0575]

[0576] Wherein, L shows the connection position of the linker. The present disclosure also covers the connection or coupling to the linker at any other chemically suitable position on the target protein binding ligand.

[0577] EGFR

[0578] Alternatively, the target protein binding ligand may be derived from a kinase inhibitor, such as a mutant EGFR inhibitor, and may have the following structure:

[0579]

[0580] Wherein, L shows the connection position of the linker. In addition, the present disclosure also covers the connection or coupling with the linker at any other chemically suitable position on the target protein binding ligand.

[0581] In some examples, the target protein binding ligand can be represented by the formula (EGFR1):

[0582]

[0583] Among them, R 2A Selected from 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 further substituted by 1 to 5 R f1 group substitution;

[0584] Among them, each R a1 are independently H or C1-C6 alkyl;

[0585] Among them, each R b1 are 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 heteroaryl;

[0586] Among them, each R f1 independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, C1-C6 alkylamino, amide, urea, oxy, halogen, pyrazolyl, imidazolyl, triazolyl, CN, -NHC(O)(C1-C3 alkyl), acyl, sulfonyl, sulfoxide, sulfonamide, sulfonimide, -(CH2) m1 C3-C7 heterocycloalkyl and C(O)OR a1 ;

[0587] R 2B is hydrogen and R 2C Yes-NHC(O)R 2D , where R 2D is selected from aryl and heteroaryl optionally substituted with 1 to 2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy and CN; or

[0588] R 2B and R 2Ctogether to form a 5- to 10-membered aryl or heteroaryl ring optionally substituted with 1 to 5 substituents each independently selected from the group consisting of C1-C6 alkyl, halogen, 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; and

[0589] Each m1 is independently 0, 1, 2 or 3.

[0590] The target protein binding ligand represented by formula (EGFR1) can be added to the linker L of the bifunctional molecule through a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker can be attached at any suitable position, for example, as long as it has the correct valence and / or is chemically suitable. For example, the linker of the bifunctional molecule can be covalently bonded to R of formula (EGFR1) at any position. 2B or R 2C moiety (as long as it has the correct valence and / or is chemically suitable).

[0591] In some examples of Formula (EGFR1), R 2A is a C3-C7 heterocycloalkyl group. Specifically, R 2A may be a compound comprising at least one optionally substituted by 1 to 3 R f1 In some embodiments, R 2A Can contain the following structures:

[0592] Among them, R f1 is a halogen; and wherein the wavy line bisects the bond forming the connection to the pyrimidinyl core of formula (EGFR1).

[0593] In some examples, the target protein binding ligand can be represented by the formula (EGFR2):

[0594]

[0595] Among them, R A1 Selected from C3-C7 heterocycloalkyl, heteroaryl, -O(C1-C6 alkyl) or -NR a1 R b1 , wherein the C3-C7 heterocycloalkyl and heteroaryl are optionally further substituted by 1 to 5 R f1 group substitution;

[0596] R A2R is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl; A3 Not present or selected from 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;

[0597] Among them, each R f1 independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, C1-C6 alkylamino, amide, urea, oxy, halogen, pyrazolyl, imidazolyl, triazolyl, CN, -NHC(O)(C1-C3 alkyl), acyl, sulfonyl, sulfoxide, sulfonamide, sulfonimide, -(CH2) m1 C3-C7 heterocycloalkyl and C(O)OR a1 ;

[0598] Among them, each R a1 are independently H or C1-C6 alkyl;

[0599] Among them, each R b1 are 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 heteroaryl;

[0600] or R a1 and R b1 together may form a C3-C7 cycloalkyl, C3-C7 heterocycloalkyl or heteroaryl ring, wherein the C3-C7 cycloalkyl, C3-C7 heterocycloalkyl and heteroaryl may each be further substituted by 1 to 3 groups selected from the group consisting of halogen, hydroxy, C1-C3 alkyl, amino, oxy, amide, sulfonyl, sulfoxide, sulfonimide, sulfonamide, C1-C3 alkoxy, CN and acyl;

[0601] X A1 selected from N and CH; and

[0602] Each m1 is independently 0, 1, 2 or 3.

[0603] In some examples of Formula (EGFR2), X A1 It's N.

[0604] In some examples of Formula (EGFR2), R A1 Selected from C3-C7 heterocycloalkyl, heteroaryl and NR a1 R b1 .

[0605] In some examples of Formula (EGFR2), R A1 is selected from C3-C7 heterocycloalkyl and heteroaryl, said C3-C7 heterocycloalkyl and heteroaryl being optionally further substituted by 1 to 5 R f1 Group substituted, wherein each R f1 R is independently selected from sulfonyl, alkoxy and halogen; A3 Not present or -C(O)NR a1 R b1 ; and R A2 It is a C1-C6 alkyl group.

[0606] In some examples of Formula (EGFR2), R A1 is a C5-C7 heterocycloalkyl group containing at least one N heteroatom (e.g., piperidinyl) or a heteroaryl group containing at least one N heteroatom in the ring (e.g., pyrazolyl).

[0607] In some examples of Formula (EGFR2), R f1 Selected from -SO2(C3-C7cycloalkyl) (e.g., -SO2(cyclopropyl)), halogen (e.g., F), hydroxy, C1-C6 alkyl, and C1-C6 alkoxy (e.g., methoxy).

[0608] In some examples of Formula (EGFR2), R A2 is a C1-C6 alkyl group or a C1-C6 haloalkyl group, such as a C1-C4 alkyl group or a C1-C4 haloalkyl group. A2 Representative examples include, but are not limited to, isopropyl, sec-butyl, and 1,1,1-trifluoroprop-2-yl.

[0609] In some examples of Formula (EGFR2), R A3 Selected from C1-C3 alkyl, C3-C7 heterocycloalkyl, heteroaryl, -NR a1 R a1 and -C(O)NR a1 R b1 .

[0610] In some examples of Formula (EGFR2), R A1 is selected from C3-C7 heterocycloalkyl (e.g., piperidinyl) and heteroaryl (e.g., pyrazolyl), wherein the C3-C7 heterocycloalkyl or heteroaryl is optionally further substituted by 1 to 3 R f1 Group substituted, the R f1The group is selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halogen, sulfonyl and sulfonamide.

[0611] In some examples, the target protein binding ligand can be represented by the formula (EGFR2a):

[0612]

[0613] Among them, R A2 and R A3 As defined in formula (2); and

[0614] R f1b is selected from H and C1-C6 alkyl (e.g., C1-C3 alkyl); and

[0615] R f1a Not present or halogen.

[0616] The target protein binding ligand (TBL) represented by formula (EGFR2) and (EGFR2a) can be added to the linker L of the bifunctional molecule through a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker can be attached at any suitable position, for example, as long as it has the correct valence and / or is chemically suitable. For example, the linker of the bifunctional molecule can be covalently bonded to R of formula (EGFR2) or (EGFR2a) at any position. A3 moiety (as long as it has the correct valence and / or is chemically suitable). A3 In those instances where it is not present, the linker of the bifunctional molecule can be covalently bonded to the heteroaryl ring as shown in Formulas (EGFR2) and (EGFR2a).

[0617] In some examples, the target protein binding ligand can be represented by the formula (EGFR3):

[0618]

[0619] Among them, R A1 Selected from C3-C7 heterocycloalkyl, heteroaryl, -O(C1-C6 alkyl) or -NR a1 R b1 , wherein the C3-C7 heterocycloalkyl and heteroaryl are optionally further substituted by 1 to 5 R f1 group substitution;

[0620] R A2 R is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl; A3'is absent or is selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, CN, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, -O(C1-C6 haloalkyl), oxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl optionally substituted with C1-C3 alkyl, C1-C6 hydroxyalkyl, aryl and heteroaryl;

[0621] Among them, each R f1 independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, C1-C6 alkylamino, amide, urea, oxy, halogen, pyrazolyl, imidazolyl, triazolyl, CN, -NHC(O)(C1-C3 alkyl), acyl, sulfonyl, sulfoxide, sulfonamide, sulfonimide, -(CH2) m1 C3-C7 heterocycloalkyl, -O(C1-C6 alkyl) and C(O)OR a1 ; where each R a1 are independently H or C1-C6 alkyl;

[0622] Among them, each R b1 are 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 heteroaryl;

[0623] or R a1 and R b1 together may form a C3-C7 cycloalkyl, C3-C7 heterocycloalkyl or heteroaryl ring, wherein the C3-C7 cycloalkyl, C3-C7 heterocycloalkyl and heteroaryl may each be further substituted by 1 to 3 groups selected from the group consisting of halogen, hydroxy, C1-C3 alkyl, amino, oxy, amide, sulfonyl, sulfoxide, sulfonimide, sulfonamide, C1-C3 alkoxy, CN and acyl;

[0624] each m1 is independently 0, 1, 2 or 3; and

[0625] n' is 0, 1 or 2.

[0626] In those instances where n' is 2, each R A3' is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, CN, amino, C1-C6 alkylamino, -O(C1-C6 haloalkyl), oxy, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl optionally substituted with C1-C3 alkyl, C1-C6 hydroxyalkyl, aryl and heteroaryl.

[0627] In some examples of formula (3), R A1 is selected from C3-C7 heterocycloalkyl and heteroaryl, wherein the C3-C7 heterocycloalkyl and heteroaryl are optionally further substituted by 1 to 5 R as defined above f1 By way of other example, R A1 The alkyl radicals may be selected from C5-C7 heterocycloalkyl radicals containing at least one N ring atom (e.g., piperidinyl) and 5- to 6-membered heteroaryl radicals containing 1, 2 or 3 N ring atoms (e.g., pyrazolyl), both of which may be optionally further substituted by 1 to 5 R radicals as defined above. f1 Group substitution.

[0628] In some examples, the target protein binding ligand can be represented by the formula (EGFR3a):

[0629]

[0630] Among them, R A2 、R A3 ' and n' are as defined in Formula (EGFR3); and

[0631] R f1b is selected from H and C1-C6 alkyl (e.g., C1-C3 alkyl); and

[0632] R f1a Not present or halogen.

[0633] In some examples of Formula (EGFR3) or (EGFR3a), R A2 It may be a C1-C6 alkyl group (such as isopropyl).

[0634] In some examples of Formula (EGFR3) or (EGFR3a), R A3 ' may be selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C3-C7 heterocycloalkyl optionally substituted with C1-C3 alkyl, and -O(C1-C6 haloalkyl).

[0635] In some examples 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 group optionally substituted by a C1-C3 alkyl group.

[0636] In some examples of formula (3) or (3a), n' is 1 and R A3 ' is -O(C1-C6 haloalkyl).

[0637] The target protein binding ligand (TBL) represented by formula (EGFR3) and (EGFR3a) can be added to the linker L of the bifunctional molecule through a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker can be attached at any suitable position, for example, as long as it has the correct valence and / or is chemically suitable. For example, the linker of the bifunctional molecule can be covalently bonded to R of formula (EGFR3) or (EGFR3a) at any position. A3 ' part (as long as it has the correct valence and / or is chemically suitable). A3 In those instances where ' is not present, the linker of the bifunctional molecule may be covalently bonded to the heteroaryl ring as shown in Formulas (EGFR3) and (EGFR3a).

[0638] Representative examples of target protein binding ligands that can be incorporated into the bifunctional molecules described herein are shown below:

[0639]

[0640]

[0641] Wherein, L in the above structure represents the connection point of the linker. In addition, the present disclosure also covers the connection or coupling with the linker at any other chemically appropriate position on the target protein binding ligand.

[0642]

[0643] As above, the linker can be attached to the target protein binding ligand at any suitable position, for example, as long as it has the correct valency and / or is chemically suitable.

[0644] As shown in the above structure, the TBL moiety may contain one or more chiral centers. As previously stated, the present disclosure encompasses each individual enantiomer of these TBL moieties, as well as mixtures of enantiomers, including racemic mixtures of these enantiomers. By way of further example, when the TBL moiety contains two or more chiral centers, the present disclosure encompasses each individual diastereomer of the TBL moiety, as well as mixtures of multiple diastereomers.

[0645] By way of specific example, the target protein binding ligand that can be introduced into the bifunctional molecule described in the present disclosure can be represented as:

[0646]

[0647] KRAS

[0648] 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 can have the following structure:

[0649]

[0650] Wherein, L shows the connection position of the linker. In addition, the present disclosure also covers the connection or coupling with the linker at any other chemically suitable position on the target protein binding ligand.

[0651] 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 can have the following structure:

[0652]

[0653] Wherein, L shows the connection position of the linker. In addition, the present disclosure also covers the connection or coupling with the linker at any other chemically suitable position on the target protein binding ligand.

[0654] Thus, in some examples, the target protein binding ligand can be represented by the formula (KRAS1):

[0655]

[0656] in:

[0657] Ring A 1 represents an optionally substituted saturated or unsaturated 5- to 10-membered N-containing ring containing at least one further heteroatom selected from N, S and O and which is optionally bridged;

[0658] Ring B 1 represents an optionally substituted moiety selected from the group consisting of a 5- to 6-membered unsaturated ring having at least one heteroatom selected from N, S and O, a 6- to 10-membered (e.g., 6-membered) aromatic hydrocarbon ring, a C 3-6 Cycloalkene ring and 8 to 10 membered spiro ring, wherein ring B 1 fused with a pyrimidine ring to form a substituted or unsubstituted bicyclic ring;

[0659] n1 is 0 or 1;

[0660] X 1 is O or S;

[0661] Y 1is an optionally substituted moiety selected from the group consisting of a 6- to 10-membered aromatic hydrocarbyl ring and a 6- to 10-membered unsaturated monocyclic or bicyclic ring containing at least one heteroatom selected from N, S and O;

[0662] L 1 Absent or selected from O, optionally substituted C 2-3 Alkynylidene and NR c Any part of Z 1 yes:

[0663] (i) any one moiety selected from the group consisting of cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, optionally substituted C 3-6 Cycloalkyl, a 5- to 6-membered saturated ring containing at least one heteroatom selected from N, S and O, and an 8- to 10-membered partially unsaturated ring containing at least one heteroatom selected from N, S and O; or

[0664] (ii) any one moiety selected from the group consisting of hydrogen, -N(R C )2, heterocyclic group, 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 Halogenated alkyl, -D-OR C 、-D-(CH2OR C )(CH2) n OR C 、-D-NR C C(O)-aryl, -D-COOH, and -DC(O)OC 1-6 Alkyl, where -D-NR C The heterocyclyl and aryl portions of C(O)-aryl and the heterocyclyl and cycloalkyl portions of -D-heterocyclyl and -D-cycloalkyl may be optionally replaced by one or more R D substituted, and wherein the aryl or heteroaryl of the -D-aryl and the -D-heteroaryl may be optionally replaced by one or more R E wherein each D is independently C optionally substituted by hydroxy 1-4 Alkylene, C 1-4 hydroxyalkyl or heteroaryl; each R C are independently hydrogen or C 1-3 alkyl;

[0665] Each R D are independently halogen, hydroxy, C 1-3 Hydroxyalkyl, C 1-3Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, cyano, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C 1-3 Alkyl-substituted pyrazolyl, araC 1-3 Alkyl-, tert-butyldimethylsilyloxy CH2-, -N(R C )2、(C 1-3 Alkoxy) C 1-3 Alkyl-, (C 1-3 alkyl) C(O), oxy, (C 1-3 Halogenated alkyl) 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)heterocyclic, -CH2heterocyclic, wherein -NHC(O)phenyl or -OC(O)NH(C 1-3 alkyl)O(C 1-3 The phenyl group of the -CH2 heterocyclyl group is optionally substituted with oxygen;

[0666] Q is a bond or O;

[0667] Each R E are independently halogen, hydroxy, HC(O)-, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl or -N(R C )2; and

[0668] m1 is 0 to 3.

[0669] The linker may be attached to the structure of formula (1) at any suitable position, for example, at a position where valence allows for partial substitution or covalent addition of the linker. 1 The appropriate substitutions on the ligands are linked to TBL.

[0670] In some embodiments of Formula (KRAS1), when L 1 C 2-3 When alkynylene, Z 1 is alkylaminocarbonyl or alkylaminoalkyl, and m1 is 0 or 1.

[0671] In some embodiments of Formula (KRAS1), when Z 1 When defined as in (ii), m1 is 0.

[0672] Y of formula (KRAS1) 1 The optional substituents may be one or more substituents independently selected from the group consisting of halogen, 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, triazole, C 1-3 Haloalkyl, -OC 1-3 Halogenated alkyl, -SC 1-3 Halogenated alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, -CH2C(O)N(R C )2. -C 3-4 Alkynyl (NR C )2、-N(R C 2. Deuterated C 2-4 Alkynyl, (C 1-3 Alkoxy)halogenated C 1-3 Alkyl- and C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally substituted with halogen or C 1-3 Alkyl substitution.

[0673] The target protein binding ligand represented by formula (KRAS1) can be added to the linker L of the bifunctional molecule through a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker can be attached at any suitable position, for example, as long as it has the correct valence and / or is chemically suitable. For example, the linker of the bifunctional molecule can be covalently bonded to Z of formula (KRAS1) at any position. 1moiety (as long as it has the correct valence and / or is chemically suitable).

[0674] In some examples, the target protein binding ligand can be represented by the formula (KRAS2):

[0675]

[0676] in:

[0677] Ring A 1 represents an optionally substituted saturated or unsaturated 8- to 10-membered N-bridged ring containing at least one further heteroatom selected from N, S and O;

[0678] Ring B 1 represents an optionally substituted moiety selected from the group consisting of a 5- to 6-membered unsaturated ring having at least one heteroatom selected from N, S and O, a 6-membered aromatic ring, a C 3-6 Cycloalkene ring and 8 to 10 membered spiro ring, wherein ring B 1 fused with a pyrimidine ring to form a substituted or unsubstituted bicyclic ring;

[0679] n1 is 0 or 1;

[0680] X 1 is O or S;

[0681] Y 1 is an optionally substituted moiety selected from the group consisting of a 6- to 10-membered aromatic hydrocarbyl ring and a 6- to 10-membered unsaturated monocyclic or bicyclic ring containing at least one heteroatom selected from N, S and O;

[0682] L 1 is O or optionally substituted C 2-3 Alkynylidene;

[0683] Z 1 is any moiety selected from the group consisting of cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, optionally substituted C 3-6 Cycloalkyl, 5- to 6-membered saturated rings containing at least one heteroatom selected from N, S and O, and 8- to 10-membered partially unsaturated rings containing at least one heteroatom selected from N, S and O; and

[0684] m1 is 0 to 3 (for example, m1 is 0 or 1).

[0685] Suitably, the L or LZ of the degrading agent is linked to the Z1 moiety.

[0686] In some embodiments of Formula (KRAS2), when L 1 is optionally substituted C 2-3 When alkynylene, Z1 It is an alkylaminocarbonyl group or an alkylaminoalkyl group.

