Compounds for targeting protein degradation

Abstract

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

Description

Technical Field

[0001] The present disclosure relates to the degradation of bromodomain-containing protein 9 (BRD9) protein. BRD9 has been associated with the proliferation of cancer, and the present disclosure relates to the treatment of cancer, for example, by degradation of BRD9. Specifically, the present disclosure relates to a novel class of bifunctional molecules that can be used for the targeted or selective degradation of BRD9, as well as methods for preparing such molecules and their therapeutic uses. The present disclosure further relates to methods for treating cancer, which methods include selective and / or targeted degradation of BRD9. Background Art

[0002] BRD9 is a protein encoded by the BRD9 gene on chromosome 5. BRD9 is a component of the BAF (BRG1 or BRM-related factor) complex (i.e., the SWI / SNF ATPase chromatin remodeling complex) and belongs to the IV family of proteins containing bromodomains (D. Hay et al., Med. Chem. Commun., 2015, 6, 1381-1386). SWI / SNF uses the energy of ATP hydrolysis to reshape chromatin and move nucleosomes. SWI / SNF participates in activating transcription by remodeling nucleosomes, thereby allowing transcription factors to enter their binding sites more. It is also necessary for the transcriptional repression of certain genes and therefore controls transcription in various ways.

[0003] Recurrent inactivating mutations in certain subunits of the SWI / SNF complex have been identified in various cancers. Despite its known role in tumor suppression, the mammalian SWI / SNF complex has recently gained attention as a potential target for therapeutic inhibition (LJ Martin et al., J. Med. Chem., 2016, 59, 4462-4475).

[0004] Studies have shown that BRD9 is preferentially used by cancers with SMARCB1 abnormalities, such as malignant rhabdoid tumors and several specific types of sarcomas (X. Zhu, Y. Liao and L. Tang, Onco Targets Ther., 2020, 13, 13191-13200). The complex containing BRD9 combines with both active promoters and enhancers to contribute to gene expression. The loss of BRD9 leads to changes in gene expression associated with apoptosis regulation, translation and developmental regulation. BRD9 is crucial for the proliferation of SMARCB1-deficient cancer cell lines, indicating that it is a therapeutic target for these deadly cancers. (Xiaofeng Wang et al., Nature Communications, 2019, 10 (1881)). Recent studies have emphasized the role of BRD9 in leukemia growth: BRD9 has been shown to be required for the proliferation of acute myeloid leukemia (AML) cells (Nature Chemical Biology, 2016, 101038 / nchembio.2115). In addition to its functionally dependent role in certain cancers, BRD9 also plays a key role in immune cells as a regulator of regulatory T cells (Tregs) via transcriptional control of Foxp3 target genes, "BioRxiv, 10.1101 / 2020.02.26.964981."

[0005] Due to the role of BRD9 in cancer proliferation, the development of BRD9 inhibitors for the treatment of cancer has received attention, including those described in WO 2014 / 114721, WO 2016 / 077375, WO 2016 / 077378, WO 2016 / 139361, WO 2019 / 152440, Martin LJ et al., entitled “Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor” (Journal of Medicinal Chemistry 2016, 59, 4462-4475); Theodoulou NH et al., entitled “Discovery of I-BRD9, a selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition” (Journal of Medicinal Chemistry 2015, 59, 1425-1439); and Clack et al., entitled “Biotinylated 1-BRD9 Inhibitors” (Journal of Medicinal Chemistry 2015, 59, 1425-1439). Paper by P. et al. (Angewandte Chemie, 2015, 127, 6315-6319).

[0006] Targeted protein degradation (TPD) is a therapeutic modality that relies on the use of synthetic molecules to repurpose the cellular degradation machinery to induce the degradation of specific pathogenic proteins. The TPD approach offers many advantages over other drug modalities (e.g., small molecule inhibitors, antibodies and protein drugs, antisense oligonucleotides, and related knockdown approaches), including: enhanced pharmacology due to removal of the catalytic protein from the cell; the ability to inhibit multiple functions of a specific drug target, including, for example, inhibition of scaffold function through target knockdown; the opportunity for systemic administration with good biodistribution; potent in vivo efficacy due to catalytic potency and long duration of action, limited only by de novo protein resynthesis; and facile chemical synthesis and formulation for applications using small molecule processes.

[0007] Most physiological post-translational regulation of protein levels and the removal of damaged, misfolded, or excess proteins are mediated by the ubiquitin-proteasome system (UPS). The UPS can be repurposed to degrade specific proteins using bifunctional chemical molecules as therapeutic agents that act by inducing the access of desired substrates to UPS proteins to trigger a series of events that ultimately lead to proteasomal degradation of the desired target and its removal from the cell.

[0008] Proteolysis targeting chimeras (PROTACs) constitute such bifunctional degraders that induce target proteins to access the UPS by recruiting specific ubiquitin E3 ligases. PROTACs are composed of two ligands connected by a linker: one ligand is used to bind the desired target protein, and the other ligand is used to recruit the ubiquitin E3 ligase.

[0009] The most commonly used E3 ligases in PROTACs are von Hippel-Lindau (VHL) and Cereblon (CRBN). PROTACs that recruit VHL are typically based on hydroxyproline-containing ligands, while PROTACs that recruit CRBN are typically characterized by the presence of a glutarimide moiety (such as thalidomide, pomalidomide, and lenalidomide or analogs) acting as a warhead. Other ligases (including the mdm2 and IAP families) have also shown utility in PROTAC design.

[0010] However, these approaches have a range of limitations that limit their utility for treating a variety of diseases. For example, limitations of current PROTAC approaches include: an inability to efficiently degrade certain targets; poor PROTAC activity in many 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 characteristics); and a high sensitivity to induced resistance mechanisms in tumors.

[0011] Due to these limitations, there remains a need to identify novel degradation mechanisms and warheads capable of delivering new bifunctional degrader molecules that exhibit efficient degradation across a range of targets and cellular systems and / or possess improved characteristics suitable for drug development.

[0012] Additional bifunctional degradation molecules have been described in WO 2019 / 238886, WO 2019 / 238817, WO 2019 / 238816 and WO 2022 / 129925.

[0013] Protein degradation compounds having an E3 ligase binding portion and a BRD9 binding portion, wherein the BRD9 binding portion binds to BRD9 and brings it to the ligase for ultimate degradation by the proteasome are described in the following literature: Ciulli et al., (J. Med. Chem. 2019, 62, 2, 699-726), WO 2017 / 223452, WO 2019 / 152440, WO 2019 / 246423, WO 2019 / 246430, WO 2020 / 051235, WO 2020 / 106915, WO 2020 / 160192, WO 2020 / 160193, WO 2020 / 160196, WO 2021 / 022163, WO 2021 / 178920, WO 2020 / 160198 and WO 2020 / 160196.

[0014] Most known BRD9 inhibitors are poorly potent. Given the important role that BRD9 plays in cancer, there remains a need to identify bifunctional degraders that exhibit efficient BRD9 degradation in a range of cell systems and / or possess improved properties suitable for drug development. Summary of the Invention

[0015] The present disclosure is based on the identification of a novel class of bifunctional molecules that can be used for the targeted and / or selective degradation of BRD9. In particular, the present disclosure provides bifunctional molecules comprising a BRD9 binding ligand and a "warhead" that facilitates proteasomal degradation of BRD9.

[0016] Removing and / or reducing BRD9 from cells or subjects in need thereof by targeted protein degradation mechanisms may find particular application in treatment (e.g., cancer treatment). Accordingly, the present disclosure further relates to methods for treating cancer comprising selective and / or targeted degradation of BRD9 and bifunctional molecules and pharmaceutical compositions for use in such methods.

[0017] The bifunctional molecules described herein comprise the following general structure:

[0018] TBL–L–Z

[0019] Wherein TBL is the target protein binding ligand that binds to BRD9, and L is a linker. Part "Z" ("warhead") regulates, facilitates and / or promotes the proteasomal degradation of the target protein BRD9, and in some cases, can be referred to as a regulator, propellant and / or promoter of proteasomal degradation. For example, in use, the TBL portion of the bifunctional molecule binds to BRD9. Part Z (which is connected via a linker or otherwise connected to TBL) then regulates, facilitates and / or promotes the degradation of BRD9, for example, by bringing the BRD9 protein close to the proteasome and / or by otherwise marking the BRD9 protein for proteasomal degradation within the cell.

[0020] Thus, the bifunctional molecules described in the present disclosure can be considered to comprise: a target protein binding ligand (TBL) (i.e., a ligand capable of binding (e.g., specifically binding) to BRD9), which binds to BRD9; a warhead or degradation tag (Z) (e.g., a portion Z that acts to regulate, favor and / or promote the degradation of the target protein); and a linker (e.g., a chemical linker) that conjugates, joins or connects TBL and Z.

[0021] The bifunctional molecules described in this disclosure have been shown to be effective degraders of BRD9. Without being bound by theory, it is hypothesized that the Z portion of the bifunctional molecules described herein does not bind to the specific E3 ligases (e.g., CRBN and VHL) typically relied upon in the classical PROTAC approach discussed above. Therefore, the bifunctional molecules described herein are believed to regulate, facilitate, and / or promote proteasomal degradation via alternative mechanisms. Therefore, this class of bifunctional molecules can be used to target a wider range of diseases (including diseases that are resistant to many PROTAC degraders).

[0022] The bifunctional molecules described herein can provide one or more properties (e.g., one or more drug-like properties) to the degraders that will facilitate, enhance, and / or promote their use in vivo. In particular, bifunctional molecules comprising a warhead Z can provide improved bioavailability levels (e.g., oral bioavailability) relative to many classic PROTAC degraders. Additionally or alternatively, bifunctional molecules comprising a warhead Z can provide improved CNS (central nervous system) penetration levels (compared to many other degrader molecules currently known in the art).

[0023] The bifunctional molecules described in the present disclosure are specifically designed to degrade BRD9. In particular, the inventors have identified that the connection of a BRD9 binding ligand to a linker that is itself attached to a warhead forms a bifunctional molecule capable of degrading BRD9. Furthermore, the inventors have identified that these bifunctional molecules can be used to provide particularly selective degradation of BRD9 relative to other types of BRD proteins (e.g., BRD4 and / or BRD7) while also maintaining good degradation levels.

[0024] According to a first aspect of the present disclosure, there is provided a bifunctional molecule comprising the following general formula:

[0025] TBL–L–Z

[0026] Wherein TBL is the target protein binding ligand that binds to BRD9;

[0027] L is a linker; and

[0028] Z comprises a structure according to formula (I):

[0029]

[0030] in

[0031] R 1 is selected from C1 to C6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl, optionally wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from halo, N, O and S and / or is substituted by a carbocyclic or heterocyclic group;

[0032] A does not exist or is CR 2 R 2' ;

[0033] B is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl;

[0034] R 2 and R 2' are each independently selected from H and C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted with one or more heteroatoms selected from N, O, S or halo, or wherein R 2 and R 2' together form an optionally substituted 3-, 4-, 5- or 6-membered carbocyclic or heterocyclic ring;

[0035] 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 halo, N, O and S;

[0036] R 4 is H, C1 to C6 alkyl, optionally, wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from N, O or S;

[0037] or where R 1 and R 4 together form an optionally substituted 5-, 6-, or 7-membered heterocyclic ring;

[0038] or when A is CR 2 R 2' hour:

[0039] R 1 and R 2 together to form an optionally substituted 5-, 6-, or 7-membered heterocyclic ring; or

[0040] R 2 and R 4 together form an optionally substituted 5-, 6-, or 7-membered heterocyclic or carbocyclic ring;

[0041] Wherein L shows the connection point of the linker;

[0042] or

[0043] Z comprises a structure according to formula (WZI):

[0044]

[0045] in:

[0046] Ring A 2A 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 additional ring heteroatoms selected from N, O, and S;

[0047] R 2A 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)-;

[0048] where R y is optionally substituted C 1-6 Alkyl or H;

[0049] R 3A is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S; and L represents the point of attachment of the linker;

[0050] or

[0051] Z comprises a structure according to formula (WI):

[0052]

[0053] where R 1A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0054] R 2A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-;

[0055] R 3A is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S;

[0056] X 1 is CH2;

[0057] X 2 and X 3 Each independently is CH2 or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl; and n is 0, 1, 2 or 3; and

[0058] L shows the connection point of the linker;

[0059] or

[0060] Z comprises a structure according to formula (A):

[0061]

[0062] Where the linker is attached to the carbonyl carbon C 1 ;

[0063] In particular, wherein Z consists of or consists essentially of a structure according to formula (A1):

[0064]

[0065] in:

[0066] R 1A1 is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S; and

[0067] Where the linker is attached to the carbonyl carbon C 1 .

[0068] In some examples, the BRD9-binding agent has Formula 1a:

[0069]

[0070] in:

[0071] Z 1 N or CR A ;

[0072] Z 2 N or CR B ;

[0073] Z 3 N or CR D ;

[0074] Z 4 N or CR E ;

[0075] where Z 1 、Z 2 、Z 3 and Z 4 The number of numbers that do not exceed 3 is N;

[0076] R A and RE Each independently selected from -H, -OC 1-3 Alkyl and –C 1-3 a group consisting of alkyl groups;

[0077] R B and R D Each independently selected from -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 alkyl, 4 to 7 membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 Alkyl)2, -N(C 1-3 Alkyl)2, -NH-R F the group formed;

[0078] R F Selected from -SO2-C 1-3 Alkyl and –C 1-3 Alkyl, wherein the –C 1-3 Alkyl is optionally substituted with a 5- to 6-membered heteroaryl; alternatively, R A and R B Together they form a benzene ring;

[0079] 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 atoms to which they are attached) form the 1-3 alkyl optionally substituted 5- to 7-membered heterocycloalkyl;

[0080] R C Choose from -H, -YR G 、-NH2、-C 1-3 the group consisting of an alkyl group and a 4- to 7-membered heterocycloalkyl group;

[0081] Y is absent or selected from -CR H R I -, -SO2- and -CO-;

[0082] R H and R Iare each independently selected from -H or -C 1-3 Alkyl; or R H and R I Together to form –C 3-4 Cycloalkyl,

[0083] R G Selected from -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ),-OR L , aryl, 5 to 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, wherein the monocyclic or bicyclic heterocycloalkyl is substituted by any suitable substituent (such as independently selected from 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 One or more groups of ) are optionally substituted;

[0084] R M1 is selected from 5 to 10 membered mono- or bicyclic aryl or heteroaryl, wherein the 5 to 10 membered mono- or bicyclic aryl or heteroaryl is substituted by -NH2, -OH, halogen, -CN, C 1-3 Alkyl, -OC 1-3 The alkyl group is optionally substituted;

[0085] R J -H or -C 1-3 alkyl;

[0086] R K Choose Free-C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 Alkyl)2, -C 2-3 Alkyl-NHC 1-3 The group consisting of alkyl, optionally substituted 4 to 7 membered monocyclic heterocycloalkyl and optionally substituted 7 to 12 membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is replaced by any suitable substituent (such as -C 1-3 alkyl) is optionally substituted;

[0087] R L For –C 1-3 Alkyl or 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being C 1-3 The alkyl group is optionally substituted;

[0088] When R C YRG When R B and R D Each 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 is not hydrogen;

[0089] and

[0090] A 2 Selected from Formula 1b or 1c:

[0091]

[0092] The wavy line is in A 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect;

[0093] R M Selected from 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 A group consisting of an alkynyl group and H;

[0094] Z 5 N or CR O ;

[0095] Z 6 N or CR P ;

[0096] Z 7 N or CR N ;

[0097] where Z 5 , Z 6 and Z 7 Only one of them is N;

[0098] Z 8 CR W or N;

[0099] R N Selected from halogen, optionally substituted -C 1-6 Alkyl, -H, C(O)C1-5 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 a group consisting of heteroalkenyl and thiol;

[0100] R O Selected from 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 the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino;

[0101] R P Selected from 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 A group consisting of aromatic groups;

[0102] Alternatively, R N and Z 5 Combined together to form an 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;

[0103] R S Selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl and optionally substituted C 3-10 a group consisting of carbocyclic groups;

[0104] R T Selected from H, optionally substituted C1-6 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 The group consisting of 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 each independently selected from 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 the group consisting of heteroalkenyl, thiol, optionally substituted sulfone, and optionally substituted amino;

[0105] 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;

[0106] R W Selected from 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 a group consisting of heteroaryl groups;

[0107] and

[0108] wherein the BRD9 binder is attached to the linker at any suitable position.

[0109] In some examples of Formula 1a above, R C The group can be H, and the linker can be attached at this position. In other words, the linker (L) can replace R CGroup. Such an example can be designated as Formula 1a".

[0110] In some embodiments, the bifunctional molecule is not:

[0111]

[0112] Target Binding Ligand (TBL)

[0113] As used herein, "target protein binding ligand" refers to a ligand or moiety that binds to BRD9 (e.g., specifically binds to BRD9). A bifunctional molecule according to the present disclosure can include a target protein binding ligand that binds to a BRD9 target protein with sufficient binding affinity such that the BRD9 target protein is more susceptible to degradation or proteolysis than if not bound by the bifunctional molecule.

[0114] The target protein binding ligand may comprise or be derived from a small molecule (or its analog or fragment) that is already known to act as a regulator, promoter and / or inhibitor of BRD9 protein function. For example, the target protein binding ligand may comprise or be derived from a small molecule that is known to inhibit the activity of a BRD9 target protein.

[0115] For example, the bifunctional molecules disclosed herein can comprise a target protein binding ligand that binds to BRD9 with sufficient binding affinity such that the BRD9 is selectively degraded. In particular, if the bifunctional molecules described herein are contacted with BRD9, the observed DC 50 The value (for degradation of BRD9) can be less than or equal to about 15 μM, less than or equal to about 10 μM, 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 25 nM, less than or equal to 10 nM, less than or equal to 5 nM, less than or equal to 1.25 nM, less than or equal to 1 nM, or less than or equal to 0.5 nM.

[0116] For further example, a target protein binding ligand that binds to BRD9 (e.g., specifically binds) can bind to BRD9 with a dissociation constant of less than or equal to about 10 μM, less than or equal to about 5 μM, or less than or equal to about 3 μM. In some instances, a target protein binding ligand that binds to BRD9 (e.g., specifically binds) can bind to BRD9 with a dissociation constant of less than or equal to 1000 nM, less than or equal to 500 nM, less than or equal to 100 nM, less than or equal to 50 nM, or less than or equal to 20 nM. In some instances, the ligand can bind to BRD9 with a dissociation constant of about 0.001 nM to about 10 μM (such as about 0.001 nM to about 8 μM, about 0.001 nM to about 5 μM, about 0.001 nM to about 3 μM, or about 0.001 nM to about 2.7 μM). In some examples, the ligand can bind to BRD9 with a dissociation constant 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, or about 0.01 nM to about 2.7 μM.

[0117] In some examples, the ligand can bind to BRD9 with a dissociation constant of about 0.1 nM to about 10 μM (such as about 0.1 nM to about 8 μM, about 0.1 nM to about 5 μM, about 0.1 nM to about 3 μM, or about 0.1 nM to about 2.7 μM). In some examples, the ligand can bind to BRD9 with a dissociation constant of about 1 nM to about 10 μM (such as about 1 nM to about 8 μM, about 1 nM to about 5 μM, about 1 nM to about 3 μM, or about 1 nM to about 2.7 μM).

[0118] For the avoidance of doubt, the dissociation constant is a measure of the tendency of an object comprising two components bound together to separate (dissociate) into the two components. As used herein, the dissociation constant is a measure of the tendency of a 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.

[0119] The binding between the BRD9 protein and the target protein binding partner can include one or more binding interactions, such as hydrogen bonding, dipole-dipole bonding, ion-dipole bonding, ion-induced dipole bonding, ionic bonding and covalent bonding. For example, the binding between the BRD9 protein and the target protein binding partner can include a salt bridge (a combination of hydrogen bonding and ionic bonding).

[0120] In some examples, the bifunctional molecules of the present disclosure can be selective degraders of BRD9 proteins, for example, bifunctional molecules can selectively degrade BRD9 rather than other proteins, such as other BRD proteins (e.g., BRD7 or BRD4). In more specific examples, bifunctional molecules can be selective degraders of certain types of BRD9 proteins. For example, the binding affinity of the molecules of the present disclosure to certain BRD9 mutants may be greater than to other types of proteins, such as other types of BRD9 proteins (e.g., wild-type BRD9).

[0121] Over the years, representative examples of BRD9-targeted drugs have been developed, including those described in the following documents: WO 2014 / 114721, WO 2016 / 077375, WO 2016 / 077378, WO 2016 / 139361, WO 2019 / 152440, Martin LJ et al., entitled "Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor" (Journal of Medicinal Chemistry 2016, 59, 4462-4475); Theodoulou NH et al., entitled "Discovery of I-BRD9, a selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition" (Journal of Medicinal Chemistry 2015, 59, 1425-1439); and Clack et al., entitled "Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor" (Journal of Medicinal Chemistry 2016, 59, 4462-4475). Paper by P. et al. (Angewandte Chemie, 2015, 127, 6315-6319).

[0122] Such BRD9 binding molecules (as referenced in the above paragraph) can be incorporated into the bifunctional molecules of the present disclosure as target binding ligands (TBLs).

[0123] As described above, the BRD9 binding agents of the present disclosure have Formula 1a:

[0124]

[0125] Among them A 2 、Z 1 、Z 2 、Z 3 、Z 4 and R C As defined above.

[0126] In some embodiments, Z in Formula 1a 1 , Z 2 , Z 3 and Z 4 The number of N that does not exceed 1 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 such embodiments, the BRD9 binding agent can have Formula 1a':

[0127]

[0128] in:

[0129] R A 、R B 、R C 、R E , Z 3 and A 2 As defined above and herein.

[0130] A 2 Selected from Formula 1b or 1c:

[0131]

[0132] The wavy line is in A 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect, 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.

[0133] Z 7 N or CR N And Z 5 N or CR O In some instances, R N (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 5N and R N (to which it is bonded) and Z 5 Combined together to form an optionally substituted C 6-10 Aromatic or optionally substituted C 2-9 When heteroaromatic, R N (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 be combined to form an optionally substituted NC 2–4 Heteroaryl groups, as shown below:

[0134]

[0135] The wavy line is in A 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect, Z 6 and R M As defined above, and wherein 1B is optionally substituted NC 2–4 Heteroarene, such as an optionally substituted 5-membered heteroarene, for example, is any one selected from the group consisting of optionally substituted pyrrole, imidazole, pyrazole, and triazole (including 1,2,3 and 1,2,4-triazole).

[0136] In some instances, when Z 5 CR O And Z 7 CR N When R N and R O Together with the carbon atoms 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:

[0137]

[0138] The wavy line is in A 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect, 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 optionally substituted benzene or a 5- to 6-membered heteroarene, such as any one selected from the group consisting of optionally substituted benzene, pyridine, pyrrole, imidazole, pyrimidine, thiophene, and pyrazole.

[0139] In some embodiments, R N (together with the carbon atom to which it is attached) and Z 5 Together they can form a benzene ring or a 5- to 6-membered heteroaromatic hydrocarbon ring (for example, ring 1C can be a benzene ring or a 5- to 6-membered heteroaromatic hydrocarbon ring), each of which can be 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 One or more groups of the cycloalkyl group are optionally and independently substituted, wherein the -C 1-5 The alkyl group may be optionally substituted with a 5- to 6-membered heteroaryl group or a phenyl group; wherein 1d is: in

[0140] Y 2 NR R or O;

[0141] Y 1 S(O) a or NR R ;

[0142] Each R R are independently H or C 1-4 alkyl;

[0143] Each R Q Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and –C(O)C 1-3 alkyl group; a is 0 to 2; and

[0144] r is 0 to 3.

[0145] In some embodiments, Z 7 CR N , that is, A 2 Selected from Formula 1b':

[0146]

[0147] The wavy line is in A 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect, and Z 5 、Z 6 、R Mand R N As defined above and herein.

[0148] As mentioned earlier, R M Can be selected from 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 optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 A group consisting of a cycloalkyl group and H. For example, R M You can choose C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 In some embodiments, R M Choose Free-C 1-5 Alkyl, -cyclopropyl, -C 1-4 A group consisting of a haloalkyl group and H, such as C 1-5 In some embodiments, R M C 1-3 alkyl.

[0149] As mentioned earlier, R N may be selected from 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 can be selected from 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 halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC1-3 A group consisting of an alkyl group and –OH. For example, R N Can be C 1-5 Alkyl or halogen.

[0150] As mentioned above, Z 5 N or CR O , where R O Selected from 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 The group consisting of heteroalkenyl, hydroxy, 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.

[0151] In some embodiments, R N -C 1-5 Alkyl or halogen, or R N and Z 5 Together they form an optionally substituted 5- to 6-membered heteroaromatic or benzene ring. In some embodiments, the optionally substituted 5- to 6-membered heteroaromatic ring may contain one or more heteroatoms selected from the group consisting of N, S and O, such as N and S, i.e., the optionally substituted 5- to 6-membered heteroaromatic ring may be an N- or S-heteroaromatic. In some embodiments, the optionally substituted 5- to 6-membered heteroaromatic ring is any one selected from the group consisting of optionally substituted pyrrole, imidazole, pyrimidine, thiophene and pyrazole.

[0152] For the avoidance of doubt, the optional substituents may be 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 One or more cycloalkyl groups, wherein the -C 1-5The alkyl group may be optionally substituted with a 5- to 6-membered heteroaryl group or a phenyl group; wherein 1d is:

[0153] in

[0154] Y 2 NR R or O;

[0155] Y 1 S(O) a or NR R ;

[0156] Each R R are independently H or C 1-4 alkyl;

[0157] Each R Q Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and –C(O)C 1-3 alkyl group; a is 0 to 2; and

[0158] r is 0 to 3.

[0159] For example, the optional substituents may 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 In some cases, the optional substituents may be independently selected from C1-C4 alkyl, allyl, crotyl, 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 an 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.

[0160] As mentioned above, Z 6 N or CR P , where R P Selected from H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl and optionally substituted C 6-10A group consisting of aromatic groups. 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 H or –C 1-3 Alkyl, i.e. Z 6 N, CH or C–C 1-3 Alkyl. For example, Z 6 Can be CH or C–C 1-3 alkyl.

[0161] In some specific embodiments, A 2 is selected from Formula 1b', wherein Formula 1b' is:

[0162]

[0163] The wavy line is in A 2 and positioned at R A and R E The bonds between said carbon atoms in the ortho position intersect;

[0164] R M Choose Free-C 1-5 Alkyl, -cyclopropyl, -C 1-4 A group consisting of a haloalkyl group and H;

[0165] R N Selected from halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 a group consisting of an alkyl group and –OH;

[0166] Z 5 N or CR O

[0167] Z 6 N or CR P , where Z 5 and Z 6 Only one of can be N;

[0168] R O H or –C 1-3 alkyl;

[0169] R P H or –C 1-3 alkyl;

[0170] where R O and R P Only one of them can be –C 1-3 alkyl;

[0171] Alternatively, R N and Z 5 Together they form a benzene ring or a 5- to 6-membered heteroaromatic ring, each of which may be 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 One or more groups of the cycloalkyl group are optionally and independently substituted, wherein the -C 1-5 The alkyl group may be optionally substituted with a 5- to 6-membered heteroaryl or phenyl group;

[0172] Where 1d is:

[0173] in

[0174] Y 2 NR R or O;

[0175] Y 1 S(O) a or NR R ;

[0176] Each R R are independently H or C 1-4 alkyl;

[0177] Each R Q Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and –C(O)C 1-3 alkyl group; a is 0 to 2; and

[0178] r is 0 to 3.

[0179] As described above, the BRD9 binder is 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 atoms on the linker that form R C 、R A 、R B 、R D or R E Alternatively, the linker can be directly attached to R C 、R A 、RB 、R D and / 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 connected to the atoms on the linker to form R C A portion of the linker originates from a covalent bond between or through an atom on the linker and R C The covalent bond between the atoms that are originally to be bound is connected to the BRD9 binder, that is, the linker replaces R C .

[0180] 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 atoms to which they are attached) form a 1-3 When the alkyl group is an optionally substituted 5- to 7-membered heterocycloalkyl 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- to 7-membered heterocycloalkyl group.

[0181] In some embodiments, the BRD9 binding agent has Formula 1a 1 , 1a 2 , 1a 3 :

[0182]

[0183] wherein the wavy line intersects the bond between the BRD9 binding agent and the linker;

[0184] A 2 , Z 1 , Z 2 , Z 3 and Z 4 As defined above and herein;

[0185] R C does not exist or as defined above and herein;

[0186] And ring 1A is –C 1-3 Alkyl optionally substituted 5- to 7-membered heterocycloalkane.

[0187] Ring 1A may contain one or two heteroatoms independently selected from the list consisting of N, S, and O. For example, Ring 1A may be selected from pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, oxane, tetrahydrothiophene, and cyclopentane sulfide. In some cases, Ring 1A may be an N-heterocycloalkane such as pyrrolidine, piperidine, or piperazine. In a specific example, Ring 1A is pyrrolidine.

[0188] For the avoidance of doubt, when a linker is identified by atoms on the linker that interact with atoms that form part of a feature on a BRD9 binder, such as R C ) is attached to the BRD9 binding agent by a covalent bond between the feature and the linker, the linker replaces a chemical group or atom (such as a hydrogen atom) with a valence of 1 of the feature to satisfy the valence. For example, when the feature on the BRD9 binding agent is a dimethylamide group (-C(O)N(CH3)2) or a dimethylaminomethylene group (-CH2N(CH3)2), the linker can replace a methyl group or a hydrogen atom on the feature.

[0189] As another alternative, the linker can be formed by atoms on the linker and 2 A covalent bond between atoms of a portion of M 、R N 、R O 、R P 、R S 、R T 、R U 、R V or R W A covalent bond between atoms that is part of R M 、R N 、R O 、R P 、R S 、R T 、R U 、R V or R W Alternatively, where R N and Z 5 Combined together to form an 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 Heteroaromatic hydrocarbons, the linker can form an optionally substituted C 6-10 Aromatic or optionally substituted C 2–9A covalent bond between atoms of a portion of the heteroarene is attached to the BRD9 binding agent.

[0190] In an exemplary BRD9 binder, wherein R N and Z 5 Combined together to form an optionally substituted thiophene, the linker can be attached to a BRD9 binder as shown in the following structure:

[0191]

[0192] The wavy line is in A 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect; and R M and Z 6 As defined above and herein.

[0193] The linker may be attached to an atom that forms part of a substituent bonded to the same position as above. For example, the linker may be attached to an atom that forms part of a substituent bonded to the same position as above. The following structure illustrates this, wherein R N and Z 5 Combined together to form an optionally substituted thiophene; the wavy line and the 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect; and Y 2 O, Y 1 N, R R is H, and R Q and r is defined as above:

[0194]

[0195] As mentioned above, the Z of BRD9 binders 1 , Z 2 , Z 3 , Z 4 and R C The definition is as follows:

[0196] Z 1 N or CR A ;

[0197] Z 2 N or CR B ;

[0198] Z 3 N or CR D ;

[0199] Z 4 N or CR E ;

[0200] where Z 1 、Z 2 、Z 3 and Z 4 The number of numbers that do not exceed 3 is N;

[0201] R A and R E Each independently selected from -H, -OC 1-3 Alkyl and –C 1-3 a group consisting of alkyl groups;

[0202] R B and R D Each independently selected from -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 alkyl, 4 to 7 membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 Alkyl)2, -N(C 1-3 Alkyl)2, -NH-R F the group formed;

[0203] R F Selected from -SO2-C 1-3 Alkyl and –C 1-3 Alkyl, wherein the –C 1-3 Alkyl is optionally substituted with a 5- to 6-membered heteroaryl; alternatively, R A and R B together to form a benzene ring; alternatively, the R C and Z 2 or R C and Z 3 (For example, R C and R B or R C and R D Together with the carbon atoms to which they are attached) form the 1-3 alkyl optionally substituted 5- to 7-membered heterocycloalkyl;

[0204] R C Choose from -H, -YR G 、-NH2、-C 1-3 the group consisting of an alkyl group and a 4- to 7-membered heterocycloalkyl group;

[0205] Y is absent or selected from -CR H R I -, -SO2- and -CO-;

[0206] R H and R I are each independently selected from -H or -C 1-3 Alkyl; or R H and R I Together to form –C 3-4 Cycloalkyl,

[0207] R G Selected from -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ),-OR L , aryl, 5 to 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, wherein the monocyclic or bicyclic heterocycloalkyl is replaced by any suitable substituent (such as selected from 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 (one or more independent groups) are optionally substituted;

[0208] R M1 is selected from 5 to 10 membered mono- or bicyclic aryl or heteroaryl, wherein the 5 to 10 membered mono- or bicyclic aryl or heteroaryl is substituted by -NH2, -OH, halogen, -CN, C 1-3 Alkyl, -OC 1-3 The alkyl group is optionally substituted;

[0209] R J -H or -C 1-3 alkyl;

[0210] R K Choose Free-C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 Alkyl)2, -C 2-3 Alkyl-NHC 1-3 The group consisting of alkyl, optionally substituted 4 to 7 membered monocyclic heterocycloalkyl and optionally substituted 7 to 12 membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is replaced by any suitable substituent (such as -C 1-3 alkyl) is optionally substituted;

[0211] R LFor –C 1-3 Alkyl or 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being C 1-3 The alkyl group is optionally substituted;

[0212] When R C YR G When R B and R D Each 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.

[0213] In the above alternative example, for R G and R K The list of groups can be replaced as follows:

[0214] R G Can be selected from -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ),-OR L , aryl, 5- to 6-membered heteroaryl (wherein aryl and heteroaryl are optionally and independently substituted with one or more halogen), 4- to 7-membered heterocycloalkyl (wherein heterocycloalkyl is independently selected from 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 one or more groups of which are optionally substituted);

[0215] R K You can choose to be free – C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 Alkyl)2, -C 2-3 Alkyl-NHC 1-3 A group consisting of an alkyl group and a 4- to 7-membered heterocycloalkyl group, wherein the heterocycloalkyl group is replaced by a -C 1-3 The alkyl group is optionally substituted; and

[0216] where R J 、R L 、R M1 As defined above.

[0217] In some examples of BRD9 binding ligands described herein (and unless otherwise indicated):

[0218] (i)R A 、R B 、R D and R E Independently selected from -OC 1-3 Alkyl, -H, halogen, -OC 1-3 Halogenated alkyl,

[0219] -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

[0220] (ii)R A 、R D and R E Independently selected from -OC 1-3 Alkyl, -H, halogen, -OC 1-3 Halogenated alkyl, -OH,

[0221] -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 they form the 1-3 Alkyl optionally substituted 5- to 7-membered heterocycloalkyl.

[0222] In such embodiments, the 5- to 7-membered heterocycloalkyl group can be as defined above for Ring 1A.

[0223] In some embodiments, R A 、R B 、R D and R E Independently selected from -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 A group consisting of haloalkyl groups.

[0224] In some cases, R A 、R B 、R D and R E At least one of them may be -H. For example, R A and R B At least one of may be -H. In certain embodiments, R A 、R B 、R D and R E At least two of them are –H.

[0225] In some embodiments, R A 、R B 、R D and R E At least one of -OC 1-3 Alkyl, halogen and -OC 1-3 Sometimes, R B and R E Choose Free-OC 1-3 Alkyl, halogen and -OC 1-3 A group consisting of haloalkyl groups.

[0226] 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 can be -H; or R H and R I Together they can form –C 3-4 Cycloalkyl.

[0227] R G It may be as defined above, or may be selected from -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 、RK and R L and optional substituents of the 4- to 7-membered monocyclic heterocycloalkyl and 7- to 12-membered bicyclic heterocycloalkyl 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.

[0228] When R G or R K When 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 one to three 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 one or two 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 one to three substituents as described herein).

[0229] When R G or R K For optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl, the optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl can be a bridged bicyclic or spirocyclic bicyclic (that is, it can be included in two rings engaged at the center of the spirocyclic ring). For example only, the optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl can be a bridged piperazinyl or a bridged piperidinyl. In other examples, the optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl can be an optionally substituted spirocyclic bicyclic heterocycloalkyl, which includes one to three ring heteroatoms selected from N, O and S (for example, one to two ring heteroatoms selected from N). In some examples, the optionally substituted 7 to 12 yuan of bicyclic heterocycloalkyl can be spirocyclic and include a first 5 yuan or 6 yuan ring and a second 3 to 6 yuan ring.

[0230] In some instances, R C Can be any one selected from the following:

[0231]

[0232] Where Y is CR H R I (e.g., CH2);

[0233] R G1 and R G2 Each independently selected from H and C1-C3 alkyl;

[0234] R J As defined above and herein; and

[0235] L shows the attachment point of the linker.

[0236] In the structures shown above, both the Y and L groups can be attached to the heterocycle via covalent bonds between atoms on the respective Y and L groups and atoms on the heterocycle. These groups can be bonded to any chemically suitable position as long as the valence is satisfied (e.g., by replacing an H atom).

[0237] Just to give a further example, R C Can be any one selected from the following:

[0238]

[0239] Where Y is CR H R I (e.g., CH2); and

[0240] L shows the attachment point of the linker.

[0241] In certain embodiments, R C To choose freedom –CH2N(C 1-3 Alkyl)2, -C(O)N(C 1-3 alkyl)2, -C(CH2CH2)N(C 1-3 alkyl)2 and CH2OCH3, wherein the wavy line is in the R C The bond between the rest of the BRD9 binder and R C Intersect the bonds between the connectors.

[0242] In some embodiments, the BRD9-binding agent has Formula 1e, 1f, or 1g:

[0243]

[0244] wherein the wavy line intersects the bond between the BRD9 binding agent and the linker;

[0245] R A 、R B 、R E 、R M 、R N , Z 3 , Z 5 and Z 6 As defined above;

[0246] R C Not present or as described above and herein for RC defined;

[0247] Ring 1A is –C 1-3 an optionally alkyl-substituted 5- to 7-membered heterocycloalkane; and

[0248] Ring 1D is optionally substituted C 6-10 Aromatic or optionally substituted C 2–9 Heteroaromatic hydrocarbons.

[0249] In some embodiments, Ring 1D is an optionally substituted benzene or an optionally substituted 5- to 6-membered heteroarene. The 5- to 6-membered heteroarene may contain one or more heteroatoms selected from the group consisting of S, N, and O, such as S. In some cases, Ring 1D may be a 5- to 6-membered N-heteroarene or S-heteroarene, for example, any one selected from the group consisting of 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 a more specific example, 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 such specific examples, the BRD9 binder may have

[0250] Formula 1g':

[0251]

[0252] 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.

[0253] In some embodiments, Ring 1A is a pyrrolidine. In a specific example, Ring 1A is a pyrrolidine that is fused to the rest of the BRD9 binder at the 3' and 4' positions and, in more specific embodiments, is bound to the linker via a covalent bond between an atom on the linker and the nitrogen atom of the pyrrolidine. In such specific embodiments, the BRD9 binder can have Formula 1f':

[0254]

[0255] 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 6As defined above and herein.

[0256] In some embodiments, the BRD9-binding agent has Formula 1e, 1f', or 1g'.

[0257] In specific embodiments, the BRD9-binding agent is any one of Formulas 1ea to 1eh, 1fa to 1fh, and 1ga:

[0258]

[0259] wherein the wavy line intersects the bond between the BRD9 binding agent and the linker;

[0260] R A 、R B 、R E 、R M , Z 3 and Z 6 As defined above and herein;

[0261] R C does not exist or as defined above and herein;

[0262] R N As defined above and herein, for example, selected from halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 a group consisting of an alkyl group and –OH;

[0263] R O As defined above and herein, for example, -H or -C 1-3 alkyl;

[0264] Each R X For example, N and Z 5 (together) forming 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 a group consisting of a haloalkoxy group;

[0265] n is 0 to 3 (such as 0);

[0266] o is 0 to 2 (such as 0);

[0267] p is 0 or 1 (such as 0); and

[0268] q is 0 to 4 (such as 0).

[0269] Each of n, o, p, and q may be zero.

[0270] In some embodiments, the BRD9-binding agent is according to Formula 1ea':

[0271]

[0272] wherein the wavy line intersects the bond between the BRD9 binding agent and the linker;

[0273] R A and R E As defined above and herein, for example, each independently selected from H and -OC 1-3 alkyl;

[0274] R B and R D As defined above and herein, for example, each independently selected from -OC 1-3 Alkyl, -H, -halo, -C 1-3 Alkyl and -OC 1-3 alkyl halide;

[0275] R C Does not exist or is –YR G ;

[0276] Y chooses free-CR H R I - and -CO- group;

[0277] R H and R I are each independently selected from -H or -C 1-3 Alkyl; or R H and R I Together to form –C 3-4 Cycloalkyl;

[0278] 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;

[0279] R J and R K As defined above and herein;

[0280] R M As defined above and herein, for example, C 1-3 alkyl; and

[0281] R N 、R O and R P Each is as defined above and herein, for example, each independently selected from halo, -C 1-3 Alkyl and -C 1-3 A group consisting of haloalkyl groups.

[0282] In even more specific embodiments, the BRD9 binding agent is any one of Formulas 1h-1z and 2a-2g:

[0283]

[0284]

[0285] where R C Does not exist or is –YR G ;

[0286] Y chooses free-CR H R I - and -CO- group;

[0287] R H and R I Each is -H; or R H and R I Together to form –C 3-4 Cycloalkyl;

[0288] 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 one or two N ring atoms; and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing one or two N ring atoms;

[0289] R J and R K As defined above and herein;

[0290] Where the wavy line intersects the bond between the BRD9 binder and the linker.

[0291] In specific examples of any of the above formulae (e.g., any of Formulae 1e, 1g, 1g', 1ea to 1eh, 1ea', 1h to 1z, and 2a to 2g, unless otherwise indicated), R G -N(C 1-3 alkyl)-, -O- or

[0292] In some examples of any of the above formulae (eg, any of Formulae 1e, 1g, 1g', 1ea to 1eh, 1ea', 1h to 1z, and 2a to 2g, unless otherwise indicated), R C Can be any one selected from the following:

[0293]

[0294] Where Y is CR H R I (e.g., CH2) or –CO-;

[0295] R H and R I As defined above and herein; and

[0296] L shows the attachment point of the linker.

[0297] In particular, in each of the structures shown above, Y can be CH2.

[0298] In some examples of any of the above formulae (eg, any of Formulae 1e, 1g, 1g', 1ea to 1eh, 1ea', 1h to 1z, and 2a to 2g, unless otherwise indicated), R C may not be present, and the linker may be attached (i.e., covalently bonded) to the parent structure at this position. Such examples may be represented by " and are therefore referred to herein as Formulae 1e", 1g", 1g', 1ea" to 1eh", 1ea", 1h" to 1z", and 2a" to 2g", respectively.

[0299] In some embodiments, the BRD9-binding agent is any one of Formula 1h, 1i, 1j, 1m, 1t, 2c, or 2e:

[0300] where R C Does not exist or is –YR G ;

[0301] Y chooses free-CR H RI - and -CO- group;

[0302] R H and R I Each is -H; or R H and R I Together to form –C 3-4 Cycloalkyl;

[0303] 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 one or two N ring atoms; and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing one or two N ring atoms;

[0304] R J and R K As defined above and herein;

[0305] Where the wavy line intersects the bond between the BRD9 binder and the linker.

[0306] In specific examples of any of the above formulae, R G -N(C 1-3 alkyl)-, -O- or

[0307] In some examples of any of the above formulae, R C Can be any one selected from the following:

[0308]

[0309] Where Y is CR H R I (e.g., CH2) or –CO-;

[0310] R H and R I As defined above and herein; and

[0311] L shows the attachment point of the linker.

[0312] In particular, in each of the structures shown above, Y can be CH2.

[0313] In some examples of any of the above formulae, RC may not be present, and the linker may be attached (i.e., covalently bonded) to the parent structure at this position. Such examples may be represented by " and are therefore referred to herein as Formula 1h", 1i", 1j", 1m", 1t", 2c", or 2e", respectively.

[0314] In some embodiments, the BRD9 binding agent is selected from the group consisting of:

[0315]

[0316]

[0317] Where the wavy line intersects the bond between the BRD9 binder and the linker.

[0318] In some cases, a BRD9-binding agent may not be:

[0319]

[0320] Where the wavy line intersects the bond between the BRD9 binder and the linker.

[0321] Warhead (Z)

[0322] Z comprises a structure according to Formula (I) or Formula (WI).

[0323] As shown in Formulas (I) and (WI), a double bond is present in Z. The stereochemistry of the double bond can be E or Z, and this is indicated by the wavy bond in Formulas (I) and (WI) (and similarly shown in other formulas and structures disclosed herein). The designation of the moiety as E or Z may depend on R 3 or R 3A The identity 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 individual E and Z stereoisomer of any of the disclosed Z moieties according to any of Formulas (I) and (WI) and other formulae 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.

[0324] For the avoidance of doubt, where the double bond of Z of Formula (I) or (WI) is shown in a structure herein as a specific stereoisomer (E or Z) in any of the specific examples of the present disclosure, it is not necessarily in that specific stereoisomer. In other words, both the E and Z stereoisomers, as well as mixtures of the two, are included within the scope of the structure, regardless of the specific stereoisomer shown.

[0325] As mentioned above, in some embodiments, Formula (I) is:

[0326]

[0327] where R 1 、R 3 、R 4 , A, B and L are as defined above.

[0328] On ring B, group R 4 and A may remain at adjacent positions on the aryl, heteroaryl, substituted aryl, or substituted heteroaryl ring. 4 and A groups may be in a 1,2 substitution pattern with each other or may be separated by 3 bonds. For the avoidance of doubt, where B is heteroaryl or substituted heteroaryl, the heteroatoms contained within ring B may be directly bonded to A or R 4 bonding.

[0329] As shown in formula (I) above, the linker is attached to moiety Z via ring B. The linker can be attached to moiety Z via a covalent bond between an atom on the linker and an atom contained in the ring system of the optionally substituted aryl or heteroaryl group of ring B. The linker can be attached to ring B at any position on the optionally substituted aromatic or heteroaromatic ring (as long as it has the correct valence and / or is chemically suitable). For example, the linker can replace a hydrogen atom at any position on the aromatic or heteroaromatic ring.

[0330] In other examples, Z may comprise a structure as shown in formula (I) above, wherein:

[0331] A, B, X, and R 4 as defined above; and wherein

[0332] R 1 is selected from optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 haloalkyl, optionally substituted benzyl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl;

[0333] R 2 and R 2' are each independently selected from H and optionally substituted C1 to C6 alkyl, or wherein R 2 and R 2' together form a 3-membered, 4-membered, 5-membered or 6-membered optionally substituted carbocyclic or heterocyclic ring; and

[0334] R 3 is selected from optionally substituted C1 to C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl and optionally substituted heterocyclyl.

[0335] In which R 1 and R 4 In those cases where together they form an optionally substituted 5-, 6- or 7-membered heterocyclic ring, Z may be represented by formula (Ia):

[0336]

[0337] Among them, A, B, R 3 and L are as defined for formula (I); and

[0338] n is 1, 2, or 3;

[0339] W is selected from CR W1 R W2 、O、NR W3 and S; and

[0340] R W1 、R W2 and R W3 are each independently selected from H and C1 to C6 alkyl; and

[0341] When n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S.

[0342] In which R 1 and R 2 In those cases where together they form an optionally substituted 5-, 6- or 7-membered heterocyclic ring, Z may be represented by formula (Ib):

[0343]

[0344] Among them, B, R 2' 、R 3 、R 4 and L are as defined for formula (I);

[0345] m is 3, 4 or 5;

[0346] Each T is independently selected from CR T1 R T2 、O、NR T3 and S; and

[0347] R T1 、R T2 and R T3 Each is independently selected from H and C1 to C6 alkyl.

[0348] In which R 2 and R 4In those cases where together they form an optionally substituted 5-, 6- or 7-membered heterocyclic or carbocyclic ring, Z may be represented by formula (Ic):

[0349]

[0350] Among them, B, R 1 、R 2' 、R 3 and L are as defined for formula (I);

[0351] p is 2, 3, or 4; and

[0352] Each U is independently selected from CR U1 R U2 、O、NR U3 and S; and

[0353] R U1 、R U2 and R U3 Each is independently selected from H and C1 to C6 alkyl.

[0354] For the various structures of Z defined in the formula herein, R 1 It may be a C1 to C6 alkyl group, such as a C1 to C4 alkyl group. 1 It can be selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.

[0355] As described above for formula (I), A is either absent or CR 2 R 2' . In which A is CR 2 R 2' In some cases, R 2 and R 2' Each is independently selected from H and C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted by one or more halogenated atoms (e.g., F, Cl or Br). 2 R 2' In another embodiment, R 2 and R 2' Each is independently selected from H and C1 to C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl and n-butyl. In some embodiments, R 2 and R 2' One of them is hydrogen and the other is C1 to C6 alkyl. For example, R 2 can be methyl, ethyl, n-propyl or isopropyl, and R 2' It can be H. In other examples, R 2 and R 2’ Both are independently selected from C1 to C6 alkyl (e.g., R 2 and R2’ Both may be methyl). In some examples, R 2 and R 2' Each is independently selected from H and C1 to C3 alkyl substituted with one or more halogen atoms (eg, trifluoromethyl).

[0356] As mentioned above, R 3 is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S. In some examples, R 3 is selected from C1 to C6 alkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl, optionally wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from halo, N, O and S and / or substituted by a carbocyclic or heterocyclic group. For example, R 3 It may be selected from heteroaryl, substituted heteroaryl, substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C3-C6 heterocycloalkyl, C1-C6 alkyl substituted by a heterocyclic group, aryl and substituted aryl.

[0357] Suitable R 3 Representative examples of radicals include, but are not limited to, thiazolyl, pyridyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydropyranyl, oxetanyl, cyclobutyl, cyclopropyl, tert-butyl, imidazolyl, oxazolyl, thienyl, 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, oxetanyl, cyclobutyl, cyclopropyl, and tert-butyl.

[0358] In each case, these R 3 The groups may be substituted, such as substituted thiazolyl, substituted pyridyl, substituted benzothiazolyl, substituted phenyl, substituted pyrazolyl, substituted isoxazolyl, substituted isothiazolyl, substituted tetrahydropyranyl, substituted oxetanyl, substituted cyclobutyl, substituted cyclopropyl and substituted tert-butyl. 3 is a substituted heteroaryl or aryl group, and one or more substituents may be present on the aromatic ring, for example, it may be monosubstituted, disubstituted or trisubstituted. 3 In the case of an optionally substituted pyrazolyl or imidazolyl group, the nitrogen atom of the pyrazolyl or imidazolyl ring may be substituted by a C1 to C6 alkyl group such as a methyl group.

[0359] Suitable R 3 Examples of groups are shown below:

[0360]

[0361] The dashed lines on the structures indicate the corresponding R 3 Each of the groups can be attached to a position in the structure shown in the formulae described herein. When a dashed line does not show a direct connection to an atom, R 3 The group may be attached to the structure of 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). 3 A hydrogen at any position on the radical may be replaced by a bond to the parent structure represented by the formulae described herein.

[0362] R 5 Can be any substituent as described herein or may be absent. In some examples, R 5 Can be selected from halo (for example, F, Cl, Br, I), CF , -CH F, -OCF , -OCH F, -OCHF , -CHF , 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). In the case where multiple substituents are present, each substituent can be independently selected from the above R 5 group.

[0363] R 6 It may be a C1 to C6 alkyl group, such as a methyl group.

[0364] G may be selected from CH2, O and NH.

[0365] Q may be a C1 to C6 alkylene group, such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0366] Suitable R 3 Additional examples of groups are shown below:

[0367]

[0368]

[0369] The dashed lines on the structures indicate the corresponding R 3Each of the groups can be attached to a position in the structure shown in the formulae described herein. When a dashed line does not show a direct connection to an atom, R 3 The group may be attached to the structure of 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). 3 A hydrogen at any position on the radical may be replaced by a bond to the parent structure represented by the formulae described herein.

[0370] R 5 Can be any substituent as described herein or may be absent. In some examples, R 5 Can be selected from halo (for example, F, Cl, Br, I), CH2OH, CF3, -CH2F, -OCF3, -OCH2F, -OCHF2, -CHF2, C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO2Me, -NH2, -NHMe, -NMe2, CO2Me, -NO2, 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). In the case where multiple substituents are present, each substituent can be independently selected from the above R 5 group.

[0371] R 6 It may be a C1 to C6 alkyl group, such as a methyl group.

[0372] G may be selected from CH2, O and NH.

[0373] Q may be a C1 to C6 alkylene group, such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0374] In another embodiment, R 3 Select from the group consisting of:

[0375]

[0376] The dashed lines indicate the corresponding R 3 Each of the groups is attached to a position in the structure of the formulae described herein.

[0377] For example, R 5 Can be selected from C1 to C6 alkyl (e.g., methyl) and halo (e.g., F). As mentioned above, one or more substituents may be present on the aromatic ring. In the case where two or more substituents are present, each substituent may be independently selected from the above R 5 Likewise, where present, unless otherwise indicated, R 5Attachment may be at any position on the aryl or heteroaryl ring (provided it has the correct valence and / or is chemically suitable).

[0378] For example, the appropriate R 3 The group may be selected from the following:

[0379]

[0380] The dashed lines on the structures indicate the corresponding R 3 The group may be attached to the position of the structure shown in formula (I) to (Ic), and R 5 、R 6 , n and G are as defined above.

[0381] Suitable R 3 Additional examples of groups are shown below:

[0382]

[0383] The dashed lines on the structures indicate the corresponding R 3 Each of the groups can be attached to a position in the structure shown in the formulae described herein. When a dashed line does not show a direct connection to an atom, R 3 The group may be attached to the structure of 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). 3 A hydrogen at any position on the radical may be replaced by a bond to the parent structure represented by the formulae described herein.

[0384] R 5 Can be any substituent as described herein or may be absent. In some examples, R 5 Can be selected from halo (for example, F, Cl, Br, I), CH2OH, CF3, -CH2F, -OCF3, -OCH2F, -OCHF2, -CHF2, C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO2Me, -NH2, -NHMe, -NMe2, CO2Me, -NO2, 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). In the case where multiple substituents are present, each substituent can be independently selected from the above R 5 group.

[0385] R 6 It may be a C1 to C6 alkyl group, such as a methyl group.

[0386] G may be selected from CH2, O and NH.

[0387] Q may be a C1 to C6 alkylene group, such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0388] For example, the appropriate R 3 The group may be selected from the following:

[0389]

[0390]

[0391] The dashed lines on the structures indicate the corresponding R 3 Each of the groups may be linked to a position of the structure shown in formulae (I) to (Ic).

[0392] In certain instances, Z comprises a structure according to Formula (II):

[0393]

[0394] in

[0395] R 1 is selected from C1 to C6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl, optionally wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from halo, N, O and S and / or is substituted by a carbocyclyl or heterocyclyl group;

[0396] R 2 and R 2’ are each independently selected from H and C1 to C6 alkyl;

[0397] R 3 is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl, optionally wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from halo, N, O and S and / or is substituted by a carbocyclyl or heterocyclyl group;

[0398] R 4 is H, C1-C6 alkyl, optionally, wherein the C1-C6 alkyl is substituted by one or more heteroatoms selected from N, O or S;

[0399] or where R 1 and R 4 Together they form a 5-, 6-, or 7-membered heterocyclic ring;

[0400] or where R 1 and R 2 Together they form a 5-, 6-, or 7-membered heterocyclic ring;

[0401] or where R 2 and R 4 together form a 5-, 6-, or 7-membered heterocyclic or carbocyclic ring; and

[0402] L shows the connection position of the linker.

[0403] As shown in formula (II), the linker is attached to the Z moiety via the aromatic ring. In particular, the linker is connected to the Z moiety by a covalent bond between an atom on the linker and a carbon atom of the aromatic ring system. The linker can be attached to the aromatic ring at any position (as long as it has the correct valence and / or is chemically suitable). For example, the linker can replace a hydrogen atom at any position on the aromatic ring.

[0404] Representative examples of compounds according to formula (II) include, but are not limited to:

[0405]

[0406] where R 3 and L are as defined herein for formulas (I) and (II);

[0407] R 1 is selected from C1 to C6 alkyl; and

[0408] R 2 Selected from C1 to C6 alkyl.