[0687] In some embodiments, the target protein binding ligand can be represented by the formula (KRAS3):

[0688]

[0689] in:

[0690] L 1 Does not exist or is selected from O and NR C any part of a group of persons;

[0691] Z 1 yes:

[0692] (ii) any one moiety selected from the group consisting of hydrogen, -N(R C )2, heterocyclic group, 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 Halogenated alkyl, -D-OR C 、-D-(CH2OR C )(CH2) n OR C 、-D-NR C C(O)-aryl, -D-COOH, and -DC(O)OC 1-6 Alkyl, among which heterocyclic and -D-NR C The aryl portion of C(O)-aryl, the heterocyclyl portion of -D-heterocyclyl, and the cycloalkyl portion of -D-cycloalkyl may be optionally replaced by one or more R D substituted, and wherein the aryl or heteroaryl of the -D-aryl and the -D-heteroaryl may be optionally replaced by one or more R E wherein each D is independently C optionally substituted by hydroxy 1-4 Alkylene, C 1-4 hydroxyalkyl or heteroaryl; each R C are independently hydrogen or C 1-3 alkyl;

[0693] Each R D are independently halogen, hydroxy, C 1-3 Hydroxyalkyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3Alkoxy, cyano, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C 1-3 Alkyl-substituted pyrazolyl, araC 1-3 Alkyl-, tert-butyldimethylsilyloxy CH2-, -N(R C )2、(C 1-3 Alkoxy) C 1-3 Alkyl-, (C 1-3 alkyl) C(O), oxy, (C 1-3 Halogenated alkyl) 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)heterocyclic, -CH2heterocyclic, wherein -NHC(O)phenyl or -OC(O)NH(C 1-3 alkyl)O(C 1-3 The phenyl group of the -CH2 heterocyclyl group is optionally substituted with oxygen;

[0694] Q is a bond or O;

[0695] Each R E are independently halogen, hydroxy, HC(O)-, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl or -N(R C )2;

[0696] R Iis aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 Alkyl, -SC 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkynyl, C 1-3 Cyanoalkyl, triazole, C 1-3 Haloalkyl, -OC 1-3 Halogenated alkyl, -SC 1-3 Halogenated alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, -CH2C(O)N(R C )2. -C 3-4 Alkynyl (NR C )2、-N(R C 2. Deuterated C 2-4 Alkynyl, (C 1-3 Alkoxy)halogenated C 1-3 Alkyl- or C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally halogenated or C 1-3 Alkyl substitution;

[0697] R II is hydrogen, halogen or C 1-3 Alkyl; and

[0698] R III It is hydrogen, hydroxyl, halogen, C 1-3 Alkyl, C 1-3 Cyanoalkyl, C 1-3 Hydroxyalkyl, HC(O)-, -CO2R C 、-CO2N(R C )2 or 5-6 membered heteroaryl.

[0699] Ring A of formula (KRAS1) 1

[0700] Ring A of formula (KRAS1) 1 represents an optionally substituted saturated or unsaturated 5- to 10-membered N-containing ring containing at least one further heteroatom selected from N, S and O and is optionally bridged. Ring A 1 Typically, A is an optionally substituted, optionally bridged, saturated 6- to 8-membered N-containing ring. 1 Contains two heteroatoms independently selected from N or O. Typically, both heteroatoms are N. In some cases, A 1is bridged, for example, by a methylene, ethylene, or propylene (typically methylene or ethylene) bridge, wherein the bridge is optionally substituted, for example, with one or more moieties selected from halogen and hydroxy. In some cases, Ring A 1 is an optionally substituted piperazine ring, which is optionally bridged between two carbon atoms of the ring.

[0701] In some instances, A 1 is an optionally substituted piperazine ring, optionally bridged between two carbon atoms of the ring, wherein the piperazine ring is optionally substituted at the nitrogen with hydroxy and at the carbon with one or more substituents selected from halogen, alkoxycarbonyl, cyano and hydroxyalkyl.

[0702] In some cases, Ring A 1 Having the formula (KRAS1a):

[0703]

[0704] in:

[0705] X 2 NH, N(C 1-6 alkyl), NOH or O;

[0706] n2' is 1 or 2;

[0707] R' is an optional substituent as defined above; and

[0708] n2 is 0 to 8, wherein, when n2 is 2 to 4, two R's may be linked to form a bridge between two different carbon atoms of the ring.

[0709] R' is typically a substituent independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 alkenyl, halogen, alkoxycarbonyl, cyano or hydroxyalkyl (e.g., C 1-6 alkyl). n2 is suitably 1 or 2. When n2 is 2, two R's may be linked to form a bridge between two different carbon atoms of the ring.

[0710] In some instances, A 1 Has the following formula:

[0711] in:

[0712] R' is one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Cyanoalkyl, C 1-3 Hydroxyalkyl, HC(=O)-, -CO2RC or -CO2N(R C )2; and n2 is 0 to 6;

[0713] And among them, R C As defined above for formula (KRAS3).

[0714] In some instances, A 1 Can be any part selected from the group consisting of:

[0715]

[0716] In some cases, A 1 is any ring selected from the group consisting of:

[0717]

[0718] For example, A 1 Can be Ring B of formula (KRAS1) 1

[0719] Ring B of formula (KRAS1) 1 represents an optionally substituted moiety selected from the group consisting of 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, a C 3-6 Cycloolefin and 8 to 10-membered spiro ring, wherein ring B 1 Fused with a pyrimidine ring to form a substituted or unsubstituted bicyclic ring.

[0720] Usually, B 1 is an optionally substituted moiety selected from a 5- to 6-membered saturated or unsaturated ring having at least one heteroatom selected from N and O, a benzene ring and C 5-6 Cycloolefins. Typically, B 1 It is 6 yuan. Sometimes, B 1 It is aromatic.

[0721] In some examples of Formula (KRAS1), B 1 yes:

[0722] (i) a 5- to 6-membered saturated or unsaturated ring containing at least one heteroatom (such as N or O) selected from the group consisting of N, S and O,

[0723] (ii) a 6- to 10-membered aromatic hydrocarbon ring,

[0724] (iii)C 3-6 Cycloalkenyl, or (iv) 8 to 10 membered spiro ring; wherein B 1 is fused with a pyrimidine ring to form a substituted or unsubstituted bicyclic ring; and wherein B in the bicyclic ring1 May be substituted with one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, alkylcarbonyl and 4- to 6-membered saturated monocyclic heterocyclic group containing one or more heteroatoms selected from N, S and O.

[0725] In some instances, B 1 is selected from the group consisting of benzene, piperidine, tetrahydropyrrole, cyclohexane, cyclohexene, tetrahydro-2H-pyran, 3,4-dihydro-2H-pyran and spiro[2.5]octane; and is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, alkylcarbonyl and oxetanyl.

[0726] In some instances, B 1 Selected from the group consisting of benzene, piperidine, tetrahydropyrrole, tetrahydro-2H-pyran and 3,4-dihydro-2H-pyran.

[0727] Sometimes, when B 1 When tetrahydropyrrole, n1 is 1 and X 1 is O or S, and when B 1 When it is not tetrahydropyrrole, n1 is 0.

[0728] Usually, B 1 is an optionally substituted 6-membered N-heteroaromatic ring, such as an optionally substituted pyridine ring.

[0729] In some cases, B 1 is any ring selected from the group consisting of:

[0730]

[0731] in:

[0732] n3 is 0 to 2;

[0733] n3' is 0 to 3; and

[0734] R a are optional substituents as defined above; and wherein, in these structures, a wavy line is shown over the bond forming the connection to the parent structure (as shown in Formulas (KRAS1), (KRAS2), and (KRAS3)).

[0735] Usually, B 1 The optional substituents are selected from halogen (such as fluorine or chlorine) and C 1-4 One or more parts of an alkyl group (such as methyl or ethyl). Typically, B 1 The optional substituents of are one or more moieties selected from fluorine, chlorine and ethyl. Typically, B1 is unsubstituted or substituted with fluorine.

[0736] In some cases, B 1 is any ring selected from the group consisting of:

[0737]

[0738] For example, B 1 Can be

[0739] Additionally, in any of the structures shown above, wavy lines are shown across the bonds forming connections to the parent structures (as shown in Formulas (KRAS1), (KRAS2), and (KRAS3)).

[0740] Part L of formula (KRAS1) 1 -(CH2) m1 -Z 1 :

[0741] L 1 is absent or is any moiety selected from the group consisting of: O, optionally substituted C 2-3 Alkynylidene and NR c , where R c As defined above in formula (KRAS1) or (KRAS3).

[0742] m1 is 0 to 3.

[0743] In some cases, L 1 is 0 and m1 is 1 or 2. Sometimes, L 1 is O and m is 1.

[0744] Z 1 yes:

[0745] (i) any one moiety selected from the group consisting of cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, optionally substituted C 3-6 Cycloalkyl, a 5- to 6-membered saturated ring containing at least one heteroatom selected from N, S and O, and an 8- to 10-membered partially unsaturated ring containing at least one heteroatom selected from N, S and O; or

[0746] (ii) any one moiety selected from the group consisting of: -N(R C )2, heterocyclic group, 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 Halogenated alkyl, -D-OR C、-D-(CH2OR C )(CH2) n OR C 、-D-NR C C(O)-aryl, -D-COOH, and -DC(O)OC 1-6 Alkyl, among which heterocyclic and -D-NR C The aryl portion of C(O)-aryl as well as the heterocyclyl portion of -D-heterocyclyl and the cycloalkyl portion of -D-cycloalkyl may be optionally replaced by one or more R D substituted, and wherein the aryl or heteroaryl of the -D-aryl and the -D-heteroaryl may be optionally replaced by one or more R E replace.

[0747] The linker of the degrader is attached to Z at any position 1 moiety (as long as it has the correct valence and / or is chemically suitable). For example, when Z 1 When an aromatic or heteroaromatic ring is included, the linker may replace a hydrogen atom at any position on the ring.

[0748] Each D is independently C optionally substituted with hydroxy 1-4 Alkylene, C 1-4 hydroxyalkyl or heteroaryl.

[0749] Each R C are independently hydrogen or C 1-3 alkyl.

[0750] Each R D are independently halogen, hydroxy, C 1-3 Hydroxyalkyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, cyano, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C 1-3 Alkyl-substituted pyrazolyl, araC 1-3 Alkyl-, tert-butyldimethylsilyloxy CH2-, -N(R C )2、(C 1-3 Alkoxy) C 1-3 Alkyl-, (C 1-3 alkyl) C(O), oxy, (C 1-3 Halogenated alkyl) 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(RC )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)heterocyclic, -CH2heterocyclic, wherein -NHC(O)phenyl or -OC(O)NH(C 1-3 alkyl)O(C 1-3 The phenyl group of the -CH2 heterocyclyl group is optionally substituted with -C(O)H or OH, and wherein the heterocyclyl group of the -CH2 heterocyclyl group is optionally substituted with oxo.

[0751] Q is a bond or O.

[0752] Each R E are independently halogen, hydroxy, HC(O)-, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl or -N(R C )2.

[0753] In some instances, Z 1 As defined in (i).

[0754] In these instances:

[0755] L 1 It can be O or substituted or unsubstituted C 2-3 Alkynyl; and

[0756] Z 1 It can be cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, C 3-6 Cycloalkyl, a 5- to 6-membered saturated ring containing at least one heteroatom selected from N, S and O, an 8- to 10-membered partially unsaturated ring containing at least one heteroatom selected from N, S and O; wherein, Z 1 The ring may be substituted by: halogen, hydroxyl, C 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3Methoxyalkyl, a substituted or unsubstituted 5- to 6-membered saturated ring containing at least one heteroatom selected from N, S and O and which may be replaced by C 1-3 alkyl, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl or cyanoalkyl.

[0757] Sometimes, when L 1 is 0, m1 is 0 or 1, and when L 1 It is C 2-3 In the case of alkynyl, m1 is 1 and Z1 is dimethylaminocarbonyl or dimethylaminomethyl.

[0758] In some instances:

[0759] L 1 It is O;

[0760] m1 is 0 or 1; and

[0761] Z 1 It is C 3-6 Cycloalkyl, a 5- to 6-membered saturated ring containing at least one heteroatom selected from N, S and O, an 8- to 10-membered partially saturated ring containing at least one heteroatom selected from N, S and O; wherein, Z 1 The ring in the can be substituted by: halogen, hydroxyl, C 1-6 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl or C substituted by a 5- to 6-membered saturated ring 1-6 Alkyl, said 5- to 6-membered saturated ring contains at least one heteroatom selected from N, S and O and may be further substituted by halogen.

[0762] In some instances:

[0763] L 1 It is O;

[0764] m1 is 1; and

[0765] Z 1 It is C 3-6 Cycloalkyl or a 5- to 6-membered saturated ring containing at least one heteroatom selected from N, S and O; wherein Z 1 The ring in the can be substituted by: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-3 Alkoxy, alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl or C substituted by a 5- to 6-membered saturated ring 1-6 Alkyl, said 5- to 6-membered saturated ring contains at least one heteroatom selected from N, S and O and may be additionally substituted by halogen.

[0766] In some instances, Z 1 yes:

[0767] (i) cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline or 1,2,3,4-tetrahydroisoquinoline, and may be substituted by halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-3 Alkoxy substitution; or

[0768] (ii) alkylcarbonylalkyl, hydroxyalkyl, dialkylamino, dialkylaminoalkyl, alkoxyalkyl, cyanoalkyl or C substituted with a 5- to 6-membered saturated ring 1-6 Alkyl, said 5- to 6-membered saturated ring contains at least one heteroatom selected from N and O and may be additionally substituted by halogen.

[0769] In some instances, Z 1 is cyclobutane, cyclopropane, piperidine, morpholine, piperazine, isoindoline or 1,2,3,4-tetrahydroisoquinoline, which may be substituted by halogen, hydroxyl, C 1-3 The alkyl group may be substituted with an alkoxy group, a methyl group, an ethyl group, an isopropyl group, an ethylcarbonylmethyl group, a hydroxyethyl group, a dimethylamino group, a dimethylaminomethyl group, a methoxyethyl group, a cyanomethyl group, a morpholinylmethyl group or a 3-fluoropyrrolidinylmethyl group.

[0770] In some instances, Z 1 As defined in (ii).

[0771] In some cases, L 1 is O, m1 is 0 and Z 1 It is C 1-6 Alkyl (such as methyl, ethyl, isopropyl or isobutyl) or optionally replaced by one or more R D Substituted-D-heterocyclyl (as defined above for formulae (KRAS1) and (KRAS3)).

[0772] Sometimes, D is methylene and the heterocyclyl is selected from the group consisting of hexahydro-1H-pyrrolopyrrolidinyl, hexahydro-3H-pyrrolopyrrolidin-3-one, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, hexahydropyrrolopyrrolidine 4(1H)-oxide, azetidinyl, pyrrolidinyl, pyrrolidin-2-one, oxetanyl, piperidinyl, 1-azabicyclo[2.2.1]heptyl, morpholinyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, thiopyranyl, 6-oxa-2-2λ 2 -azaspiro[3.4]octyl, 7-oxa-2λ 2-azaspiro[3.5]nonyl, 2',3'-dihydrospiro[cyclopropane-1,1'-indenyl], (2S)-1-azabicyclo[2.2.1]heptan-2-yl and tetrahydrofuranyl, each of which is optionally substituted by one or more R D replace.

[0773] Sometimes, D is methylene, and the heterocyclyl is optionally substituted by one or more R D Substituted hexahydro-1H-pyrrolopyrrolidinyl.

[0774] In some cases, the heterocyclyl is separated by one or more R D Substituted hexahydro-1H-pyrrolopyrrolidinyl, wherein R D independently selected from the group consisting of: halogen (such as fluorine), hydroxyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Alkyl, C 1-3 alkoxy, phenyl or pyrazolyl.

[0775] Sometimes, the heterocyclic group is D Hexahydro-1H-pyrrolopyrrolidinyl substituted by a group, these R D One of the groups is halogen (such as fluorine), hydroxyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Alkyl, C 1-3 alkoxy, phenyl or pyrazolyl, and two of them are independently C 1-3 alkyl.

[0776] Sometimes, the heterocyclic group is C 1-3 Alkyl-substituted azetidinyl.

[0777] In some cases, the heterocyclyl group is pyrrolidinyl substituted with any of the following moieties selected from the group consisting of hydroxyalkyl, haloalkyl, C 1-3 Alkyl, alkoxy, araC 1-3 Alkyl, -Q-phenyl and -NHC(O)phenyl, and wherein araC 1-3 The aryl portion of the alkyl group or the phenyl portion of -Q-phenyl and -NHC(O)phenyl are each optionally substituted with one or more R D , such as SO2F replacement.

[0778] The heterocyclic group may be a pyrrolidinyl group substituted with two groups, wherein the first group is C 1-3 Alkyl and the second group is C 1-3 Alkoxy or halogen.

[0779] Sometimes, the heterocyclic group is C 1-3 Alkyl-substituted pyrrolidin-2-ones.

[0780] In some cases, the heterocyclyl group is a piperidinyl group substituted with any one of the group consisting of: acetyl, (C 1-3 Alkoxy), C 1-3 Alkoxy or -C(O)CH2Cl.

[0781] Usually, L 1 is O, m1 is 0, D is ethylene or propylene, and heterocyclyl is morpholinyl or oxa-5-azabicyclo[2.2.1]heptan-5-yl.

[0782] Sometimes, L 1 is O, m1 is 0 and Z 1 is -D-heteroaryl, wherein the heteroaryl portion is optionally replaced by one or more R E D may be methylene or ethylene, and heteroaryl may be pyridyl, pyrazolyl, imidazolyl, triazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, benzimidazolyl, imidazo[1,2-a]pyridyl or pyrimidinyl, each optionally substituted by one or more R E Replace. R E Can be one or more independently selected from the group consisting of: halogen, C 1-4 Alkyl, -N(R C )2 or C 1-4 For example, heteroaryl can be C 1-4 Alkyl or -N(R C Alternatively, the heteroaryl group may be an imidazolyl group substituted with any one moiety selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 As another alternative, the heteroaryl group is replaced by C 1-4 Alkyl-substituted triazolyl.

[0783] In some cases, L 1 is O, m1 is 0 and Z 1 -D-aryl, wherein the aryl moiety is optionally replaced by one or more R E Substitution (as defined above for Formulas (KRAS1) and (KRAS3)).

[0784] In other cases, L 1 is O, m1 is 0 and Z 1 is -D-cycloalkyl, wherein the cycloalkyl portion is optionally replaced by one or more R ESubstitution (as defined above for Formulas (KRAS1) and (KRAS3)).

[0785] Sometimes, L 1 is O, m1 is 0 and Z 1 Yes-DN(R C )2. For example, D can be ethylene and each R C Can be independently selected from C 1-3 alkyl.

[0786] 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.

[0787] In other cases, L 1 is O, m1 is 0 and Z 1 Yes-DC 1-6 Alternatively, L 1 can be O, m1 can be 0 and Z 1 Can be -D-OR C As another alternative, L 1 can be O, m1 can be 0 and Z 1 It can be -D-(CH2OR C )(CH2) n OR C In addition, L 1 can be O, m1 can be 0 and R 2 Can be -D-NR C C(O)-aryl.

[0788] The portion of formula (KRAS1) -(C(X 1 )) n1 Y 1 :

[0789] In some cases, X 1 is 0. Sometimes, n1 is 0.

[0790] Y 1 is an optionally substituted moiety selected from the group consisting of a 6- to 10-membered aromatic hydrocarbon ring and a 6- to 10-membered unsaturated monocyclic or bicyclic ring containing at least one heteroatom selected from N, S, and O. For example, Y 1 It can be an optionally substituted 6 to 10 membered aromatic hydrocarbon ring, such as an optionally substituted moiety selected from naphthyl, phenyl, 1,2,3,4-tetrahydronaphthyl and 2,3-dihydro-1H-indenyl. 1 is substituted naphthyl, for example naphthyl substituted with one or more substituents selected from the group consisting of hydroxy, ethynyl, halogen (such as chlorine or fluorine), C 1-4 Alkyl and C 1-4Alkoxy.

[0791] In some instances, Y 1 is an 8- to 10-membered unsaturated bicyclic ring containing at least one heteroatom selected from N and S, or a 6- to 10-membered aromatic hydrocarbon ring; wherein the ring may be substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, C 1-6 Alkyl, C 2-3 Alkenyl, C 2-3 alkynyl and a 5- to 6-membered unsaturated monocyclic heterocyclic group containing one or more heteroatoms selected from the group consisting of N, S and O.

[0792] In some instances, Y 1 selected from the group consisting of benzene, naphthalene, benzo[b]thiophene, thieno[3,2-b]pyridine, isoquinoline, indole and indazole, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, C 1-6 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl and phenylthio.

[0793] In some cases, Y 1 is an optionally substituted heteroaryl, such as an optionally substituted moiety selected from the group consisting of isoquinazolyl, indazolyl, or benzo[d][1,3]dioxolyl. For example, Y 1 Can be halogen or C 2-4 Alternatively, Y 1 Can be chlorinated or C 1-3 As another alternative, Y 1 It may be benzo[d][1,3]dioxolyl substituted by two halogens.

[0794] In some cases, Y 1 Having the formula (KRAS1b):

[0795]

[0796] in:

[0797] X 3 Any one selected from the group consisting of: CH, CR b and N;

[0798] n4 is 0 to 4; and

[0799] R b are optional substituents described above.

[0800] The wavy lines in formula (1b) are shown on the bonds forming the connection to the parent structure (as shown in formula (1)).

[0801] Typically, n4 is 2 or 1 (e.g., 2). Typically, X 3 Is CH or CR b .

[0802] R b It may be any one or more substituents selected from the group consisting of: hydroxyl, C 2-4 Alkynyl (such as ethynyl), halogen (such as chlorine or fluorine), C 1-4 Alkoxy (such as methoxy), C 1-4 Alkyl, C 2-4 Haloalkynyl (such as haloethynyl), C 1-4 Halogenated alkyl, C 2-4 Alkenyl (such as vinyl), C 2-4 Halogenated alkenyl, C 1-4 Halogenated alkoxy (such as halogenated methoxy), C 3-4 Cycloalkyl (such as cyclopropyl), C 1-4 Alkenylol and amino groups. For example, R b It may be any one or more substituents selected from the group consisting of: hydroxyl, C 2-4 Alkynyl (such as ethynyl), halogen (such as chlorine or fluorine), C 1-4 Alkoxy (such as methoxy), C 1-4 Alkyl, C 2-4 Haloalkynyl (such as haloethynyl) and C 1-4 Halogenated alkyl.

[0803] In some instances, R b (or optional substituents) are any one or more substituents selected from the group consisting of halogen, 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, triazole, C 1-3 Haloalkyl, -OC 1-3 Halogenated alkyl, -SC 1-3 Halogenated alkyl, C 1-3 Alkoxy, hydroxy C 1-3 Alkyl, -CH2C(O)N(R 5 )2. -C 3-4 Alkynyl (NR 5 )2、-N(R 5 2. Deuterated C 2-4 Alkynyl, (C1-3 Alkoxy)halogenated C 1-3 Alkyl- and C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally substituted with halogen or C 1-3 Alkyl substitution.

[0804] In some instances:

[0805] A 1 Has the following formula:

[0806]

[0807] B 1 is benzene, piperidine or tetrahydropyrrole, each of which is optionally substituted with halogen or C 1-6 Alkyl substituted; wherein, when B 1 When it is tetrahydropyrrole, n1 is 1 and X 1 is O, and when B 1 When it is not tetrahydropyrrole, n1 is 0;

[0808] Y 1 It can be halogenated, hydroxylated, 1-6 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl-substituted naphthyl;

[0809] L 1 is O;

[0810] m1 is 1; and

[0811] Z 1 is cyclobutyl, cyclopropyl, piperidinyl, morpholinyl, piperazinyl, isoindolyl or 1,2,3,4-tetrahydroisoquinolinyl, each of which is optionally substituted by halogen, hydroxyl, C 1-3 The alkyl group may be substituted with an alkoxy group, a methyl group, an ethyl group, an isopropyl group, an ethylcarbonylmethyl group, a hydroxyethyl group, a dimethylamino group, a dimethylaminomethyl group, an alkoxyalkyl group, a cyanomethyl group, a morpholinylmethyl group or a 3-fluoropyrrolidinylmethyl group.

[0812] CBP and / or p300 inhibitors

[0813] In some cases, the target protein binding ligand can be derived from CBP and / or a p300 inhibitor. For example, the target protein binding ligand can have the following structure:

[0814]

[0815] Wherein, L shows the connection position of the linker. In addition, the present disclosure also covers the connection or coupling with the linker at any other chemically suitable position on the target protein binding ligand.

[0816] In some examples, the target protein binding ligand can be represented by formula (C1):

[0817]

[0818] in:

[0819] The linker portion of the divalent compound is connected to R B or R A ;

[0820] X A and X C are independently selected from C and N, provided that X A and X C At least one of them is C and X A and X C Only one or several of them are N;

[0821] X B Selected from CR XB1 , O and NR XB2 , where R XB1 is any substituent selected from the group consisting of: H, optionally substituted C 1-8 alkyl and an optionally substituted 3-10 membered carbocyclyl; and wherein R XB2 is absent or is any substituent selected from the group consisting of: H, optionally substituted C 1-8 alkyl and optionally substituted 3-10 membered carbocyclyl;

[0822] A A Not present or selected from the group consisting of: CR AA1 R AA2 , CO, O, S, SO, SO2 and NR AA1 , where R AA1 and R AA2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, 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 1-8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0823] 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 3-20 membered cycloalkyl or heterocyclyl ring (e.g., a 4-20 membered heterocyclyl ring);

[0824] A B is any substituent selected from the group consisting of aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, wherein each substituent is replaced by R A substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO2, OR AB1 SR AB1 NR AB1 R AB2 , OCOR AB1 、OCO2R AB1 、OCONR AB1 R AB2 、COR AB1 、CO2R AB1 、CONR AB1 R AB2 、SOR AB1 、SO2R AB1 、SO2NR AB1 R AB2 NR AB3 CO2R AB1 NR AB3 COR AB1 NR AB3 C(O)NR AB1 R AB2 NR AB3 SOR AB1 NR AB3 SO2R AB1 NR 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 C1-8 Alkoxy C 1-8 Alkyl, optionally substituted C 1-8 Alkylamino, optionally substituted C 1-8 Alkylamino C 1-8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0825] R AB1 、R AB2 and R AB3 are independently selected from 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 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0826] R AB1 and R AB2 or R AB1 and R AB3 Together with the atoms to which they are attached, they form a 4-20 membered heterocyclyl ring; R A Not present or selected from hydrogen, halogen, CN, NO2, OR A1 SR A1 NR A1 R A2 , OCOR A1 、OCO2R A1 、OCONR A1 R A2 、COR A1 、CO2R A1 、CONR A1 R A2 、SOR A1 、SO2R A1 、SO2NR A1 R A2 NR A3 CO2R A1 NR A3 COR A1 NR A3 C(O)NR A1 R A2 NR A3 SORA1 NR A3 SO2R A1 NR 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 1-8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0827] R A1 、R A2 and R A3 independently selected from hydrogen, optionally substituted C1-C8 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 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or R A1 and R A2 or R A1 and R A3 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

[0828] R B Not present or selected from the group consisting of: 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 、RB1 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 2-8 Alkenylene, optionally substituted C 2-8 Alkyne, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 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 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R B1 is absent or is a divalent moiety selected from the group consisting of: optionally substituted C 1-8 Alkylene, optionally substituted C 2-8 Alkenylene, optionally substituted C 2-8 Alkynylidene, optionally substituted C 1-8 Alkoxy C 1-8 Alkylene, optionally substituted C 1-8 Haloalkylene, optionally substituted C 1-8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 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 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0829] R B2 and R B3 are independently selected from the group consisting of: 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 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0830] R B2 and R B3 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and

[0831] R C Selected from 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 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0832] R C1 and R C2 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0833] R C1 and R C2 Together with the atoms to which they are attached they form a 4-20 membered heterocyclyl ring.

[0834] The target protein binding ligand represented in formula (C1) can be added to the linker L of the bifunctional molecule through a covalent bond between an atom on the target protein binding ligand (TBL) and an atom on the linker (L). The linker can be attached at any suitable position, for example, as long as it has the correct valence and / or is chemically suitable.

[0835] For example, the linker of the bifunctional molecule can be connected by R A or R B The group is covalently bonded to the TBL shown in formula (C1). For example, the linker can be covalently bonded to R A or R B An atom in any of the groups (so long as it has the correct valence and / or is chemically suitable) (e.g., by replacing a hydrogen atom).

[0836] In some examples, the linker is attached to R A In other examples, the linker is connected to R B .

[0837] For the avoidance of doubt, when it is specified to connect the connector to R A And R A Defined as absent, the linker is instead attached (e.g., covalently bonded) to A B Similarly, when it is specified that the connector be connected to R B And R B Defined as absent, instead a linker is attached (eg, covalently bonded) to X C .

[0838] In a more specific example, X A Is C and X B and X C are N, i.e. the compound has formula (C2):

[0839]

[0840] wherein the linker portion of the divalent compound is connected to R B or R A , and A A 、A B 、R A 、R B and R C As defined above for formula (C1).

[0841] A of formula (C1 and C2) A -A B -R A part

[0842] In some examples, A is represented by formula (C3) A -A B-R A part:

[0843]

[0844] in:

[0845] A A and R A As defined above for formula (C1);

[0846] X 4 Selected from CR X41 and N, where R X41 is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 1-6 alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0847] R AB4 Absent, optionally with A A forming a ring, or any one of the following moieties selected from the group consisting of hydrogen, halogen, 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 RAB7 、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 、R AB5 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 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R AB5 Absent or a divalent or trivalent moiety selected from the group consisting of: optionally substituted C 1-8 Alkylene, optionally substituted C 2-8 Alkenylene, optionally substituted C 2-8 Alkynylidene, 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 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0848] R AB6 、R AB7 and R AB8 are each independently absent or selected from the group consisting of 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 C1-8 Alkyl, optionally substituted C 1-8 Alkylamino C 1-8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0849] R AB6 and R AB7 or R AB6 and R AB8 Together with the atoms to which they are attached they form a 3-20 membered cycloalkyl or heterocyclyl ring.

[0850] In some cases, A A Does not exist.

[0851] In some examples, A is represented by formula (C4) or (C5) B -R A :

[0852]

[0853] Among them, R A As defined above. For the avoidance of doubt, when A A When absent, the bond bisected by the wavy line is connected to the central ring motif of formula (C1) or (C2). A When present, connect the bond bisected by the tilde to A A .

[0854] In some cases, A A It is NR AA1 , where R AA1 Selected from the group consisting of: 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 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0855] In some examples, A is represented by any one of formulas (C4) to (C8) A -A B -R A :

[0856]

[0857] Among them, R A As defined above.

[0858] In some examples, A is represented by any one of formulas (C6), (C7), and (C8). A -A B -R A , where R A As defined above for formula (C1).

[0859] In some instances, R A is selected from the group consisting of optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. A is aromatic. For example, R A can be selected from optionally substituted aryl (such as phenyl) and optionally substituted heteroaryl (such as pyrazolyl or pyridinyl). Sometimes, R A is an optionally substituted heteroaryl. For example, R A It may be selected from optionally substituted pyrazolyl (such as N-methylpyrazolyl) and optionally substituted pyridinyl.

[0860] In more specific examples, A is represented by any one of formulas (C9) to (C12). A -A B -R A :

[0861]

[0862] In even more specific examples, A is represented by any of the terms in formula (C9) A -A B -R A . In formulas (C1) to (C12): R of any item B part

[0863] As described above, R B Not present or selected from the group consisting of: 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 、RB1 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 2-8 Alkenylene, optionally substituted C 2-8 Alkyne, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 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 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl. As described above, in some instances, R B The "linker" portion that is attached to the bifunctional molecule.

[0864] In some instances, R B Selected from optionally substituted C 1-8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl. B is an optionally substituted 4-8 membered heterocyclyl. B is an optionally substituted 4-8 membered N-heterocyclyl, such as an optionally substituted 5-7 membered N-heterocyclyl. B is an optionally substituted 6-membered N-heterocyclyl, such as an optionally substituted piperidinyl. B is a piperidinyl group, wherein the piperidinyl group is bonded to the linker via a nitrogen atom.

[0865] R in any one of formulas (C1) to (C12) C part

[0866] As described above, R CSelected from 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 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0867] R C1 and R C2 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or R C1 and R C2 Together with the atoms to which they are attached they form a 4-20 membered heterocyclyl ring.

[0868] In some instances, R C Selected from the group consisting of: COR C1 and CONR C1 R C2 , where R C1 and R C2 As defined above. Sometimes, R C1 and R C2 are independently selected from the group consisting of hydrogen and optionally substituted C 1-6 Alkyl. For example, R C1 and R C2 can be independently selected from hydrogen and unsubstituted C 1-6 Alkyl (such as unsubstituted C 1-3 alkyl). In some cases, R C1 It is C 1-6 Alkyl (such as C 1-3 alkyl, for example, methyl) and R C2 is hydrogen. In some instances, R C Selected from COMe and CONHMe.

[0869] PARP

[0870] In other examples, the target protein binding ligand can be derived from a polymerase inhibitor, such as a PARP1 inhibitor. For example, the target protein binding ligand can have the following structure:

[0871]

[0872] Wherein, L shows the connection position of the linker. The present disclosure also covers the connection or coupling to the linker at any other chemically suitable position on the target protein binding ligand.

[0873] In other examples, the target protein binding ligand can be derived from a polymerase inhibitor, such as a POLQ inhibitor. For example, the target protein binding ligand can have the following structure:

[0874]

[0875] Wherein, L shows the connection position of the linker. The present disclosure also covers the connection or coupling to the linker at any other chemically suitable position on the target protein binding ligand.

[0876] In other examples, the target protein binding ligand can be derived from a deubiquitinase inhibitor, such as a USP1 inhibitor. For example, the target protein binding ligand can have the following structure:

[0877]

[0878] Wherein, L shows the connection position of the linker. The present disclosure also covers the connection or coupling to the linker at any other chemically suitable position on the target protein binding ligand.

[0879] Representative examples of possible target protein binding ligand moieties for each of the various target protein binding ligand classes are described below.

[0880] SMARCA2 / SMARCA4

[0881] In some cases, the target protein binding ligand may be derived from a SMARCA2 inhibitor. For example, the target protein binding ligand may have a structure as shown in Formula 1T:

[0882]

[0883] wherein the wavy line intersects the bond between the SMARCA2 / SMARCA4 binder and the linker; and wherein:

[0884] R 1T is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, hydroxyl, -COOR at 、-CON(R at)2. C6-C 10 Aryl or C5-C9 heteroaryl; wherein the alkyl, alkenyl, alkoxy, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, 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; R 2T Yes-NR 3T R 4T OR 3T ;

[0885] A T Not present or selected from O, CR 5T R 6T , optionally with one or more R 7T Substituted C6-C 10 Aryl, optionally substituted by one or more R 7T substituted 3 to 8 membered heteroaryl and optionally substituted by one or more R 8T substituted 3- to 8-membered heterocycloalkyl;

[0886] Each R 3T 、R 4T 、R 3T 、R 4T 、R 5T 、R 6T and R 7T independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

[0887] Each R 8T are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl and aryl; or R 3T and R 5T Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, COOR at and-OCOR at ; where each R at independently selected from hydrogen and C1-C4 alkyl; or

[0888] R 3T and an R 8TTogether with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and-OCOR at ; where each R at Independently selected from hydrogen and C1-C4 alkyl.

[0889] In some embodiments, R 1T is a C6-C 10 Aryl, said groups being independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and-OCOR at ; where each R at Independently selected from hydrogen and C1-C4 alkyl.

[0890] In some embodiments, R 1T is a C6-C 10 Aryl, said groups being independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl and amino.

[0891] In some embodiments, R 1T Is a group of the following structure:

[0892]

[0893] in:

[0894] mt is 0, 1, 2, 3, or 4;

[0895] R 9T Selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and-OCOR at ; where each R at independently selected from hydrogen and C1-C4 alkyl; and

[0896] Each R 10T independently selected from hydrogen, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and-OCOR at ; where each Rat independently selected from hydrogen and C1-C4 alkyl,

[0897] Among them, the wavy line and R 1 The bonds between T and the rest of the molecule intersect.

[0898] In some embodiments, R 1T Is a group of the following structure:

[0899]

[0900] in:

[0901] R 9T Selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and-OCOR at ; where each R at independently selected from hydrogen and C1-C4 alkyl; and

[0902] Each R 11T independently selected from hydrogen, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, -COOR at and-OCOR at ; where each R at independently selected from hydrogen and C1-C4 alkyl,

[0903] Among them, the wavy line and R 1 The bonds between T and the rest of the molecule intersect.

[0904] In some embodiments, R 1T Is a group of the following structure:

[0905]

[0906] Among them, the wavy line and R 1T and the bonds between the rest of the molecule intersect.

[0907] In some embodiments, R 2T Yes-NR 3T R 4T .

[0908] In some embodiments, A T Selected from CR 5T R 6T , optionally with one or more R 7T substituted 3 to 8 membered heteroaryl and optionally substituted by one or more R 8TSubstituted 3- to 8-membered heterocycloalkyl.

[0909] In some embodiments, A 1T is selected from 3- to 8-membered heteroaryl and 3- to 8-membered heterocycloalkyl.

[0910] In some embodiments, A 1T is selected from the group consisting of piperidinyl, piperazinyl, pyridinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, pyrazolyl, imidazolyl, imidazolidinyl and diazabicyclo[3.2.1]octyl.

[0911] In some embodiments, A 1T is selected from piperidinyl, pyrazolyl and diazabicyclo[3.2.1]octyl.

[0912] In some embodiments, mt is 0, 1, or 2.

[0913] In some embodiments, R 3T is selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0914] In some embodiments, R 3T is selected from hydrogen and C1-C4 alkyl.

[0915] In some embodiments, R 3T It's hydrogen.

[0916] In some embodiments, R 4T is selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0917] In some embodiments, R 4T is selected from hydrogen and C1-C4 alkyl.

[0918] In some embodiments, R 4T It's hydrogen.

[0919] In some embodiments, R 5T is selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0920] In some embodiments, R 5T is selected from hydrogen and C1-C4 alkyl.

[0921] In some embodiments, R 5T It's hydrogen.

[0922] In some embodiments, R 3T and R 5T Together with the atoms to which they are attached they form a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl.

[0923] In some embodiments, R 6Tis selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0924] In some embodiments, R 6T is selected from hydrogen and C1-C4 alkyl.

[0925] In some embodiments, R 6T It's hydrogen.

[0926] In some embodiments, R 7T is selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0927] In some embodiments, R 7T is selected from hydrogen and C1-C4 alkyl.

[0928] In some embodiments, R 7T It's hydrogen.

[0929] In some embodiments, R 8T is selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0930] In some embodiments, R 8T is selected from hydrogen and C1-C4 alkyl.

[0931] In some embodiments, R 8T It's hydrogen.

[0932] In some embodiments, R 3T and an R 8T Together with the atoms to which they are attached they form a 5- or 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl.

[0933] In some embodiments, R 9T is selected from the group consisting of hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl and amino.

[0934] In some embodiments, R 9T Selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy and amino.

[0935] In some embodiments, R 9T Selected from hydroxyl and amino.

[0936] In some embodiments, R 9T It is a hydroxyl group.

[0937] In some embodiments, each R 10T Independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl and amino.

[0938] In some embodiments, each R 10T Independently selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0939] In some embodiments, each R 10T are independently selected from halogen.

[0940] In some embodiments, each R 11T Independently selected from hydrogen, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl and amino.

[0941] In some embodiments, each R 11T Independently selected from hydrogen, halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0942] In some embodiments, each R 11T Independently selected from hydrogen, halo and C1-C4 alkyl.

[0943] In some embodiments, each R 11T are independently selected from hydrogen and halogen.

[0944] In some embodiments, the SMARCA binder has Formula 2T:

[0945]

[0946] wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and

[0947] in:

[0948] mt is 0, 1, 2, 3, or 4;

[0949] A 1T Selected from optionally one or more R 7T substituted 3 to 8 membered heteroaryl and optionally substituted by one or more R 8T substituted 3- to 8-membered heterocycloalkyl;

[0950] Each R 3T 、R 4T 、R 7T and R 8T R is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl; 9T is selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy and amino; and

[0951] Each R 10TIndependently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl and amino.