[0409] In some cases, R 1 is a methyl group, and R 2 It is n-propyl.

[0410] In some instances, when R 1 and R 4 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring, Z can be represented by formula (IIaa):

[0411]

[0412] Among them, A, R 3 and L are as defined herein for formulas (I) and (II);

[0413] n is 1, 2, or 3; and

[0414] W is selected from CR W1 R W2 、O、NR W3 and S; and

[0415] R W1 、R W2 and R W3 are each independently selected from H and optionally substituted C1 to C6 alkyl; and

[0416] When n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S.

[0417] In some cases, each W is CR W1 R W2 .

[0418] Representative examples of compounds according to formula (IIaa) include, but are not limited to:

[0419]

[0420] where R 3 and L are as defined above for formula (I);

[0421] R 2 R may be selected from H or C1-C6 alkyl (such as methyl, ethyl, isopropyl or trifluoromethyl) which is optionally substituted by one or more heteroatoms selected from halogen; 2' may be a C1-C6 alkyl group (such as methyl); and

[0422] R W1 It may be selected from C1-C6 alkyl groups (such as methyl or ethyl).

[0423] Representative examples of compounds according to formula (IIaa) include, but are not limited to:

[0424]

[0425] where R 3 and L are as defined above for formula (I);

[0426] R 2 R may be selected from H or C3-C6 cycloalkyl, C1-C4 alkoxy or C1-C6 alkyl optionally substituted with one or more heteroatoms selected from halogen (such as cyclopropyl, methyl, ethyl, n-propyl, isopropyl, methylmethoxy, difluoromethyl or trifluoromethyl); 2' may be a C1-C6 alkyl group (such as a methyl group) or a C1-C4 alkoxy group (such as a methoxy group); and R W1 It may be selected from C1-C6 alkyl groups (such as methyl or ethyl).

[0427] For example, when R 1 and R 4 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring, Z can be represented by formula (IIa):

[0428]

[0429] where R 2 、R 2' 、R 3 and L are as defined above, e.g., as defined for formula (II);

[0430] n is 1, 2, or 3; and

[0431] W is selected from CR W1 R W2 、O、NR W3 and S; and

[0432] R W1 、R W2 and R W3 are each independently selected from H and C1 to C6 alkyl; and

[0433] When n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S.

[0434] In some cases, each W is CH2.

[0435] In some examples, Z can be represented by formula (IIa'):

[0436]

[0437] where R 3 and L is as defined above;

[0438] R 2 is a C1 to C3 alkyl group; R 2' is H; n is 2; and each W is CH2.

[0439] By way of further example, Z may be selected from one of the following:

[0440]

[0441] where R 3 and L are as defined above and herein.

[0442] Alternatively, Z may be selected from one of the following structures:

[0443]

[0444] where R 3 and L are as defined above and herein.

[0445] The present invention also relates to any compound comprising a moiety selected from one of the following structures:

[0446] where R 3 As defined above and herein.

[0447] The present invention also relates to a compound selected from one of the following structures:

[0448]

[0449] where R 3 As defined above and herein.

[0450] The group G is configured to enable the compound to be connected to another chemical structure (such as a linker moiety or a linker-target protein binding ligand moiety) via forming a new covalent bond. After forming the new covalent bond, the group G can form a part of a linker as defined herein.

[0451] 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.

[0452] By way of example only, G may be represented as follows:

[0453]

[0454] where R G is absent or is C1 to C6 alkyl, optionally substituted by one or more heteroatoms selected from N, O and S; X G is a group selected from the group consisting of: -CO2H, -(CO)-N-hydroxysuccinimide, -(CO)-pentafluorophenol ester, -CHO, -COR G1 、-OH、-NH2、-NHR G2 , halo (e.g., iodine and bromine), an O-leaving group (such as -OTs (tosylate), OMs (mesylate), -OTf (triflate)), alkynyl, azide, dienyl, aminooxy, tetrazinyl, (E)-cyclooctenyl, cyclooctynyl, norbornyl, boronic acid, boronate, alkylborane, or an organometallic group (e.g., organotin, zinc, or other suitable reagent); and

[0455] R G1 and R G2 Each is independently selected from H, hydroxyl or C1-C6 alkyl.

[0456] In this structure, the wavy line is shown over the bond forming the connection to the aromatic portion of the compound.

[0457] G through R G The group is attached to the aromatic portion of the compound. GIn the absence of G Directly attached to the aromatic portion of the compound.

[0458] Representative examples of suitable G moieties are shown below:

[0459]

[0460] When R 1 and R 2 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring, Z can be represented by formula (IIb):

[0461]

[0462] where R 2’ 、R 3 and L are as defined above, e.g., as defined for formula (II);

[0463] m is 3, 4 or 5;

[0464] Each T is independently selected from CR T1 R T2 、O、NR T3 and S; and

[0465] R T1 、R T2 and R T3 Each is independently selected from H and C1 to C6 alkyl.

[0466] For example, in some cases, each T is CH2.

[0467] When R 2 and R 4 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring or carbocyclic ring, Z can be represented by formula (IIc):

[0468]

[0469] where R 1 、R 2' 、R 3 and L are as defined above, e.g., as defined for formula (II);

[0470] p is 2, 3, or 4; and

[0471] Each U is independently selected from CR U1 R U2 、O、NR U3 and S; and

[0472] R U1 、R U2 and R U3Each is independently selected from H and C1 to C6 alkyl.

[0473] For example, in some cases, each T is CH2.

[0474] Representative examples of Z are shown below:

[0475]

[0476]

[0477] Additional representative examples of Z are shown below:

[0478]

[0479]

[0480]

[0481]

[0482]

[0483] The dotted lines in the above structures indicate that the linker can be attached to the Z moiety at any position on the aromatic ring (as long as it has the correct valence and / or is chemically suitable). For example, the linker can replace a hydrogen atom at any position on the aromatic ring. By way of further example, in the case where B is a phenyl ring, the linker can be attached to the side chain amide group in a para-substituted pattern, as shown in Formula (IId).

[0484]

[0485] Alternatively, it is worth noting that while Formulas (I) to (IId) indicate that the linker is attached to the Z moiety via ring B (which may be an aromatic ring in some cases), the present disclosure also extends to instances where the linker is attached at any other position in the Z moiety (as 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 moiety. Thus, in some instances, Z can be represented as shown in Formula (III):

[0486]

[0487] where R 1 ,A,R 3 、R 4 , B and L are as defined for Formula (I) (or any one of Formulas (Ia) to (IId)).

[0488] The dashed line indicated by the square brackets on Formula (III) indicates that the linker can be attached via a covalent bond to any atom on the Z moiety, so long as it has the correct valence, is chemically suitable, and / or so long as attachment of the linker at this alternative position does not disrupt the function of the Z moiety in promoting and / or facilitating proteasomal degradation.

[0489] In some embodiments, the Z portion may not be:

[0490]

[0491] In some embodiments, the Z moiety can be, for example, of Formula (Ia), (Ib), (IIaa), (IIa), or (IIb).

[0492] The inventors have discovered that certain exemplary bifunctional molecules comprising a Z moiety of Formula (Ia), (Ib), (IIaa), (IIa), or (IIb) can be used to more selectively degrade BRD9 over other proteins, such as other BRD proteins, e.g., BRD4.

[0493] As described above, Z may comprise a structure according to Formula (I), Formula (WZI), or Formula (WI).

[0494] Formula (WZI) is:

[0495]

[0496] in:

[0497] Ring A 2A 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 additional ring heteroatoms selected from N, O, and S;

[0498] R 2A 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)-;

[0499] where R y is optionally substituted C 1-6 Alkyl or H;

[0500] R 3Ais selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S; and L represents the point of attachment of the linker;

[0501] Formula (WI) is:

[0502]

[0503] where R 1A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0504] R 2A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-;

[0505] R 3A is selected from C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; X 1 is CH2;

[0506] X 2 and X 3 Each independently is CH2 or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl; and n is 0, 1, 2 or 3; and

[0507] L shows the attachment point of the linker.

[0508] In some examples, when Z has Formula (WZI) or Formula (WI) or any subformula described below, it may not be:

[0509]

[0510] In the embodiment of formula (WI), R 1A and R 2A At least one of exists.

[0511] As shown in the above formula (WZI), the linker can be connected via R 2A The group is attached to the moiety Z. In such examples, the linker can be attached to R via an atom on the linker. 2AThe linker may be connected 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 connected to the moiety Z by a covalent bond to the NR y The moiety Z is connected to the moiety Z through a covalent bond to the nitrogen atom of the -CH(aryl)- or -CH(substituted aryl)- group or to the benzylic carbon atom of the -CH(aryl)- or -CH(substituted aryl)- group, for example, through a covalent bond to the benzylic carbon atom of the -CH(aryl)- or -CH(substituted aryl)- group.

[0512] As described above, in some examples of Formula (WZI) or Formula (WI), R 2A In such examples, the linker can be connected to the heterocycle (e.g., ring A) by atoms on the linker. 2A ) is attached to moiety Z by covalent bonds between atoms contained therein.

[0513] In all examples, 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 at R 2A The aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y It is bonded to any position on -CH(aryl)-, -CH(aryl)-, or -CH(substituted aryl)-, or to any position on the heterocycle represented by, for example, Formula (WZI) or Formula (WI).

[0514] As mentioned above, Ring A 2A 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 additional ring heteroatoms selected from N, O and S, such as N and O.

[0515] When Ring A 2A When bicyclic or tricyclic, and unless otherwise specified, it may contain rings connected by bonds, fused rings, bridged rings, and / or rings connected at a spiro center.

[0516] When Ring A 2A When bicyclic, it may be a bridged bicyclic ring (i.e., it may comprise two rings that share three or more atoms) or it may be a spiro bicyclic ring (i.e., it may comprise two rings that share one atom, e.g., the two rings may be joined at a spiro center).

[0517] When Ring A 2A 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 examples, Ring A 2Ais a 7-membered 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 2A is a 7- or 8-membered bridged bicyclic N-heterocycloalkyl group optionally containing one additional ring atom selected from N.

[0518] When Ring A 2A When a spirocyclic bicyclic ring is present, it may be an optionally substituted 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl group optionally containing one or two additional ring heteroatoms selected from N, O, and S. In some examples, Ring A 2A 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 2A is bicyclic and comprises a first 5- to 7-membered ring and a second 3- to 7-membered ring. For example, ring A 2A 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 comprising one or two additional ring heteroatoms selected from N, O, and S. In some examples, ring A 2A 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 additional ring heteroatom selected from N.

[0519] In some embodiments, Z comprises a structure according to Formula (WZIa):

[0520]

[0521] in:

[0522] R 1A 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 two R 1A 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 N-heterocycloalkyl), optionally wherein C 3-5 Cycloalkyl or 5- to 7-membered heterocycloalkyl is attached to ring A at the spiro center A ;

[0523] R 2A 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)-;

[0524] where R y is optionally substituted C 1-6 Alkyl or H;

[0525] R 3A is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S;

[0526] X 1 is CH2;

[0527] X 2 、X 3 and X 4 Each independently is CH2, O or NR x ;

[0528] R x is H or C1 to C6 alkyl, or one of R 1A group and an R x The groups combine to form an optionally substituted C 1-3 bridge;

[0529] n is 0, 1, 2, or 3;

[0530] m is 0, 1, 2, 3 or 4; and

[0531] L shows the attachment point of the linker.

[0532] In some examples, when n is 1, 2, or 3 (ie, when 1, 2, or 3 X 4 When a group exists), X adjacent to (or directly bonded to) the N of the heterocyclic ring represented by formula (WZIa) 4 The group is CH2.

[0533] In some examples, Z comprises a structure according to Formula (WZIb):

[0534]

[0535] in:

[0536] R 1A 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 two R 1AThe 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 N-heterocycloalkyl), optionally wherein C 3-5 Cycloalkyl or 5- to 7-membered heterocycloalkyl is attached to ring A at the spiro center A ;

[0537] R 2A 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)-;

[0538] where R y is optionally substituted C 1-6 Alkyl or H;

[0539] R 3A is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S;

[0540] X 1 and X 4 Each is CH2;

[0541] X 2 and X 3 Each independently is CH2, O or NR x ; The condition is X 2 and X 3 If there is no or only one of them, it is O;

[0542] R x is H or C1 to C6 alkyl; or one of R 1A group and an R x The groups combine to form an optionally substituted C 1-3 bridge;

[0543] n is 0, 1, 2, or 3;

[0544] m is 0, 1, 2, 3 or 4; and

[0545] L shows the attachment point of the linker.

[0546] In some examples, Z comprises a structure according to Formula (WZIb'):

[0547]

[0548] in:

[0549] R 1A 、R 3A 、X 1 、X 2 、X 3 、X 4 , n, m and L are as defined above for formulae (WZIa) and (WZIb).

[0550] In some examples, Z comprises a structure according to Formula (WZIb"):

[0551]

[0552] in:

[0553] R 2A 、R 3A 、X 1 、X 2 、X 3 、X 4 , n and L are as defined above for formulae (WZIa) and (WZIb).

[0554] As described above, in some embodiments of Formulas (WZIa), (WZIb), (WZIb'), and (WZIb") (and other formulae described herein), the optionally substituted C 1-3 The bridge can be made of two R 1A group, or in some cases, by an R 1A group and an R x Group formation. 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 methylene or ethylene. 1-3 Where the bridge is substituted, it may comprise one to three (e.g., one or two) substituents (selected from any suitable substituents described herein). For example, a C1 to C3 alkylene bridging group may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl, and C1 to C3 alkoxy.

[0555] In further embodiments, Z may comprise a structure according to Formula (WI):

[0556]

[0557] where R1A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0558] R 2A 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)-;

[0559] where R y is H or C1 to C6 alkyl;

[0560] R 3A is selected from C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; X 1 is CH2;

[0561] X 2 and X 3 Each independently is CH2 or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl; n is 0, 1, 2 or 3; and

[0562] L shows the connection point of the linker;

[0563] And further, wherein Z is not:

[0564]

[0565] In an alternative embodiment of formula (WI), for the R given above 3A The list of options can be replaced by one 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 by one or more heteroatoms selected from halo, N, O and S.

[0566] In some embodiments, R 2A 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)-.

[0567] In some examples of Formula (WI), R 1Aor R 2A At least one of exists.

[0568] For example, in R 1A In the absence of R 2A 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, in R 1 In the absence of 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)-.

[0569] For example, in R 2A In the absence of R 1A 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 further example, in R 2A In the absence of at least one R 1A 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 two R 1A The groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-6 Cycloalkyl or optionally substituted 5 to 7 membered N-heterocycloalkyl, optionally wherein C 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl is attached to ring A at the center of the spirocycle A .

[0570] In some examples of Formula (WI), R 1A and R 2A For example, in some cases, R 2A There is and at least one R 1A 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 two R 1A The groups combine to form an optionally substituted C 1-3 bridge, optionally substituted C 3-6 cycloalkyl or optionally substituted 5- to 7-membered N-heterocycloalkyl.

[0571] In the compounds of formula (WZI) and formula (WI) (and subformulae thereof), R 1A and / or R 2A The heterocyclic ring may be covalently linked at any suitable position (e.g., Ring A 2A or Ring A A ), for example, as long as it has the correct valence and / or is chemically suitable. For example, R 1A and / or R 2A A hydrogen atom at any position on the heterocyclic nucleus may be replaced, for example, as shown in formula (WI).

[0572] In R 1A and R 2A When both are present, they may be covalently attached to the heterocycle (e.g., Ring A) at the same or different positions. 2A or Ring A A ). For example, in some cases, R 1A and R 2A The heterocyclic ring may be covalently linked to the heterocyclic nucleus via different carbon atoms. 1A and R 2A Covalent attachment to the heterocyclic core may be via the same carbon atom.

[0573] For further example, Z can be represented by formula (WIa) or (WIb):

[0574]

[0575] where R 1A 、R 2A 、R 3A 、X 1 、X 2 、X 3 and n are as defined above and herein with respect to Formula (WI) and subformulae thereof listed below.

[0576] For further example, Z can be represented by formula (WIc'):

[0577]

[0578] in:

[0579] R 1AR is absent (i.e., m is 0) or selected from the group consisting of: an aryl group having 6 to 10 carbon ring atoms, which is optionally substituted by one to three substituents; a heteroaryl group having 5 to 10 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, which is optionally substituted by one to three substituents; a C3 to C8 cycloalkyl group, which is optionally substituted by one to three substituents; a heterocycloalkyl group having 3 to 10 ring atoms and containing 1 to 3 ring heteroatoms each independently selected from N, O and S, which is optionally substituted by one to three substituents; a C1 to C6 alkyl group, which is optionally substituted by one to three substituents; and / or two R 1A The groups combine to form C optionally substituted with one to three substituents. 1-3 bridge, C optionally substituted by one to three substituents 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl optionally substituted by one to three substituents (eg, wherein C 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl is attached to ring A at the center of the spirocycle A );

[0580] R 2A is absent or selected from the group consisting of: an aryl group having 6 to 10 carbon ring atoms, the aryl group being optionally substituted with one to three substituents; a heteroaryl group having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl group being optionally substituted with one to three substituents; a heterocycloalkyl group having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl group being optionally substituted with one to three substituents; -NR y -CH(aryl)-, wherein the aryl group has 6 to 10 carbon ring atoms and is optionally substituted with one to three substituents; and -CH(heteroaryl)-, wherein the heteroaryl group has 5 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O and S, and the heteroaryl group is optionally substituted with one to three substituents;

[0581] where R y is H or C1 to C6 alkyl;

[0582] R 3ASelected from the group consisting of: C1 to C6 alkyl optionally substituted by one to three substituents; C3 to C8 cycloalkyl optionally substituted by one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted by one to three substituents; aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted by one to three substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted by one to three substituents;

[0583] X 1 is CH2;

[0584] X 2 and X 3 are each independently CH2, or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl, or one of R 1A group and an R x The groups combine to form C optionally substituted with one to three substituents. 1-3 Bridge; the condition is that there is no or only 1 or 2 X 2 and X 3 is a heteroatom; and

[0585] m is 0, 1, 2, or 3;

[0586] n is 0, 1, 2, or 3; and

[0587] L shows the attachment point of the linker.

[0588] For further example, Z can be represented by formula (WIc):

[0589]

[0590] in:

[0591] R 1A is absent or selected from the group consisting of: an aryl group having 6 to 10 carbon ring atoms, the aryl group being optionally substituted with one to three substituents; a heteroaryl group having 5 to 10 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl group being optionally substituted with one to three substituents; a C3 to C8 cycloalkyl group; a C1 to C6 alkyl group optionally substituted with one to three substituents;

[0592] R 2Ais absent or selected from the group consisting of: an aryl group having 6 to 10 carbon ring atoms, the aryl group being optionally substituted with one to three substituents; a heteroaryl group having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl group being optionally substituted with one to three substituents; a heterocycloalkyl group having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl group being optionally substituted with one to three substituents; -NR y -CH(aryl)-, wherein the aryl group has 6 to 10 carbon ring atoms and is optionally substituted with one to three substituents; and -CH(heteroaryl)-, wherein the heteroaryl group has 5 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O and S, and the heteroaryl group is optionally substituted with one to three substituents;

[0593] where R y is H or C1 to C6 alkyl;

[0594] R 3A Selected from the group consisting of: C1 to C6 alkyl optionally substituted by one to three substituents; C3 to C8 cycloalkyl optionally substituted by one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl being optionally substituted by one to three substituents; aryl having 6 to 10 carbon ring atoms, the aryl being optionally substituted by one to three substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted by one to three substituents;

[0595] X 1 is CH2;

[0596] X 2 and X 3 are each independently CH2, or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl; provided that there is no or only 1 or 2 X 2 and X 3 is a heteroatom; and

[0597] n is 0, 1, 2, or 3; and

[0598] L shows the attachment point of the linker.

[0599] For further example, Z can be represented by formula (WId'):

[0600]

[0601] in:

[0602] R 1A is absent (i.e., when m is 0) or is selected from the group consisting of: phenyl, the phenyl being optionally substituted by one to three substituents selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O, and S, the heteroaryl being optionally substituted by one to three substituents selected from the group consisting of halo, 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 each independently selected from N, O, and S; C3 to C8 cycloalkyl; C1 to C6 alkyl, and C1 to C6 haloalkyl;

[0603] and / or two of the R 1A Groups combine to form C 1-3 Bridge, C 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl (e.g., wherein C 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl is attached to ring A at the center of the spirocycle A );

[0604] R 2A is absent or selected from the group consisting of: phenyl, the phenyl being optionally substituted by one to three substituents selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted by one to three substituents each independently selected from the group consisting of halo, 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 each independently selected from N, O and S, the heterocycloalkyl being optionally substituted by one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; -NR y -CH(phenyl)-, wherein the phenyl is optionally substituted by one to three substituents each independently selected from the group consisting of halo, 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 each independently selected from N, O, and S, and the heteroaryl is optionally substituted by one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy;

[0605] where R y is H or C1 to C6 alkyl;

[0606] R 3A 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 one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; phenyl, optionally substituted with one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; and heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, optionally substituted with one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0607] X 1 is CH2;

[0608] X 2 and X 3 are each independently CH2, or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl, or one of R 1A 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

[0609] m is 0, 1, 2, or 3;

[0610] n is 0, 1, 2, or 3; and

[0611] L shows the attachment point of the linker.

[0612] For further example, Z can be represented by formula (WId):

[0613]

[0614] in:

[0615] R 1Ais absent or is selected from the group consisting of: phenyl, the phenyl being optionally substituted by one to three substituents selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O, and S, the heteroaryl being optionally substituted by one to three substituents selected from the group consisting of halo, 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;

[0616] R 2A is absent or selected from the group consisting of: phenyl, the phenyl being optionally substituted by one to three substituents selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl being optionally substituted by one to three substituents each independently selected from the group consisting of halo, 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 each independently selected from N, O and S, the heterocycloalkyl being optionally substituted by one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; -NR y -CH(phenyl)-, wherein the phenyl is optionally substituted by one to three substituents each independently selected from the group consisting of halo, 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 each independently selected from N, O, and S, and the heteroaryl is optionally substituted by one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl, and C1 to C6 alkoxy;

[0617] where R y is H or C1 to C6 alkyl;

[0618] R 3Ais 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 C8 cycloalkyl optionally substituted with one to three substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, the heterocycloalkyl optionally substituted with one to three substituents; phenyl optionally substituted with one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; and heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, the heteroaryl optionally substituted with one to three substituents each independently selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0619] X 1 is CH2;

[0620] X 2 and X 3 are each 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

[0621] n is 0, 1, 2, or 3; and

[0622] L shows the attachment point of the linker.

[0623] For further example, Z can be represented by formula (WIe'):

[0624]

[0625] in:

[0626] R 1A is absent (i.e., when m is 0) or is selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms containing 1 or 2 heteroatoms each independently selected from N, O and S; C3 to C7 cycloalkyl; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each 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 a substituent selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy; and / or wherein two R 1A Groups combine to form C 1-3 Bridge, C 3-5 Cycloalkyl or 5 to 7 membered N-heterocycloalkyl (eg, wherein the C3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl is attached to ring A at the center of the spirocycle A );

[0627] R 2A is absent or selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; -NR y -CH(phenyl)-; and -CH(heteroaryl), wherein the heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O, and S; and further, wherein the phenyl, heteroaryl, heterocycloalkyl, -CH(phenyl)-, and -CH(heteroaryl) are each optionally substituted with a substituent selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl, and C1 to C3 alkoxy;

[0628] where R y is H or C1 to C6 alkyl;

[0629] R 3A Selected from the group consisting of: C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; C3 to C6 cycloalkyl; phenyl; and heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the C3 to C6 cycloalkyl, phenyl and heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy;

[0630] X 1 is CH2;

[0631] X 2 and X 3 are each independently CH2 or O; provided that X 2 and X 3 If there is no or only one of them, it is O;

[0632] m is 0, 1, 2, or 3;

[0633] n is 1, 2, or 3; and

[0634] L shows the attachment point of the linker.

[0635] For further example, Z can be represented by formula (WIe):

[0636]

[0637] in:

[0638] R 1A is absent or selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms containing 1 or 2 heteroatoms each 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 a substituent selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy;

[0639] R 2A is absent or selected from the group consisting of: phenyl; heteroaryl having 5 to 6 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; -NR y -CH(phenyl)-; and -CH(heteroaryl), wherein the heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O, and S; and further, wherein the phenyl, heteroaryl, heterocycloalkyl, -CH(phenyl)-, and -CH(heteroaryl) are each optionally substituted with a substituent selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl, and C1 to C3 alkoxy;

[0640] where R y is H or C1 to C6 alkyl;

[0641] R 3A Selected from the group consisting of: C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; C3 to C6 cycloalkyl; phenyl; and heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the C3 to C6 cycloalkyl, phenyl and heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy;

[0642] X 1 is CH2;

[0643] X 2 and X 3 are each independently CH2 or O; provided that X 2 and X 3 None or only one of them is O; and

[0644] n is 1, 2, or 3; and

[0645] L shows the attachment point of the linker.

[0646] In further embodiments, Z comprises a structure according to Formula (WZII):

[0647]

[0648] where R 2A is not present or as described in any of the embodiments disclosed herein;

[0649] R 3A As described in any one of the embodiments disclosed herein;

[0650] X 5 CR b 2. NR b , O or 5- to 7-membered heterocycloalkyl (e.g., 5- to 7-membered heterocycloalkyl);

[0651] Each R 1A 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 two R 1A 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 (WZII) at the center of the spirocycle);

[0652] R b is H or optionally substituted C 1-3 alkyl;

[0653] n1 is 0, 1, 2, or 3;

[0654] m is 0, 1, or 2; and

[0655] L shows the attachment point of the linker.

[0656] In yet further embodiments, Z comprises a structure according to any one of Formulas (WZIIa) to (WZIIe):

[0657]

[0658] in:

[0659] R 2A As described in any one of the embodiments disclosed herein;

[0660] R 3AAs described in any one of the embodiments disclosed herein;

[0661] Each R 1A 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 two R 1A The groups combine to form an optionally substituted C 3-5 Cycloalkyl (optionally, wherein the C 3-5 The cycloalkyl group is attached to the heterocycle shown in formula (ZIIa) at the center of the spirocycle);

[0662] X 5 C(R b )2、NR b or O;

[0663] R b is H or optionally substituted C 1-3 alkyl;

[0664] n1 is 0, 1, 2, or 3;

[0665] n' is 1 or 2;

[0666] m is 0, 1, or 2; and

[0667] L shows the attachment point of the linker.

[0668] For example, Z may comprise a structure according to Formula (WZIIIa) to (WZIIIh):

[0669]

[0670] in:

[0671] R 2A As described in any one of the embodiments disclosed herein;

[0672] R 3A As described in any one of the embodiments disclosed herein;

[0673] Each R 1A independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0674] X 5 CH2、NR b or O;

[0675] R b is H or optionally substituted C 1-3 alkyl;

[0676] n1 is 0, 1, or 2;

[0677] n' is 1 or 2;

[0678] m is 0, 1, or 2; and

[0679] L shows the attachment point of the linker.

[0680] In even further embodiments, Z comprises a structure according to Formula (WZIVa) to (WZIVj):

[0681]

[0682] in:

[0683] R 2A is not present or as described in any of the embodiments disclosed herein;

[0684] R 3A As described in any one of the embodiments disclosed herein;

[0685] Each R 1A independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0686] n1 is 0, 1, or 2;

[0687] n' is 1 or 2;

[0688] m is 0, 1, or 2; and

[0689] L shows the attachment point of the linker.

[0690] In further examples, Z comprises a structure according to Formula (WIf):

[0691]

[0692] where R 1A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[0693] R 2A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, and -CH(substituted aryl)-;

[0694] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted C1 to C6 alkyl, substituted aryl, and substituted heteroaryl; and

[0695] where R 1A and R 2A At least one of the exists;

[0696] n is 0, 1, 2, or 3; and

[0697] L shows the attachment point of the linker.

[0698] In some examples, R of formula (WIf) 1A 、R 2A and R 3A The groups may be selected from those defined above for any one or more of formula (WIc'), (WIc), (WId'), (WId), (WIe') or (WIe).

[0699] In some examples of Formula (WZI), (WI), and the various subformulae described above and herein, n can be 1, 2, or 3 and / or n1 can be 0, 1, or 2.