[0952] In some embodiments of the SMARCA binder of Formula 2T, mt is 0, 1, or 2;

[0953] A 1T is selected from 3- to 8-membered heteroaryl and 3- to 8-membered heterocycloalkyl;

[0954] R 3T and R 4T All are hydrogen;

[0955] R 9T is hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy and amino;

[0956] Each R 10T Independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0957] In some embodiments of the SMARCA binder of Formula 2T, mt is 0, 1, or 2;

[0958] A 1T is selected from the group consisting of piperidinyl, piperazinyl, pyridinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, pyrazolyl, imidazolyl, imidazolidinyl and diazabicyclo[3.2.1]octyl;

[0959] R 3T and R 4T All are hydrogen;

[0960] R 9T is hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy and amino;

[0961] Each R 10T Independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halo, C1-C4 alkyl and C1-C4 haloalkyl.

[0962] In some embodiments of the SMARCA binder of Formula 2T, mt is 0, 1, or 2;

[0963] A 1T is selected from piperidinyl, pyrazolyl and diazabicyclo[3.2.1]octyl;

[0964] R 3T and R 4T All are hydrogen;

[0965] R 9Tis hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy and amino;

[0966] Each R 10T Independently selected from hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0967] In some embodiments, the SMARCA binder has Formula 3T:

[0968]

[0969] wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and

[0970] in:

[0971] R 9T is hydroxy or amino; and

[0972] Each R 11T are independently selected from H and halogen.

[0973] In some embodiments, the SMARCA2 binding agent has Formula 4T:

[0974]

[0975] The wavy line intersects the bond between the SMARCA2 binder and the linker.

[0976] In some embodiments, the SMARCA2 binding agent has the formula 5T:

[0977]

[0978] wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein:

[0979] R 9T is hydroxy or amino; and

[0980] Each R 11T are independently selected from H and halogen.

[0981] In some embodiments, the SMARCA2 binding agent has Formula 6T:

[0982]

[0983] The wavy line intersects the bond between the SMARCA2 binder and the linker.

[0984] In some embodiments, the SMARCA2 binding agent has Formula 7T:

[0985]

[0986] wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein:

[0987] R 9T is a hydroxyl group or an amino group;

[0988] Each R 11T are independently selected from H and halogen.

[0989] In some embodiments, the SMARCA2 binding agent has Formula 8T:

[0990]

[0991] The wavy line intersects the bond between the SMARCA2 binder and the linker.

[0992] In some embodiments, the SMARCA2 binding agent has Formula 9T:

[0993]

[0994] wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein:

[0995] m is 0, 1, 2, 3, or 4;

[0996] R 4 is selected from hydrogen and C1-C4 alkyl;

[0997] R 9 selected from hydroxy, C1-C4 alkoxy and amino; and

[0998] Each R 10 is independently selected from hydroxy, C1-C4 alkoxy, halogen, C1-C4 alkyl and amino. In some embodiments of the SMARCA binder of Formula 9T,

[0999] mt is 0, 1, or 2;

[1000] R 4T It is hydrogen;

[1001] R 9T selected from hydroxy, C1-C4 alkoxy and amino; and

[1002] Each R 10T Independently selected from hydroxy, C1-C4 alkoxy, halogen and C1-C4 alkyl.

[1003] In some embodiments, the SMARCA2 binding agent has the formula 10T:

[1004]

[1005] wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein:

[1006] R 9T is hydroxy or amino; and

[1007] Each R 11T are independently selected from H and halogen.

[1008] In some embodiments, the SMARCA2 binding agent has the formula 11T:

[1009]

[1010] The wavy line intersects the bond between the SMARCA2 binder and the linker.

[1011] In some embodiments, the SMARCA2 binding agent has the formula 12T:

[1012]

[1013] wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and wherein:

[1014] m is 0, 1, 2, 3, or 4;

[1015] n is 0, 1, 2, or 3;

[1016] Each R 4T 、R 7T and R 8T independently selected from hydrogen and C1-C4 alkyl;

[1017] R 9T selected from hydroxy, C1-C4 alkoxy and amino; and

[1018] Each R 10T Independently selected from hydroxy, C1-C4 alkoxy, halogen, C1-C4 alkyl and amino.

[1019] In some embodiments of the SMARCA binder of Formula 12T,

[1020] mt is 0, 1, or 2;

[1021] nt is 0;

[1022] R 4T It is hydrogen;

[1023] R 9T selected from hydroxy, C1-C4 alkoxy and amino; and

[1024] Each R 10T Independently selected from hydroxy, C1-C4 alkoxy, halogen and C1-C4 alkyl.

[1025] In some embodiments, the SMARCA2 binding agent has the formula 13T:

[1026]

[1027] wherein the wavy line intersects the bond between the SMARCA2 binder and the linker; and

[1028] in:

[1029] R 9 is hydroxy or amino; and

[1030] Each R 11 are independently selected from H and halogen.

[1031] In some embodiments, the SMARCA2 binding agent has the formula 14T:

[1032]

[1033] The wavy line intersects the bond between the SMARCA2 binder and the linker.

[1034] I. Kinase and phosphatase inhibitors:

[1035] Examples of kinase inhibitors can be found in Jones et al., Small-Molecule Kinase Downregulators (2017, Cell Chem. Biol., 25: 30-35). Other kinase inhibitors that can be used according to some examples of the present disclosure include (but are not limited to):

[1036] 1. Erlotinib derivative tyrosine kinase inhibitors:

[1037]

[1038] wherein R is a linker, for example, connected via an ether group;

[1039] 2. Kinase inhibitor sunitinib (derivative):

[1040]

[1041] (derivatized, wherein R is a linker attached, for example, to a pyrrole moiety); 3. Kinase inhibitor Sorafenib (derivatized):

[1042]

[1043] (derivatized, wherein R is a linker attached, for example, to an amide moiety); 4. Kinase inhibitor dasatinib (derivatized):

[1044]

[1045] (derivatized, where R is a linker attached, for example, to a pyrimidine);

[1046] 5. Kinase inhibitor lapatinib (derivative):

[1047]

[1048] (derivatized, wherein the linker is attached, for example, via the terminal methyl group of a sulfonylmethyl group);

[1049] 6. Kinase inhibitor U09-CX-5279 (derivatized):

[1050]

[1051] derivatized, wherein the linker is attached, for example, via an amine (aniline), a carboxylic acid, or an amine or cyclopropyl group alpha to the cyclopropyl group;

[1052] 7. Kinase inhibitors identified in the following literature: Millan et al., Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease, (2011,). Med. Chem. 54:7797), including kinase inhibitors Y1W and Y1X (derivatized) having the following structures:

[1053]

[1054] (1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thiol}benzyl)urea derivatized, wherein the linker is attached, for example, via an isopropyl group;

[1055]

[1056] 1-(3-tert-Butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thiol}benzyl)urea

[1057] derivatized, wherein the linker is attached, for example, preferably via either an isopropyl or tert-butyl group;

[1058] 8. Kinase inhibitors identified in Schenkel et al., Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors (2011, J. Med. Chem., 54(24):8440-8450), including compounds 6TP and OTP (derivatized) having the following structures:

[1059]

[1060] 4-Amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide thienopyridine 19

[1061] derivatized, wherein the linker is attached, for example, via a terminal methyl group bound to an amide moiety;

[1062]

[1063] 4-amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide thienopyridine 8

[1064] derivatized, wherein the linker is attached, for example, via a terminal methyl group bound to an amide moiety;

[1065] 9. Kinase inhibitors identified in Van Eis et al., "2,6-Naphthyridines aspotent and selective inhibitors of the novel protein kinase C isozymes", (2011 Dec., Biorg. Med. Chem. Lett., 15, 21(24):7367-72), including the kinase inhibitor 07U having the following structure:

[1066]

[1067] derivatized with 2-methyl-N-1-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine, wherein the linker is attached, for example, via a secondary amine or a terminal amino group;

[1068] 10. Kinase inhibitors identified 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:

[1069]

[1070] derivatized, wherein the linker is attached, for example, via either terminal hydroxyl group;

[1071] 11. Kinase inhibitors identified in Lountos et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", (2011, J. Struct. Biol. 176292), including kinase inhibitors XK9 and NXP (derivatized) having the following structures:

[1072]

[1073] N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazone]phenyl}-7-nitro-1H-indole-2-carboxamide;

[1074]

[1075] derivatized with N-{4-[(1E)-N-carbamimidoylethanehydrazone]phenyl}-1H-indole-3-carboxamide, wherein the linker is attached, for example, via a terminal hydroxyl group (XK9) or a hydrazone group (NXP);

[1076] 12. The kinase inhibitor afatinib (derivatized) (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butyramide) (derivatized, wherein the linker is attached, for example, via an aliphatic amine group);

[1077] 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 hydrogen phosphate hexahydrate) (derivatized, wherein the linker is attached, for example, via a methoxy group);

[1078] 14. Kinase inhibitor gefitinib (derivatized) (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine):

[1079]

[1080] (derivatized, wherein the linker is attached, for example, via a methoxy or ether group);

[1081] 15. The kinase inhibitor Lenvatinib (derivatized) (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide) (derivatized, wherein the linker is attached, for example, via a cyclopropyl group);

[1082] 16. The kinase inhibitor vandetanib (derivatized)(N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized, wherein the linker is attached, for example, via a methoxy or hydroxy group);

[1083] 17. Kinase inhibitor Gleevec (also known as imatinib) (derivative):

[1084]

[1085] (derivatized, wherein R is a linker attached, for example, via an amide group or via an aniline amine group); 18. Kinase inhibitor Pazopanib (derivatized) (VEGFR3 inhibitor):

[1086]

[1087] (derivatized, where R is a linker attached, for example, to a phenyl moiety or via an aniline amine group);

[1088] 19. Kinase inhibitor AT-9283 (derivative), Aurora kinase inhibitor

[1089]

[1090] (wherein R is a linker attached, for example, to a phenyl moiety);

[1091] 20. Kinase inhibitor TAE684 (derivative) ALK inhibitor

[1092]

[1093] (wherein R is a linker attached, for example, to a phenyl moiety);

[1094] 21. Kinase inhibitors Nilotinib (derivative) Abl inhibitors:

[1095]

[1096] (derivatized, wherein R is a linker attached, for example, to a phenyl moiety or an aniline amine group); 22. Kinase inhibitor NVP-BSK805 (derivatized) JAK2 inhibitor

[1097]

[1098] (derivatized, wherein R is a linker attached, for example, to a phenyl moiety or an oxadiazole group); 23. AlK inhibitors derived from the kinase inhibitor crizotinib

[1099]

[1100] (derivatized, where R is a linker attached, for example, to a phenyl moiety or an oxadiazole group); 24. Kinase inhibitors JNJ FMS (derivatized) inhibitors

[1101]

[1102] (derivatized, wherein R is a linker attached, for example, to a phenyl moiety); 25. Kinase inhibitors Foretinib (derivatized) Met inhibitors

[1103]

[1104] (derivatized, where R is a linker attached, for example, to a hydroxyl or ether group on a phenyl or quinoline moiety);

[1105] 26. Allosteric protein tyrosine phosphatase inhibitor PTP1B

[1106] (derivative):

[1107]

[1108] derivatized, wherein, as indicated, a linker (e.g.) is attached at R;

[1109] 27. Inhibitors of the SHP-2 domain of tyrosine phosphatase (derivatized):

[1110]

[1111] derivatized, wherein a linker is attached, for example, at R;

[1112] 28. Inhibitors of BRAF (derivatized) (wt and / or mutant forms):

[1113]

[1114] derivatized, wherein the linker group is attached, for example, at R, for example, the kinase inhibitor vemurafenib (PLX4032) (derivatized) (propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide) (derivatized, wherein the linker is attached, for example, via a sulfonylpropyl group);

[1115] 29. Inhibitors of tyrosine kinase ABL (derivatized)

[1116]

[1117] Derivatized, wherein the linker (for example) is connected at R; 30. Kinase inhibitor OSI-027 (derivative) mTORCl / 2 inhibitor

[1118]

[1119] derivatized, wherein a linker is attached, for example, at R;

[1120] 31. Kinase inhibitor OSI-930 (derivative) c-Kit / KDR inhibitor

[1121]

[1122] Derivatized, wherein the linker (for example) is attached at R; and 32. Kinase inhibitor OSI-906 (derivatized) IGFIR / IR inhibitor

[1123]

[1124] derivatized, wherein a linker is attached, for example, at R;

[1125] (derivatized, wherein "R" represents the site for attachment of a linker on the piperazine moiety).

[1126] II. Compounds Targeting Human BET Bromodomain-Containing Proteins:

[1127] Compounds targeting proteins containing human BET bromodomains include, but are not limited to, compounds that bind to the targets described below, where the "R" surface is a site for linker attachment, for example: 1. JQI, Filippakopoulos et al., Selective inhibition of BET bromodomains. Nature (2010):

[1128]

[1129] 2. I-BET, Nicodeme et al., Supression of Inflammation by a SyntheticHistone Mimic. Nature (2010). Chung et al., Discovery and Characterization of SmallMolecule Inhibitors of the BET Family Bromodomains. J. Med. Chem. (2011):

[1130]

[1131] 3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. (2011, J. Med. Chem. 54: 6761-6770).

[1132]

[1133] 4.I-BET151, Dawson et al., Inhibition of BET Recruitment to Chromatin asan Effective Treatment for MLL-fusion Leukemia. Nature (2011):

[1134]

[1135] (wherein, in each case, R represents a site for linker attachment.)

[1136] BRD9

[1137] Representative examples of BRD9 targeting agents have been developed for several years and include those described in WO 2014 / 114721, WO 2016 / 077375, WO 2016 / 077378, WO 2016 / 139361, WO 2019 / 152440, Martin L.J. et al. (Journal of Medicinal Chemistry 2016, 59, 4462-4475), entitled “Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor”; Theodoulou N.H. et al. (Journal of Medicinal Chemistry 2015, 59, 1425-1439), entitled “Discovery of I-BRD9, a selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition”; and Clack et al. (Journal of Medicinal Chemistry 2015, 59, 1425-1439). Paper by P. et al. (Angewandte Chemie, 2015, 127, 6315-6319).

[1138] These BRD9 binding molecules (as referenced in the above paragraphs) can be introduced into the bifunctional molecules of the present disclosure as target binding ligands (TBLs).

[1139] The BRD9 binder may have the formula BRD91a:

[1140]

[1141] in:

[1142] Z 1 Is N or CR A ;

[1143] Z 2 Is N or CR B ;

[1144] Z 3 Is N or CR D ;

[1145] Z 4 Is N or CR E ;

[1146] Among them, Z 1 , Z 2 , Z 3 and Z 4No more than 3 of them are N;

[1147] R A and R E are independently selected from the group consisting of: -H, -OC 1-3 Alkyl and -C 1-3 alkyl;

[1148] R B and R D Each independently selected from the group consisting of: -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, 4-7 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 ;

[1149] R F Selected from -SO2-C 1-3 Alkyl and -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with a 5- to 6-membered heteroaryl group;

[1150] Alternatively, R A and R B Together they form a benzene ring;

[1151] 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) to form an optionally -C 1-3 Alkyl-substituted 5-7 membered heterocycloalkyl;

[1152] R C Selected from the group consisting of: -H, -YR G 、-NH2、-C 1-3 Alkyl and 4-7 membered heterocycloalkyl;

[1153] Y is absent or selected from the group consisting of: -CR H R I -, -SO2- and -CO-;

[1154] R H and R I are independently selected from -H or -C 1-3 Alkyl; or R H and R I Together form -C 3-4 Cycloalkyl, R G Selected from the group consisting of: -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ),-OR L , aryl, 5-6 membered heteroaryl, wherein the aryl and heteroaryl are optionally and independently substituted by one or more halogen, optionally substituted 4 to 7 membered monocyclic heterocycloalkyl and optionally substituted 7 to 12 membered bicyclic heterocycloalkyl, the monocyclic or bicyclic heterocycloalkyl is optionally substituted by any suitable substituent, such as one or more groups independently selected from the following: halogen, -OH, -NH2, -C 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl and -CH2-R M1 ;

[1155] R M1 Selected from 5-10 membered monocyclic or bicyclic aryl or heteroaryl, which is optionally substituted by -NH2, -OH, halogen, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl substitution;

[1156] R J Is -H or -C 1-3 alkyl;

[1157] R K Selected from the group consisting of: -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, said monocyclic or bicyclic heterocycloalkyl being optionally substituted by any suitable substituent, such as -C 1-3 alkyl;

[1158] R L -C 1-3alkyl or 4-7 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by C 1-3 Alkyl substituted; wherein, when R C YR G When R B and R D are independently selected from -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 to R E At least one of them is not hydrogen;

[1159] as well as

[1160] A 2 Selected from Formula 1b or 1c:

[1161]

[1162] Among them, the wavy lines intersect at A 2 With R A and R E Bonds between adjacent carbon atoms;

[1163] R M Selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclic group, C 2-6 Alkynyl and H;

[1164] Z 5 Is N or CR O ;

[1165] Z 6 Is N or CR P ;

[1166] Z 7 Is N or CR N ;

[1167] Among them, Z 5 , Z 6 and Z 7 Only one of them is N;

[1168] Z 8 It's CR W or N;

[1169] R N Selected from the group consisting of 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 heteroalkenyl and thiol;

[1170] R O Selected from the group consisting of: 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 heteroalkenyl, hydroxy, thiol, and optionally substituted amino; R P Selected from the group consisting of: 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 Combined together to form optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 heteroaromatic hydrocarbon; optionally wherein R N and R O Together with the carbon atoms to which they are attached, they form an optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 heteroaromatics;

[1171] R S Selected from the group consisting of: H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl and optionally substituted C 3-10 Carbocyclic group;

[1172] R T Selected from the group consisting of: 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 heteroalkenyl, optionally substituted sulfone and optionally substituted sulfonamide, or R T and R U Together with the atoms to which they are attached, they form an optionally substituted C 2-9 Heterocyclyl; R U and R V are independently selected from the group consisting of: H, halogen, hydroxy, 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 heteroalkenyl, thiol, optionally substituted sulfone, and optionally substituted amino;

[1173] Alternatively, R T and R U Together with the atoms to which they are attached, they form an optionally substituted C 2-9 heterocyclic group;

[1174] R W Selected from the group consisting of: 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 and optionally substituted C 2-9 heteroaryl;

[1175] and

[1176] The BRD9 binder is connected to the linker at any suitable position.

[1177] In some embodiments, Z of formula BRD91a1 , Z 2 , Z 3 and Z 4 No more than one of them is N. Sometimes, Z 1 CR A , Z 2 CR B , Z 3 N or CR D And Z 4 CR E , that is, only Z 3 Can be N. In these embodiments, the BRD9 binder can have the formula BRD91a':

[1178]

[1179] in:

[1180] R A 、R B 、R C 、R E , Z 3 and A 2 As defined above and herein.

[1181] A 2 Selected from formula BRD91b or BRD91c:

[1182]

[1183] Among them, the wavy lines intersect at A 2 With R A and R E The bond between adjacent carbon atoms, and Z 5 , Z 6 , Z 7 , Z 8 、R M 、R S 、R T 、R U and R V As defined above and herein.