[0700] In which R 1A In the absence of Z, Z can be represented by formula (WII):

[0701]

[0702] where R 2A 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);

[0703] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[0704] X 1 is CH2;

[0705] X 2 and X 3 are each independently CH2 or O; provided that X 2 and X 3 None or only one of them is O; and n is 0, 1, 2 or 3; and

[0706] L shows the attachment point of the linker.

[0707] In which R 1A In the absence of Z, Z may be represented by formula (WIIa):

[0708]

[0709] where R 2A 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);

[0710] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[0711] n is 0, 1, 2, or 3; and

[0712] L shows the attachment point of the linker.

[0713] For example, in formula (WII) or (WIIa), n can be 1 or 2.

[0714] By way of further example, Z can be represented by formula (WIIb):

[0715]

[0716] where R 2A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[0717] X 1 is CH2;

[0718] X 2 and X 3 are each independently CH2 or O; provided that X 2 and X 3 If there is no or only one of them, it is O;

[0719] n is 1 or 2; and

[0720] L shows the attachment point of the linker.

[0721] For further example, Z can be represented by formula (WIIc):

[0722]

[0723] where R 2A is selected from heterocycloalkyl and substituted heterocycloalkyl;

[0724] R 3Ais selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[0725] X 1 is CH2;

[0726] X 2 and X 3 are each independently CH2 or O; provided that X 2 and X 3 If there is no or only one of them, it is O;

[0727] n is 1 or 2; and

[0728] L shows the attachment point of the linker.

[0729] In some cases, Z can be represented by formula (WIId):

[0730]

[0731] where R 2A is selected from heterocycloalkyl and substituted heterocycloalkyl;

[0732] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[0733] n is 1 or 2; and

[0734] L shows the attachment point of the linker.

[0735] In other examples, Z can comprise a structure according to Formula (WIIe):

[0736]

[0737] where R 2A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[0738] n is 1 or 2; and

[0739] L shows the attachment point of the linker.

[0740] In other examples, Z can comprise a structure according to Formula (WIIf):

[0741]

[0742] where R 2A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[0743] L shows the attachment point of the linker.

[0744] In which R 2A In those instances where it is absent, Z may comprise a structure according to formula (WIII):

[0745]

[0746] where R 1A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl;

[0747] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[0748] n is 0, 1, 2, or 3; and

[0749] L shows the attachment point of the linker.

[0750] In some examples, n can be 1 or 2.

[0751] In some examples where n is 2, Z can be represented by formula (WIIIa):

[0752]

[0753] where R 1A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl;

[0754] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[0755] L shows the attachment point of the linker.

[0756] In some instances where n is 1, Z can be represented by formula (WIIIb):

[0757]

[0758] where R 1A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C1-C6 alkyl;

[0759] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[0760] L shows the attachment point of the linker.

[0761] As shown above, the bifunctional molecule of formula (WIIIb) contains at least two stereocenters and therefore exists in several diastereomeric (and enantiomeric) forms. In some examples, the group R 1A and L can exist in a trans relationship (eg, these groups are held and / or oriented on opposite sides of the heterocyclic core). In other examples, the group R 1A and L can exist in a cis relationship (e.g., these groups remain and / or are oriented on the same side of the heterocyclic core). By way of further example, the bifunctional molecule of formula (WIIIb) can encompass at least the following diastereoisomeric forms:

[0762]

[0763] In which R 1A does not exist and R 2A In those examples selected from CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-, Z may be represented by formula (WIV):

[0764]

[0765] where R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[0766] R 4A is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

[0767] n is 0, 1, 2, or 3; and

[0768] L shows the attachment point of the linker.

[0769] In some examples, Z can comprise a structure according to Formula (WIVa):

[0770]

[0771] where R3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[0772] R 4A is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

[0773] L shows the attachment point of the linker.

[0774] In either of Formula (WIV) or (WIVa), R 4A It may be selected from an aryl group or a substituted aryl group.

[0775] For the various structures of Z defined herein by formulae (WI) to (WIV) (and subformulae thereof) (unless otherwise indicated), R 1A It may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1 to C6 alkyl and substituted C1 to C6 alkyl.

[0776] In some instances, R 1A is optionally substituted aryl or optionally substituted heteroaryl.

[0777] In R 1A In the case of a substituted aryl group or a substituted heteroaryl group, the aryl group or heteroaryl group may contain one or more substituents selected from the group consisting of C1 to C6 alkyl (e.g., methyl), C1 to C6 alkoxy (e.g., methoxy), C1 to C6 haloalkyl and halo.

[0778] For example, R 1A It may be phenyl, which is optionally substituted by one to three substituents selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy. 1A It may be: a heteroaryl group having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, which is optionally substituted by one to three substituents selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; a C3 to C8 cycloalkyl group.

[0779] Suitable R 1A Representative examples of groups include, but are not limited to, phenyl, substituted phenyl, pyrazolyl, and substituted pyrazolyl.

[0780] In some instances, R 1A is a cycloalkyl group, such as a C3 to C7 cycloalkyl group or a C3 to C6 cycloalkyl group.

[0781] In some instances, R1A is C1 to C6 alkyl, such as C1 to C3 alkyl, which is optionally substituted with one to three substituents as defined herein.

[0782] Suitable R 1A Additional non-limiting examples of groups are shown below:

[0783]

[0784]

[0785] Suitable R 1A Additional non-limiting examples of groups are:

[0786]

[0787] Suitable R 1A Additional non-limiting examples of groups are:

[0788]

[0789] In the structure shown above, the lines intersecting the wavy lines represent the exemplary R 1A A covalent bond between the group and a carbon atom on the heterocycloalkyl nucleus that is attached to R in the parent structure of Z 1A While specific substitution patterns are shown in the exemplary aryl and heteroaryl structures above, it should be understood that other substitution patterns are also encompassed within the scope of the present disclosure.

[0790] In other examples, such as with respect to formula (WZII), two R 1A Groups can combine to form C 1-3 Bridge or C 3-5 Cycloalkyl. For example, two R 1A Groups can combine to form C 3-5 In such examples, C 3-5 The cycloalkyl group can be attached to the heterocycle of the parent structure at the spiro center.

[0791] With respect to the various structures of Z defined by Formulae (WZI) to (WZIV), (WI) to (WIV) (and subformulae) described herein (unless otherwise indicated), R 2A It 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 C1-6 Alkyl (such as methyl) or H.

[0792] In some instances, R 2A is present in Z (and / or a bifunctional molecule described herein) as a divalent group. In other words, as shown in Formulas (WI) to (WIVa) (unless otherwise indicated), for R 2A The various groups defined are covalently linked to atoms of the heterocyclic core of Z and may also be covalently linked to atoms of the linker. Thus, these groups can be considered as divalent free radical species.

[0793] where R 2A is selected from optionally substituted aryl and optionally substituted heteroaryl, R 2A can be selected from aryl groups having 6 to 10 carbon ring atoms, which are optionally substituted with one to three substituents; and heteroaryl groups having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S, which are optionally substituted with one to three substituents. For further example, R 2A Can be selected from the following: phenyl, the phenyl being optionally substituted by one to three substituents selected from H, C1 to C6 alkyl, halo, 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 being optionally substituted by one to three substituents selected from C1-C6 alkyl (e.g., C1 to C3 alkyl), halo (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 2A Suitable examples of include, but are not limited to, optionally substituted phenyl and optionally substituted pyrazolyl.

[0794] In R 2A In the case of optionally substituted heterocycloalkyl, the heterocycloalkyl may have 3 to 10 ring atoms and contain 1 to 3 heteroatoms each independently selected from N, O and S, and the heterocycloalkyl may be optionally substituted by one to three substituents. In some instances, 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.

[0795] Suitable R 2A Additional examples of groups are shown below:

[0796]

[0797] In the above structure, R 6ACan be selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl and C1-C6 alkoxy. 6A It can be selected from H and C1-C6 alkyl.

[0798] Suitable R 2A Additional examples of groups are shown below:

[0799]

[0800] where R 6A is selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl and C1-C6 alkoxy. 6A It can be selected from H and C1-C6 alkyl.

[0801] In the structure shown above, the lines intersecting the wavy lines represent the exemplary R 2A A covalent bond between the group and a carbon atom on the heterocycloalkyl nucleus that is attached to R in the parent structure of Z 2A Groups (as shown in the various Formulas (WI) to (WIV) (and sub-general formulae thereof) described herein and unless otherwise indicated). Although specific substitution patterns are shown in the exemplary structures above, it should be understood that other substitution patterns are also encompassed within the scope of the present disclosure.

[0802] 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 aromatic ring (e.g., as long as it is chemically suitable and has the correct valence).

[0803] For the various structures of Z defined in various formulae (WI) to (WIV) (and their subformulae) described herein, R 3A is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S. In some examples, R 3A is selected from the group consisting of C1 to C6 alkyl, aryl, heteroaryl, substituted C1 to C6 alkyl, substituted aryl and substituted heteroaryl.

[0804] In some instances, R 3ASelected from the group consisting of: C1 to C6 alkyl optionally substituted by a heterocycloalkyl group having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each 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 each 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 halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy. By way of further example, in some cases, aryl and heteroaryl may be optionally substituted by one or two substituents selected from halo (e.g., F) and C1 to C3 alkyl (e.g., methyl).

[0805] Suitable R 3A Representative examples of radicals include, but are not limited to, thiazolyl, pyridyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, oxetanyl, cyclobutyl, cyclopropyl, tert-butyl, imidazolyl, oxazolyl, thienyl, 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, cyclobutyl, cyclopropyl, and tert-butyl.

[0806] In each case, these R 3A 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 cyclobutyl, substituted cyclopropyl and substituted tert-butyl. 3A is a substituted heteroaryl or aryl group, and one or more substituents may be present on the aromatic ring, for example, it may be monosubstituted, disubstituted or trisubstituted. 3A In the case of an optionally substituted pyrazolyl or imidazolyl group, the nitrogen atom of the pyrazolyl or imidazolyl ring may be substituted by a C1 to C6 alkyl group such as a methyl group.

[0807] Suitable R 3A 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 morpholine substituents, optionally substituted benzothiazolyl, and optionally substituted pyridinyl. 3A For substituted aryl or heteroaryl groups, one or more substituents may be present on the aromatic ring, for example, the aromatic ring may be monosubstituted, disubstituted or trisubstituted.

[0808] Suitable R 3A Representative examples of groups include, but are not limited to, optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, tert-butyl, C1-C6 alkyl containing a morpholine substituent, optionally substituted benzothiazolyl, and optionally substituted pyridinyl.

[0809] Suitable R 3A Additional examples of groups are shown below:

[0810]

[0811]

[0812] The dashed lines on the structures indicate the corresponding R 3A Each of the groups can be attached to a position in the structure shown in the formulae described herein. When a dashed line does not show a direct connection to an atom, R 3A The group may be attached to the structure of 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 A hydrogen at any position on the radical may be replaced by a bond to the parent structure represented by the formulae described herein.

[0813] R 5A Can be any substituent described herein or may be absent. In some examples, R 5A Can be selected from halo (for example, F, Cl, Br, I), CF3, -CH2F, -CHF2, OCF3, -OCH2F, -OCHF2, C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO2Me, -NH2, -NHMe, -NMe2, CO2Me, -NO2, CHO and COMe. As described above, one or more substituents may be present on the aromatic ring (for example, n may be 0 to 5, such as 0 to 4, 0 to 3 or 0 to 2). In the case where more than one substituent is present, each substituent may be independently selected from the above R 5A group.

[0814] R 6A It may be a C1 to C6 alkyl group, for example, a methyl group.

[0815] G may be selected from CH2, O and NH.

[0816] Q may be a C1 to C6 alkylene group, such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0817] In another embodiment, R 3Select from the group consisting of:

[0818]

[0819] The dashed lines indicate the corresponding R 3 Each of the groups is attached to a position in the structure of the formulae described herein.

[0820] For example, R 5A Can be selected from C1 to C6 alkyl (e.g., methyl) and halo (e.g., F). As mentioned above, one or more substituents may be present on the aromatic ring. In the case where two or more substituents are present, each substituent may be independently selected from the above R 5A Likewise, where present and unless otherwise indicated, R 5A Attachment may be at any position on the aryl or heteroaryl ring (provided it has the correct valence and / or is chemically suitable).

[0821] In the above structure, the lines intersecting the wavy lines represent the exemplary R 3A A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in various formulas (WZI) to (WZV), (WI) to (WIV) (and subformulae thereof) described herein). 3A In the case of an aryl or heteroaryl group, the covalent bond (as shown in the various formulas 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 3A A hydrogen at any position on the group may be replaced by a bond to the structure represented by formula (I).

[0822] For example, the appropriate R 3A The group may be selected from the following:

[0823]

[0824]

[0825] The dashed lines on the structures indicate the corresponding R 3A The group may be attached to a position of the structure represented by the formula described herein, and R 5A 、R 6A , n and G are as defined above.

[0826] In other examples, suitable R 3A The group may be selected from the following:

[0827]

[0828] The lines intersecting the wavy lines represent the exemplary R shown above. 3A A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in the various formulas described herein), and R 5A As defined above.

[0829] In other examples, suitable R 3A The group may be selected from the following:

[0830]

[0831] The lines intersecting the wavy lines represent the exemplary R shown above. 3A A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in the various formulas described herein), and R 5A As defined above.

[0832] For example, the appropriate R 3A The group may be selected from the following:

[0833]

[0834] Likewise, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 3A A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in the various formulae (WZI) to (WZV), (WI) to (WIV) (and subformulae thereof) described herein).

[0835] For example, the appropriate R 3A The group may be selected from the following:

[0836]

[0837] Likewise, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 3A A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in the various formulae (WZI) to (WZV), (WI) to (WIV) (and subformulae thereof) described herein).

[0838] For example, R 3A The group can be:

[0839]

[0840] Likewise, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 3A A covalent bond between the group and a carbon atom of the parent structure of Z (as shown in the various formulae (WZI) to (WZV), (WI) to (WIV) (and subformulae thereof) described herein).

[0841] As mentioned above, R 4A can be selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl. In some examples, R 4A may 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 each independently selected from N, O and S; wherein the aryl and heteroaryl groups are optionally substituted with one or two substituents selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy. In some examples, R 4A Phenyl may be optionally substituted.

[0842] For example, the appropriate R 4A The group may be selected from the following:

[0843]

[0844] R 7A Can be any substituent described herein or may be absent. In some examples, R 7A can be selected from C1 to C6 alkyl, halo, C1 to C6 haloalkyl and C1 to C6 alkoxy. 6A 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. In the case where two or more substituents are present, each substituent can be independently selected from the above R 7A Likewise, where present and unless otherwise indicated, R 7A Covalent bonding to the aryl or heteroaryl ring can be at any position provided it has the correct valence and / or is chemically suitable.

[0845] For further example, representative examples of Z are shown below:

[0846]

[0847]

[0848]

[0849]

[0850] For further example, representative examples of Z are shown below:

[0851]

[0852] In the exemplary structures shown above, R 3A R can be selected from those disclosed herein3A In some cases, in the exemplary structures shown above, R 3A Can be selected from the group consisting of:

[0853]

[0854]

[0855] In the exemplary structures shown above, R 3A R can be selected from those disclosed herein 3A In some cases, in the exemplary structures shown above, R 3A It can be:

[0856] In a specific example, Z has the formula:

[0857]

[0858] where R 3A As defined above.

[0859] For example, Z can be any of the structures shown below:

[0860]

[0861] In a specific example, Z has the formula:

[0862] where R 3A As defined above. For example, Z can be any one of the structures shown below:

[0863]

[0864] For example, Z can be one of the structures shown below:

[0865]

[0866] Alternatively, it is noted that while the various formulae (WZI) to (WZV) and (WI) to (WIV) (and subformulae thereof) described herein indicate that the linker is linked to the heterocyclic nucleus (directly or indirectly via R 2A In some embodiments, the linker is attached to the Z portion, but the disclosure also extends to instances where the linker is attached 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. Thus, in some instances, Z can be represented as shown in formula (WZV) or (WV):

[0867]

[0868] Ring A 2A 、R 1A 、R 2A 、R 3A 、X 1 、X 2 、X 3 , n, and L are as defined in any of the embodiments of Formula (W) or its subformulae (e.g., Formula (WZI) or (WI) (or any of one or more of Formulas (WZIa) to (WZIV) or (WIa) to (WIVa))).

[0869] The dashed line illustrated by the square brackets above formulae (WZV) and (WV) indicates that the linker can be covalently attached to any atom on the Z moiety so long as it has the correct valence, is chemically suitable, and / or so long as attachment of the linker at this alternative position does not disrupt the function of the Z moiety in promoting and / or facilitating proteasomal degradation.

[0870] As noted above, in some embodiments, Z may comprise a structure according to Formula (A):

[0871]

[0872] Where the linker is attached to the carbonyl carbon C 1 ;

[0873] In particular, in some embodiments, Z consists of or consists essentially of a structure according to Formula (A1):

[0874]

[0875] where R 1A1 It can be any suitable chemical group.

[0876] For example, R 1A1 is selected from alkyl (e.g., C1 to C6 alkyl, e.g., t-Bu), cycloalkyl (e.g., cyclobutyl or cyclopentyl), heterocycloalkyl (e.g., morpholine, tetrahydrofuran or tetrahydropyran), substituted cycloalkyl, alkylcycloalkyl (e.g., CH2-cyclohexyl), substituted alkylcycloalkyl, alkylheterocycloalkyl (e.g., CH2-morpholine), substituted alkylheterocycloalkyl, aryl (e.g., benzene), substituted aryl, alkylaryl (e.g., benzyl), substituted alkylaryl, heteroaryl (e.g., pyridyl), substituted heteroaryl, alkylheteroaryl (e.g., CH2 -ppyridyl), substituted alkylheteroaryl, alkylamino (e.g., (CH2)2NMe2), alkylamide (e.g., (CH2)2N(Me)COMe), alkoxyalkyl ((CH2)2OMe), alkylcarbonyl (e.g., (CH2)2COMe), alkylcarboxylic acid ((CH2)3COOH), optionally wherein the alkyl (e.g., C1 to C6 alkyl) is substituted with one or more heteroatoms selected from halo, N, O and S; and

[0877] Where the linker is attached to the carbonyl carbon C 1 .

[0878] In embodiments of the invention as defined by Formula (A1) or any of the formulas defined herein, the term "substituted" with respect to substituted cycloalkyl, substituted alkylcycloalkyl, substituted heterocycloalkyl, substituted alkylheterocycloalkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl also encompasses monocyclic, bicyclic, and tricyclic ring systems wherein the additional rings are attached by covalent bonds at fused ring junctions, at spiro ring junctions, or via bridged ring systems, or any combination thereof.

[0879] In an embodiment, Z consists of or consists essentially of a structure according to Formula (A1), wherein R 1A1 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 by one or more heteroatoms selected from halo, N, O and S and / or is substituted by a carbocyclic or heterocyclic group.

[0880] In an embodiment, R 1A1 Selected from the group consisting of optionally substituted heteroaryl, C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloheteroalkyl, C1-C6 alkyl substituted with a heterocyclic group, aryl and substituted aryl.

[0881] In an embodiment, R 1A1 Select from the group consisting of:

[0882]

[0883] The dashed lines indicate the corresponding R 1 Each of the groups is attached to a position of the structure shown in Formula (I), or wherein when the dashed line is not attached to an atom, the dashed line indicates the position of the corresponding R 1A1 Each of the groups is attached to the structure through any position on the aromatic or heteroaromatic ring;

[0884] Each R 3A1 independently selected from the group consisting of halo, CF3, -CH2F, -CHF2, -OCF3, -OCH2F, -OCHF2, C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO2Me, -NH2, -NHMe, -NMe2, CO2Me, -NO2, CHO and COMe;

[0885] n is 0 to 3;

[0886] R 4A1 is a C1-C6 alkyl group;

[0887] G is CH2, O or NH; and

[0888] Q is a C1 to C6 alkylene group.

[0889] In another embodiment, R 1A1 Select from the group consisting of:

[0890]

[0891] where R 3A1 and n are as defined above.

[0892] In another embodiment, R 1A1 Select from the group consisting of:

[0893]

[0894] The dashed lines indicate the corresponding R 1A1 Each of the groups is attached to a position of the structure represented by the formulae described herein.

[0895] For example, the appropriate R 1A1 The group may be selected from the following:

[0896]

[0897] Likewise, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 1A1 A covalent bond between a group and a carbon atom of the parent structure of Z (as shown in the various formulae (A1) to (A3) (and subformulae thereof) described herein).

[0898] For example, the appropriate R 1A1 The group may be selected from the following:

[0899]

[0900] Likewise, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 1A1 A covalent bond between a group and a carbon atom of the parent structure of Z (as shown in the various formulae (A1) to (A3) (and subformulae thereof) described herein).

[0901] In the above embodiment, the direct connection to C 1 The atom is suitably N.

[0902] In an embodiment, the bifunctional molecule comprises a structure according to formula (A2):

[0903]

[0904] in

[0905] C 1 and R 1A1 As defined for formula (A1);

[0906] R 2A1 is selected from H, C1 to C6 alkyl, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl, optionally wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from halo, N, O and S and / or is substituted by a carbocyclic or heterocyclic group.

[0907] In an embodiment, the bifunctional molecule comprises a structure according to Formula (A2a):

[0908]

[0909] in

[0910] C 1 and R 1A1 As defined in formula (A1);

[0911] A is CR'R";

[0912] R' and R" are each independently selected from H and C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted with one or more heteroatoms selected from N, O or S, or wherein R' and R" together form a 3-membered, 4-membered, 5-membered or 6-membered carbocyclic or heterocyclic ring;

[0913] q is 1 to 3.

[0914] In the embodiments of formulas A2 and A2a, R 2A1 is selected from H, C1 to C6 alkyl. In other embodiments, R 2A1 Not for H.

[0915] In an alternative embodiment, the bifunctional molecule comprises a structure according to formula (A3):

[0916]

[0917] in:

[0918] C 1 and R 1A1 As defined in formula (A1);

[0919] Ring A A3 is an optionally substituted monocyclic, bicyclic or tricyclic N-heterocycle optionally containing one to four additional ring heteroatoms selected from N, O and S.

[0920] In an embodiment, the bifunctional molecule comprises a structure according to formula (A3), wherein:

[0921] Ring A A3 is an optionally substituted 4- to 9-membered (e.g., 5- to 6-membered) monocyclic N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O, and S; or

[0922] Ring A A3 is an optionally substituted 6- to 12-membered (e.g., 7- to 8-membered) bridged N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O, and S; or

[0923] Ring A A3 is an optionally substituted bicyclic N-heterocycloalkyl comprising a first ring which is an optionally substituted 3- to 7-membered N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O, and S, and a second ring which is an optionally substituted 3- to 7-membered cycloalkyl or N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O, and S, wherein the first and second rings are joined at the center of the spirocycle;

[0924] or

[0925] Ring A A3 is an optionally substituted fused bicyclic N-heterocycloalkyl comprising a first ring which is an optionally substituted 4- to 9-membered N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O, and S, and a second ring which is an optionally substituted 4- to 9-membered cycloalkyl or heterocycloalkyl ring optionally containing one or two additional ring heteroatoms selected from N, O, and S; or

[0926] Ring A A3 is an optionally substituted fused bicyclic N-heterocycloalkyl comprising a first ring which is an optionally substituted 4- to 9-membered N-heterocycloalkyl optionally containing one or two additional ring heteroatoms selected from N, O, and S, and a second ring which is a 6- to 10-membered aryl, heteroaryl, substituted aryl, or substituted heteroaryl.

[0927] In an embodiment, the bifunctional molecule comprises a structure selected from the group consisting of:

[0928]

[0929]

[0930] Among them C 1 and R 1A1 As defined in formula (A1).

[0931] In an embodiment, the bifunctional molecule comprises a structure selected from the group consisting of:

[0932]

[0933] Among them C 1 and R 1A1 As defined in formula (A1).

[0934] In an embodiment, the bifunctional molecule comprises a structure selected from the group consisting of:

[0935]

[0936]

[0937] Among them C 1 and R 1A1 As defined in formula (A1).

[0938] In an embodiment, the bifunctional molecule comprises a structure selected from the group consisting of:

[0939]

[0940]

[0941] Connector (L)

[0942] 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, for example, be a covalent linker, meaning that the linker is coupled to Z and / or TBL by a covalent bond.

[0943] The linker plays the role of connecting the target protein binding ligand and Z part to each other, while also allowing the two parts to bind to their respective targets and / or perform their intended functions. In particular, the linker can play the role of connecting the target protein binding ligand to Z, while also reducing the possibility that the Z part destroys, interferes with and / or suppresses the target protein binding ligand from binding to the target protein. Additionally or alternatively, the linker can play the role of connecting Z to the target protein binding ligand, while also reducing the possibility that the target protein binding ligand destroys, interferes with and / or suppresses the cellular interaction of Z (for example, its role in regulating, being conducive to and / or promoting the proteasome degradation of the target protein).

[0944] In other words, the linker can facilitate target protein degradation by allowing each end of the bifunctional molecule to bind to various components of the cellular environment (or another type of cellular interaction). For example, the linker can be configured to allow the target protein binding ligand to bind to the target protein without interference, disruption and / or inhibition by the Z portion of the bifunctional molecule. Additionally or alternatively, the linker can be configured to allow the Z portion to interact with various components in the cellular environment to modulate, facilitate and / or promote proteasomal degradation of the target protein without interference, disruption and / or inhibition by the target protein binding ligand of the bifunctional molecule.

[0945] In many cases, a wide range of linkers are acceptable. The choice of linker may depend on the target protein targeted for degradation (target protein) and / or the specific target protein binding ligand that binds to BRD9.

[0946] 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 geometry. As will be appreciated by those skilled in the art, the length and / or flexibility of the linker can vary depending on the structure and / or properties of the target protein binding ligand.

[0947] In some examples, TBL is directly linked to the Z moiety via a covalent bond, i.e., the linker is a covalent bond. Such direct linkage is also encompassed within the term "linker" in the context of this disclosure (and unless otherwise indicated).

[0948] By way of example only, a linker may comprise any number of atoms between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30, or between 1 and 10. In some cases, a linker may comprise any number of atoms between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30, or between 1 and 10 in a single linear chain. In some examples of the present disclosure, a linker may comprise any number of atoms between 1 and 25 (e.g., 3 and 25) or between 1 and 20 (e.g., 3 and 20) or between 1 and 18 (e.g., 3 and 18) in a single linear chain.

[0949] The flexibility of the joint may 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, amide (CN) bonds are not considered to be rotatable due to high rotational barriers. In some cases, the joint may include one or more parts selected from rings, double bonds, and amides to reduce the flexibility of the joint. In other cases, the joint may include a single bond (e.g., primarily a single non-cyclic bond) in a greater number and / or ratio to increase the flexibility of the joint. It will also be understood that the length of the joint may affect flexibility. For example, a shorter joint comprising fewer bonds may also reduce the flexibility of the joint.

[0950] In some examples, the number of rotatable bonds present in the linker can be any number between 1 and 20, between 1 and 15, between 1 and 10, or between 1 and 8. In some examples, the number of rotatable bonds present in the linker can be any number between 2 and 9, between 2 and 8, or between 3 and 6.

[0951] 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 1 and 8.

[0952] The structure of the linker (L) can be represented as follows:

[0953] (L x ) q

[0954] Each L x represents a subunit of L; and

[0955] q is an integer greater than or equal to 1.

[0956] For example, q can be any integer between 1 and 30, between 1 and 20, or between 1 and 5.

[0957] For example, in the case where q is 1, the linker comprises only one L x subunit and can be represented as L1. In the case where q is 2, the linker comprises two L x subunits, which are covalently linked to each other and can be represented as L1-L2. In another example, when q is 3, the linker comprises three L x Subunits, which are covalently linked to each other and can be represented as L1-L2-L3. For even higher integer values ​​of q, L can comprise the following subunits L1, L2, L3, L4, ... up to L q .

[0958] L xEach of 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, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl.

[0959] R L1 、R L2 、R L3 、R L4 、R L5 、R L6 、R L7 、R L8 , and R L9 Each of can be independently selected from H, halo, 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.

[0960] 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 designated 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.

[0961] The TBL and Z moieties can be covalently linked to L via any group that is suitable and chemically stable to 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.