[1184] Z 7 Is N or CR N And Z 5 Is N or CR O In some instances, R N (the carbon to which it is bonded) and Z 5 Together they can be combined to form optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 For the avoidance of doubt, when Z 5 N and R N(the carbon to which it is bonded) and Z 5 Combined together to form optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 Heteroaromatic hydrocarbons, R N (the carbon to which it is bonded) and Z 5 Combined together to form an optionally substituted NC 2-4 Heteroaromatic hydrocarbons. For example, when Z 5 When N, R N and N can combine to form optionally substituted NC 2-4 Heteroaryl groups, as shown below:

[1185]

[1186] Among them, the wavy lines intersect at A 2 With R A and R E The bond between adjacent carbon atoms, Z 6 and R M As defined above, and wherein 1B is optionally substituted NC 2-4 The heteroarene, such as an optionally substituted 5-membered heteroarene, for example, is selected from any one of the group consisting of optionally substituted pyrrole, imidazole, pyrazole and triazole (including 1,2,3 and 1,2,4-triazole).

[1187] In some instances, when Z 5 CR O And Z 7 CR N When R N and R O Together with the carbon to which they are bonded, they may combine to form optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 Heteroaromatic hydrocarbons, as shown below:

[1188]

[1189] Among them, the wavy lines intersect at A 2 With R A and R E The bond between adjacent carbon atoms, Z 6 and R M As defined above, and wherein, as described above, Ring 1C is an optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 Heteroarene. For example, Ring 1C may be an optionally substituted benzene or a 5-6 membered heteroarene, such as any one selected from the group consisting of optionally substituted benzene, pyridine, pyrrole, imidazole, pyrimidine, thiophene and pyrazole.

[1190] In some embodiments, R N (to the carbon atom to which it is attached) and Z 5 Together they can form a benzene ring or a 5-6 membered heteroaromatic hydrocarbon ring (for example, ring 1C can be a benzene ring or a 5-6 membered heteroaromatic hydrocarbon), each of which can be optionally and independently substituted by one or more groups selected from the following: halogen, -OH, -NH2, -NH-C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Halogenated alkyl, 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, wherein the -C 1-5 The alkyl group may be optionally substituted with a 5-6 membered heteroaryl group or a phenyl group; wherein 1d is: in,

[1191] Y 2 It is NR R or O;

[1192] Y 1 It is S(O) a or NR R ;

[1193] Each R R are independently H or C 1-4 alkyl;

[1194] Each R Q Independently selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and -C(O)C 1-3 alkyl;

[1195] a is 0 to 2; and

[1196] r is 0 to 3.

[1197] In some embodiments, Z 7 It's CR N , that is, A 2 Selected from formula BRD91b':

[1198]

[1199] Among them, the wavy lines intersect at A 2 With R A and R E The bond between adjacent carbon atoms, and Z 5 , Z 6、R M and R N As defined above and herein.

[1200] R M Can be selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclic group, C 2-6 Alkynyl and H. In some embodiments, R M Can be selected from the group consisting of: optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl and H. For example, R M Can be selected from the group consisting of: C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl and H. In some embodiments, R M Selected from the group consisting of: -C 1-5 Alkyl, -cyclopropyl, -C 1-4 Haloalkyl and H, such as C 1-5 In some embodiments, R M C 1-3 alkyl.

[1201] R N may be selected from the group consisting of 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 may be selected from the group consisting of halogen, optionally substituted C 1-6 Alkyl, H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 In some embodiments, R N Selected from the group consisting of: halogen, -C 1-5 Alkyl, -C 1-3Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 Alkyl and -OH. For example, R N Can be C 1-5 Alkyl or halogen.

[1202] Z 5 Can be N or CR O , where R O Selected from the group consisting of: 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 heteroalkenyl, hydroxyl, thiol and optionally substituted amino. For example, R O It can be H or optionally substituted C 1-6 Alkyl groups, such as C 1-3 In some embodiments, R O Can be H or -C 1-3 alkyl.

[1203] In some embodiments, R N -C 1-5 Alkyl or halogen, or R N and Z 5 Together they form an optionally substituted 5-6 membered heteroaromatic or benzene ring. In some embodiments, the optionally substituted 5-6 membered heteroaromatic ring may contain one or more heteroatoms selected from N, S and O, such as N and S, i.e., the optionally substituted 5-6 membered heteroaromatic ring may be an N- or S-heteroaromatic. In some embodiments, the optionally substituted 5-6 membered heteroaromatic ring is any one selected from the group consisting of optionally substituted pyrrole, imidazole, pyrimidine, thiophene and pyrazole.

[1204] For the avoidance of doubt, the optional substituents may be one or more groups selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Halogenated alkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, 1d, C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5Cycloalkyl, wherein the -C 1-5 The alkyl group may be optionally substituted with a 5-6 membered heteroaryl group or a phenyl group; wherein 1d is: in,

[1205] Y 2 It is NR R or O;

[1206] Y 1 It is S(O) a or NR R ;

[1207] Each R R are independently H or C 1-4 alkyl;

[1208] Each R Q Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and -C(O)C 1-3 alkyl;

[1209] a is 0 to 2; and

[1210] r is 0 to 3.

[1211] For example, the optional substituents may be independently selected from the group consisting of halogen, -OH, -NH2, -NH-C 1-3 Alkyl-C 1-5 Alkyl, C 1-5 Halogenated alkyl, C 1-5 Alkoxy and C 1-4 In some cases, the optional substituents may be independently selected from C1-C4 alkyl, allyl, butenyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Halogenated alkyl, C 3-5 In some embodiments, when R N and Z 5 Combined together to form optionally substituted C 6-10 Aryl or optionally substituted C 2-9 When heteroaryl, C 6-10 Aryl or C 2-9 The heteroaryl group is unsubstituted.

[1212] Z 6 Can be N or CR P , where R P Selected from the group consisting of: H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C3-10 Carbocyclyl and optionally substituted C 6-10 Aryl. For example, R P It can be H or optionally substituted C 1-6 Alkyl groups, such as H or C 1-6 In some embodiments, R P Is H or -C 1-3 Alkyl, i.e. Z 6 N, CH or CC 1-3 Alkyl. For example, Z 6 Can be CH or CC 1-3 alkyl.

[1213] In some embodiments, A 2 Selected from formula BRD91b', wherein formula BRD91b' is:

[1214] Among them, the wavy lines intersect at A 2 With R A and R E Bonds between adjacent carbon atoms;

[1215] R M Selected from the group consisting of: -C 1-5 Alkyl, -cyclopropyl, -C 1-4 Haloalkyl and H; R N Selected from the group consisting of: halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 Alkyl and -OH;

[1216] Z 5 Is N or CR O ;

[1217] Z 6 Is N or CR P , where Z 5 and Z 6 Only one of them can be N;

[1218] R O Is H or -C 1-3 alkyl;

[1219] R P Is H or -C 1-3 alkyl;

[1220] Among them, R O and R P Only one of them can be -C 1-3 alkyl;

[1221] Alternatively, R N and Z 5 Together they form a benzene ring or a 5-6 membered heteroaromatic ring, each of which may be optionally and independently substituted by one or more groups selected from halogen, -OH, -NH2, -NH-C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Halogenated alkyl, 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, wherein the -C 1-5 The alkyl group may be optionally substituted with a 5-6 membered heteroaryl group or a phenyl group; wherein 1d is: in,

[1222] Y 2 It is NR R or O;

[1223] Y 1 It is S(O) a or NR R ;

[1224] Each R R are independently H or C 1-4 alkyl;

[1225] Each R Q Independently selected from the group consisting of: C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and -C(O)C 1-3 alkyl;

[1226] a is 0 to 2; and

[1227] r is 0 to 3.

[1228] The BRD9 binder can be attached to the linker at any suitable position (as long as it has the correct valence and / or is chemically suitable). For example, the linker can be connected to the linker by an atom on the linker that forms R C 、R A 、R B 、R D or R E Alternatively, the linker may be directly attached to R C 、R A 、R B 、R Dand / or R E The bound ring, i.e. the linker, can replace R C 、R A 、R B 、R D or R E In some embodiments, the linker is formed by atoms on the linker and R C A covalent bond between atoms of a part or through an atom on the linker and R C Additionally, the covalent bond between the bound atoms is connected to the BRD9 binder, i.e., the linker replaces R C .

[1229] Alternatively, when 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) to form an optionally -C 1-3 When the alkyl group is a 5-7 membered heterocycloalkyl group substituted by an alkyl group, the linker can be attached to the BRD9 binding agent via a covalent bond between an atom on the linker and an atom forming part of the 5-7 membered heterocycloalkyl group.

[1230] In some embodiments, the BRD9 binding agent has the formula BRD91a 1 、BRD91a 2 、BRD91a 3 :

[1231]

[1232] Among them, the wavy line intersects the bond between the BRD9 binder and the linker;

[1233] A 2 , Z 1 , Z 2 , Z 3 and Z 4 As defined above and herein;

[1234] R C not existing or as defined above and herein;

[1235] and Ring 1A is optionally replaced by -C 1-3 Alkyl-substituted 5- to 7-membered heterocycloalkyl.

[1236] Ring 1A may contain one or two heteroatoms independently selected from N, S, and O. For example, Ring 1A may be selected from tetrahydropyrrole, piperidine, piperazine, morpholine, oxolane, oxirane, tetrahydrothiophene, and tetrahydrothiopyran. In some cases, Ring 1A may be an N-heterocycloalkane, such as tetrahydropyrrole, piperidine, or piperazine. In a specific embodiment, Ring 1A is tetrahydropyrrole.

[1237] For the avoidance of doubt, when a linker is formed by atoms on the linker and a feature on the BRD9 binder (such as R C ) is attached to the BRD9-binding agent by a covalent bond between atoms of a portion of a molecule, such as a molecule of ...

[1238] As another alternative, the linker can be formed by atoms on the linker and A 2 Atoms that are part of (e.g., forming R M 、R N 、R O 、R P 、R S 、R T 、R U 、R V or R W A covalent bond between an atom that is a part of R is connected to the BRD9 binder, or the linker can replace R M 、R N 、R O 、R P 、R S 、R T 、R U 、R V or R W Alternatively, when R N With Z 5 Combined together to form optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 When heteroaromatic; optionally wherein, R N With R O Together with the carbon atoms to which they are attached, they form an optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 Heteroaromatic hydrocarbons, wherein the linker can form an optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 A covalent bond between atoms of a portion of the heteroarene is attached to the BRD9 binding agent.

[1239] In an exemplary BRD9 binder, when R N With Z 5 When combined together to form an optionally substituted thiophene, the linker can be attached to a BRD9 binding agent as shown in the following structure:

[1240]

[1241] Among them, the wavy lines intersect at A 2 With R A and R E The bond between adjacent carbon atoms; and R M and Z 6 As defined above and herein.

[1242] A linker may be attached to an atom, thereby forming part of a substituent bonded at the same position as specified above. For example, a linker may be attached to an atom, thereby forming part of a substituent bonded at the same position as specified above. This is illustrated in the following structure, wherein R N and Z 5 Combined together to form an optionally substituted thiophene; the wavy line intersects at A 2 With R A and R E bonds between adjacent carbon atoms; and Y 2 It's O, Y 1 It's N, R R is H, and R Q and r is defined as above:

[1243]

[1244] As defined above, Z of a BRD9 binder 1 , Z 2 , Z 3 , Z 4 and R C It can be defined as follows:

[1245] Z 1 Is N or CR A ;

[1246] Z 2 Is N or CR B ;

[1247] Z 3 Is N or CR D ;

[1248] Z 4 Is N or CR E ;

[1249] Among them, Z 1 , Z 2 , Z 3 and Z 4 No more than 3 of them are N;

[1250] R A and R E are independently selected from the group consisting of: -H, -OC 1-3 Alkyl and -C 1-3 alkyl;

[1251] R B and R D Each independently selected from the group consisting of: -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, 4-7 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 ;

[1252] R F Selected from -SO2-C 1-3 Alkyl and -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with a 5- to 6-membered heteroaryl group;

[1253] 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 C and R D together with the carbon atom to which they are attached) to form an optionally -C 1-3 Alkyl-substituted 5-7 membered heterocycloalkyl; R C Selected from -H, -YR G 、-NH2、-C 1-3 Alkyl and 4-7 membered heterocycloalkyl;

[1254] Y is absent or selected from -CRH R I -, -SO2- and -CO-;

[1255] R H and R I are independently selected from -H or -C 1-3 Alkyl; or R H and R I Together form -C 3-4 Cycloalkyl, R G Selected from the group consisting of: -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ),-OR L , aryl, 5-6 membered heteroaryl, wherein the aryl and heteroaryl are optionally and independently substituted by one or more halogen, optionally substituted 4 to 7 membered monocyclic heterocycloalkyl and optionally substituted 7 to 12 membered bicyclic heterocycloalkyl, the monocyclic or bicyclic heterocycloalkyl is optionally substituted by any suitable substituent, such as one or more groups independently selected from the following: halogen, -OH, -NH2, -C 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl and -CH2-R M1 ;

[1256] R M1 Selected from 5-10 membered monocyclic or bicyclic aryl or heteroaryl, which is optionally substituted by -NH2, -OH, halogen, -CN, C 1-3 Alkyl, -OC 1-3 Alkyl substitution;

[1257] R J Is -H or -C 1-3 alkyl;

[1258] R K Selected from the group consisting of: -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 heterocycloalkyl and optionally substituted 7 to 12 membered bicyclic heterocycloalkyl, said monocyclic or bicyclic heterocycloalkyl being optionally substituted by any suitable substituent, such as -C 1-3 alkyl;

[1259] R L -C 1-3 alkyl or 4-7 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by C1-3 Alkyl substituted; wherein, when R C YR G When R B and R D are independently selected from -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 to R E At least one of them is not hydrogen.

[1260] In some examples of BRD9 binding ligands described herein (and unless otherwise specified): (i) R A 、R B 、R D and R E Independently selected from the group consisting of: -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 Independently selected from the group consisting of: -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, and R B and R C Together to form optionally -C 1-3 Alkyl-substituted 5- to 7-membered heterocycloalkyl.

[1261] In these embodiments, the 5-7 membered heterocycloalkyl group can be as defined above for Ring 1A.

[1262] In some embodiments, R A 、R B 、R D and RE Independently selected from the group consisting of: -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. For example, R A 、R B 、R D and R E Can be independently selected from -OC 1-3 Alkyl, -H, halogen, and -OC 1-3 Halogenated alkyl.

[1263] In some cases, R A 、R B 、R D and R E At least one of may be -H. For example, R A and R B At least one of may be -H. In a specific embodiment, R A 、R B 、R D and R E At least two of them are -H.

[1264] In some embodiments, R A 、R B 、R D and R E At least one of: 1-3 Alkyl, halogen and -OC 1-3 Sometimes, R B and R E Selected from the group consisting of: -OC 1-3 Alkyl, halogen and -OC 1-3 Halogenated alkyl.

[1265] In some embodiments, R C -H or -YR G Y can be -CR H R I - or -CO-, where R H and R I As defined above. H and R I Each of which can be -H; or R H and R ITogether they can form -C 3-4 Cycloalkyl.

[1266] R G It may be as defined above, or may be selected from the group consisting of: -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ),-OR L and optionally substituted 4 to 7 membered monocyclic heterocycloalkyl and optionally substituted 7 to 12 membered bicyclic heterocycloalkyl, wherein R J 、R K and R L and optional substituents are as defined above. J Can be -H or -C 1-3 Alkyl, and R K Can be selected from -C 1-3 alkyl, optionally substituted 4 to 7 membered monocyclic heterocycloalkyl and optionally substituted 7 to 12 membered bicyclic heterocycloalkyl. L Can be -C 1-3 alkyl.

[1267] When R G or R K When it is an optionally substituted 4 to 7 membered monocyclic heterocycloalkyl, the optionally substituted 4 to 7 membered monocyclic heterocycloalkyl may be a 5 to 7 membered monocyclic heterocycloalkyl containing 1 to 3 ring heteroatoms selected from N, O and S. In some examples, the optionally substituted 4 to 7 membered monocyclic heterocycloalkyl may be a 5 to 7 membered monocyclic heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N. In some examples, the optionally substituted 4 to 7 membered monocyclic heterocycloalkyl may be piperazinyl, piperidinyl or diazepanyl (each of which may optionally contain 1 to 3 substituents as described herein).

[1268] When R G or R K When being optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl, the optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl can be the bicyclic or spirocyclic bicyclic (i.e. it can be included in two rings connected in the center of spiral) of bridged connection. For example only, the optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl can be the piperazinyl of bridged connection or the piperidinyl of bridged connection. In other examples, the optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl can be the spirocyclic bicyclic heterocycloalkyl of optionally substituted, which comprises 1 to 3 ring heteroatoms selected from N, O and S (for example, 1 to 2 ring heteroatoms selected from N). In some instances, the optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl can be spirocyclic and comprises the first 5 or 6 rings and the second 3 to 6 rings.

[1269] In some instances, R C Can be any one of the following:

[1270]

[1271] Where Y is CR H R I (e.g., CH2);

[1272] R G1 and R G2 are independently selected from H and C1-C3 alkyl;

[1273] R J As defined above and herein; and

[1274] L shows the point of attachment of the linker.

[1275] In the structures shown above, both the Y and L groups can be attached to the heterocycle via covalent bonds between atoms on the Y and L groups and atoms on the heterocycle, respectively. These groups can be bonded to any chemically suitable position as long as the valence is satisfied (e.g., by replacing an H atom, respectively).

[1276] Only by other examples, R C Can be any one selected from the following:

[1277]

[1278] Where Y is CR H R I (e.g., CH2); and

[1279] L shows the point of attachment of the linker.

[1280] In a specific embodiment, R C is any one selected from the group consisting of: -CH2N(C 1-3 Alkyl)2, -C(O)N(C 1-3 alkyl)2, -C(CH2CH2)N(C 1-3 alkyl)2 and CH2OCH3, where the wavy line and R C and the bonds between the other parts of the BRD9 binder and R C and the bonds between the joints intersect.

[1281] In some embodiments, the BRD9 binding agent has the formula BRD91e, BRD91f, or BRD91g:

[1282]

[1283] Among them, the wavy line intersects the bond between the BRD9 binder and the linker;

[1284] R A 、R B 、R E 、R M 、R N , Z 3 , Z 5 and Z 6 As defined above;

[1285] R C does not exist, or as described above and herein for R C defined;

[1286] Ring 1A is optionally substituted with -C 1-3 Alkyl-substituted 5-7 membered heterocycloalkyl; and

[1287] Ring 1D is optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 Heteroaromatic hydrocarbons.

[1288] In some embodiments, ring 1D is an optionally substituted benzene or an optionally substituted 5-6 membered heteroaromatic hydrocarbon. The 5-6 membered heteroaromatic hydrocarbon may contain one or more heteroatoms selected from S, N and O, such as S. In some cases, ring 1D may be a 5-6 membered N-heteroaromatic hydrocarbon or an S-heteroaromatic hydrocarbon, for example, any one selected from thiophene, pyrazole, imidazole, pyrrole, pyrimidine and pyridine. In a specific example, ring 1D is a thiophene fused to the rest of the BRD9 binder at the 2' and 3' positions, and in an even more specific example, is a thiophene bonded to the linker by a covalent bond between an atom on the linker and a carbon atom at the 5' position of the thiophene. In these specific examples, the BRD9 binder may have the formula BRD91g':

[1289] wherein the wavy line intersects the bond between the BRD9 binder and the linker; and wherein R A 、R B 、R C 、R E 、R M , Z 3 and Z 6 As defined above.

[1290] In some embodiments, Ring 1A is a tetrahydropyrrole. In specific examples, Ring 1A is a tetrahydropyrrole fused to the remainder of the BRD9 binder at the 3' and 4' positions, and in even more specific embodiments, is a tetrahydropyrrole bonded to the linker via a covalent bond between an atom on the linker and the nitrogen atom of the tetrahydropyrrole. In these specific embodiments, the BRD9 binder can have the formula BRD91f':

[1291]

[1292] wherein the wavy line intersects the bond between the BRD9 binder and the linker; and wherein R A 、R E 、R M 、R N , Z 3 , Z 5 and Z 6 As defined above and herein.

[1293] In some embodiments, the BRD9 binding agent has the formula BRD91e, BRD91f', or BRD91g'.