[0962] 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 、CONR L6 NR L7 CO, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl.

[0963] In some instances, L x At least one of contains a ring structure and is, for example, selected from a heterocyclyl, a heteroaryl, a carbocyclyl or an aryl.

[0964] In alternative examples, the linker can be or comprise an alkyl linker comprising a repeating subunit -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.

[0965] 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 the repeating subunit 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.

[0966] In some examples described herein, the structure of the linker (L) can be or include a structure represented by formula (L1a): L 1A -L 2A -L 3A (L1a)

[0967] Among them L 1AThere 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-);

[0968] L 2A -NR L2A C=O- or -C=ONR L2A -;and

[0969] 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-);

[0970] where R L2A is H or C1-C6 alkyl (e.g., C 1- C3 alkyl).

[0971] In another example, the structure of the linker (L) can be or include a structure represented by formula (L1b):

[0972] L 1B -L 2B -L 3B -L 4B -L 5B (L1b);

[0973] 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-);

[0974] L 2B -NRL2A C=O- or -C=ONR L2A -;

[0975] L 3B Selected from C1-C 15 Alkylene, -[(CH2)2O] 1-6 (CH2)2-;

[0976] L 4B -NR L2A C=O- or -C=ONR L2A -, where R L2A is H or C1-C6 alkyl (e.g., C 1- C3 alkyl); L 5B 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 -、-NR L2A (CH2)2-, -(CH2)5NR L2A -、-CH2NR L2A CH2-);

[0977] where R L2A is H or C1-C6 alkyl (e.g., C 1- C3 alkyl).

[0978] In some examples described herein, the structure of the linker (L) can be or include a structure represented by formula (L1c): L 1C -L 2C -L 3C -L 4C (L1c)

[0979] 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 additional ring heteroatoms selected from N, O, and S;

[0980] 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 -、-CH2NRL2A CH2-);

[0981] L 3C -R L2B C=O- or –(C=O)R L2B -;and

[0982] 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-);

[0983] in:

[0984] R L2A is H or C1-C6 alkyl (e.g., C 1- C3 alkyl); and

[0985] R L2B NR L2A or an N-linked 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 additional ring heteroatoms selected from N, O, and S.

[0986] In the example of the linker (L) represented by formula L1c, L 1C and L 2C In such cases, L 3C R in L2B is an N-linked optionally substituted 4 to 7 membered monocyclic N-heterocycloalkyl group optionally containing one or two additional ring heteroatoms selected from N, O and S, and L 3C For R L2B ligation, suitably covalently linked to the terminal subunit of the linker of the TBL.

[0987] In some examples described herein, the structure of the linker (L) can be or include a structure represented by formula (L1d): 1D -L 2D -L 3D (L1d)

[0988] Among them L 1D Not present or selected from C1-C3 alkylene, CO, C1-C3 alkylene (N(C1-C3 alkyl));

[0989] L 2D 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 of which optionally contains one or two additional ring heteroatoms selected from N, O, and S; wherein R L2A is H or C1-C6 alkyl (e.g., C 1- C3 alkyl); and L 3D It is absent or selected from C1-C3 alkylene, -O-, -N(C1-C3 alkyl)- and CO.

[0990] In another example, the structure of the linker (L) can be or include a structure represented by formula (L1e):

[0991] L 1E -L 2E -L 3E (L1e);

[0992] Among them L 1E is C1-C3 alkylene (e.g., methylene) or CO;

[0993] 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 additional ring heteroatoms selected from N, O and S; and

[0994] L 3E is selected from C1-C3 alkylene (eg, methylene).

[0995] In some instances, L 1A , L 1B , L 1C , L 1D or L 1E is a terminal subunit of the linker structure connected (ie, covalently bonded) to the W moiety, and L 3A , L 5B , L 4C , L 3D , L 3E is the terminal subunit of the linker structure that is connected (ie, covalently bonded) to the TBL moiety.

[0996] In L 1A , L 1B or L 1D If any of the two does not exist, L 2A , L 2B or L 2D Directly attached (ie, covalently bonded) to the W moiety.3D In the absence of L 2D Directly attached (ie, covalently bonded) to the TBL moiety.

[0997] As described above, multiple linker moieties, such as L 1C , L 2D , L 2E 、R L2B Examples of moieties include, but are not limited to, bicyclic or tricyclic, and unless otherwise specified, these moieties may contain rings connected by bonds, fused rings, bridged rings, and / or rings connected at a spiro center.

[0998] When L 1C , L 2D , L 2E 、R L2B When any of the examples of is a bicyclic ring, it can be a bridged bicyclic ring (i.e., it can comprise two rings that share three or more atoms) or it can be a spirocyclic bicyclic ring (i.e., it can comprise two rings that share one atom, e.g., the two rings can be connected at the center of the spirocyclic ring).

[0999] When L 1C , L 2D , L 2E 、R L2B When any of the examples of 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 examples, L 1C , L 2D , L 2E and R L2B Examples of can be 7-membered 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, R L2B L 1C , L 2D , L 2E Examples may be 7- or 8-membered bridged bicyclic N-heterocycloalkyl groups optionally containing one additional ring atom selected from N.

[1000] When L 1C , L 2D , L 2E and R L2B When any of the examples of is a spirocyclic bicyclic ring, it can be an optionally substituted 7- to 12-membered spirocyclic 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 L2BExamples of L may be 7-12 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 comprise 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 L 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 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 additional ring heteroatom selected from N.

[1001] In some instances, L 1C , L 2D , L 2E and R L2B The structure of the example can be any one selected from the following:

[1002] Among them L 1A and L 3A As defined above;

[1003] X 5 C(R b )2、NR b or O;

[1004] R b is H or optionally substituted C 1-3 alkyl;

[1005] n1 is 0, 1, 2, or 3;

[1006] n' is 1 or 2;

[1007] m is 0, 1, or 2

[1008] The dashed lines on the above structures indicate that a linker can be attached to the depicted structure at any position shown (as long as it has the correct valence and / or is chemically suitable).

[1009] In some instances, L 1C , L 2D , L 2E and RL2B Examples of are any one selected from the following:

[1010]

[1011] The dashed lines on the above structures indicate that a linker can be attached to the depicted structure at any position shown (as long as it has the correct valence and / or is chemically suitable).

[1012] 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).

[1013] In some of the examples described herein, the linker (L) can be or include a structure represented by formula (L1f): L 1F (L1f)

[1014] 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.

[1015] In some instances, L 1F is selected from C1-C3 alkylene (such as methylene).

[1016] In any of the examples described herein, the linker is or comprises one or more of:

[1017]

[1018]

[1019] Wherein q1 is any integer between 1 and 20 or between 1 and 10 (eg, between 1 and 5).

[1020] Alternatively, in any of the examples described herein, the linker is or comprises one or more of:

[1021]

[1022]

[1023]

[1024] Wherein q2 is any integer between 1 and 20 or between 1 and 10 (eg, 3, 4, 6, or 10).

[1025] As a further alternative, in any of the examples described herein, the linker is or comprises one or more of:

[1026]

[1027]

[1028] wherein q1 is any integer between 1 and 20 or between 1 and 10 (eg, between 1 and 5), and q2 is any integer between 1 and 20 or between 1 and 10 (eg, 3, 4, 5, 6, or 10).

[1029] In particular examples, the linker is or comprises one or more of the following structures:

[1030]

[1031]

[1032] In yet further alternatives, in any of the examples described herein, the linker is or comprises one or more of:

[1033]

[1034] wherein q3 is 1 to 8, such as 1 to 5, and q4 is 1 to 12, such as 1 to 10.

[1035]

[1036]

[1037] In particular examples, the linker is or comprises one or more of the following structures:

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049] In some cases, the structure shown above represents the entire linker. In other examples, the linker of the bifunctional molecule can contain multiple structures shown above.

[1050] In these structures, wavy lines are shown on the bonds forming connections with the TBL and Z moieties, respectively.

[1051] In some instances, the bond formed with the TBL and / or Z moiety is connected to the ring structure. In many of the structures described herein, the bond is shown as being connected at a specific position on the ring structure. However, the present disclosure also encompasses connection or coupling to the TBL and Z moieties at any chemically suitable position on these ring structures.

[1052] The present disclosure contemplates the use of any of the linkers disclosed herein in combination with any of the Z moieties and TBL moieties described herein.

[1053] In certain examples, the linker may not be:

[1054]

[1055] In a more specific example, the bifunctional molecule may not comprise:

[1056]

[1057] In other cases, the connector may not be:

[1058]

[1059] In some examples, the bifunctional molecule comprising the general formula TBL-LZ can be selected from any one of the following:

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067] wherein Z and TBL are as defined above and herein.

[1068] In some examples, the bifunctional molecule comprising the general formula TBL-LZ comprises one of the following structures:

[1069] where R 2 and R 3 As defined above and herein, and the bond indicates the connection to the rest of the bifunctional molecule.

[1070] Exemplary bifunctional molecules

[1071] It should 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 stereoisomeric mixtures of the bifunctional molecules. For example, where the bifunctional molecule contains one or more chiral centers, the present disclosure encompasses each individual enantiomer of the bifunctional molecule as well as mixtures of enantiomers, including racemic mixtures of such enantiomers. By further example, where the bifunctional molecule contains two or more chiral centers, the present disclosure encompasses each individual diastereomer of the bifunctional molecule as well as mixtures of various diastereomers.

[1072] Unless otherwise indicated, the various structures shown herein encompass all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational)) of the structures. For example, the disclosure encompasses the R and S configurations for each asymmetric center, as well as the Z and E double bond isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the disclosed compounds are understood to be within the scope of the disclosure. Furthermore, unless otherwise indicated, all tautomeric forms of the bifunctional molecules described herein are understood to be within the scope of the disclosure.

[1073] As used herein, reference to a "bifunctional molecule" may further include pharmaceutically acceptable salts thereof.

[1074] For the avoidance of doubt, a bifunctional molecule may comprise any combination of a target binding protein (TBL), a linker (L), and a warhead (Z) so long as they have the correct valence and / or are chemically suitable. For example, a bifunctional compound may comprise Z of formula (I), (II), or (III) (including the corresponding subformulas defined herein, such as (Ia), (Ib), (Ic), (IIa), (IIaa), (IIb), (IIc), and (IId)), L of any formula or subformula defined herein, and a warhead of formula 1a, 1a', 1b, 1c, 1b', 1a 1 , 1a2 , 1a 3 , 1e, 1f, 1g, 1f', 1g', 1ea to 1eh, 1fa to 1fh, 1ga, 1ea', 1h to 1z or 2a to 2g, or any combination of TBLs comprising formula 1a, 1a', 1b, 1c, 1b', 1a1, 1a2, 1a3, 1e, 1f, 1g, 1f', 1g', 1ea to 1eh, 1fa to 1fh, 1ga, 1ea', 1h to 1z or 2a to 2g. In other examples, the bifunctional compound comprises Z of Formula (WZI) to (WZV), (WI), (WII), (WIII), (WIV), or (WV) (including the corresponding subformulae defined herein, such as (WIa) to (WIf), (WIIa) to (WIIf), (WIIIa), (WIIIb), and (WIVa), (A), (A1) to (A3)), L of any formula or subformula defined herein, and any combination of TBL.

[1075] In some embodiments:

[1076] (i) Z is represented by formula (I), (Ia), (Ib), (Ic), (IIaa), (IIa) or (IIb) as defined above; and

[1077] (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[1078] In other embodiments:

[1079] (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; and

[1080] (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[1081] In a specific embodiment:

[1082] (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; and

[1083] (ii) TBL is represented by formula (1h), (1i) or (1j) as defined above.

[1084] In other specific embodiments:

[1085] (i) Z is represented by formula (Ib) or (IIb) as defined above; and

[1086] (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[1087] In a yet more specific embodiment:

[1088] (i) Z is represented by formula (Ib) or (IIb) as defined above; and

[1089] (ii) TBL is represented by formula (1h), (1i) or (1j) as defined above.

[1090] In certain embodiments:

[1091] (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above;

[1092] (ii) TBL is represented by Formula 1a″ as defined above.

[1093] In these specific embodiments, L can be represented by formula L1a or L1b.

[1094] In yet another embodiment:

[1095] (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above;

[1096] (ii) TBL is represented by any one of Formulas 1e", 1g", 1g'", 1ea" to 1eh", 1ea", 1h" to 1z", and 2a" to 2g" as defined above; and

[1097] (iii) L is represented by formula L1a or L1b as defined above.

[1098] In an even more specific embodiment:

[1099] (i) Z is represented by Formula (WI), (WII), (WIIa), (WIIb), (WIIc), (WIId), (WIIe), (WIIf), (WIII), (WIIIa), (WIIIb), (WIV) or (WIVa) as defined above; and

[1100] (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[1101] In some instances:

[1102] (i) Z is represented by Formula (WI), (WII), (WIIa), (WIIb), (WIIc), (WIId), (WIIe), (WIIf), (WIII), (WIIIa), (WIIIb), (WIV) or (WIVa) as defined above;

[1103] Where Z is not:

[1104]

[1105] (ii) TBL is a target protein binding ligand that binds BRD9, wherein TBL is not:

[1106]

[1107] In some embodiments:

[1108] (i) Z is represented by any one of Formula (WZI), (WZII), (WZIIa) to (WZIIe), (WZIIIa) to (WZIIIh), or (WZIVa) to (WZIVj) as defined above;

[1109] (ii) TBL is represented by Formula 1a″ as defined above; and

[1110] (iii) L is represented by the formula L1c as defined above.

[1111] In some embodiments:

[1112] (i) Z is represented by any one of Formula (WZI), (WZII), (WZIIa) to (WZIIe), (WZIIIa) to (WZIIIh), or (WZIVa) to (WZIVj) as defined above;

[1113] (ii) TBL is represented by any one of Formulas 1e", 1g", 1g'", 1ea" to 1eh", 1ea", 1h" to 1z", and 2a" to 2g" as defined above; and

[1114] (iii) L is represented by the formula L1c as defined above.

[1115] In some cases, the bifunctional molecule is not:

[1116]

[1117] In some more specific examples, the bifunctional molecule is any of the following formulae:

[1118] A2 to A76, BRD9a to BRD9ac, B1 to B84, B86, B88 to B96, B98 to B104, B106 to B127, B130 to B149, B152 to B156, B158 to B162, B164, B165, B169, B173 to B175, B180 to B215, and C1 to C107 or A2 to A76, BRD9 Any combination of TBL, L and Z represented in a to BRD9ac, B1 to B84, B86, B88 to B96, B98 to B104, B106 to B127, B130 to B149, B152 to B156, B158 to B162, B164, B165, B169, B173 to B175, B180 to B215 and C1 to C107, as shown in Table 1 below:

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153]

[1154]

[1155]

[1156]

[1157]

[1158]

[1159]

[1160] Table 1 shows the structures of exemplary bifunctional molecules A2 to A76, BRD9a to BRD9ac, B1 to B84, B86, B88 to B96, B98 to B104, B106 to B127, B130 to B149, B152 to B156, B158 to B162, B164, B165, B169, B173 to B175, B180 to B215, and C1 to C107.

[1161] Indicative structures of illustrative examples are shown in Table 1. Unless otherwise indicated herein (eg, in the detailed experimental section), absolute stereochemistry and double bond geometry are arbitrarily assigned as appropriate.

[1162] In some more specific examples, the bifunctional molecule is any one of formulas B202, C6, C35, and C77.

[1163] Isotope-labeled compounds

[1164] The present disclosure also encompasses various deuterated forms of compounds of any of the formulae disclosed herein (including formulae (I), (II), (III), (WZI) to (WZV), (WI), (WII), (WIII), (WIV), (WV), (A), (A1) to (A3), 1T, 2T, 3T, 4T, 5T, 6T, 7T, 8T, 9T, 11T, 12T, 13T, 14T (including the corresponding subformulae as defined herein)) or pharmaceutically acceptable salts and / or corresponding tautomeric forms thereof (including subformulae, as defined above) disclosed herein. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. One of ordinary skill in the art will know how to synthesize deuterated forms of compounds of any of the formulae disclosed herein, including the compounds mentioned above. For example, deuterated materials, such as alkyl groups, can be prepared by conventional techniques (see, for example, methyl-d3-amine, Catalog No. 489,689-2, available from Aldrich Chemical Co., Milwaukee, WI).

[1165] The present disclosure also includes the following compounds disclosed herein (including Formulas (I), (II), (III), (WZI) to (WZV), (WI), (WII), (WIII), (WIV), (WV), (A), (A1) to (A3), 1a, 1a', 1b, 1c, 1b', 1a 1 , 1a 2 , 1a 3, 1e, 1f, 1g, 1f', 1g', 1ea to 1eh, 1fa to 1fh, 1ga, 1ea', 1h to 1z or 2a to 2g (including the corresponding subformulae defined herein)) or pharmaceutically acceptable salts thereof and / or corresponding tautomeric forms of the present disclosure (including the subformulae defined above), but in fact one or more atoms are replaced by an atom with 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 2 H. 3 H. 11 C. 13 C. 14 C. 18 F. 123 I or 125 I. Compounds of the present disclosure containing the aforementioned isotopes and / or other isotopes of other atoms, as well as pharmaceutically acceptable salts of the compounds, are within the scope of the present invention. Isotopically labeled compounds of the present disclosure, for example, have incorporated radioactive isotopes (such as 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14 isotopes, i.e. 14 C is particularly preferred due to its ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).

[1166] Degradation activity

[1167] Degradation can be determined by measuring the amount of the BRD9 target protein in the presence of a bifunctional molecule as described herein and / or comparing it with the amount of the BRD9 target protein observed in the absence of the bifunctional molecule. For example, the amount of the BRD9 target protein in the cell contacted with and / or treated with a bifunctional molecule as described herein can be determined. The amount can be compared with the amount of the BRD9 target protein in the cell not yet contacted with and / or treated with a bifunctional molecule. If the amount of the BRD9 target protein in the cell contacted with and / or treated with a bifunctional molecule is reduced, it can be considered that the bifunctional molecule is conducive to and / or promotes degradation and / or proteolysis of the BRD9 target protein.

[1168] The amount of BRD9 target protein can be determined using methods known in the art, for example, by immunoblotting assays, Western blot analysis, and / or ELISA on cells that have been contacted and / or treated with the bifunctional molecule.

[1169] If a reduction of at least 10%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in the amount of the BRD9 target protein is observed after administration of the bifunctional molecule to the cells, then selective degradation and / or increased proteolysis can be considered to have occurred.

[1170] For example, if after bifunctional molecule is applied to cell 4 hours or longer time (for example, 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) observe that the amount of BRD9 target protein is reduced by at least 10% (for example, reduce at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%), then it can be considered that selective degradation and / or increased proteolysis have occurred.In a particular example, if the amount of BRD9 target protein is observed to reduce by at least 40%, then it is considered that selective degradation and / or increased proteolysis have occurred. Bifunctional molecule can be applied with any concentration (for example, concentration is between 0.01nM to 10 μM, such as 0.01nM, 0.1nM, 1nM, 10nM, 100nM, 1 μM and 10 μM). In some cases, degradation of the BRD9 target protein is increased by at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100% following administration of the bifunctional molecule at a concentration of about 100 nM (e.g., after an incubation period of about 8 hours).

[1171] One measure of the degrader activity of a bifunctional molecule is DC 50 As used herein, DC 50 The concentration required to achieve 50% of the maximum degradation of the BRD9 target protein. The bifunctional molecules described herein can comprise 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 of DC 50 In some cases, the bifunctional molecule comprises a DC of less than or equal to 50 nM, less than or equal to 25 nM, less than or equal to 10 nM, less than or equal to 5 nM, less than or equal to 1.5 nM, less than or equal to 1 nM, or less than or equal to 0.5 nM. 50 In some cases, the bifunctional molecules of the invention comprise less than 1.25 nM DC in any of the following BRD9 degradation assays. 50 .

[1172] Another measure of the degrader activity of a bifunctional molecule is D max As used herein, D maxThe bifunctional molecules described herein can comprise at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or about 100% of the D max In a particular embodiment, the bifunctional molecule comprises at least 40% D max In some cases, the bifunctional molecules of the invention comprise less than 1.25 nM DC in any of the following BRD9 degradation assays. 50 and 75% or higher of D max .

[1173] In some cases, the bifunctional molecules of the invention comprise 75% or greater D in any of the following BRD9 degradation assays. max .

[1174] Another measure of the efficacy of the bifunctional molecules may be their effect on cell viability and / or their IC 50 For example, the antiproliferative effects of the bifunctional molecules described herein can be assessed 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 a bifunctional molecule 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.

[1175] Bioavailability

[1176] The bifunctional molecules described herein can provide enhanced bioavailability levels for the degraders, such as enhanced oral bioavailability levels.

[1177] As used herein, bioavailability is the fraction or proportion of an administered active agent (e.g., a bifunctional molecule described herein) that reaches the systemic circulation of a subject. As used herein, oral bioavailability is the fraction or proportion of an orally administered active agent that reaches the systemic circulation of a subject.

[1178] Oral bioavailability is calculated by comparing the area under the curve (AUC) for intravenous administration of a particular active agent with the AUC for oral administration of the active agent. The AUC value is the definite integral of the curve showing the change in the concentration of the active agent in plasma over time. As used herein, AUC0-INF is the area under the curve starting at time zero (and extrapolated to infinity) and represents the total active agent exposure over time

[1179] Oral bioavailability (F) can be calculated using the following formula:

[1180] F=100. AUC po .D iv

[1181] AUC iv .D po

[1182] in:

[1183] D iv = intravenous dose;

[1184] D po =Oral administration dose;

[1185] AUC iv = the area under the curve from time zero to infinity after intravenous administration; and

[1186] AUC po = area under the curve from time zero to infinity after oral administration.

[1187] The bifunctional molecules described herein can have an oral bioavailability of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In some cases, the oral bioavailability of the bifunctional molecules described herein can be about 28%.

[1188] Pharmaceutical composition

[1189] The present disclosure provides pharmaceutical compositions comprising the bifunctional molecules described herein. In such 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 BRD9 target protein.

[1190] Thus, provided is a pharmaceutical composition comprising a bifunctional molecule as described herein and a pharmaceutically acceptable carrier.

[1191] 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 comprise water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases etc.

[1192] In addition to the above-mentioned carrier components, the pharmaceutical compositions described above may alternatively or additionally include one or more appropriate additional carrier components (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.

[1193] The pharmaceutical composition can be in the form of any formulation typically used for administration 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.

[1194] The pharmaceutical composition is formulated to be compatible with its intended route of administration.Examples of routes of administration include parenteral (e.g., intravenous, intradermal, subcutaneous, oral, transdermal, topical, transmucosal, vaginal and rectal) administration.

[1195] Pharmaceutical compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), topical (including cutaneous, buccal and sublingual), rectal, nasal and pulmonary administration (e.g., by inhalation). If applicable, the compositions may be conveniently presented in discrete dosage units and may be prepared by any method well known in the pharmaceutical art. The methods generally comprise combining the active compound with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation.

[1196] Pharmaceutical compositions suitable for oral administration in which the carrier is a solid are most preferably in the form of unit dose formulations (such as boluses, capsules or tablets, each containing a predetermined amount of active compound). Tablets can be prepared by compressing or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active compound in the form of a free-flowing powder or granules in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be prepared by molding the active compound with an inert liquid diluent. The tablets can be optionally coated, and if not coated, 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. Capsules are similar to capsules, in which the active compound is sealed in a rice paper envelope together with any auxiliary ingredients. Bifunctional molecules can also be formulated into dispersible particles, which can, for example, be suspended in water or sprinkled on food before administration. The particles can be packaged in, for example, sachets. Compositions suitable for oral administration in which the carrier is a liquid may be present in the form of a solution or suspension in an aqueous or non-aqueous liquid, or in the form of a water-in-oil liquid emulsion. Compositions for oral administration include controlled-release dosage forms, for example, tablets, in which the active compound is formulated in a suitable release-controlling matrix, or coated with a suitable release-controlling membrane.

[1197] 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. Such formulations are conveniently present in unit dose or multidose containers, which are sealed after the introduction of the formulation until needed for use. Alternatively, the bifunctional molecule can be in powder form, which is constituted together with a suitable vehicle (such as sterile pyrogen-free water).

[1198] The pharmaceutical composition can also be formulated as a long-acting implant, which can be administered by intramuscular injection or implantation (eg, subcutaneously or intramuscularly). The implant can include, for example, a suitable polymer or hydrophobic material or an ion exchange resin.

[1199] Pharmaceutical compositions suitable for topical formulation may be provided, for example, as a gel, cream or ointment.

[1200] The bifunctional molecules described herein may be present in pharmaceutical compositions in the form of pharmaceutically and / or physiologically acceptable salts, solvates, or derivatives.

[1201] 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, 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, sulfuric acid, phosphoric acid, and sulfamic acid).

[1202] 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. Such 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.

[1203] It may be convenient or desirable to prepare, purify and / or process corresponding pharmaceutically and / or physiologically acceptable solvates of the bifunctional molecules described herein, which may be used in any of the uses / methods. The term solvate is used herein to refer to a complex of solutes, such as a compound or a salt of the compound, and a solvent. If the solvent is water, the solvent 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.

[1204] Purpose of the Z section

[1205] As described herein, the Z moiety can form part of a bifunctional molecule intended for use in methods of targeted protein degradation, wherein the Z moiety acts to modulate, facilitate and / or promote proteasomal degradation of a BRD9 target protein.

[1206] Thus, according to another aspect of the present disclosure, there is provided a use of a moiety Z (e.g., as defined in any one of formulas (I) to (III)) or a compound comprising the moiety Z in a method for BRD9 degradation (e.g., an in vitro or in vivo method for targeted protein degradation). For example, moiety Z may be particularly useful as a promoter or propellant for BRD9 degradation.

[1207] Also provided is the use of a moiety Z (eg, as defined in any one of formulae (I) to (III)) or a compound comprising the moiety Z in the manufacture of a bifunctional molecule suitable for BRD9 degradation.

[1208] Treatment methods and uses

[1209] The bifunctional molecules disclosed herein can regulate, facilitate and / or promote proteasomal degradation of the BRD9 target protein. Therefore, a method for selectively degrading the BRD9 target protein in a cell and / or increasing its proteolysis is provided, the method comprising contacting the cell with a bifunctional molecule as described herein and / or treating the cell with the bifunctional molecule. The method can be performed in vivo or in vitro.

[1210] In particular, provided is a method of selectively degrading and / or increasing proteolysis of a BRD9 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.

[1211] Therefore, the bifunctional molecules of the present invention can be used in medicine and / or therapy. Specifically, the bifunctional molecules of the present invention can be used to treat and / or prevent any disease or condition regulated by the BRD9 target protein. For example, the bifunctional molecules of the present invention can be used to treat any disease regulated by the BRD9 target protein (by reducing the level of the protein in cells (e.g., cells of a subject)).

[1212] Further provided are uses of bifunctional molecules as described herein in the manufacture of a medicament for treating and / or preventing any disease or condition regulated by a BRD9 target protein. In addition, provided are uses of a Z moiety (e.g., as defined in any one of formulas (I) to (III)) in the manufacture of a medicament for treating and / or preventing any disease or condition regulated by a BRD9 target protein.

[1213] 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 BRD9 protein activity.

[1214] Such diseases and conditions include diseases and conditions whose pathology is at least in part associated with abnormal (e.g., elevated) levels of BRD9 protein and / or overexpression of BRD9 protein. For example, bifunctional molecules can be used to treat and / or prevent the disease in which elevated levels of BRD9 protein are observed in a subject suffering from the disease. In other examples, the disease and / or condition can be one in which the pathology is at least in part associated with inappropriate BRD9 protein expression (e.g., expression at the wrong time and / or in the wrong cells) or excessive BRD9 protein expression.

[1215] Thus, provided is a method for treating and / or preventing a disease or condition associated with and / or caused by abnormal levels of BRD9 protein activity, the method comprising administering a therapeutically effective amount of a bifunctional compound as described herein.

[1216] Representative examples of diseases and / or conditions that can be treated and / or prevented by using the bifunctional compounds include, but are not limited to, cancer.

[1217] A recent review article summarizes the potential mechanism of action of BRD9 in carcinogenesis, and also describes various strategies for targeting BRD9 as cancer therapy (Zhu et al., OncoTargets and Therapy, 2020, Vol. 13, pp. 13191-13200). Previous studies have shown that BRD9 is essential for the proliferation of SMARCB1-deficient cancer cell lines, indicating that it is a therapeutic target for these cancers. (Xiaofeng Wang et al., Nature Communications, 2019, 10 (1881)). Recent studies have also emphasized the role of BRD9 in leukemia growth: BRD9 has been shown to be required for the proliferation of acute myeloid leukemia (AML) cells (Nature Chemical Biology, 2016, 101038 / nchembio.2115). In addition to its functionally dependent role in certain cancers, BRD9 also plays a key role in immune cells as a regulator of regulatory T cells (Tregs) through transcriptional control of Foxp3 target genes, "BioRxiv, 10.1101 / 2020.02.26.964981."

[1218] Representative examples of cancers that can be treated and / or prevented using the bifunctional molecules include, but are not limited to:

[1219] (i) brain tumors, such as, for example, acoustic neuroma, astrocytomas (such as pilocytic astrocytoma, fibrillary astrocytoma, protoplasmic astrocytoma, blastocyst astrocytoma, anaplastic astrocytoma and glioblastoma), brain lymphoma, brain metastases, pituitary tumors (such as prolactinoma),

[1220] HGH (human growth hormone)-producing tumors and ACTH (adrenocorticotropic hormone)-producing tumors, craniopharyngiomas, medulloblastomas, meningiomas, and oligodendrogliomas;

[1221] (ii) neural tumors (tumors), such as, for example, autonomic nervous system tumors (such as sympathetic neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma, pheochromoma) and glomus cervical tumor), peripheral nervous system tumors (such as amputee neuroma, neurofibroma, schwannoma (neurilemmoma, neurothecoma) and malignant schwannoma) and central nervous system tumors (such as brain and bone marrow tumors);

[1222] (iii) bowel cancer, such as, for example, rectal cancer, colon cancer, colorectal cancer, anal cancer, large intestine cancer, small intestine and duodenal tumours;

[1223] (iv) eyelid tumors such as basal cell tumors or basal cell carcinomas;

[1224] (v) pancreatic cancer or pancreatic epithelial cancer;

[1225] (vi) bladder cancer or urothelial carcinoma;

[1226] (vii) lung cancer (bronchial cancer), such as, for example, small cell bronchial carcinoma (oat cell carcinoma) and non-small cell bronchial carcinoma (NSCLC) (such as lamellar carcinoma, adenocarcinoma and large cell bronchial carcinoma);

[1227] (viii) breast cancer, such as, for example, breast cancer (such as invasive ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma);

[1228] (ix) Non-Hodgkin's lymphoma (NHL), such as, for example, Burkitt's lymphoma, low-grade non-Hodgkin's lymphoma (NHL), and mycosis fungoides;

[1229] (x) cancer of the uterus, endometrium, or uterine corpus;

[1230] (xi) CUP syndrome (cancer of unknown primary);

[1231] (xii) ovarian cancer or epithelial ovarian cancer, such as mucinous, endometrial or serous carcinoma;

[1232] (xiii) Gallbladder cancer;

[1233] (xiv) bile duct cancer, such as, for example, Klatskin tumor;

[1234] (xv) testicular cancer, such as, for example, seminoma and non-seminoma;

[1235] (xvi) lymphomas (lymphosarcoma), such as, for example, malignant lymphomas, Hodgkin's disease, non-Hodgkin's lymphomas (NHL), such as chronic lymphatic leukemia, leukemic reticuloendothelioma, immunocytomas, plasmacytomas (multiple myeloma (MM)), immunoblastomas, Burkitt's lymphoma, T-zone mycosis fungoides, large cell anaplastic lymphoblastoma, and lymphoblastoma;

[1236] (xvii) laryngeal cancers, such as, for example, vocal cord tumors, supraglottic, glottic and subglottic laryngeal tumors;

[1237] (xviii) bone cancers, such as, for example, osteochondroma, enchondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumor, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulosarcoma, plasmacytoma, fibrous dysplasia, juvenile bone cyst, and aneurysmal bone cyst;

[1238] (xix) head and neck tumors, such as, for example, tumors of the lip, tongue, floor of mouth, oral cavity, gums, palate, salivary glands, pharynx, nasal cavity, paranasal sinuses, larynx, and middle ear;

[1239] (xx) liver cancer, such as, for example, liver cell carcinoma or hepatocellular carcinoma (HCC);

[1240] (xxi) leukemias, such as, for example, acute leukemias, such as acute lymphoblastic / lymphoblastic leukemia (ALL), acute myeloid leukemia (AML); chronic leukemias, such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML);

[1241] (xxii) gastric cancer or gastric epithelial cancer, such as, for example, papillary, tubular and mucinous adenocarcinomas, signet ring cell carcinoma, adenosquamous carcinoma, small cell carcinoma and undifferentiated carcinoma;

[1242] (xxiii) melanomas, such as, for example, epidermal spreading, nodular, lentigo maligna, and acral lentiginous melanoma;

[1243] (xxiv) renal cancer, such as, for example, renal cell carcinoma or adrenal carcinoma or Gravets' tumor;

[1244] (xxv) esophageal cancer or esophageal epithelial cancer;

[1245] (xxvi) Penile cancer;

[1246] (xxvii) prostate cancer;

[1247] (xxviii) cancer of the throat or pharynx, such as, for example, nasopharyngeal cancer, oropharyngeal cancer, and hypopharyngeal cancer;

[1248] (xxix) retinoblastoma, such as, for example, vaginal cancer or vaginal epithelial cancer;

[1249] (xxx) Lamellar carcinoma, adenocarcinoma, carcinoma in situ, malignant melanoma and sarcoma;

[1250] (xxxi) thyroid cancer, such as, for example, papillary, follicular and medullary thyroid cancer, and anaplastic cancer;

[1251] (xxxii) myeloma, epidermoid carcinoma and lamellar epithelial carcinoma of the skin;

[1252] (xxxiii) Thymoma, urethral cancer and vulvar cancer.

[1253] In a specific example, the cancer is any one selected from the group consisting of hematopoietic malignancies (including but not limited to AML, MM) and solid tumors (including but not limited to lung cancer, liver cancer, colon cancer, brain cancer, thyroid cancer, pancreatic cancer, breast cancer, ovarian cancer and prostate cancer).

[1254] Other specific examples of cancers that can be treated by targeted protein degradation of BRD9 include cancers with SMARCB1 abnormalities, e.g., SMARCB1 -deficient cancers such as malignant rhabdoid tumors and several specific types of sarcomas, and leukemias such as acute myeloid leukemia (AML).

[1255] As used herein, the term "patient" or "subject" is used to describe an animal, such as a mammal (e.g., a human or domestic animal), to whom treatment with a composition according to the present disclosure is provided, including prophylactic treatment. For treatment of those infections, disorders, or disease states specific to a particular animal (e.g., a human patient), the term patient refers to that particular animal, including domestic animals (such as dogs or cats) or farm animals (such as horses, cattle, sheep, etc.). Generally speaking, in the present invention, the term patient refers to a human patient, unless otherwise specified or implied from the context of the term's use.

[1256] Determination

[1257] The present disclosure also encompasses a method for screening bifunctional molecules (e.g., bifunctional molecules that can effectively regulate, facilitate, and / or promote proteolysis of a BRD9 target protein) to identify BRD9 binding partners and linkers suitable for use in bifunctional molecules described herein. This method can help identify linkers suitable for specific BRD9 binding partners, thereby further optimizing degradation levels.

[1258] The method may include:

[1259] a. Providing a bifunctional molecule, the bifunctional molecule comprising:

[1260] (i) comprising a compound according to Z (e.g., a compound of formula (including (I), (II), (III), (WI), (WII),

[1261] a first ligand of a structure as defined in any one of (WIII), (WIV), (WV), and any subformula);

[1262] (ii) a second ligand that binds to the BRD9 target protein (e.g., a formula as defined herein (including Formula 1a,

[1263] 1a', 1b, 1c, 1b', 1a 1 , 1a 2 , 1a 3, 1e, 1f, 1g, 1f', 1g', 1ea to 1eh, 1fa to 1fh, 1ga, 1ea', 1h to 1z, 2a to 2g and any subformulae); and

[1264] (iii) a linker covalently linking the first ligand and the second ligand;

[1265] b. contacting the cell with the bifunctional molecule; and

[1266] c. Detecting the degradation of the BRD9 target protein in the cells.

[1267] The method may further comprise the following steps:

[1268] d. detecting degradation of the BRD9 target protein in the cell in the absence of the bifunctional molecule; and

[1269] e. comparing the level of degradation of the BRD9 target protein in the cell contacted with the bifunctional molecule to the level of degradation of the BRD9 target protein in the absence of the bifunctional molecule;

[1270] Wherein an increased level of degradation of the BRD9 target protein in the cell contacted with the bifunctional molecule indicates that the bifunctional molecule has facilitated and / or promoted degradation of the BRD9 target protein.

[1271] In such methods, the step of detecting the degradation of BRD9 target protein can include a change in the level of the BRD9 protein in the detection cell. For example, the reduction in the level of BRD9 protein indicates the degradation of BRD9 protein. The reduction in the increase of the BRD9 protein level in the cell contacted with the bifunctional molecule (compared to any reduction in the BRD9 protein level observed in the cell in the absence of the bifunctional molecule) indicates that the bifunctional molecule has been conducive to and / or promoted the degradation of the BRD9 target protein.

[1272] The method can further include providing a plurality of linkers, each linker being used to covalently link the first ligand and the second ligand together to form a plurality of bifunctional molecules. The degradation levels provided by each of the plurality of bifunctional molecules can be detected and compared. Those bifunctional molecules that exhibit higher levels of BRD9 protein degradation indicate preferred and / or optimal linkers for use with the selected BRD9 protein binding partner.

[1273] The method can be performed in vivo or in vitro.

[1274] Compound Library

[1275] The present disclosure also provides a library of bifunctional molecules comprising a plurality of bifunctional molecules comprising a plurality of Z moieties covalently linked to a selected BRD9 protein binding partner.

[1276] Thus, the BRD9 binding partner can be pre-selected and the Z moiety may not be determined in advance.The library can be used to determine the activity of candidate Z moieties of bifunctional molecules in modulating, promoting and / or facilitating selective protein degradation of BRD9 protein.

[1277] The present disclosure also includes a bifunctional molecule library comprising a plurality of bifunctional molecules comprising a plurality of BRD9 protein binding ligands and a selected Z portion. Thus, the Z portion of the bifunctional molecule can be preselected and the BRD9 target protein can be determined without prior knowledge. The library can be used to determine the activity of a putative BRD9 protein binding ligand and its value as a binding agent for BRD9 protein for facilitating BRD9 degradation.

[1278] Manufacturing method

[1279] According to a further aspect of the present disclosure, there is provided a method of preparing a bifunctional molecule as described herein.

[1280] The method for preparing a bifunctional molecule may comprise the following steps:

[1281] (a) providing a compound comprising a compound according to Z (e.g., a compound of formula (including (I), (II), (III), (WI), (WII), (WIII),

[1282] a first ligand or portion of a structure as defined in any of (WIV), (WV) and any subformula);

[1283] (b) providing a second ligand or moiety (e.g., a formula as defined herein (including formulas 1a, 1a', 1b, 1c, 1b', 1a', 1b', 1c ... 1 , 1a 2 , 1a 3 , 1e, 1f, 1g, 1f', 1g', 1ea to 1eh, 1fa to 1fh, 1ga, 1ea', 1h to 1z, 2a to 2g and any subformulae); and

[1284] (c) linking (eg, covalently linking) the first ligand or moiety and the second ligand or moiety using a linker as defined herein.

[1285] In other examples, the method of preparing a bifunctional molecule may include the following steps:

[1286] (a) providing a BRD9 protein binding ligand (e.g., a formula as defined herein (including formulas 1a, 1a', 1b, 1c, 1b', 1a 1 , 1a 2 , 1a 3 、1e、1f、1g、1f'、1g'、1ea to 1eh、1fa to 1fh、1ga、1ea'、1h

[1287] to 1z, 2a to 2g and any subformulae));

[1288] (b) linking (e.g., covalently linking) a linker (as defined herein) to the BRD9 protein binding ligand to

[1289] Providing a BRD9 protein binding ligand-linker conjugate (TBL-L);

[1290] (c) further reacting the linker portion of the conjugate to add and / or form a structure according to Z (e.g., as defined by any of Formulas (including (I), (II), (III), (WI), (WII), (WIII), (WIV), (WV), and any sub-general formulas) defined herein) thereon to provide a bifunctional molecule having the general formula TBL-LZ.

[1291] Parts Kit

[1292] According to a further aspect of the present disclosure, there is provided a kit of independent parts from which a bifunctional molecule as defined herein can be prepared, for example according to the manufacturing method defined above.

[1293] Parts kits may contain:

[1294] (i) a first ligand comprising a structure according to Z as defined above (e.g., as defined by any one of Formulae (including (I), (II), (III), (WI), (WII), (WIII), (WIV), (WV), and any subformulae) defined herein);

[1295] (ii) a second ligand that binds to BRD9 as defined above (e.g., a ligand of formula (including formula 1a, 1a', 1b, 1c, 1b', 1a', 1 , 1a 2 , 1a 3 , 1e, 1f, 1g, 1f', 1g', 1ea to 1eh, 1fa to 1fh, 1ga, 1ea', 1h to 1z, 2a to 2g and any subformulae); and

[1296] (iii) a linker covalently linking the first ligand and the second ligand as defined above.

[1297] In some cases, the first ligand, the second ligand, and the linker are independent of each other.

[1298] Terms

[1299] This disclosure may also be defined with reference to the following set of terms:

[1300] 1. A bifunctional molecule comprising the following general formula:

[1301] TBL–L–Z

[1302] Wherein TBL is the target protein binding ligand that binds to BRD9;

[1303] L is a linker; and

[1304] Z comprises a structure according to formula (I):

[1305]

[1306] in

[1307] R 1 is selected from C1 to C6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl, optionally wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from halo, N, O and S and / or is substituted by a carbocyclic or heterocyclic group;

[1308] A does not exist or is CR 2 R 2' ;

[1309] B is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl;

[1310] R 2 and R 2' are each independently selected from H and C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted with one or more heteroatoms selected from N, O or S, or wherein R 2 and R 2' Together they form a 3-membered, 4-membered, 5-membered or 6-membered carbocyclic or heterocyclic ring;

[1311] 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 halo, N, O and S;

[1312] R 4 is H, C1 to C6 alkyl, optionally, wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from N, O or S;

[1313] or where R 1 and R 4 Together they form a 5-, 6-, or 7-membered heterocyclic ring;

[1314] or when A is CR 2 R 2' hour:

[1315] R 1 and R 2 together to form a 5-membered, 6-membered or 7-membered heterocyclic ring; or

[1316] R 2 and R 4 Together they form a 5-, 6- or 7-membered heterocyclic or carbocyclic ring;

[1317] Wherein L shows the connection point of the linker;

[1318] or

[1319] Z comprises a structure according to formula (WZI):

[1320]

[1321] in:

[1322] Ring A 2A 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 additional ring heteroatoms selected from N, O, and S;

[1323] R 2A 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)-;

[1324] where Ry is optionally substituted C 1-6 Alkyl or H;

[1325] R 3A is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S; and L represents the point of attachment of the linker;

[1326] or

[1327] Z comprises a structure according to formula (WI):

[1328]

[1329] where R 1A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1 to C6 alkyl, and substituted C1 to C6 alkyl;

[1330] R 2A is absent or selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-;

[1331] R 3A is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S;

[1332] X 1 is CH2;

[1333] X 2 and X 3 Each independently is CH2 or selected from O and NR x heteroatoms, where R x is H or C1 to C6 alkyl; and n is 0, 1, 2 or 3; and

[1334] L shows the connection point of the linker;

[1335] or

[1336] Z consists of or consists essentially of a structure according to formula (A1):

[1337]

[1338] in:

[1339] R 1A1 is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally, wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S; and wherein the linker is attached to the carbonyl carbon C 1 ;

[1340] And further,

[1341] wherein the BRD9 binder has Formula 1a:

[1342]

[1343] in:

[1344] Z 1 N or CR A ;

[1345] Z 2 N or CR B ;

[1346] Z 3 N or CR D ;

[1347] Z 4 N or CR E ;

[1348] where Z 1 、Z 2 、Z 3 and Z 4 The number of numbers that do not exceed 3 is N;

[1349] R A and R E Each independently selected from -H, -OC 1-3 Alkyl and –C 1-3 a group consisting of alkyl groups;

[1350] R B and R D Each independently selected from -OC 1-3Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 alkyl, 4 to 7 membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 Alkyl)2, -N(C 1-3 Alkyl)2, -NH-R F the group formed;

[1351] R F Selected from -SO2-C 1-3 Alkyl and –C 1-3 Alkyl, wherein the –C 1-3 Alkyl is optionally substituted with a 5- to 6-membered heteroaryl; alternatively, R A and R B Together they form a benzene ring;

[1352] 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 atoms to which they are attached) form the 1-3 alkyl optionally substituted 5- to 7-membered heterocycloalkyl;

[1353] R C Choose from -H, -YR G 、-NH2、-C 1-3 the group consisting of an alkyl group and a 4- to 7-membered heterocycloalkyl group;

[1354] Y is absent or selected from -CR H R I -, -SO2- and -CO-;

[1355] R H and R I are each independently selected from -H or -C 1-3 Alkyl; or R H and R I Together to form –C 3-4 Cycloalkyl,

[1356] R G Selected from -NH2, -OH, -C 1-3Alkyl, -N(R J R K ),-OR L , aryl, 5 to 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, wherein the monocyclic or bicyclic heterocycloalkyl is substituted by any suitable substituent (such as independently selected from 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 One or more groups of ) are optionally substituted;

[1357] R M1 is selected from 5 to 10 membered mono- or bicyclic aryl or heteroaryl, wherein the 5 to 10 membered mono- or bicyclic aryl or heteroaryl is substituted by -NH2, -OH, halogen, -CN, C 1-3 Alkyl, -OC 1-3 The alkyl group is optionally substituted;

[1358] R J -H or -C 1-3 alkyl;

[1359] R K Choose Free-C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 Alkyl)2, -C 2-3 Alkyl-NHC 1-3 The group consisting of alkyl and optionally substituted 4 to 7 membered monocyclic heterocycloalkyl and optionally substituted 7 to 12 membered bicyclic heterocycloalkyl, the monocyclic or bicyclic heterocycloalkyl being replaced by any suitable substituent (such as -C 1-3 alkyl) is optionally substituted;

[1360] R L For –C 1-3 Alkyl or 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being C 1-3 The alkyl group is optionally substituted;

[1361] When R C YR G When R B and R D Each 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 –C1-3 Alkyl-OC 1-3 Alkyl; wherein the substituent R A to R E At least one of is not hydrogen;

[1362] and

[1363] A 2 Selected from Formula 1b or 1c:

[1364]

[1365] The wavy line is in A 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect;

[1366] R M Selected from 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 A group consisting of an alkynyl group and H;

[1367] Z 5 N or CR O ;

[1368] Z 6 N or CR P ;

[1369] Z 7 N or CR N ;

[1370] where Z 5 , Z 6 and Z 7 Only one of them is N;

[1371] Z 8 CR W or N;

[1372] R N Selected from 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 2-9Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 a group consisting of heteroalkenyl and thiol;

[1373] R O Selected from 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 the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino;

[1374] R P Selected from 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 A group consisting of aromatic groups;

[1375] Alternatively, R N and Z 5 Combined together to form an 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;

[1376] R S Selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl and optionally substituted C 3-10 a group consisting of carbocyclic groups;

[1377] R T Selected from 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 2-6Alkenyl, optionally substituted C 2-6 The group consisting of 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 each independently selected from 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 the group consisting of heteroalkenyl, thiol, optionally substituted sulfone, and optionally substituted amino;

[1378] 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;

[1379] R W Selected from 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 a group consisting of heteroaryl groups;

[1380] and

[1381] wherein the BRD9 binder is attached to the linker at any suitable position.

[1382] 2. The bifunctional molecule according to item 1, wherein Z 1 、Z 2 、Z 3 and Z 4 The number of them that are at most 1 is N.

[1383] 3. The bifunctional molecule according to clause 1 or clause 2, wherein the BRD9 binding agent has formula 1a':

[1384]

[1385] in:

[1386] R A 、R B 、R C 、R E 、Z 3 and A 2 As defined in clause 1 or 2.

[1387] 4. A bifunctional molecule according to any one of clauses 1 to 3, wherein A 2 is selected from Formula 1b', wherein Formula 1b' is:

[1388] The wavy line is in A 2 and positioned at R A and R E The bonds between said carbon atoms in the ortho position intersect;

[1389] R M Choose Free-C 1-5 Alkyl, -cyclopropyl, -C 1-4 A group consisting of a haloalkyl group and H;

[1390] R N Selected from halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 a group consisting of an alkyl group and –OH;

[1391] Z 5 N or CR O

[1392] Z 6 N or CR P , where Z 5 and Z 6 Only one of can be N;

[1393] R O H or –C 1-3 alkyl;

[1394] R P H or –C 1-3 alkyl;

[1395] where R O and R P Only one of them can be –C 1-3 alkyl;

[1396] Alternatively, R N and Z 5 Together they form a benzene ring or a 5- to 6-membered heteroaromatic ring, each of which may be selected from halogen, -OH, -NH2, -NH-C1-3 Alkyl and –C 1-5 Alkyl, C 1-5 Halogenated alkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, Formula 1d (shown below), C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 One or more groups of the cycloalkyl group are optionally and independently substituted, wherein the -C 1-5 The alkyl group may be optionally substituted with a 5- to 6-membered heteroaryl or phenyl group; in

[1397] Y 2 NR R or O;

[1398] Y 1 S(O) a or NR R ;

[1399] Each R R are independently H or C 1-4 alkyl;

[1400] Each R Q Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and –C(O)C 1-3 alkyl group; a is 0 to 2; and

[1401] r is 0 to 3.

[1402] 5. The bifunctional molecule of any one of clauses 1 to 4, wherein the BRD9 binding agent has formula 1e, 1f or 1g:

[1403]

[1404] wherein the wavy line intersects the bond between the BRD9 binder and the linker; wherein R A 、R B 、R C 、R E 、R M 、R N 、Z 3 、Z 5 and Z 6 As defined in any of clauses 1 to 4;

[1405] where R C' does not exist or as in any of clauses 1 to 4 with respect to R C defined;

[1406] Ring 1A is –C 1-3 an optionally alkyl-substituted 5- to 7-membered heterocycloalkane; and

[1407] Ring 1D is optionally substituted C 6-10 Aromatic or optionally substituted C 2–9 Heteroaromatic hydrocarbons.

[1408] 6. The bifunctional molecule according to clause 5, wherein Ring 1A comprises one or two heteroatoms independently selected from the list consisting of N, S and O.

[1409] 7. The bifunctional molecule according to item 5, wherein ring 1A is selected from the list consisting of pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, oxane, tetrahydrothiophene and cyclopentane sulfide.

[1410] 8. The bifunctional molecule of any one of clauses 1 to 5, wherein the BRD9 binding agent has formula 1e, 1f' or 1g':

[1411]

[1412] wherein the wavy line intersects the bond between the BRD9 binder and the linker; wherein R A 、R B 、R C 、R E 、R M 、R N , Z 3 , Z 5 and Z 6 As defined in any one of clauses 1 to 4.

[1413] 9. A bifunctional molecule according to any one of clauses 1 to 8, wherein R A 、R B 、R C 、R D and R E Independently selected from -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.

[1414] 10. A bifunctional molecule according to any one of clauses 1 to 9, wherein R A 、R B 、R D and R EAt least two of them are -H.

[1415] 11. A bifunctional molecule according to any one of clauses 1 to 10, wherein R A 、R B 、R D and R E At least one of -OC 1-3 Alkyl, -H, halogen, and -OC 1-3 A group consisting of haloalkyl groups.

[1416] 12. A bifunctional molecule according to any one of clauses 1 to 11, wherein R M For –C 1-5 alkyl.

[1417] 13. A bifunctional molecule according to any one of clauses 1 to 12, wherein R N -C 1-5 Alkyl or halogen, or R N and Z 5 Together they form an optionally substituted 5- to 6-membered heteroarene or benzene ring.

[1418] 14. The bifunctional molecule according to clause 13, wherein the optionally substituted 5- to 6-membered heteroaromatic ring comprises one or more heteroatoms selected from the group consisting of N, S and O.

[1419] 15. The bifunctional molecule according to item 13, wherein the optionally substituted 5- to 6-membered heteroarene ring is an N- or S-heteroarene.

[1420] 16. The bifunctional molecule according to item 13, wherein the optionally substituted 5- to 6-membered heteroaromatic ring is any one selected from the group consisting of optionally substituted pyrrole, imidazole, pyrimidine, thiophene and pyrazole.

[1421] 17. The bifunctional molecule of any one of clauses 1 to 16, wherein the BRD9 binder is of any one of formulae 1ea to 1eh and 1fa to 1fi and 1ga:

[1422]

[1423] wherein the wavy line intersects the bond between the BRD9 binding agent and the linker;

[1424] R A 、R B 、R E 、R M , Z 3 and Z 6 as defined in any of clauses 1 to 11;

[1425] RC does not exist or as defined in any of clauses 1 to 11;

[1426] R N Selected from halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 a group consisting of an alkyl group and –OH;

[1427] R O H or –C 1-3 alkyl;

[1428] Each R X 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 a group consisting of a haloalkoxy group;

[1429] n is 0 to 3;

[1430] o is 0 to 2;

[1431] p is 0 or 1; and

[1432] q is 0 to 4.

[1433] 18. The bifunctional molecule of any one of clauses 1 to 17, wherein the BRD9 binding agent is according to formula 1ea':

[1434]

[1435] wherein the wavy line intersects the bond between the BRD9 binding agent and the linker;

[1436] R A and R E Each independently selected from H and -OC 1-3 alkyl;

[1437] R B and R D Each independently selected from -OC 1-3 Alkyl, -H, -halo, -C 1-3 Alkyl and -OC 1-3 alkyl halide;

[1438] R C Does not exist or is –YR G ;

[1439] Y chooses free-CRH R I - and -CO- group;

[1440] R H and R I are each independently selected from -H or -C 1-3 Alkyl; or R H and R I Together to form –C 3-4 Cycloalkyl;

[1441] 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;

[1442] R J and R K As defined in Clause 1;

[1443] R M C 1-3 alkyl; and

[1444] R N 、R O and R P Each independently selected from the group consisting of halogenated, -C 1-3 Alkyl and -C 1-3 A group consisting of haloalkyl groups.

[1445] 19. The bifunctional molecule of any one of clauses 1 to 18, wherein the BRD9 binder is of any one of Formulas 1h to 1z and 2a to 2g:

[1446]

[1447]

[1448] where R C Does not exist or is –YR G ;

[1449] Y chooses free-CR H R I - and -CO- group;

[1450] R H and R IEach is -H; or R H and R I Together to form –C 3-4 Cycloalkyl;

[1451] 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 one or two N ring atoms; and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing one or two N ring atoms;

[1452] R J and R K As defined in Clause 1;

[1453] Where the wavy line intersects the bond between the BRD9 binder and the linker.

[1454] 20. A bifunctional molecule according to any one of clauses 1 to 19, wherein R C exists and is any one selected from the following:

[1455]

[1456] Where Y is CR H R I (e.g., CH2);

[1457] R G1 and R G2 Each independently selected from H and C1-C3 alkyl;

[1458] R J As defined in claim 1; and

[1459] L shows the attachment point of the linker.

[1460] 21. A bifunctional molecule according to any one of clauses 1 to 20, wherein:

[1461] (i) When R 1 and R 4 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring together, Z is represented by formula (Ia):

[1462]

[1463] Among them, A, B, R3 and L are as defined for formula (I); and

[1464] n is 1, 2, or 3;

[1465] W is selected from CR W1 R W2 、O、NR W3 and S;

[1466] R W1 、R W2 and R W3 are each independently selected from H and C1 to C6 alkyl; and wherein when n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S;

[1467] (ii) When R 1 and R 2 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring together, Z is represented by formula (Ib):

[1468]

[1469] Among them, B, R 2' 、R 3 、R 4 and L are as defined for formula (I);

[1470] m is 3, 4 or 5;

[1471] Each T is independently selected from CR T1 R T2 、O、NR T3 and S; and

[1472] R T1 、R T2 and R T3 are each independently selected from H and C1 to C6 alkyl; or

[1473] (iii) When R 2 and R 4 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring or carbocyclic ring together, Z is represented by formula (Ic):

[1474]

[1475] Among them, B, R 1 、R 2' 、R 3 and L are as defined for formula (I);

[1476] p is 2, 3, or 4; and

[1477] Each U is independently selected from CR U1 R U2 、O、NR U3 and S; and

[1478] R U1 、R U2 and R U3 Each is independently selected from H and C1 to C6 alkyl.