[1294] In a specific embodiment, the BRD9-binding agent is any one of Formulas BRD91ea to BRD91eh, BRD91fa to BRD91fh, and BRD91ga:

[1295]

[1296]

[1297] Among them, the wavy line intersects the bond between the BRD9 binder and the linker;

[1298] R A 、R B 、R E 、R M , Z 3 and Z 6 As defined above and herein;

[1299] R C does not exist, or as defined above and herein;

[1300] R N As defined above and herein, for example, selected from the group consisting of: halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 Alkyl and -OH; R OAs defined above and herein, for example, -H or -C 1-3 alkyl;

[1301] Each R X For example, for R N and Z 5 (Together) the optionally substituted C 6-10 Aryl or optionally substituted C 2-9 The optional substituents of the heteroaryl group are defined as follows, for example, each R X Can be independently selected from halogen, -OH, -NH2, -NH-C 1-3 Alkyl-C 1-5 Alkyl, C 1-5 Halogenated alkyl, C 1-5 Alkoxy and C 1-4 haloalkoxy;

[1302] n is 0 to 3 (e.g., 0);

[1303] o is 0 to 2 (e.g., 0);

[1304] p is 0 or 1 (e.g., 0); and

[1305] q is 0 to 4 (eg, 0).

[1306] Each of n, o, p, and q may be 0.

[1307] In some embodiments, the BRD9 binding agent is according to the formula BRD91ea':

[1308]

[1309] Among them, the wavy line intersects the bond between the BRD9 binder and the linker;

[1310] R A and R E As defined above and herein, for example, independently selected from H and -OC 1-3 Alkyl; R B and R D As defined above and herein, for example, each independently selected from -OC 1-3 Alkyl, -H, -halogen, -C 1-3 Alkyl and -OC 1-3 alkyl halide;

[1311] R C Does not exist or is -YR G ;

[1312] Y is selected from the group consisting of: -CR H R I -and -CO-;

[1313] R H and R I are independently selected from -H or -C 1-3 Alkyl; or R H and R I Together form -C 3-4 Cycloalkyl; R G Selected from the group consisting of: -N(R J R K )(For example, -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;

[1314] R J and R K As defined above and herein;

[1315] R M As defined above and herein, for example, C 1-3 Alkyl; and

[1316] R N 、R O and R P Each as defined above and herein, for example, each independently selected from the group consisting of: halogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl.

[1317] In an even more specific embodiment, the BRD9 binding agent is any one of Formulas BRD91h to BRD91z and BRD92a to BRD92g:

[1318]

[1319]

[1320]

[1321] Among them, R C Does not exist or is -YR G ;

[1322] Y is selected from the group consisting of: -CR H R I -and -CO-;

[1323] RH and R I -H; or R H and R I Together form -C 3-4 Cycloalkyl;

[1324] R G Selected from the group consisting of: -N(R J R K )(For example, -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;

[1325] R J and R K As defined above and herein;

[1326] The wavy line intersects the bond between the BRD9 binder and the linker.

[1327] In specific examples of any of the above formulae (e.g., any of Formulae BRD91e, BR91g, BRD91g', BRD91ea to BRD91eh, BRD91ea', BRD91h to BRD91z, and BRD92a to BRD92g, and unless otherwise specified), R G -N(C 1-3 alkyl)-, -O- or

[1328] In some examples of any of the above formulae (e.g., any of Formulae BRD91e, BRD91g, BRD91g', BRD91ea to BRD91eh, BRD91ea', BRD91h to BRD91z, and BRD92a to BRD92g, and unless otherwise specified), R C It can be any one selected from the following:

[1329]

[1330] Where Y is CR H R I (e.g., CH2) or -CO-;

[1331] R H and R I As defined above and herein; and

[1332] L shows the point of attachment of the linker.

[1333] Specifically, in each of the structures shown above, Y can be CH2.

[1334] In some cases, a BRD9-binding agent may not be:

[1335]

[1336] The wavy line intersects the bond between the BRD9 binder and the linker.

[1337] III. Heat shock protein 90 (HSP90) inhibitors:

[1338] HSP90 inhibitors useful according to the present disclosure include, but are not limited to:

[1339] 1. HSP90 inhibitors identified in the following literature: Vallee et al., "Tricyclic Series of HeatShock Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90 Molecular Chaperone (2011,]. Med. Chem., 54:7206), including YKB (N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide):

[1340]

[1341] derivatized, wherein the linker is attached, for example, via a terminal amide group;

[1342] 2. HSP90 inhibitor p54 (modified) (8-[(2,4-dimethylphenyl)thiol]-3]pent-4-yn-1-yl-3H-purin-6-amine):

[1343]

[1344] wherein the linker is attached, for example, via a terminal ethynyl group;

[1345] 3. HSP90 inhibitors (modified) identified in Brough et al., "4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer", (2008,). 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) having the following structure:

[1346]

[1347] derivatized, wherein the linker is attached, for example, via an amide group (at the amine or an alkyl group on the amine);

[1348] 4. HSP90 inhibitors (modified) identified in the following literature: Wright et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, (2004 Jun., Chem. Biol. 11(6):775-85), including the HSP90 inhibitor PU3 having the following structure:

[1349]

[1350] wherein the linker group is attached, for example, via a butyl group; and

[1351] 5. 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 any derivative thereof (e.g., 17-alkylamino-17-demethoxygeldanamycin ("17-AAG") or 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin ("17-DMAG")) (derivatized, wherein A (e.g.) is linked via an amide group). IV. HDM2 / MDM2 inhibitors:

[1352] The HDM2 / MDM2 inhibitors of the present invention include (but are not limited to):

[1353] 1. HDM2 / MDM2 inhibitors 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 degradationinduced by a small molecule: En route to chemical proteomics, (2008, Biorg. Med. Chem. Lett., 18:5904-5908), including (or in addition to) the following compounds nutlin-3, nutlin-2 and nutlin-1 (derivatized) and all derivatives and analogs thereof:

[1354]

[1355] (derivatized, wherein the linker is attached, for example, at the methoxy group or as a hydroxyl group);

[1356]

[1357] (derivatized, wherein the linker is attached, for example, at a methoxy or hydroxy group);

[1358]

[1359] (derivatized, wherein the linker is attached, for example, via a methoxy group or as a hydroxyl group); and V. HDAC inhibitors:

[1360] HDAC inhibitors (derivatized) useful in some examples of the present disclosure include, but are not limited to:

[1361] 1.Finnin, MS et al., Structures of Histone Deacetylase Homologue Bound to the TSA and SAHA Inhibitors. (1999, Nature, 40: 188-193).

[1362]

[1363] (derivatized, wherein "R" represents a site for, for example, linker attachment; and 2. a compound as defined by formula (I) of PCT WO0222577 (the entire contents of which are incorporated herein by reference) ("deacetylase inhibitors") (derivatized, wherein the linker is attached, for example, via a hydroxyl group);

[1364] VI. Human lysine methyltransferase inhibitors:

[1365] Human lysine methyltransferase inhibitors useful in some embodiments of the present disclosure include, but are not limited to:

[1366] 1. Chang et al., Structural Basis for G9a-Like protein LysineMethyltransferase Inhibition by BIX-1294 (2009, Nat. Struct. Biol., 16(3):312).

[1367]

[1368] (derivatized, where "R" represents a site for, for example, linker attachment;

[1369] 2. Liu, F. et al., Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline asaPotent and Selective Inhibitor of Histone Methyltransferase G9a. (2009, J. Med. Chem., 52(24):7950).

[1370]

[1371] (derivatized, where "R" indicates a potential site for linker attachment);

[1372] 3. Azacitidine (derivatized) (4-amino-1-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (derivatized, wherein the linker is attached, for example, via a hydroxyl group or an amino group); and 4. Decitabine (derivatized) (4-amino-1-(2-deoxy-bD-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) (derivatized, wherein the linker is attached, for example, via a hydroxyl group or either of the amino groups).

[1373] VII. Angiogenesis Inhibitors:

[1374] Angiogenesis inhibitors useful in some aspects of the present disclosure include, but are not limited to:

[1375] 1. GA-1 (derivatized) and its derivatives and analogs having the structure described below and bound to a linker: Sakamoto et al., Development of Protacs to target cancer-promoting proteins forubiquitination and degradation, (2003 Dec., Mol. Cell Proteomics, 2(12):1350-1358);

[1376] 2. Estradiol (derivatized), which can be conjugated to a linker as generally described in Rodriguez-Gonzalez et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, (2008, Oncogene 27:7201-7211);

[1377] 3. Estradiol, testosterone (derivatized) and related derivatives, including but not limited to DHT and its derivatives and analogs, having the following structure and conjugated to a linker as generally described in Sakamoto et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, (2003 Dec., Mol. Cell Proteomics, 2(12): 1350-1358); and

[1378] 4. Ovopseudocalcin, fumagillin (derivatized) and derivatives and analogs thereof having the following structures and conjugated to linkers as generally described 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. Pat. No. 7,208,157, the entire contents of which are incorporated herein by reference.

[1379] VIII. Immunosuppressive compounds:

[1380] Immunosuppressive compounds useful in some embodiments of the present disclosure include, but are not limited to:

[1381] 1. AP21998 (derivatized), having a structure as generally described in Schneekloth et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation (2004, J. Am. Chem. Soc., 126: 3748-3754) and conjugated to a linker;

[1382] 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (derivatized, wherein the linker is attached, for example, to any hydroxyl group) and beclomethasone dipropionate (derivatized, wherein the linker is attached, for example, to the propionate salt);

[1383] 3. Methotrexate (derivatized, wherein the linker can be attached, for example, to any terminal hydroxyl group); 4. Cyclosporine (derivatized, wherein the linker can be attached, for example, to the butyl group);

[1384] 5. Tacrolimus (FK-506) and rapamycin (derivatized, wherein a linker group may be attached, for example, at one of the methoxy groups); and

[1385] 6. Actinomycin (derivatized, where a linker may be attached, for example, at one of the isopropyl groups).

[1386] IX. Compounds targeting the aryl hydrocarbon receptor (AHR):

[1387] Compounds targeting the aryl hydrocarbon receptor (AHR) according to some examples of the present disclosure include (but are not limited to):

[1388] 1. Apigenin (derivatized in a manner conjugated to a linker as generally described in Lee et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Vol. 8, No. 17, pp. 2058-2062, November 23, 2007); and

[1389] 2. SRI and LGC006 (derivatized to allow linker attachment) as described below; Boitano et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells (2010 Sep., Science, 329(5997):1345-1348).

[1390] XI. Compounds targeting FKBP:

[1391]

[1392] (derivatized, where "R" represents the linker attachment site).

[1393] XIV. Compounds Targeting Thyroid Hormone Receptor (TR)

[1394] 1. Thyroid hormone receptor ligand (derivatized)

[1395]

[1396] (derivatized, wherein "R" represents the linker attachment site and MOMO represents a methoxymethoxy group).

[1397] XV. Compounds Targeting HIV Protease

[1398] 1. HIV protease inhibitors (derivatives)

[1399]

[1400] (Derivatized, where "R" represents the linker attachment site). See, 2010, J. Med. Chem., 53: 521-538.

[1401] 2. HIV protease inhibitors

[1402]

[1403] (Derivatized, where "R" indicates a potential site for linker attachment.) See, 2010, J. Med. Chem., 53: 521-538.

[1404] XVI. Compounds Targeting HIV Integrase

[1405] 1. HIV integrase inhibitors (derivatives)

[1406]

[1407] (Derivatized, where "R" represents the linker attachment site). See, 2010, J. Med. Chem., 53: 6466.

[1408] 2. HIV integrase inhibitors (derivatives)

[1409]

[1410] 3. HIV integrase inhibitor Isentress (derivative)

[1411]

[1412] (Derivatized, where "R" represents the linker attachment site). See, 2010, J. Med. Chem., 53: 6466.

[1413] XVII. Compounds Targeting HCV Protease

[1414] 1. HCV protease inhibitors (derivatives)

[1415]

[1416] (derivatized, where "R" represents the linker attachment site).

[1417] XVIII. Compounds Targeting Acyl Protein Thioesterases 1 and 2 (APT1 and APT2) 1. Inhibitors of APT1 and APT2 (Derivatized)

[1418]

[1419] (Derivatized, where "R" represents the linker attachment site). See, 2011, Angew. Chem. Int. Ed., 50: 9838-9842.

[1420] XIX. Compounds Targeting Ubiquitin-Specific Protease 1 (Usp1)

[1421] Additional examples of USP1 binding ligands are provided below.

[1422] Compounds represented by formula USP1A, USP2A or USP3A:

[1423]

[1424] in:

[1425] A is aryl or heteroaryl, each optionally substituted by any one or more substituents selected from the group consisting of: C 1-4Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 3-7 Cyclohaloalkyl, C 1-4 haloalkoxy, halogen, hydroxy, and amino;

[1426] B is a heteroaryl group containing at least one N ring atom, which is optionally substituted with any one or more substituents selected from the group consisting of: C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4 haloalkoxy, halogen, hydroxy, and amino;

[1427] R 1 and R 1 ' are independently selected from H and C 1-2 alkyl;

[1428] n is 1 to 3;

[1429] Y is an aryl or heteroaryl group, each of which is optionally substituted by any one or more selected from the group consisting of: C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 3-7 Cyclohaloalkyl, C 1-4 haloalkoxy, halogen, hydroxy, and amino;

[1430] R 2 and R 4 are independently selected from the group consisting of: H and C 1-4 alkyl;

[1431] R 3 Select from the group consisting of: LZ or C 1-4 Alkyl-LZ;

[1432] X 1 and X 2 Each independently selected from the group consisting of: N, CLZ and CR 5 , where R 5 is selected from the group consisting of: H and C1-C4 alkyl; and wherein X 1 and X 2 One of them is CLZ;

[1433] Among them, The bonds shown indicate whether the bond is a single or double bond;

[1434] Wherein, when the bond is a double bond, X 3 and X 4 Independently selected from the group consisting of: CL-Z and CR 6 ; and wherein X 3 and X 4 One is CLZ; and

[1435] Wherein, when the bond is a single bond, X 3 and X 4 Independently selected from the group consisting of: CR 6 LZ and CR 6 2, and where X 3 and X 4 One of them is CR 6 LZ;

[1436] Among them, each R 6 Independently selected from the group consisting of: H, C 1-4 Alkyl, NH2, NHMe and NMe2;

[1437] X 5 is N or CH;

[1438] X 6 Selected from C=O, CR 7 2. NH and NMe, where each R 7 Independently selected from the group consisting of: H and C 1-4 alkyl;

[1439] X 7 is N or CH;

[1440] L is a Linker (as defined above); and

[1441] Z is as defined above and herein.

[1442] In some cases, the compound targeting Usp1 is a compound represented by formula USP1, USP2, or USP3:

[1443]

[1444] in:

[1445] A is an aryl group or a heteroaryl group, each of which is optionally substituted by any one or more selected from the group consisting of: C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C3-7 Cyclohaloalkyl, C 1-4 haloalkoxy, halogen, hydroxy, and amino;

[1446] B is a heteroaryl group comprising at least one N ring atom, which is optionally substituted with any one or more selected from the group consisting of: C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4 haloalkoxy, halogen, hydroxy, and amino;

[1447] R 1 and R 1 ' are independently selected from H and C 1-2 alkyl;

[1448] n is 1 to 3;

[1449] R 2 and R 4 are independently selected from the group consisting of: H and C 1-4 alkyl;

[1450] R 3 Select from the group consisting of: LZ or C 1-4 Alkyl-LZ;

[1451] X 1 and X 2 Each independently selected from the group consisting of: N, CLZ and CR 5 , where R 5 is selected from the group consisting of: H and C1-C4 alkyl; and wherein X 1 and X 2 One of them is CLZ;

[1452] X 3 and X 4 Independently selected from the group consisting of: CR 6 LZ and CR 6 2, where each R 6 Independently selected from the group consisting of: H and C 1-4 alkyl; and wherein X 3 and X 4 One of them is CR 6 LZ;

[1453] X 7 is N or CH;

[1454] L is a Linker (as defined above and herein); and

[1455] Z is as defined above and herein.

[1456] By way of other example, the compound targeting Usp1 may comprise a compound represented by formula USP1a, USP2a or USP3a:

[1457]

[1458] Among them, 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.

[1459] The groups A, B, Y, and X are provided below. 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, which apply to any one or more of the formulae described herein with respect to compounds targeting Usp1 (unless otherwise indicated) (Formulae USP1A, USP2A, USP3A, USP1, UPS2, UPS3, USP1a, USP2a, and USP3a).

[1460] As mentioned above, A may be an aryl group or a heteroaryl group, each of which is optionally substituted by any one or more selected from the group consisting of: C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 3-7 Cyclohaloalkyl, C 1-4 haloalkoxy, halogen, hydroxy and amino. For the avoidance of doubt, when A is heteroaryl, it is optionally substituted at one or more carbon or heteroatoms.

[1461] When A is a heteroaryl group, it may contain one or more nitrogen atoms, such as two nitrogen atoms. Sometimes, the heteroaryl group is monocyclic. Sometimes, the heteroaryl group is an N-heteroaryl group.

[1462] In some examples, A is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, optionally substituted with any one or more substituents selected from the group consisting of: C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 3-7 Cyclohaloalkyl, C 1-4 Haloalkoxy, halogen, hydroxy and amino.

[1463] By way of further example, A may be selected from the group consisting of phenyl, pyrimidinyl, and pyrazolyl, optionally substituted with any one or more substituents selected from the group consisting of: 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 1-4 Fluorinated alkyl, such as trifluoromethyl), C 3-7 Cyclohaloalkyl (e.g., C 3-7 Cyclofluoroalkyl), C 1-4 Haloalkoxy (e.g., C 1-4 By way of even further example, A may be selected from the group consisting of phenyl, pyrimidinyl and pyrazolyl, optionally substituted with any one or two substituents selected from the group consisting of: 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 Sometimes, A is selected from the group consisting of phenyl and pyrimidinyl, which are optionally substituted with any one or two substituents selected from the group consisting of: C 1-4 Alkyl (e.g., isopropyl), C 3-7 Cycloalkyl (e.g., cyclopropyl) and C 1-4 In some examples, A can be selected from N-alkyl, 4-alkylpyrazolyl, 4,6-dialkylpyrimidinyl, and 2,4-dialkylpyridinyl (wherein each alkyl group is C 1-4 alkyl).

[1464] Representative examples of suitable A groups include, but are not limited to:

[1465] Among them, RC Selected from the group consisting of methoxy, cyclopropyl and difluoromethoxy.

[1466] Among them, R A It is methyl, ethyl, fluoro or difluorotrifluoroethyl.

[1467] In the structures shown above, the lines intersecting the wavy lines represent covalent bonds between the exemplary A groups shown above and carbon atoms on the heteroaryl core that are attached to the A groups (as shown in the various formulae described herein). Although specific substitution patterns are shown in the exemplary aryl and heteroaryl structures above, it is understood that other substitution patterns are also contemplated within the scope of this disclosure.

[1468] As described above, B is a heteroaryl group containing at least one N ring atom, which is optionally substituted with any one or more selected from the group consisting of: C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4 haloalkoxy, halogen, hydroxy and amino. For the avoidance of doubt, B is optionally substituted at one or more carbon or heteroatoms.