[1479] 22. A bifunctional molecule according to any one of the preceding clauses, wherein R 3 is selected from the group consisting of heteroaryl, substituted heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl, C1-C6 alkyl substituted by a heterocyclic group, aryl and substituted aryl,

[1480] Optionally, wherein R 3 Selected from:

[1481]

[1482] The dashed lines indicate the corresponding R 3 Each of the groups is attached to a position of the structure shown in Formula (I) to (Ic), or wherein when the dashed line is not attached to an atom, the dashed line indicates the position of the corresponding R 3 Each of the groups is attached to the structure via any position on the aromatic or heteroaromatic ring;

[1483] Each R 5 independently selected from the group consisting of halo, CF3, -CH2F, -CHF2, -OCF3, -OCH2F, -OCHF2, C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO2Me, -NH2, -NHMe, -NMe2, CO2Me, -NO2, CHO and COMe;

[1484] n is 0 to 3;

[1485] R 6 is a C1 to C6 alkyl group;

[1486] G is CH2, O and NH; and

[1487] Q is a C1 to C6 alkylene group.

[1488] 23. A bifunctional molecule according to any one of the preceding clauses, wherein A is CR 2 R 2' , optionally, wherein: (i) R 2 and R 2'One of them is hydrogen and the other is C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted by one or more halogen atoms; or (ii) R 2 and R 2’ Two of them are selected from C1 to C6 alkyl groups.

[1489] 24. The bifunctional molecule according to any one of the preceding clauses, wherein B is a phenyl group.

[1490] 25. The bifunctional molecule according to any one of the preceding clauses, wherein Z is represented by formula (IIaa):

[1491]

[1492] Among them, A, R 3 and L are as defined for formula (I);

[1493] n is 1, 2, or 3; and

[1494] W is selected from CR W1 R W2 、O、NR W3 and S; and

[1495] R W1 、R W2 and R W3 are each independently selected from H and C1 to C6 alkyl; and

[1496] When n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S.

[1497] 26. The bifunctional molecule according to any one of the preceding clauses, wherein Z is represented by formula (IIa):

[1498]

[1499] where R 2 、R 2' 、R 3 and L is as defined in any of the preceding clauses,

[1500] n is 1, 2, or 3; and

[1501] W is selected from CR W1 R W2 、O、NR W3 and S; and

[1502] R W1 、R W2 and R W3are each independently selected from H and C1 to C6 alkyl; and

[1503] When n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S.

[1504] 27. A bifunctional molecule according to any one of the preceding clauses, wherein Z is represented by formula (IIb)

[1505]

[1506] where R 2' 、R 3 and L is as defined in any of the preceding clauses;

[1507] m is 3, 4, or 5; and

[1508] Each T is independently selected from CR T1 R T2 、O、NR T3 and S; and

[1509] R T1 、R T2 and R T3 Each is independently selected from H and C1 to C6 alkyl.

[1510] 28. The bifunctional molecule according to any one of items 1 to 25, wherein Z is represented by formula (Ia) or (IIaa).

[1511] 29. The bifunctional molecule according to any one of clauses 1 to 20, wherein Z is represented by formula (WZIa):

[1512]

[1513] in:

[1514] R 1A 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 two R 1A 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 N-heterocycloalkyl), optionally wherein C 3-5 Cycloalkyl or 5- to 7-membered heterocycloalkyl is attached to ring A at the spiro center A ;

[1515] R2A 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)-;

[1516] where R y is optionally substituted C 1-6 Alkyl or H;

[1517] R 3A is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S;

[1518] X 1 is CH2;

[1519] X 2 、X 3 and X 4 Each independently is CH2, O or NR x ;

[1520] R x is H or C1 to C6 alkyl, or one of R 1A group and an R x The groups combine to form an optionally substituted C 1-3 bridge;

[1521] n is 0, 1, 2, or 3;

[1522] m is 0, 1, 2, 3 or 4; and

[1523] L shows the attachment point of the linker.

[1524] 30. The bifunctional molecule according to any one of clauses 1 to 20, wherein Z is represented by formula (WZII):

[1525]

[1526] where R 2A does not exist or as described in clauses 1 or 29;

[1527] R 3A as set out in clauses 1 or 29;

[1528] X 5 CRb 2. NR b , O or 5- to 7-membered heterocycloalkyl (e.g., 5- to 7-membered heterocycloalkyl);

[1529] Each R 1A 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 two R 1A 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 (WZII) at the center of the spirocycle);

[1530] R b is H or optionally substituted C 1-3 alkyl;

[1531] n1 is 0, 1, 2, or 3;

[1532] m is 0, 1, or 2; and

[1533] L shows the attachment point of the linker.

[1534] 31. The bifunctional molecule according to any one of clauses 1 to 20, wherein Z is represented by any one of formulae (WZIIa) to (WZIIe):

[1535]

[1536] in:

[1537] R 2A as defined in clause 1 or 29;

[1538] R 3A as defined in clause 1 or 29;

[1539] Each R 1A 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 two R 1A The groups combine to form an optionally substituted C 3-5 Cycloalkyl (optionally, wherein the C 3-5 The cycloalkyl group is attached to the heterocycle shown in formula (ZIIa) at the center of the spirocycle);

[1540] X 5 C(R b )2、NR b or O;

[1541] R b is H or optionally substituted C 1-3 alkyl;

[1542] n1 is 0, 1, 2, or 3;

[1543] n' is 1 or 2;

[1544] m is 0, 1, or 2; and

[1545] L shows the attachment point of the linker.

[1546] 32. The bifunctional molecule according to any one of clauses 1 to 20, wherein Z is represented by formula (WII):

[1547]

[1548] where R 2A 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);

[1549] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[1550] X 1 is CH2;

[1551] X 2 and X 3 are each independently CH2 or O; provided that X 2 and X 3 None or only one of them is O; and n is 0, 1, 2 or 3; and

[1552] L shows the attachment point of the linker.

[1553] 33. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIIa):

[1554]

[1555] where R 2A 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);

[1556] R 3Ais selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[1557] n is 0, 1, 2, or 3; and

[1558] L shows the attachment point of the linker.

[1559] 34. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIIb):

[1560]

[1561] where R 2A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[1562] X 1 is CH2;

[1563] X 2 and X 3 are each independently CH2 or O; provided that X 2 and X 3 If there is no or only one of them, it is O;

[1564] n is 1 or 2; and

[1565] L shows the attachment point of the linker.

[1566] 35. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIIc):

[1567]

[1568] where R 2A is selected from heterocycloalkyl and substituted heterocycloalkyl;

[1569] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[1570] X 1 is CH2;

[1571] X 2 and X 3 are each independently CH2 or O; provided that X 2 and X3 If there is no or only one of them, it is O;

[1572] n is 1 or 2; and

[1573] L shows the attachment point of the linker.

[1574] 36. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIId):

[1575]

[1576] where R 2A is selected from heterocycloalkyl and substituted heterocycloalkyl;

[1577] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[1578] n is 1 or 2; and

[1579] L shows the attachment point of the linker.

[1580] 37. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIIe):

[1581]

[1582] where R 2A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[1583] n is 1 or 2; and

[1584] L shows the attachment point of the linker.

[1585] 38. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIIf):

[1586]

[1587] where R 2A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[1588] L shows the attachment point of the linker.

[1589] 39. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIII):

[1590]

[1591] where R 1A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl;

[1592] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[1593] n is 0, 1, 2, or 3; and

[1594] L shows the attachment point of the linker.

[1595] 40. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIIIa):

[1596]

[1597] where R 1A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1 to C6 alkyl;

[1598] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[1599] L shows the attachment point of the linker.

[1600] 41. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIIIb):

[1601]

[1602] where R 1A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl and C1-C6 alkyl;

[1603] R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group; and

[1604] L shows the attachment point of the linker.

[1605] 42. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIV):

[1606]

[1607] where R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[1608] R 4A is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

[1609] n is 0, 1, 2, or 3; and

[1610] L shows the attachment point of the linker.

[1611] 43. The bifunctional molecule according to any one of clauses 1 to 19, wherein Z is represented by formula (WIVa):

[1612]

[1613] where R 3A is selected from C1 to C6 alkyl, aryl, heteroaryl, substituted aryl and substituted heteroaryl, optionally wherein the C1 to C6 alkyl is substituted with a heterocycloalkyl group;

[1614] R 4A is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

[1615] L shows the attachment point of the linker.

[1616] 44. The bifunctional molecule of any preceding clause, wherein n is 1 or 2.

[1617] 45. A bifunctional molecule according to any one of clauses 35 to 37, wherein R 1A :

[1618] (i) selected from the group consisting of: phenyl, optionally substituted by one to three substituents selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; heteroaryl having 5 to 6 ring atoms containing 1 to 3 heteroatoms each independently selected from N, O and S, optionally substituted by one to three substituents selected from the group consisting of halo, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; C3 to C8 cycloalkyl; or

[1619] (ii) is selected from the group consisting of phenyl, substituted phenyl, pyrazolyl and substituted pyrazolyl.

[1620] 46. ​​A bifunctional molecule according to any one of clauses 35 to 37, wherein R 1A is a C3 to C7 cycloalkyl group or a C1 to C3 alkyl group.

[1621] 47. A bifunctional molecule according to any one of clauses 35 to 37, wherein R 1A Selected from any of the following structures:

[1622]

[1623] 48. A bifunctional molecule according to any one of clauses 28 to 34, wherein R 2A :

[1624] (i) is selected from phenyl, which is optionally substituted by one to three substituents selected from H, C1 to C6 alkyl, halo, C1 to C6 haloalkyl and C1 to C6 alkoxy; and heteroaryl having 5 to 6 ring atoms and containing 1 or 2 N atoms, which is optionally substituted by one to three substituents selected from C1-C6 alkyl, halo, C1-C6 haloalkyl and C1 to C6 alkoxy;

[1625] (ii) is selected from optionally substituted phenyl and optionally substituted pyrazolyl; or

[1626] (iii) one selected from the following structures:

[1627]

[1628] where R 6 Selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl and C1-C6 alkoxy.

[1629] 49. A bifunctional molecule according to any one of clauses 28 to 34, wherein R 2A :

[1630] (i) optionally substituted heterocycloalkyl, wherein the heterocycloalkyl has 3 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O and S;

[1631] (ii) is selected from optionally substituted piperidinyl and optionally substituted piperazinyl; or

[1632] (iii) one selected from the following structures:

[1633]

[1634] where R 6 is selected from H, C1 to C6 alkyl, halo, C1 to C6 haloalkyl and C1 to C6 alkoxy.

[1635] 50. A bifunctional molecule according to any one of clauses 28 to 45, wherein R 3A :

[1636] (i) is selected from C1 to C6 alkyl groups optionally substituted by heterocycloalkyl groups having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S; aryl groups having 6 to 10 carbon ring atoms; and aryl groups having 5 to 10 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O and S.

[1637] O and S 1 to 3 heteroatoms heteroaryl; wherein the aryl and the heteroaryl are optionally substituted by one or two substituents selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy; or

[1638] (ii) is selected from optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazolyl,

[1639] optionally substituted oxazolyl, tert-butyl, C1-C6 alkyl containing a morpholine substituent, optionally substituted benzothiazolyl, and optionally substituted pyridinyl.

[1640] 51. A bifunctional molecule according to any one of clauses 28 to 45, wherein R 3A Select one of the following structures:

[1641]

[1642] where R 5A is absent or selected from halo (e.g., F, Cl, Br, I), CF3, -CH2F, -CHF2, OCF3, -OCH2F, -OCHF2, C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO2Me, -NH2, -NHMe, -NMe2, CO2Me, -NO2, CHO and COMe.

[1643] 52. A bifunctional molecule according to any one of clauses 28 to 45, wherein R 3A Select one of the following structures:

[1644]

[1645] 53. A bifunctional molecule according to any one of clauses 38 to 40 and 46 to 48, wherein R 4A :

[1646] (i) is selected from aryl having 6 to 10 carbon ring atoms; and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O and S; wherein the aryl and the heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy; or

[1647] (ii) optionally substituted phenyl.

[1648] 54. The bifunctional molecule of clause 1, wherein Z comprises one of the following structures:

[1649]

[1650]

[1651]

[1652]

[1653] wherein R in each of the above structures 3A One of the following:

[1654]

[1655] 55. The bifunctional molecule according to any of the preceding clauses, wherein the linker comprises 1 to 25 or 1 to 18 atoms in a single linear chain.

[1656] 56. The bifunctional molecule according to any of the preceding clauses, wherein the linker comprises 1 to 10 or 1 to 8 rotatable bonds.

[1657] 57. The bifunctional molecule according to any one of the preceding clauses, wherein the linker (L) is a covalent bond, or the structure of the linker (L) is:

[1658] (L x ) q

[1659] wherein each Lx represents a subunit of L, which is 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, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl groups;

[1660] where R L1 、R L2 、R L3 、R L4 、R L5 、R L6 、R L7 、R L8 and R L9 are each independently selected from H, halo, 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

[1661] q is an integer between 1 and 30.

[1662] 58. The bifunctional molecule of any preceding clause, wherein the bifunctional molecule is not:

[1663]

[1664]

[1665] Wherein the BRD9 binding agent is not:

[1666]

[1667] Where the wavy line intersects the bond between the BRD9 binder and the linker.

[1668] 59. A bifunctional molecule according to clause 1, wherein:

[1669] (i) Z is represented by formula (I), (Ia), (Ib), (Ic), (IIaa), (IIa) or (IIb) as defined above; and

[1670] (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[1671] 60. A bifunctional molecule according to clause 1, wherein:

[1672] (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; and

[1673] (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[1674] 61. A bifunctional molecule according to clause 1, wherein:

[1675] (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; and

[1676] (ii) TBL is represented by formula (1h), (1i) or (1j) as defined above.

[1677] 62. A bifunctional molecule according to clause 1, wherein:

[1678] (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above;

[1679] (ii) TBL is represented by Formula 1a″ as defined above; and

[1680] (iii) L is represented by the formula L1a or L1b.

[1681] 63. A bifunctional molecule according to clause 1, wherein:

[1682] (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above;

[1683] (ii) TBL is represented by any one of Formulas 1e", 1g", 1g'", 1ea" to 1eh", 1ea", 1h" to 1z", and 2a" to 2g" as defined above; and

[1684] (iii) L is represented by formula L1a or L1b as defined above.

[1685] 64. A bifunctional molecule according to clause 1, wherein:

[1686] (i) Z is represented by formula (Ib) or (IIb) as defined above; and

[1687] (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[1688] 65. A bifunctional molecule according to clause 1, wherein:

[1689] (i) Z is represented by formula (Ib) or (IIb) as defined above; and

[1690] (ii) TBL is represented by formula (1h), (1i) or (1j) as defined above.

[1691] 66. A bifunctional molecule according to clause 1, wherein:

[1692] (i) Z is represented by Formula (WI), (WII), (WIIa), (WIIb), (WIIc), (WIId), (WIIe), (WIIf), (WIII), (WIIIa), (WIIIb), (WIV) or (WIVa) as defined above; and

[1693] (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[1694] 67. A bifunctional molecule according to clause 1, wherein:

[1695] (i) Z is represented by any one of Formula (WZI), (WZII), (WZIIa) to (WZIIe), (WZIIIa) to (WZIIIh), or (WZIVa) to (WZIVj), as defined herein;

[1696] (ii) TBL is represented by Formula 1a" as defined herein; and

[1697] (iii) L is represented by formula L1c as defined herein.

[1698] 68. A bifunctional molecule according to clause 1, wherein:

[1699] (i) Z is represented by any one of Formula (WZI), (WZII), (WZIIa) to (WZIIe), (WZIIIa) to (WZIIIh), or (WZIVa) to (WZIVj), as defined herein;

[1700] (ii) TBL is represented by any of Formulas 1e", 1g", 1g'", 1ea" to 1eh", 1ea", 1h" to 1z", and 2a" to 2g" as defined herein; and

[1701] (iii) L is represented by formula L1c as defined herein.

[1702] 69. A bifunctional molecule according to clause 1, wherein:

[1703] (i) Z is represented by Formula (WI), (WII), (WIIa), (WIIb), (WIIc), (WIId), (WIIe), (WIIf), (WIII), (WIIIa), (WIIIb), (WIV) or (WIVa) as defined above;

[1704] Where Z is not:

[1705] and

[1706] (ii) TBL is a target protein binding ligand that binds BRD9, wherein TBL is not:

[1707]

[1708] 70. The bifunctional molecule according to any of the preceding clauses, wherein the bifunctional molecule has a structure as shown in Table 1.

[1709] 71. A pharmaceutical composition comprising a bifunctional molecule according to any of the preceding clauses and a pharmaceutically acceptable carrier, optionally wherein the bifunctional molecule is present in the composition in the form of a pharmaceutically acceptable salt, solvate or derivative.

[1710] 72. The bifunctional molecule according to any one of clauses 1 to 70 or the pharmaceutical composition according to clause 71 for use in medicine.

[1711] 73. The bifunctional molecule or pharmaceutical composition for use according to clause 72, wherein the use comprises the treatment and / or prevention of any disease or condition associated with and / or caused by abnormal levels of BRD9 activity.

[1712] 74. The bifunctional molecule or pharmaceutical composition for use according to clause 72 or 73, wherein the disease or disorder is cancer.

[1713] 75. A method of treating and / or preventing any disease or condition associated with and / or caused by abnormal levels of BRD9 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 clauses 1 to 70 or a pharmaceutical composition according to clause 71.

[1714] 76. The method of clause 75, wherein the disease or condition is cancer.

[1715] 77. A method of selectively degrading BRD9 and / or increasing its proteolysis in a cell, the method comprising contacting the cell with a bifunctional molecule as defined in any one of clauses 1 to 70 or a pharmaceutical composition as defined in clause 71 and / or treating the cell with the same.

[1716] 78. Use of a bifunctional molecule as defined in any one of clauses 1 to 70 in a method for targeted BRD9 degradation.

[1717] 79. A method of preparing a bifunctional molecule as defined in any one of clauses 1 to 70.

[1718] 80. A method of screening a bifunctional molecule according to any one of clauses 1 to 70, the method comprising:

[1719] a. Providing a bifunctional molecule, the bifunctional molecule comprising:

[1720] (i) a first ligand comprising a structure according to Z as defined in any one of clauses 1 and 21 to 54;

[1721] (ii) a second ligand that binds to BRD9 as defined in any one of clauses 1 to 20;

[1722] as well as

[1723] (iii) a linker as defined in any one of clauses 1 and 55 to 57, which linker is covalently linked to the first ligand

[1724] and a second ligand;

[1725] b. contacting the cell with the bifunctional molecule;

[1726] c. detecting degradation of BRD9 in the cells;

[1727] d. detecting degradation of BRD9 in the cell in the absence of the bifunctional molecule; and

[1728] e. comparing the level of BRD9 degradation in the cell contacted with the bifunctional molecule to the level of BRD9 degradation in the absence of the bifunctional molecule;

[1729] wherein an increased level of degradation of BRD9 in said cell contacted with said bifunctional molecule indicates that said bifunctional molecule has facilitated and / or promoted said degradation of BRD9,

[1730] Optionally, wherein detecting degradation of BRD9 comprises detecting a change in the level of a target protein in said cell.

[1731] 81. A compound library comprising a plurality of bifunctional molecules according to any one of clauses 1 to 70.

[1732] 82. A kit of parts comprising:

[1733] (i) a first ligand comprising a structure according to Z as defined in any one of clauses 1 and 21 to 54;

[1734] (ii) a second ligand that binds to BRD9 as defined in any one of clauses 1 to 20; and individually,

[1735] (iii) a linker as defined in any one of clauses 1 and 55 to 57, which covalently links the first ligand and the second ligand.

[1736] definition

[1737] In the present disclosure, many terms are quoted, and these terms are understood to have the meanings provided below, unless the context indicates otherwise. The nomenclature used herein to define compounds (particularly compounds described herein) is intended to comply with the rules of the International Union of Pure and Applied Chemistry (IUPAC) on chemical compounds, particularly "IUPAC Chemical Terminology (Golden Book)" (see AD Jenkins et al., Pure & Appl. Chem., 68, 2287-2311 (1996)). For the avoidance of doubt, if IUPAC rules are contrary to the definitions provided herein, the definitions herein shall prevail.

[1738] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group. The chain can be saturated or unsaturated, for example, in some cases, the chain can contain one or more double bonds or triple bonds.

[1739] As used herein, “C1-C n "Alkyl" can be selected from straight or branched hydrocarbon groups containing 1 to n carbon atoms. For example, "C1-C6 alkyl" can be selected from straight or branched hydrocarbon groups containing 1 to 6 carbon atoms, and C1-C3 alkyl can be selected from straight or branched hydrocarbon groups containing 1 to 3 carbon atoms. Representative examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, etc. When the C1-C6 alkyl group is substituted, any hydrogen atom, CH3, CH2 or CH group can be replaced by a substituent as long as the valence is satisfied. In the case where the C1-C6 alkyl contains a divalent hydrocarbon radical (containing 1 to 6 carbon atoms), this portion may sometimes be referred to herein as C1-C6 alkylene.

[1740] The term "cycloalkyl" defines all monovalent groups derived from cycloalkanes by removing one hydrogen atom from a ring carbon atom. The term "cycloalkane" refers to a saturated monocyclic unbranched hydrocarbon having the general formula C n H 2n , where n is an integer ≥ 3. As used herein, a "cycloalkyl" is typically a ring containing 3 to 10 carbon atoms, in some cases 3 to 8 carbon atoms, or in some cases 5 to 6 carbon atoms. The ring may be saturated or unsaturated, for example, in some cases the ring may contain one or more double bonds or triple bonds. As used herein, C n -C n'Cycloalkyl groups are cycloalkyl groups containing n to n' carbon atoms in the ring, where n and n' are integers.

[1741] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic ring having at least one heteroatom selected from O, N and S (e.g., one to five ring heteroatoms independently selected from the group consisting of O, N and S) in one or more rings of the ring system. One or more rings may also contain one or more double bonds, as long as the one or more rings are not fully aromatic. The one or more rings of the heterocycloalkyl may contain 3 to 10 atoms, in some cases, 3 to 8 atoms. The one or more rings may be aliphatic. The one or more rings may be saturated or unsaturated, for example, in some cases, the one or more rings may contain one or more double bonds or triple bonds. Any N heteroatom present in the heterocycloalkyl group may be substituted by a C1 to C6 alkyl group. In some cases, the heterocycloalkyl group is monocyclic or bicyclic, such as a monocyclic ring. C n -C n' Heterocycloalkyl is a heterocycloalkyl group containing n to n' carbon atoms in the ring, wherein n and n' are integers. Representative examples of heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, dithiolanyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, morpholinyl, dioxanyl, oxazolidinyl, tetrahydropyranyl, diazaspiroundecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, and the like. As used herein, "substituted heterocycloalkyl" refers to a heterocycloalkyl group as defined herein that contains one or more substituents on the heterocycloalkyl ring.

[1742] The term "heterocyclyl" refers to a monovalent radical derived from a heterocycle. A heterocycle is a cyclic compound (a compound comprising one or more linked rings of atoms) whose ring members are at least two different elements (e.g., carbon and nitrogen).

[1743] As used herein, a "halo" group can be F, Cl, Br, or I, typically F.

[1744] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom has been replaced by a halo atom (such as fluoro, chloro, or bromo, typically fluoro). For example, a C1-C6 haloalkyl group refers to an alkyl group containing 1 to 6 carbon atoms in which at least one hydrogen atom has been replaced by a halo atom. Trifluoromethyl and 1,1-difluoroethyl are examples of haloalkyl groups.

[1745] The term "alkenyl" is well known in the art and defines a monovalent group derived from an alkene by removing a hydrogen atom from any carbon atom, wherein the term "alkene" is intended to define a alkene having the general formula CnH 2nA non-cyclic branched or unbranched hydrocarbon, wherein n is an integer ≥ 2. Examples of alkenyl groups include vinyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. When the alkenyl group is substituted, any hydrogen atom may be replaced by a substituent as long as the valence is satisfied. When the alkenyl group comprises a divalent hydrocarbon radical, the moiety may sometimes be referred to herein as an alkenylene group.

[1746] The term "alkynyl" is well known in the art and defines a monovalent group derived from an alkyne by removing a hydrogen atom from any carbon atom, wherein the term "alkyne" is intended to define a radical having the general formula CnH 2n-2 A non-cyclic branched or unbranched hydrocarbon, wherein n is an integer ≥ 2. Examples of alkynyl groups include ethynyl, n-propyl alkynyl, isopropyl alkynyl, n-butyl alkynyl, sec-butyl alkynyl, isobutyl alkynyl, and tert-butyl alkynyl. When the alkynyl group is substituted, any hydrogen atom may be replaced by a substituent as long as the valence is satisfied. When the alkynyl group comprises a divalent hydrocarbon radical, the moiety may sometimes be referred to herein as an alkynylene group.

[1747] As used herein, "benzyl" refers to a -CHPh group. As used herein, "substituted benzyl" refers to a benzyl group, as defined herein, that includes one or more substituents on the CH and / or aromatic rings. When a benzyl group is substituted, any hydrogen atom may be replaced with a substituent as long as the valences are satisfied.

[1748] As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon system having 6 to 14 carbon atoms (in some cases, 6 to 10 carbon atoms). Representative examples of suitable "aryl" groups include, but are not limited to, phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl, and anthracenyl. As used herein, "substituted aryl" refers to an aryl group as defined herein that includes one or more substituents on the aromatic ring. When an aryl group is substituted, any hydrogen atom may be replaced by a substituent as long as the valence is satisfied.

[1749] As used herein, "heteroaryl" can be a monocyclic or fused ring system having one or more aromatic rings containing one or more, in some cases 1 to 3, in some cases 1 to 2, in some cases a single O, N and / or S heteroatom. The term "heteroaryl" can refer to a monocyclic or polycyclic heteroaromatic system having 5 to 10 ring atoms. n -C n'Heteroaryl is a heteroaryl group containing n to n' carbon atoms in the ring, wherein n and n' are integers. Representative examples of heteroaryl groups may include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, and the like. As used herein, "substituted heteroaryl" refers to a heteroaryl group as defined herein that contains one or more substituents on the heteroaromatic ring.

[1750] As used herein, a "carbocycle" is a ring containing 3 to 10 carbon atoms, in some cases 3 to 8 carbon atoms, or in some cases 5 to 6 carbon atoms. The ring can be aliphatic. Thus, as used herein, references to "carbocyclyl" and "substituted carbocyclyl" groups can refer to aliphatic carbocyclyl groups and aliphatic substituted carbocyclyl groups. The ring can be saturated or unsaturated, for example, in some cases the ring can contain one or more double bonds or triple bonds. n -C n' Carbocycle is a carbocycle containing n to n' carbon atoms in the ring, wherein n and n' are integers. Representative examples of carbocyclyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynyl, etc. As used herein, "substituted carbocyclyl" refers to a carbocyclyl group as defined herein that includes one or more substituents on the carbocycle. When the carbocyclyl group is substituted, any hydrogen atom can be replaced by a substituent as long as the valence is satisfied.