[1469] In some instances, B is a monocyclic five-membered or six-membered heteroaryl group containing at least one N ring atom (e.g., containing 1, 2, or 3 N ring atoms). By way of further example, B can be selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, and oxadiazolyl, optionally substituted with any one or more substituents selected from the group consisting of: C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4 Halogenated alkoxy, halogen, hydroxyl and amino. Typically, B is a monocyclic 5-membered heteroaryl. Sometimes, B contains at least 2 nitrogen atoms. By way of other example, B can be selected from the group consisting of: imidazolyl, pyrazolyl and triazolyl (e.g., 1,2,3-triazolyl), which is optionally substituted with any one or more substituents selected from the group consisting of: C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cyclohaloalkyl, C 1-4In some examples, B can be selected from the group consisting of imidazolyl, pyrazolyl, and triazolyl (e.g., 1,2,3-triazolyl), optionally substituted with any one or more substituents selected from the group consisting of C 1-4 Alkyl (e.g., isopropyl, methyl or ethyl), C 1-4 Haloalkyl (e.g., trifluoromethyl or fluoroethyl) and C 1-4 Alkoxy (such as methoxy).

[1470] Representative examples of suitable B groups include, but are not limited to:

[1471]

[1472] Among them, Q A is selected from the group consisting of methyl, isopropyl, ethyl, fluoroethyl and methoxy;

[1473]

[1474] Among them, Q E Selected from isopropyl, methyl, ethyl and fluoroethyl.

[1475] In the structures shown above, the lines intersecting the wavy lines represent covalent bonds between the exemplary B groups shown above and the carbon atoms on the aryl core to which the B groups are attached (as shown in the various formulae described herein). Although specific substitution patterns are shown in the exemplary heteroaryl structures above, it will be understood that other substitution patterns are also contemplated within the scope of this disclosure.

[1476] As mentioned above, Y may be an aryl group or a heteroaryl group, each of which is optionally substituted with any one or more selected from the group consisting of: C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 3-7 Cyclohaloalkyl, C 1-4 Haloalkoxy, halogen, hydroxy and amino.

[1477] For the avoidance of doubt, Y is the combination of B and CR 1 R 1 ' connected diradicals. With respect to Y, any reference to a monovalent group is intended to indicate a diradical capable of connecting B to CR 1 R 1 ' connected diradicals. For example, the reference to phenyl represents the connection of B with CR 1 R 1 'Connected diphenyl.

[1478] Typically, when Y is phenyl, B and CR 1 R1 'They are in opposition to each other.

[1479] Typically, when Y is a heteroaryl, it is a monocyclic 6-membered heteroaryl. The heteroaryl group is typically an N-heteroaryl group containing at least one nitrogen atom. Typically, the N-heteroaryl group contains two nitrogen atoms.

[1480] For example, Y can be phenyl, pyrimidinyl (such as pyrimidine-1,5-diyl) or pyridinyl, which is optionally selected from halogen and C 1-4 The alkoxy group is substituted with any one or more substituents.

[1481] Representative examples of Y include (but are not limited to):

[1482]

[1483] Among them, Z A is selected from H and halogen (eg, F); and Z C selected from H and methoxy; and

[1484]

[1485] As mentioned above, R 1 and R 1 ' are independently selected from H and C 1-2 For example, R 1 and R 1 ' can be H respectively.

[1486] As described above, n can be 1 to 3. In some examples, n is 1.

[1487] As mentioned above, R 2 and R 4 are independently selected from the group consisting of: H and C 1-4 For example, R 2 and R 4 Both can be H.

[1488] When n is 1 and R 1 、R 1 '、R 2 and R 4 In those instances where each of is H, the bifunctional molecule may comprise a compound of formula USP1a, USP2a, or USP3a:

[1489]

[1490] Among them, A, B, R 3 、X 1 、X 2 and X4 As defined above (and herein) for Formulas USP1, USP2 and USP3.

[1491] With respect to Formula USP2 (and Formula (USP2a), as previously described), X 1 and X 2 Each independently selected from the group consisting of: N, CLZ and CR 5 , where R 5 is selected from the group consisting of: H and C1-C4 alkyl; and wherein, X 1 and X 2 One of them is CLZ.

[1492] In X 1 In those cases where it is CLZ, X 2 Can be N or CR 5 , where R 5 is selected from the group consisting of: H and C1-C4 alkyl (eg, methyl). 1 In some instances of CLZ, X 2 It can be CH.

[1493] In X 2 In those cases where it is CLZ, X 1 Can be N or CR 5 , where R 5 is selected from the group consisting of: H and C1-C4 alkyl (eg, methyl). 2 In some instances of CLZ, X 2 It can be CH.

[1494] In some examples of the present disclosure, the bifunctional molecule comprises a compound of formula USP2b, USP2c, USP2d, or USP2e:

[1495]

[1496] wherein A, B, L and Z are as defined above and herein with respect to the Usp target binding ligand.

[1497] Relative to formula USP3, X 3 and X 4 Independently selected from the group consisting of: CR 6 LZ and CR 6 2, where each R 6 Independently selected from the group consisting of: H and C 1-4 alkyl; and wherein X 3 and X 4 One of them is CR6 LZ.

[1498] In X 3 It's CR 6 In those instances of LZ, X 4 Can be CR 6 2, where each R 6 Independently selected from the group consisting of: H and C 1-4 For example, X 3 Can be CH-LZ and X 4 It can be CH2.

[1499] In X 4 It's CR 6 In those instances of LZ, X 3 Can be CR 6 2, where each R 6 Independently selected from the group consisting of: H and C 1-4 For example, X 4 Can be CH-LZ and X 3 It can be CH2.

[1500] In some examples of the present disclosure, the compound targeting Usp1 is a compound represented by formula USP3b, USP3c, USP3d or USP3e:

[1501]

[1502] Among them, A, B, X 6 、 L and Z are as defined above and herein.

[1503] Specifically, in some examples, X of any one of Formulas USP3b to USP3e is 6 It is C=O.

[1504] Other representative examples of compounds targeting Usp1 according to the present disclosure are shown below.

[1505]

[1506] wherein L and Z are as defined above and herein.

[1507] XX. Compounds targeting aggregation-prone proteins (including, for example, synuclein binders)

[1508]

[1509] Wherein, L shows the connection position of the linker. The present disclosure also covers the connection or coupling to the linker at any other chemically suitable position on the target protein binding ligand.

[1510] XXI. Compounds Targeting Apoptotic and Anti-apoptotic Factors (Including Bcl2 and Bcl-XL)

[1511]

[1512] Wherein, L shows the connection position of the linker. The present disclosure also covers the connection or coupling to the linker at any other chemically suitable position on the target protein binding ligand.

[1513] Isotope-labeled compounds

[1514] The present disclosure also includes various deuterated forms of the compounds disclosed herein or any formula disclosed herein, including Formula (ZI), (ZII), (ZIIIa to ZIIIf), (ZIVa to ZIVj), (I), (II), (III), (IV), (IVa), (ZV), (V), (VI) and (VIa); (EGFR1), (EGFR2) and (EGFR3); (KRAS1), (K RAS2) and (KRAS3); (C1) to (C12); (BRD91), 1T, 2T, 3T, 4T, 5T, 6T, 7T, 8T, 9T, 10T, 11T, 12T, 13T, 14T or (USP1A), (USP2A) and (USP3A) (including the corresponding subgeneric formulas defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof disclosed herein (including the subgeneric formulas as defined above). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. One of ordinary skill in the art would know how to synthesize deuterated forms of compounds of any formula disclosed herein, including Formula (ZI), (ZII), (ZIIIa to ZIIIf), (ZIVa to ZIVj), (I), (II), (III), (IV), (IVa), (ZV), (V), (VI) and (VIa), respectively; (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 (USP1A), (USP2A) and (USP3A) (including the corresponding subgeneric formulae defined herein), or pharmaceutically acceptable salts thereof and / or corresponding tautomeric forms disclosed herein (including the subgeneric formulae defined above). For example, deuterated materials, such as alkyls, can be prepared by conventional techniques (see, for example, methyl-d3-amine, available from Aldrich Chemical Co., Milwaukee, Wisconsin, Catalog No. 489,689-2).

[1515] The present disclosure also includes isotopically labeled compounds identical to those recited in any formula disclosed herein, including Formulas (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), respectively. ); (BRD91), 1T, 2T, 3T, 4T, 5T, 6T, 7T, 8T, 9T, 10T, 11T, 12T, 13T, 14T or (USP1A), (USP2A) and (USP3A) (including the corresponding subgeneric formulae as defined herein), or pharmaceutically acceptable salts thereof and / or corresponding tautomeric forms disclosed herein (including the subgeneric formulae as defined above), but in the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine, such as 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 containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Isotopically labeled compounds of the present disclosure, for example, compounds into which radioactive isotopes such as 3 H or 14 C, 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).

[1516] Degradation activity

[1517] Degradation can be determined by measuring the amount of target protein in the presence of bifunctional molecules as described herein and / or comparing it with the amount of target protein observed in the absence of the bifunctional molecules. For example, the amount of target protein in the cell contacted with and / or treated with the bifunctional molecules as described herein can be determined. This amount can be compared with the amount of target protein in the cell not contacted with and / or treated with the bifunctional molecules (for example, as a control). If the amount of target protein in the cell contacted with and / or treated with the bifunctional molecules reduces, it can be considered that the bifunctional molecules help and / or promote degradation and / or proteolysis of the target protein.

[1518] The amount of target protein can be determined using methods known in the art, for example, by immunoblotting, immunoblotting analysis, and / or ELISA using cells that have been contacted and / or treated with the bifunctional molecule.

[1519] Selective degradation and / or increased proteolysis can be considered to have occurred if a decrease of at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in the amount of target protein is observed following administration of the bifunctional molecule to the cells compared to a control.

[1520] For example, if a decrease of at least 10% (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) in the amount of 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 cell, then selective degradation and / or increased proteolysis can be considered to have occurred. The bifunctional molecule can be administered at any concentration, for example, a concentration between 0.01 nM and 10 μM, such as 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM and 10 μM. In some cases, after administration of the bifunctional molecule at a concentration of about 100 nM (e.g., after an incubation period of about 8 hours), an increase in degradation of the target protein of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100% is observed.

[1521] One measure of the degradative activity of a bifunctional molecule is DC 50 As used herein, DC 50 The concentration required to achieve 50% of maximal degradation of the target protein. The bifunctional molecules described herein may include a DC less than or equal to 10000 nM, less than or equal to 1000 nM, less than or equal to 500 nM, less than or equal to 100 nM, or less than or equal to 75 nM. 50In some cases, the bifunctional molecule comprises less than or equal to 50 nM, less than or equal to 25 nM, or less than or equal to 10 nM of DC 50 .

[1522] Another measure of the degradation activity of bifunctional molecules is D max As used herein, D max represents the maximum percentage of target protein degradation. The bifunctional molecules described herein can comprise at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or about 100% of D max .

[1523] Yet another measure of the potency of the described bifunctional molecules could be their effect on cell viability and / or their IC 50 For example, the anti-proliferative effect of the bifunctional molecules as described herein can be evaluated in a cell viability assay to provide IC 50 As used herein, IC 50 The values ​​represent the concentration at which 50% cell viability is observed in a cell viability assay (following administration of the bifunctional molecules described herein). With respect to cell viability, the bifunctional molecules described herein may comprise 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 can comprise an IC of less than 5 nM. 50 value.

[1524] Pharmaceutical composition

[1525] The present disclosure provides pharmaceutical compositions comprising the bifunctional molecules described herein. In these compositions, the bifunctional molecules can be appropriately formulated so that they can be introduced into the cellular environment in a manner that allows a sufficient portion of the molecule to enter the cell to induce degradation of the target protein.

[1526] Thus, there is provided a pharmaceutical composition comprising a bifunctional molecule as described herein and a pharmaceutically acceptable carrier.

[1527] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, phosphate buffered saline and / or saline. Pharmaceutically acceptable carriers can 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, alcohol / water solutions, emulsions, or suspensions, including saline and buffered vehicles. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, glucose and sodium chloride, lactated Ringer's solution, or fixed oils. Preservatives and other additives, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like, may also be present.

[1528] In addition to the above-mentioned carrier components, the pharmaceutical compositions described above may alternatively or additionally include one or more other carrier components as appropriate, such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc., as well as substances included to make the preparation isotonic with the blood of the intended recipient.

[1529] The pharmaceutical composition can be present in any formulation typical for administration of a pharmaceutical compound to a subject. Representative examples of typical formulations include, but are not limited to, capsules, granules, tablets, powders, lozenges, suppositories, vaginal suppositories, nasal sprays, gels, creams, ointments, sterile aqueous formulations, sterile solutions, aerosols, implants, and the like.

[1530] Pharmaceutical compositions are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral administration, e.g., intravenous, intradermal, subcutaneous, oral, transdermal, topical, transmucosal, vaginal, and rectal administration.

[1531] Pharmaceutical compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), topical (including skin, oral and sublingual), rectal, nasal and pulmonary administration (e.g., by inhalation). Where appropriate, the compositions may conveniently be presented in discrete dosage units and may be prepared by any method well known in the pharmaceutical art. The methods generally comprise the steps of combining the active compound with a liquid carrier or a finely divided solid carrier or both, and then, if desired, shaping the product into the desired formulation.

[1532] Pharmaceutical compositions suitable for oral administration in which the carrier is a solid are most preferably presented as unit dose formulations, such as pills, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing a free-flowing form of the active compound, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding the active compound with an inert liquid diluent. Tablets can be optionally coated, and if uncoated, can be optionally scored. Capsules can be prepared by filling the active compound (alone or mixed with one or more auxiliary ingredients) into a capsule shell and then sealing it in a conventional manner. Caches are similar to capsules, in which the active compound, along with any auxiliary ingredients, is sealed in a rice paper coating. The bifunctional molecules can also be formulated as dispersible granules, for example, which can be suspended in water or sprinkled on food before administration. Granules can be packaged, for example, in sachets. Wherein, the composition that is suitable for oral administration is liquid and can exist as solution or suspension in aqueous or non-aqueous liquid, or exist as oil-in-water liquid emulsion.Composition for oral administration includes controlled release dosage form, for example, wherein, active compound is formulated in suitable controlled release matrix, or with tablet coated with suitable controlled release membrane.

[1533] Pharmaceutical compositions suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oily vehicles. Injectable formulations can be suitable for bolus injection or continuous infusion. These formulations are conveniently presented in unit dose or multidose containers, which are sealed after introduction of the formulation until needed for use. Alternatively, the bifunctional molecule can be in powder form, which is reconstituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.

[1534] The pharmaceutical composition can also be formulated as a long-acting depot preparation, which can be administered by intramuscular injection or by implantation (eg, subcutaneously or intramuscularly). Depot preparations can include, for example, a suitable polymer or hydrophobic material, or an ion exchange resin.

[1535] Pharmaceutical compositions suitable for topical formulation may, for example, be provided as a gel, cream or ointment.

[1536] The bifunctional molecules described herein can be present in pharmaceutical compositions as pharmaceutically and / or physiologically acceptable salts, solvates, or derivatives.

[1537] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are generally considered suitable for use in medicine (including in a veterinary setting). For example, pharmaceutically acceptable salts can be salts that can be in contact with the tissues of mammalian subjects (e.g., humans) without undue toxicity, irritation, allergic reaction, etc. For other examples of suitable pharmaceutically acceptable salts, SM 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.

[1538] Representative examples of pharmaceutically and / or physiologically acceptable salts of the bifunctional molecules of the present disclosure can 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, malonic 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; and inorganic acids such 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, cyclopentylpropionate, digluconate, dodecylsulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like.

[1539] In some examples, salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium 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. Other pharmaceutically acceptable salts, when appropriate, may include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[1540] Pharmaceutically and / or physiologically functional derivatives of the compounds of the present invention are derivatives that can be converted into the parent compound in vivo. These pharmaceutically 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.

[1541] It may be convenient or desirable to prepare, purify and / or process the corresponding pharmaceutically and / or physiologically acceptable solvates of the bifunctional molecules described herein, which can be used in any of the described uses / methods. In this article, the term solvate is used to refer to a complex of a solute (such as a compound or a salt of a compound) and a solvent. If the solvent is water, the solvate may be referred to as a hydrate, e.g., a monohydrate, dihydrate, trihydrate, etc., depending on the number of water molecules present per substrate molecule.

[1542] Uses of Part Z

[1543] As described herein, moiety Z may form part of a bifunctional molecule intended for use in a targeted protein degradation approach, wherein moiety Z acts to regulate, assist and / or promote proteasomal degradation of the target protein.

[1544] Thus, according to other aspects of the present disclosure, there is provided the use of a moiety Z as described herein or a compound comprising moiety Z (e.g., as defined in any one of formulas (I) to (V)) in a method for targeted protein degradation (e.g., an in vitro or in vivo method for targeted protein degradation). For example, moiety Z can be used as a promoter or facilitator for targeted protein degradation.

[1545] Also provided is the use of moiety Z or a compound comprising moiety Z (eg as defined in any one of formulae (I) to (V)) in the production of a bifunctional molecule suitable for targeted protein degradation.

[1546] Treatment methods and uses

[1547] The bifunctional molecules disclosed herein can modulate, assist, and / or promote proteasomal degradation of a target protein. Thus, a method for selectively degrading and / or enhancing proteolysis of a target protein in a cell is provided, comprising contacting the cell with and / or treating the cell with a bifunctional molecule as described herein. The method can be performed in vivo or in vitro.

[1548] Specifically, provided is a method for selectively degrading and / or increasing proteolysis of a target protein 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.

[1549] As such, the bifunctional molecules of the present disclosure may find application in medicine and / or therapy. Specifically, the bifunctional molecules of the present disclosure may find application in the treatment and / or prevention of any disease or condition regulated by a target protein. For example, the bifunctional molecules of the present disclosure may be useful in the treatment of any disease that is regulated by a target protein by reducing the level of the target protein in cells, such as cells of a subject. If the level of the target protein in the cell is reduced after administration of a degrader of the present invention (wherein the activity of the selected protein is associated with a disease state or condition), it will be understood that the degrader is useful in the treatment of the disease.

[1550] Also provided are uses of bifunctional molecules as described herein in the manufacture of a medicament for treating and / or preventing any disease or condition that is modulated by a target protein. Additionally provided are uses of moiety Z (e.g., as defined in any one of formulae (I) to (V)) in the manufacture of a medicament for treating and / or preventing any disease or condition that is modulated by a target protein.

[1551] Diseases and / or conditions that can 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.

[1552] These diseases and the patient's condition comprise those that its pathology is at least in part relevant with abnormal (for example, raising) level of protein and / or the overexpression of protein.For example, bifunctional molecule can be wherein, in the experimenter suffering from this disease, observe the treatment of the disease of protein level raising and / or prevention and obtain application.In other examples, disease and / or the patient's condition can be those that its pathology is at least in part relevant with incorrect protein expression (for example, at wrong time and / or expressing in wrong cell), excessive protein expression or mutant protein expression.In one example, when mutant protein disturbs the normal biological activity of cell, tissue or organ, then cause mutant protein disease.

[1553] Thus, provided is a method of treating and / or preventing a disease or condition associated with and / or caused by abnormal protein activity levels, comprising administering a therapeutically effective amount of a bifunctional compound as described herein.

[1554] Representative examples of diseases and / or conditions that can be treated and / or prevented by using the described bifunctional compounds include, but are not limited to, cancer, asthma, multiple sclerosis, ciliary disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marei-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Glafford's syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle cell disease, hexosaminidase A deficiency, and Turner syndrome.

[1555] Other 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-Barre 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 syndrome, and vasculitis.

[1556] Other examples include: ceruloplasminemia, achondroplasia type II, achondroplasia, acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenoleukodystrophy, ALA-D hematoporphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ochrochromia, alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse angiokeratoma of the body, retinal angiomatosis (von Hippel-Lindau disease), disease), Apert syndrome, spider digits (Marfan syndrome), Stickler syndrome, arthrogryposis multiplex congenita (arthrochalasia type of Ehlers-Danlos syndrome), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson cutisgyrata syndrome, familial Mediterranean fever, Benjamin syndrome syndrome), beta-thalassemia, bilateral acoustic neurofibromas (neurofibromatosis type II), factor V Leiden thrombophilia, incontinentia pigmenti, Bloom's syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tubercular sclerosis), prion diseases, Birt-Hogg-Dube syndrome, brittle bone disease (osteogenesis imperfecta), Rubinstein-Taybi syndrome, bronze diabetes / bronzed cirrhosis (hemochromatosis), bulbar muscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disorder, Campomelic dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), Cri du chatchat), CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodystrophy syndrome (achondroplasia), otospondyloepiphyseal dysplasia syndrome, self-destructive facial disorder, galactosemia, Ehlers-Danlos syndrome syndrome), thanatosthenic dysplasia, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotruncal-dysfacial syndrome, Cooley's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint disorder (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kuiper-Barr syndrome (myotonic dystrophy), Beare-Stevenson cutisgyrata syndrome syndrome), primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne type and Becker type (DBMD), Usher syndrome, degenerative neurological diseases, including deGrouchy syndrome and Dejerine-Sottas syndrome, developmental disabilities, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globuloid sclerosis (Krabbe disease), congenital thymic atrophy, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, hematopoietic protoporphyria, erythroid 5-aminolevulinic acid synthase deficiency, hematopoietic porphyria, hematopoietic protoporphyria, erythropoietic protoporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial baroneuropathy, primary pulmonary hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, hereditary encephalopathy, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome Günther disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease, Huntington disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroitin dysgenesis, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, prosopagnosia, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Glafford's syndrome, Kniest dysplasia, dysplasia), lacunar dementia, Langer-Sardino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders, including Kniest dysplasiadysplasia), Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Nieto-Philosophy disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Lundy disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (self-destructive facial disorder), primary pulmonary hypertension, primary Alzheimer's disease, prion disease, progeria (Hutchinson Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elasticum), R b(retinoblastoma), Recklinghausen disease (neurofibromatosis type 1), relapsing polyserositis, retinopathy, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast cancer, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tubercular sclerosis), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), SED Strudwick (spondyloepiphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal dysplasia congenita), SEMD, Strudwick type (spondyloepiphyseal dysplasia, Strudwick type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (mixed porphyria), ascending hereditary spastic paralysis of infancy, speech and communication disorders, sphingolipidosis, hexosaminidase A deficiency, spinal cord microscopy Cerebral ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, giant plaque neuropathy (hereditary stress-prone peripheral neuropathy), maxillofacial dysostosis syndrome, Triple X syndrome (Triple X syndrome), Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (VHL disease), visual impairment and blindness (Alstrom syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weissenbacher-Zweymüller syndrome and xeroderma pigmentosum.

[1557] Representative examples of cancers that can be treated and / or prevented using the described bifunctional molecules include, but are not limited to, squamous cell c...

Claims

1. A bifunctional molecule comprising the following general formula: TBL-LZ in, TBL is the target protein binding ligand; L is a connector; and Z comprises a structure according to formula (ZI): in: Ring A 2 is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl or an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each of which optionally contains one or two further ring heteroatoms selected from N, O and S; R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-; Among them, R y is optionally substituted C 1-6 Alkyl or H; R 3 Selected from C 1-6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylheterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally wherein the C 1-6 The alkyl group is substituted with one or more heteroatoms selected from halogen, N, O and S; and L shows the connection point of the linker; And in addition, Z is not: or a pharmaceutically acceptable salt thereof.

2. The bifunctional molecule according to claim 1, wherein Ring A 2 is an optionally substituted 5- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- or 8-membered bridged bicyclic N-heterocycloalkyl, or an optionally substituted 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl, each of which optionally contains one or two further ring heteroatoms selected from N, O and S.

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

4. The bifunctional molecule according to any one of claims 1 to 3, wherein Z comprises a structure according to formula (ZIa): in: R 1 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl, and / or wherein two R 1 The groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-5 cycloalkyl or optionally substituted 5 to 7 membered heterocycloalkyl (e.g., 5 to 7 membered N-heterocycloalkyl, optionally wherein the C 3-5 Cycloalkyl or said 5- to 7-membered heterocycloalkyl is attached to ring A at the spiro center; R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-; Among them, R y is optionally substituted C 1-6 Alkyl or H; R 3 Selected from C 1-6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylheterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally wherein the C 1-6 The alkyl group is substituted with one or more heteroatoms selected from halogen, N, O and S; X 1 It is CH2; X 2 , X 3 and X 4 are independently CH2, O or NR x ; R x is H or C1 to C6 alkyl, or wherein one R 1 Group and an R x The groups combine to form C 1-3 bridge; n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; and L shows the attachment point of the linker.

5. The bifunctional molecule according to any one of claims 1 to 4, wherein Z comprises a structure according to formula (ZIb): in: R 1 is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl, and / or wherein two R 1 The groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-5 cycloalkyl or optionally substituted 5 to 7 membered heterocycloalkyl (eg, 5 to 7 membered heterocycloalkyl), optionally wherein the C 3-5 Cycloalkyl or said 5- to 7-membered heterocycloalkyl is attached to ring A at the spiro center; R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-; Among them, R y is optionally substituted C 1-6 Alkyl or H; R 3 Selected from C 1-6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylheterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally wherein the C 1-6 The alkyl group is substituted with one or more heteroatoms selected from halogen, N, O and S; X 1 and X 4 They are CH2; X 2 and X 3 are independently CH2, O or NR x ; The condition is X 2 and X 3 None or only one of them is O; R x is H or C1 to C6 alkyl; or wherein one R 1 Group and an R x The groups combine to form C 1-3 bridge; n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; and L shows the attachment point of the linker.

6. The bifunctional molecule according to any one of claims 1 to 5, wherein Z comprises a structure according to formula (ZII): Among them, R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-; Among them, R y is optionally substituted C 1-6 Alkyl or H; R 3 is selected from C1 to C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; X 5 Yes CR b 2. NR b , O or 5- to 7-membered heterocycloalkyl (e.g., 5- to 7-membered N-heterocycloalkyl); Each R 1 are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl, and / or wherein two R 1 The groups combine to form an optionally substituted C 1-3 bridge or optionally substituted C 3-5 Cycloalkyl (optionally wherein the C 3-5 The cycloalkyl group is attached to the heterocyclic ring of formula (ZII) at the spiro center; R b is H or optionally substituted C 1-3 alkyl; n1 is 0, 1, 2, or 3; m is 0, 1, or 2; and L shows the point of attachment of the linker.

7. The bifunctional molecule according to any one of claims 1 to 6, wherein Z comprises structures according to formula (ZIIa) to (ZIIe): Among them, R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-; Among them, R y is optionally substituted C 1-6 Alkyl or H; R 3 is selected from C1 to C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted by heterocycloalkyl; Each R 1 are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl, and / or wherein two R 1 The groups combine to form an optionally substituted C 3-5 Cycloalkyl, optionally wherein the C 3-5 The cycloalkyl group is connected to the heterocyclic ring represented by formula (ZIIa) at the spiro center; X 5 is C(R b )2. NR b or O; R b is H or optionally substituted C 1-3 alkyl; n1 is 0, 1, 2, or 3; n' is 1 or 2; m is 0, 1, or 2; and L shows the point of attachment of the linker.

8. The bifunctional molecule according to any one of claims 1 to 7, wherein Z comprises structures according to formula (ZIVa) to (ZIVj): Among them, R 2 is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-; Among them, R y is optionally substituted C 1-6 Alkyl or H; R 3 is selected from C1 to C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted by heterocycloalkyl; Each R 1 independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl; n1 is 0, 1, or 2; n' is 1 or 2; m is 0, 1, or 2; and L shows the attachment point of the linker.

9. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IIa): Among them, R 2 is selected from the group consisting of 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 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; n is 0, 1, 2 or 3; and L shows the connection point of the linker; And where Z is not:

10. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IIb): Among them, R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; X 1 It is CH2; X 2 and X 3 are independently CH2 or O; provided that X 2 and X 3 None or only one of them is O; n is 1 or 2; and L shows the connection point of the linker; And where Z is not:

11. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IIc): Among them, R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; X 1 It is CH2; X 2 and X 3 are independently CH2 or O; provided that X 2 and X 3 None or only one of them is O; n is 1 or 2; and L shows the attachment point of the linker.

12. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IId): Among them, R 2 is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; n is 1 or 2; and L shows the point of attachment of the linker.

13. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IIe): Among them, R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; n is 1 or 2; and L shows the attachment point of the linker.

14. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IIf): Among them, R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and L shows the point of attachment of the linker.

15. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (III): Among them, R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and n is 0, 1, 2 or 3; and L shows the attachment point of the linker.

16. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IIIa): Among them, R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and L shows the point of attachment of the linker.

17. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IIIb): Among them, R 1 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl; R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; and L shows the attachment point of the linker.

18. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IV): Among them, R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; R 4 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and n is 0, 1, 2 or 3; and L shows the point of attachment of the linker.

19. The bifunctional molecule according to claim 1, wherein Z comprises a structure according to formula (IVa): Among them, R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with heterocycloalkyl; R 4 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and L shows the point of attachment of the linker.

20. The 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. The bifunctional molecule according to any one of claims 6 to 8, 15, 16 and 17, wherein Each R 1 Independently: (i) selected from the group consisting of: phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; C3 to C8 cycloalkyl; or (ii) is selected from the group consisting of phenyl, substituted phenyl, pyrazolyl and substituted pyrazolyl.

22. The bifunctional molecule according to claim 6 or claim 7, wherein Two R's 1 The groups combine to form C 3-5 Cycloalkyl.

23. The bifunctional molecule according to any one of claims 6 to 8, 15, 16 and 17, wherein R 1 It is a C3 to C7 cycloalkyl group or a C1 to C3 alkyl group.

24. The bifunctional molecule according to any one of claims 6 to 8, 15, 16 and 17, wherein R 1 Select one of the following structures:

25. The bifunctional molecule according to any one of claims 1 to 14, wherein R 2 ： (i) is selected from phenyl optionally substituted by 1 to 3 substituents selected from H, C1 to C6 alkyl, halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy; and heteroaryl having 5 to 6 ring atoms and containing 1 or 2 N atoms, the heteroaryl optionally substituted by 1 to 3 substituents selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl and C1 to C6 alkoxy; (ii) is selected from optionally substituted phenyl and optionally substituted pyrazolyl; (iii) is selected from one of the following structures: Among them, R 6 is selected from H, C1-C6 alkyl, halogen, C1-C6 haloalkyl and C1-C6 alkoxy; or (iv) does not exist.

26. The bifunctional molecule according to any one of claims 1 to 14, wherein R 2 ： (i) is an optionally substituted heterocycloalkyl group, wherein the heterocycloalkyl group has 3 to 10 ring atoms and contains 1 to 3 heteroatoms independently selected from N, O and S; (ii) is selected from optionally substituted piperidinyl and optionally substituted piperazinyl; (iii) is selected from one of the following structures: Among them, R 6 is selected from H, C1 to C6 alkyl, halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy; or (iv) does not exist.

27. A bifunctional molecule according to any one of the preceding claims, wherein R 3 ： (i) is selected from C1 to C6 alkyl optionally substituted by heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms independently selected from N, O and S; 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 by one or two substituents selected from the group consisting of halogen, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy; or (ii) is selected from optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, tert-butyl, C1-C6 alkyl containing a morpholino substituent, optionally substituted benzothiazolyl and optionally substituted pyridinyl.

28. A bifunctional molecule according to any one of the preceding claims, wherein R 3 Select one of the following structures: Among them, R 5 Selected from halogen (e.g., F, Cl, Br, I), CF3, -CH2F, -CHF2, C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO2Me, -NH2, -NHMe, -NMe2, CO2Me, -NO2, CHO and COMe.

29. A bifunctional molecule according to any one of the preceding claims, wherein R 3 Select one of the following structures:

30. The bifunctional molecule according to claim 1, wherein Z contains one of the following structures: Among them, R in each of the above structures 3 is one of:

31. The bifunctional molecule according to any one of claims 1 to 30, wherein The linker comprises 1 to 25 or 1 to 18 atoms in a single linear chain.

32. The bifunctional molecule according to any one of claims 1 to 31, wherein The linker comprises 1 to 10 or 1 to 8 rotatable bonds.

33. The bifunctional molecule according to any one of claims 1 to 32, wherein The linker (L) is a covalent bond or the structure of the linker (L) is: (L x ) q Among them, each L x represents a subunit of L, said subunit being independently selected from CR L1 R L2 ,O,C=O,S,SO,SO2,NR L3 ,SONR L4 ,SONR L5 C=O、CONR L6 NR L7 CO、C(R L8 )=C(R L9 ), C≡C, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Among them, R L1 , R L2 , R L3 , R L4 , R L5 , R L6 , R L7 , R L8 and R L9 are independently selected from H, halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, -OH, -O(C1 to C6 alkyl), -NH2, -NH(C1 to C6 alkyl), -NO2, -CN, -CONH2, -CONH(C1 to C6 alkyl), -CON(C1 to C6 alkyl)2, -SO2(C1 to C6 alkyl), -CO2(C1 to C6 alkyl) and -CO(C1 to C6 alkyl); and q is an integer between 1 and 30.

34. The bifunctional molecule according to any one of claims 1 to 33, wherein The linker (L) can be represented as shown in formula (L1a): <h2 style=";text-align:left;direction:ltr">L<h2 style=";text-align:left;direction:ltr"> 1A <h2 style=";text-align:left;direction:ltr"> -L<h2 style=";text-align:left;direction:ltr"> 2A <h2 style=";text-align:left;direction:ltr"> -L3<h2 style=";text-align:left;direction:ltr"> A <h2 style=";text-align:left;direction:ltr"> (L1a) Among them, L 1A There is no or is selected from C1-C6 alkylene, 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 Yes - NR L2A C=O- or -C=ONR L2A -;as well as L 3A Selected from C1-C3 alkylene (e.g., ethylene), C1-C6 alkoxy and C1-C6 alkylamino; Among them, R L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl); Alternatively, the structure of the linker (L) can be represented as shown in formula (L1b): L 1B -L 2B -L 3B -L 4B -L 5B (L1b); Among them, L 1B Not present or selected from C1-C3 alkylene, C1-C6 alkoxy and C1-C6 alkylamino; L 2B Yes - NR L2A C=O- or -C=ONR L2A -; L 3B Selected from C1-C 15 Alkylene, -[(CH2)2O] 1-6 (CH2)2-; L 4B Yes - NR L2A C=O- or -C=ONR L2A -, where R L2A is H or C1-C6 alkyl; L 5B Selected from C1-C3 alkylene (e.g., ethylene), C1-C6 alkoxy and C1-C6 alkylamino; Among them, R L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl); Alternatively, the structure of the linker (L) can be represented as shown in formula (L1c): L 1C -L 2C -L 3C -L 4C (L1c) Among them, 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, each of which optionally contains one or two further ring heteroatoms selected from N, O and S; L 2C There is no or is selected from 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-); L 3C Yes-R L2B C=O- or -(C=O)R L2B -;as well as L 4C selected from 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-); in: R L2A is H or C1-C6 alkyl; and R L2B YesNR L2A ; or an N-attached 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 one or two further ring heteroatoms selected from N, O and S; Alternatively, the structure of the linker (L) can be represented as shown in formula (L1d): IT 1D -IT 2D -IT 3D (L1d) Among them, L 1D Not present or selected from C1-C3 alkylene, CO, C1-C3 alkylene (N (C1-C3 alkyl); L 2D YesNR L2A or 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 one or two further ring heteroatoms selected from N, O and S; wherein R L2A is H or C1-C6 alkyl; and L 3D Not present or selected from C1-C3 alkylene, -O-, -N(C1-C3 alkyl)- and CO; Alternatively, the structure of the linker (L) can be represented as shown in formula (L1e): L 1E -L 2E -L 3E (L1e); Among them, L 1E is C1-C3 alkylene or CO; L 2E is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each optionally containing one or two further ring heteroatoms selected from N, O and S; and L 3E Selected from C1-C3 alkylene; Alternatively, the linker (L) may be represented by formula (L1f): L 1F (L1f) Among them, L 1F Selected from C1-C3 alkylene, CO and C1-C3 alkylene (NR L1C ), where R L1C It is H or C1-C3 alkyl.

35. The bifunctional molecule according to any one of claims 1 to 34, wherein The target protein binding ligand (TBL) is selected from the group consisting of: (i) kinase binders; (ii) bromodomain-containing protein binders; (iii) epigenetic regulator compounds; (iv) transcription factor binders; (vi) phosphatase binders, (vii) ubiquitin E3 ligase and / or deubiquitinating enzyme binders; (viii) nuclear hormone receptor binders; (ix) aggregation-prone protein binders; (x) apoptotic and anti-apoptotic factor binders; and (xi) polymerase binders.

36. A pharmaceutical composition comprising a bifunctional molecule according to any one of claims 1 to 35, and a pharmaceutically acceptable carrier, optionally wherein: The bifunctional molecule is present in the composition as a pharmaceutically acceptable salt, solvate or derivative.

37. Use of a bifunctional molecule according to any one of claims 1 to 35 or a pharmaceutical composition according to claim 36 for use in medicine.

38. A bifunctional molecule or pharmaceutical composition for use according to claim 37, wherein Such uses include the treatment and / or prevention of any disease or condition associated with and / or caused by abnormal levels of protein activity.

39. The bifunctional molecule or pharmaceutical composition for use according to claim 37 or 38 for the treatment and / or prevention of cancer.

40. A method for treating and / or preventing any disease or condition associated with and / or caused by abnormal levels of protein activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional molecule as defined in any one of claims 1 to 35 or a pharmaceutical composition according to claim 36.

41. The method of claim 40, wherein: The disease or condition is cancer.

42. A method for selectively degrading a target protein in a cell and / or increasing proteolysis of the target protein, the method comprising contacting the cell with a bifunctional molecule as defined in any one of claims 1 to 35 or a pharmaceutical composition according to claim 36 and / or treating the cell with a bifunctional molecule as defined in any one of claims 1 to 35 or a pharmaceutical composition according to claim 36.

43. A method for selectively degrading a target protein and / or increasing proteolysis of the target protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a bifunctional molecule as defined in any one of claims 1 to 35 or a pharmaceutical composition according to claim 36.

44. Use of a moiety Z as defined in any one of claims 1 to 35 in a method for target protein degradation.

45. Use of a moiety Z as defined in any one of claims 1 to 35 in the production of a bifunctional molecule suitable for target protein degradation.

46. ​​A compound comprising a Z moiety according to formula (VI): in, A 2 , R 2 and R 3 As defined in any one of claims 1 to 30; and G is configured so that it can link the Z moiety to another chemical structure via the formation of a new covalent bond.

47. A compound comprising the following structure: LZ in, Z is as defined in any one of claims 1 to 35; and L is the connector.

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

49. A method for preparing a bifunctional molecule as defined in any one of claims 1 to 35.

50. A method for screening a bifunctional molecule according to any one of claims 1 to 35, comprising: a. Providing a bifunctional molecule comprising: (i) a first ligand comprising the structure of Z as defined in any one of claims 1 to 30; (ii) a second ligand that binds to the target protein; and (iii) a linker covalently linking the first and second ligands; b. contacting a cell with the bifunctional molecule; c. detecting degradation of the target protein in the cell; d. detecting degradation of the target protein in the cell in the absence of the bifunctional molecule; as well as e. comparing the degradation level of the target protein in the cell contacted with the bifunctional molecule with the degradation level of the target protein in the absence of the bifunctional molecule; Wherein, the increase in the degradation level of the target protein in the cells contacted with the bifunctional molecule indicates that the bifunctional molecule has helped and / or promoted the degradation of the target protein, Optionally, detecting the degradation of the target protein comprises detecting a change in the level of the target protein in the cell.

51. The method of claim 50, wherein: The joint is as defined in any one of claims 31 to 34.

52. A compound library comprising a plurality of bifunctional molecules according to any one of claims 1 to 35.

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