[1751] As used herein, "heterocycle" (or heterocyclyl) may contain at least one heteroatom selected from O, N and S. The heterocycle may be monocyclic or polycyclic, with each ring containing 3 to 10 atoms, in some cases 3 to 8 atoms. One or more rings may be aliphatic. Thus, as used herein, references to "heterocyclyl" and "substituted heterocyclyl" groups may refer to aliphatic heterocyclyl groups and aliphatic substituted heterocyclyl groups. One or more rings may be saturated or unsaturated, for example, in some cases, the one or more rings may contain one or more double bonds or triple bonds. n -C n'Heterocycle is a heterocycle containing n to n' carbon atoms in the ring, wherein n and n' are integers. Any N heteroatom present in the heterocyclic group can be replaced by C1 to C6 alkyl. In some cases, the heterocyclic group is a monocycle or a bicycle, such as a monocycle. In other examples, the heterocyclic group can be a bicycle, and in some cases it can be a fused ring. Representative examples of heterocyclic groups include but are not limited to pyrrolidinyl, tetrahydrofuranyl, dioxolane, dithiolanyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, morpholinyl, dioxane, oxazolidinyl, tetrahydropyranyl, diazaspiroundecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, pyrrolidinyl, thienyl etc. As used herein, "substituted heterocyclyl" refers to a heterocyclyl group as defined herein containing one or more substituents on the heterocycle.

[1752] As used herein, the term "optionally substituted" means that a moiety may contain one or more substituents.

[1753] As used herein, a "substituent" may include, but is not limited to, a hydroxyl group, a thiol group, a carboxyl group, a cyano group (CN), a nitro group (NO2), a halo group, a haloalkyl group (e.g., a C1 to C6 haloalkyl group or a C1 to C4 haloalkyl group), an alkyl group (e.g., a C1 to C6 haloalkyl group or a C1 to C4 haloalkyl group), a 10 or C1 to C6, which itself may be unsubstituted or substituted, for example, by one or more selected from the group consisting of aryl, halo and hydroxy), alkenyl groups (e.g., C2 to C6), alkynyl groups (e.g., C2 to C6), aryl groups (e.g., phenyl and substituted phenyl, for example, benzyl or benzoyl), morpholine, NC 1-6Alkylene morpholine, alkoxy group (e.g., C1 to C6 alkoxy or C1 to C4 alkoxy), haloalkoxy (e.g., C1 to C4 haloalkoxy), aryloxy (e.g., phenoxy and substituted phenoxy), hydroxyalkynyl (e.g., C2 to C6), thioether (e.g., C1 to C6 alkyl or arylthioether), alkylthio (e.g., C1 to C6 alkylthio), cyanoalkyl (e.g., C1 to C6), oxo, keto (e.g., C1 to C6 keto), ester (e.g., C1 to C6 alkyl or aryl ester, which may be present as an oxyester or carbonyl ester on the substituted portion), thioester (e.g., C1 to C6 alkyl or arylthioesters), alkylene esters (such that the attachment is on the alkylene group rather than on the ester functional group, the ester functional group being optionally substituted with a C1 to C6 alkyl or aryl group), amines (including monoalkylamino, dialkylamino, five-membered or six-membered cyclic alkyleneamines, the alkyleneamines being optionally substituted with one or more halogen groups, further including C1 to C6 alkylamines or C1 to C6 dialkylamines, wherein the alkyl group may be substituted with one or two hydroxyl groups, and also including alkylphenylamino or alkylphenyl(alkyl)amino groups), amides (including -C(O)NH2, -C(O)NH(alkyl) (such as -C(O)NH(C 1-4 alkyl)), –C(O)N(alkyl)2 (such as –C(O)N(C 1-4 Alkyl)2), -NHC(O)alkyl (such as -NHC(O)C 1-4 alkyl), -NHC(O)(phenyl), -N(alkyl)C(O)(alkyl) (such as -N(C 1-4 alkyl)C(O)(C 1-4 alkyl)), -N(alkyl)C(O)(phenyl) (such as -N(C 1-4 alkyl)C(O)(phenyl)),NC 1-6 alkyleneamino, amide (e.g., which may be substituted with one or two C1 to C6 alkyl groups (including carboxamide optionally substituted with one or two C1 to C6 alkyl groups), aminoalkyl (e.g., C1 to C4 aminoalkyl), alkanol (e.g., C1 to C6 alkyl, C1 to C4 alkyl or aryl alkanol) or carboxylic acid (e.g., C1 to C6 alkyl or aryl carboxylic acid), sulfoxide, sulfone, sulfinimide, sulfonamide, and carbamate (such as -OC(O)-NR2 or -N(R)-C(O)-OR, wherein each R in this context is independently selected from C1 to C6 alkyl or aryl), heteroaryl (which itself may be, for example, 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 (defined above), C3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 The cycloalkyl group is substituted with one or more substituents, wherein -C 1-5 alkyl groups are optionally substituted with 5- to 6-membered heteroaryl or phenyl), heterocyclyl, arylalkyl (such as arylC 1-4 alkyl), heteroarylalkyl (such as heteroaryl C 1-4 Alkyl), -OC 1-4 Alkylphenyl, -C(O)alkyl (such as -C(O)(C 1-4 alkyl)), -C(O)alkylphenyl (such as C(O)(C 1-4 alkylphenyl)), -C(O)haloalkyl (such as –C(O)( C1-4 haloalkyl)), -SO2(alkyl) (such as –SO2(C 1-4 alkyl)), -SO2(phenyl), -SO2haloalkyl (such as OSO2(C 1-4 haloalkyl)), -SO2NH2, -SO2NH(alkyl) (such as -SO2NH(C 1-4 alkyl)), -SO2NH(phenyl), -NHSO2(alkyl) (such as –NHSO2(C 1-4 alkyl)), -NHSO2(phenyl), -NHSO2(haloalkyl) (such as -NHSO2(C 1-4 Halogenated alkyl)), -SC 1-3 Haloalkyl, -CH2C(O)N(R C )2. -C 3-4 Alkynyl (NR C 2. Deuterated C 2-4 Alkynyl, (C 1-3 Alkoxy)halogenated C 1-3 Alkyl-, C 3-6 Cycloalkyl (wherein the C 3-6 Cycloalkyl is halogenated or C 1-3 alkyl optionally substituted), azido, sulfonyl, HC(O)-, -CO2R C or -CO2N(R C )2, where R C is hydrogen or C 1-3 alkyl.

[1754] The term "analog," as used herein, refers to a compound or moiety that has structural similarity to a specified compound or moiety. Despite this structural similarity, an analog may exhibit different chemical and / or biological properties. An analog may have approximately 90% similarity to a specified compound or moiety, meaning it may share approximately 90% of its structure with the specified compound or moiety. In some examples, an analog may have approximately 92%, 94%, 96%, or 98% similarity to a specified compound or moiety.

[1755] As used herein, when a group comprising carbon atoms is defined as "saturated," only single bonds bind the carbon atoms to each other. When a group comprising carbon atoms is defined as "unsaturated," at least two of the two carbon atoms are connected by a double or triple bond. For the avoidance of doubt, an unsaturated compound may contain any number of double and / or triple bonds.

[1756] The term "spirocyclic" is used to refer to a moiety comprising two or more ring systems wherein at least two of the ring systems are linked by only one atom, typically a quaternary carbon atom.

[1757] "Monocyclic" is used herein to refer to a moiety comprising one atomic ring. "Bicyclic" is used herein to refer to a moiety having two connected atomic rings. "Tricyclic" is used herein to refer to a moiety having three connected atomic rings. "Polycyclic" is used herein to refer to a moiety comprising two or more connected rings. Unless the context indicates otherwise, bicyclic and polycyclic ring systems may comprise fused ring systems (wherein at least two rings share a common bond). In other examples, two or more rings may be connected by bonds between atoms on each of the two or more rings. In other examples, a bicyclic ring system may comprise a spirocyclic center (as defined above).

[1758] As used herein, the term "bridged" refers to a cyclic moiety or ring comprising two bridgehead atoms (typically two carbon atoms of a cyclic compound or ring) connected by one or more atoms located outside the ring (such as one to three atoms located outside the ring). A bridged ring comprises two rings that share three or more atoms. In some instances, the bridgehead atoms are separated by at least one carbon atom within the ring. In some instances, the rings can be bridged by 1 to 3 bridging atoms located outside the ring to form a bridged group (optionally, wherein the bridging atoms are selected from C, N, O, and S). As used herein, "C 1-3 A "bridge" is a bridging group comprising 1 to 3 carbon bridging atoms. The bridging group may include one to three atoms located outside the ring, one, two or three of which are carbon. In some cases, the bridging group may additionally comprise non-carbon atoms (such as heteroatoms selected from N, O and S). For example, as used herein, "C 1-3The term "bridge" may refer to a bridging group comprising 1 to 3 atoms, one, two or three of which are carbon and the remainder (if any) are selected from N, O and S. The bridging group may be a C1 to C3 alkylene group (such as a methylene, ethylene or propylene group). The C1 to C3 alkylene bridging group may be optionally substituted with any suitable substituent described herein. For example, the C1 to C3 alkylene bridging group may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1 to C3 alkyl, C1 to C3 haloalkyl and C1 to C3 alkoxy.

[1759] The term "fused" is used to refer to a moiety comprising two or more ring systems wherein at least two of the ring systems are connected via a [1,2] ring junction, i.e., a moiety comprising two or more ring systems wherein two or more of the rings share a bond in the respective ring structures.

[1760] The term "aliphatic" refers to acyclic or cyclic, saturated or unsaturated moieties, excluding aromatic moieties, where "aromatic" defines a cyclic conjugated molecular entity whose stability (due to delocalization) is significantly higher than the stability of the assumed local structure. Hückel's rule is commonly used in the art to assess aromaticity; a monocyclic planar (or nearly planar) system of trigonally (or sometimes diagonally) hybridized atoms containing (4n+2) π electrons (where n is a non-negative integer) will exhibit aromaticity. This rule is generally restricted to n = 0 to 5.

[1761] The term "hydrocarbyl" refers to a monovalent free radical derived from a hydrocarbon by removing a hydrogen atom from the hydrocarbon. A hydrocarbon is any molecule containing only the elements carbon and hydrogen. Hydrocarbons can be aliphatic, aromatic, unsaturated, or saturated.

[1762] As used herein, alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen group -O-. As used herein, C 1- C6 alkoxy refers to a C6 alkoxy group attached to the parent molecular moiety through an oxygen group -O- 1- C6 alkyl group (as defined above), and C 1- C4 alkoxy refers to a C4 alkoxy group attached to the parent molecular moiety through an oxygen group -O- 1- C4...

Claims

1. A bifunctional molecule comprising the following general formula: TBL–L–Z Wherein TBL is the target protein binding ligand that binds to BRD9; L is a linker; and Z comprises a structure according to formula (I): in R 1 is selected from C1 to C6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl, optionally wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from halo, N, O and S and / or is substituted by a carbocyclic or heterocyclic group; A does not exist or is CR 2 R 2' ; B is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl; R 2 and R 2' are each independently selected from H and C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O or S, or wherein R 2 and R 2' Together they form a 3-membered, 4-membered, 5-membered or 6-membered carbocyclic or heterocyclic ring; R 3 is selected from C1-C6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylheterocycloalkyl, substituted alkylheterocycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, substituted alkylheteroaryl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O and S; R 4 is H, C1 to C6 alkyl, optionally, wherein the C1 to C6 alkyl is substituted by one or more heteroatoms selected from N, O or S; or where R 1 and R 4 Together they form a 5-, 6-, or 7-membered heterocyclic ring; or when A is CR 2 R 2' hour: R 1 and R 2 together to form a 5-membered, 6-membered or 7-membered heterocyclic ring; or R 2 and R 4 Together they form a 5-, 6- or 7-membered heterocyclic or carbocyclic ring; Wherein L shows the connection point of the linker; and wherein the BRD9 binder (TBL) has Formula 1a: in: Z 1 N or CR A ; Z 2 N or CR B ; Z 3 N or CR D ; Z 4 N or CR E ; where Z 1 、Z 2 、Z 3 and Z 4 The number of numbers that do not exceed 3 is N; R A and R E Each independently selected from -H, -OC 1-3 Alkyl and –C 1-3 a group consisting of alkyl groups; R B and R D Each independently selected from -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 alkyl, 4 to 7 membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 Alkyl)2, -N(C 1-3 Alkyl)2, -NH-R F the group formed; 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; 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 they form the 1-3 alkyl optionally substituted 5- to 7-membered heterocycloalkyl; R C Choose from -H, -YR G 、-NH2、-C 1-3 the group consisting of an alkyl group and a 4- to 7-membered heterocycloalkyl group; Y is absent or selected from -CR H R I -, -SO2- and -CO-; R H and R I are each independently selected from -H or -C 1-3 Alkyl; or R H and R I Together to form –C 3-4 Cycloalkyl, R G Selected from -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ),-OR L , aryl, 5 to 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 being independently selected from 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 One or more groups of are optionally substituted; R M1 is selected from 5 to 10 membered mono- or bicyclic aryl or heteroaryl, wherein the 5 to 10 membered mono- or bicyclic aryl or heteroaryl is substituted by -NH2, -OH, halogen, -CN, C 1-3 Alkyl, -OC 1-3 The alkyl group is optionally substituted; R J -H or -C 1-3 alkyl; R K Choose Free-C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 Alkyl)2, -C 2-3 Alkyl-NHC 1-3 The group consisting of an optionally substituted 4- to 7-membered monocyclic heterocycloalkyl and an optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is replaced by -C 1-3 The alkyl group is optionally substituted; R L For –C 1-3 Alkyl or 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being C 1-3 The alkyl group is optionally substituted; When R C YR G When R B and R D Each 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 Substituent R A to R E At least one of is not hydrogen; and A 2 Selected from Formula 1b or 1c: The wavy line is in A 2 and positioned at R A and R E The bonds between adjacent carbon atoms intersect; R M Selected from 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 A group consisting of an alkynyl group and H; Z 5 N or CR O ; Z 6 N or CR P ; Z 7 N or CR N ; where Z 5 、Z 6 and Z 7 Only one of them is N; Z 8 CR W or N; R N Selected from 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 a group consisting of heteroalkenyl and thiol; R O Selected from 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 the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino; R P Selected from 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 A group consisting of aromatic groups; Alternatively, R N and Z 5 Combined together to form an 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; R S Selected from H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl and optionally substituted C 3-10 a group consisting of carbocyclic groups; R T Selected from 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 The group consisting of 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 heterocyclic group; R U and R V are each independently selected from 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 the group consisting of heteroalkenyl, thiol, optionally substituted sulfone, and optionally substituted amino; 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; R W Selected from 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 a group consisting of heteroaryl groups; and wherein the BRD9 binding agent is attached to the linker at any suitable position; and (iii) wherein the bifunctional molecule is not:

2. The bifunctional molecule according to claim 1, wherein Z 1 、Z 2 、Z 3 and Z 4 The number of them that are at most 1 is N.

3. The bifunctional molecule of claim 1 or claim 2, wherein the BRD9 binding agent has formula 1a': in: R A 、R B 、R C 、R E 、Z 3 and A 2 As defined in claim 1 or 2.

4. The bifunctional molecule according to any one of claims 1 to 3, wherein A 2 is selected from Formula 1b', wherein Formula 1b' is: The wavy line is in A 2 and positioned at R A and R E The bonds between said carbon atoms in the ortho positions intersect; R M Choose Free-C 1-5 Alkyl, -cyclopropyl, -C 1-4 A group consisting of a haloalkyl group and H; R N Selected from halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 a group consisting of an alkyl group and –OH; Z 5 N or CR O Z 6 N or CR P , where Z 5 and Z 6 Only one of can be N; R O H or –C 1-3 alkyl; R P H or –C 1-3 alkyl; where R O and R P Only one of them can be –C 1-3 alkyl; Alternatively, R N and Z 5 Together they form a benzene ring or a 5- to 6-membered heteroaromatic ring, each of which may be 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 One or more groups of the cycloalkyl group are optionally and independently substituted, wherein the -C 1-5 The alkyl group may be optionally substituted with a 5- to 6-membered heteroaryl or phenyl group; in Y 2 NR R or O; Y 1 S(O) a or NR R ; Each R R are independently H or C 1-4 alkyl; Each R Q Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and –C(O)C 1-3 alkyl group; a is 0 to 2; and r is 0 to 3.

5. The bifunctional molecule of any one of claims 1 to 4, wherein the BRD9 binding agent has Formula 1e, 1f or 1g: wherein the wavy line intersects the bond between the BRD9 binder and the linker; wherein R A 、R B 、R C 、R E 、R M 、R N 、Z 3 、Z 5 and Z 6 As defined in any one of claims 1 to 4; where R C' There is no or any one of claims 1 to 4 for R C defined; Ring 1A is –C 1-3 an optionally alkyl-substituted 5- to 7-membered heterocycloalkane; and Ring 1D is optionally substituted C 6-10 Aryl or optionally substituted C 2-9 Heteroaryl.

6. The bifunctional molecule according to claim 5, wherein Ring 1A: (i) contains one or two heteroatoms independently selected from the list consisting of N, S and O; or (ii) selected from the list consisting of pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, oxane, tetrahydrothiophene and cyclopentane sulfide.

7. The bifunctional molecule of any one of claims 1 to 5, wherein the BRD9 binding agent has formula 1e, 1f' or 1g': 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 、R N 、Z 3 、Z 5 and Z 6 As defined in any one of claims 1 to 4.

8. The bifunctional molecule according to any one of claims 1 to 7, wherein R A 、R B 、R C 、R D and R E Independently selected from -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.

9. The bifunctional molecule according to any one of claims 1 to 8, wherein: (i)R A 、R B 、R D and R E At least two of are –H; and / or (ii)R A 、R B 、R D and R E At least one of -OC 1-3 Alkyl, -H, halogen, and -OC 1-3 A group consisting of haloalkyl groups.

10. The bifunctional molecule according to any one of claims 1 to 9, wherein R M For –C 1-5 alkyl.

11. The bifunctional molecule according to any one of claims 1 to 10, wherein R N -C 1-5 Alkyl or halogen, or R N and Z 5 together to form an optionally substituted 5- to 6-membered heteroarene or benzene ring, optionally wherein: (i) the optionally substituted 5- to 6-membered heteroaromatic ring contains one or more heteroatoms selected from the group consisting of N, S and O; (ii) the optionally substituted 5- to 6-membered heteroarene ring is an N- or S-heteroarene; or (iii) the optionally substituted 5- to 6-membered heteroaromatic ring is any one selected from the group consisting of optionally substituted pyrrole, imidazole, pyrimidine, thiophene and pyrazole.

12. The bifunctional molecule of any one of claims 1 to 11, wherein the BRD9 binder is any one of formulae 1ea to 1eh and 1fa to 1fi and 1ga: wherein the wavy line intersects the bond between the BRD9 binding agent and the linker; R A 、R B 、R E 、R M 、Z 3 and Z 6 As defined in any one of claims 1 to 11; R C not existing or as defined in any one of claims 1 to 11; R N Selected from halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 a group consisting of an alkyl group and –OH; R O H or –C 1-3 alkyl; Each R X 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 a group consisting of a haloalkoxy group; n is 0 to 3; o is 0 to 2; p is 0 or 1; and q is 0 to 4.

13. The bifunctional molecule of any one of claims 1 to 12, wherein the BRD9 binding agent is according to formula 1ea': wherein the wavy line intersects the bond between the BRD9 binding agent and the linker; R A and R E Each independently selected from H and -OC 1-3 alkyl; R B and R D Each independently selected from -OC 1-3 Alkyl, -H, -halo, -C 1-3 Alkyl and -OC 1-3 alkyl halide; R C Does not exist or is –YR G ; Y chooses free-CR H R I - and -CO- group; R H and R I are each independently selected from -H or -C 1-3 Alkyl; or R H and R I Together to form –C 3-4 Cycloalkyl; R G Choose from –N(R J R K )、-、-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 heterocycloalkylene; R J and R K As defined in claim 1; R M C 1-3 alkyl; and R N 、R O and R P Each independently selected from the group consisting of halogenated, -C 1-3 Alkyl and -C 1-3 A group consisting of haloalkyl groups.

14. The bifunctional molecule of any one of claims 1 to 12, wherein the BRD9 binder is any one of Formulas 1h to 1z and 2a to 2g: where R C Does not exist or is –YR G ; Y chooses free-CR H R I - and -CO- group; R H and R I Each is -H; or R H and R I Together to form –C 3-4 Cycloalkyl; R G Selected from the group consisting of: –N(R J R K )、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 one or two N ring atoms; and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing one or two N ring atoms; R J and R K As defined in claim 1; Where the wavy line intersects the bond between the BRD9 binder and the linker.

15. A bifunctional molecule according to any one of claims 1 to 14, wherein R C exists and is any one selected from the following: Where Y is CR H R I ; R G1 and R G2 Each independently selected from H and C1-C3 alkyl; R J as defined in claim 1; and L shows the attachment point of the linker.

16. A bifunctional molecule according to any one of claims 1 to 15, wherein: (i) When R 1 and R 4 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring together, Z is represented by formula (Ia): Among them, A, B, R 3 and L are as defined for formula (I); and n is 1, 2, or 3; W is selected from CR W1 R W2 、O、NR W3 and S; R W1 、R W2 and R W3 are each independently selected from H and C1 to C6 alkyl; and wherein when n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S; (ii) When R 1 and R 2 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring together, Z is represented by formula (Ib): Among them, B, R 2' 、R 3 、R 4 and L are as defined for formula (I); m is 3, 4 or 5; Each T is independently selected from CR T1 R T2 、O、NR T3 and S; and R T1 、R T2 and R T3 are each independently selected from H and C1 to C6 alkyl; or (iii) When R 2 and R 4 When Z and Z form a 5-membered, 6-membered or 7-membered heterocyclic ring or carbocyclic ring together, Z is represented by formula (Ic): Among them, B, R 1 、R 2' 、R 3 and L are as defined for formula (I); p is 2, 3, or 4; and Each U is independently selected from CR U1 R U2 、O、NR U3 and S; and R U1 、R U2 and R U3 Each is independently selected from H and C1 to C6 alkyl.

17. A bifunctional molecule according to any one of the preceding claims, wherein R 3 is selected from the group consisting of heteroaryl, substituted heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl, C1-C6 alkyl substituted by a heterocyclic group, aryl and substituted aryl, Optionally, wherein R 3 Selected from: The dashed lines indicate the corresponding R 3 Each of the groups is connected to a position of the structure represented by formula (I) to (Ic), or or wherein when the dashed line is not attached to an atom, the dashed line indicates the corresponding R 3 Each of the groups is attached to the structure via any position on the aromatic or heteroaromatic ring; Each R 5 independently selected from the group consisting of halo, CH2OH, CF3, -CH2F, -CHF2, OCF3, -OCH2F, -OCHF2, C1 to C6 alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO2Me, -NH2, -NHMe, -NMe2, CO2Me, -NO2, CHO and COMe; n is 0 to 3; R 6 is a C1 to C6 alkyl group; G is CH2, O and NH; and Q is a C1 to C6 alkylene group.

18. A bifunctional molecule according to any one of the preceding claims, wherein A is CR 2 R 2' , optionally, wherein: (i)R 2 and R 2' One of them is hydrogen and the other is C1 to C6 alkyl, optionally wherein the C1 to C6 alkyl is substituted by one or more halogen atoms; or (ii) R 2 and R 2’ Two of them are selected from C1 to C6 alkyl groups.

19. The bifunctional molecule according to any one of the preceding claims, wherein Z is represented by formula (IIaa): Among them, A, R 3 and L are as defined for formula (I); n is 1, 2, or 3; and W is selected from CR W1 R W2 、O、NR W3 and S; and R W1 、R W2 and R W3 are each independently selected from H and C1 to C6 alkyl; and When n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S; Optionally, wherein: (i) Z is represented by formula (IIa): where R 2 、R 2' 、R 3 and L as defined in any one of the preceding claims, n is 1, 2, or 3; and W is selected from CR W1 R W2 、O、NR W3 and S; and R W1 、R W2 and R W3 are each independently selected from H and C1 to C6 alkyl; and When n is 2 or 3, each W is independently selected from CR W1 R W2 、O、NR W3 and S.

20. The bifunctional molecule of any preceding claim, wherein the linker comprises 1 to 25 or 1 to 18 atoms in a single linear chain.

21. The bifunctional molecule of any preceding claim, wherein the linker comprises 1 to 10 or 1 to 8 rotatable bonds.

22. The bifunctional molecule according to any one of the preceding claims, wherein the linker (L) is a covalent bond, or the structure of the linker (L) is: (L x ) q wherein each Lx represents a subunit of L, which is 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, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl groups; where R L1 、R L2 、R L3 、R L4 、R L5 、R L6 、R L7 、R L8 and R L9 are each independently selected from H, halo, 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.

23. The bifunctional molecule according to any one of claims 1 to 22, wherein the linker (L) can be represented by formula (L1a): L 1A —L 2A —L 3A (L1a) Among them L 1A Not present or selected from C1-C6 alkylene, C1-C6 alkoxy and C1-C6 alkylamino; L 2A -NR L2A C=O- or -C=ONR L2A -;and L 3A Selected from C1-C3 alkylene, C1-C6 alkoxy and C1-C6 alkylamino; where R L2A is H or C1-C6 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 -NR L2A C=O- or -C=ONR L2A -; L 3B Selected from C1-C 15 Alkylene, -[(CH2)2O] 1-6 (CH2)2-; L 4B -NR L2A C=O- or -C=ONR L2A -, where R L2A is H or C1-C6 alkyl; L 5B Selected from C1-C3 alkylene, C1-C6 alkoxy and C1-C6 alkylamino; where R L2A is H or C1-C6 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 additional ring heteroatoms selected from N, O, and S; L 2C Not present or selected from C1-C3 alkylene, C1-C6 alkoxy and C1-C6 alkylamino; L 3C -R L2B C=O- or –(C=O)R L2B -;and L 4C Selected from C1-C3 alkylene, C1-C6 alkoxy and C1-C6 alkylamino; in: R L2A is H or C1-C6 alkyl; and R L2B NR L2A or an N-linked 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 additional 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 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 of which optionally contains one or two additional ring heteroatoms selected from N, O, and S; wherein R L2A is H or C1-C6 alkyl; and L 3D is absent 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 of which optionally contains one or two additional ring heteroatoms selected from N, O and S; and L 3E Selected from C1-C3 alkylene; Alternatively, the linker (L) can 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 is H or C1-C3 alkyl.

24. The bifunctional molecule of any preceding claim, wherein the bifunctional molecule has a structure as shown in Table 1.

25. A pharmaceutical composition comprising the bifunctional molecule according to any one of the preceding claims and a pharmaceutically acceptable carrier, optionally wherein the bifunctional molecule is present in the composition in the form of a pharmaceutically acceptable salt, solvate or derivative.

26. The bifunctional molecule according to any one of claims 1 to 24 or the pharmaceutical composition according to claim 25 for use in medicine.

27. The bifunctional molecule or pharmaceutical composition for use according to claim 26, wherein the use comprises the treatment and / or prevention of any disease or condition associated with and / or caused by abnormal levels of BRD9 activity.

28. The bifunctional molecule or pharmaceutical composition for use according to claim 26 or 27, wherein the disease or disorder is cancer.

29. A method for selectively degrading BRD9 in a cell and / or increasing its proteolysis, said method comprising contacting said cell with a bifunctional molecule as defined in any one of claims 1 to 24 or a pharmaceutical composition as defined in claim 25 and / or treating said cell with the same.

30. A method of preparing a bifunctional molecule as defined in any one of claims 1 to 24.

31. A method for screening a bifunctional molecule according to any one of claims 1 to 24, the method comprising: a. Providing a bifunctional molecule, the bifunctional molecule comprising: (i) a first ligand comprising the structure of Z as defined in any one of claims 1 and 16 to 19; (ii) a second ligand that binds to BRD9 as defined in any one of claims 1 to 15; and (iii) a linker as defined in any one of claims 1 and 20 to 23, which covalently links the first ligand and the second ligand; b. contacting the cell with the bifunctional molecule; c. detecting degradation of BRD9 in the cells; d. detecting degradation of BRD9 in the cell in the absence of the bifunctional molecule; as well as e. comparing the level of BRD9 degradation in the cell contacted with the bifunctional molecule to the level of BRD9 degradation in the absence of the bifunctional molecule; wherein an increased level of degradation of BRD9 in said cell contacted with said bifunctional molecule indicates that said bifunctional molecule has facilitated and / or promoted said degradation of BRD9, Optionally, wherein detecting degradation of BRD9 comprises detecting a change in the level of a target protein in said cell.

32. A compound library comprising a plurality of bifunctional molecules according to any one of claims 1 to 24.

33. A compound library comprising a plurality of TBL or L or Z moieties of the bifunctional molecule according to any one of claims 1 to 24.

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