Compounds for targeted protein degradation

Abstract

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

Description

[Technical Field]

[0001] The present disclosure relates to degradation of bromodomain-containing protein 9 (BRD9) protein. BRD9 is associated with cancer growth, and the present disclosure relates to treating cancer, for example, through degradation of BRD9. Specifically, the present disclosure relates to a novel class of bifunctional molecules useful for 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, including selective and / or targeted degradation of BRD9. [Background technology]

[0002] BRD9 is a protein encoded by the BRD9 gene on chromosome 5. BRD9 is a component of the BAF (BRG1 or BRM-associated factor) complex, a SWI / SNF ATPase chromatin remodeling complex, and belongs to family IV of bromodomain-containing proteins (D. Hay et al., Med. Chem. Commun., 2015, 6, 1381-1386). SWI / SNF utilizes the energy of ATP hydrolysis to remodel chromatin and mobilize nucleosomes. SWI / SNF is involved in activating transcription by remodeling nucleosomes, thereby allowing increased access to transcription factor binding sites. It is also required for transcriptional repression of some genes, thus regulating transcription in various ways.

[0003] Recurrent inactivating mutations in specific subunits of the SWI / SNF complex have been identified in different cancers. Despite their known role in tumor suppression, mammalian SWI / SNF complexes have recently attracted attention as potential targets 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 some specific types of sarcomas (X. Zhu, Y. Liao, and L. Tang, Onco Targets Ther., 2020, 13, 13191-13200). BRD9-containing complexes bind to both active promoters and enhancers, where they contribute to gene expression. Loss of BRD9 results in changes in gene expression related to the regulation of apoptosis, translation, and development. BRD9 is essential for the growth of SMARCB1-deficient cancer cell lines, suggesting that it may be a therapeutic target for these deadly cancers (Xiaofeng Wang et al., Nature Communications, 2019, 10(1881)). Recent studies have highlighted the role of BRD9 in leukemia proliferation: BRD9 was shown to be required for the proliferation of acute myeloid leukemia (AML) cells (Nature Chemical Biology, 2016, 101038 / nchembio.2115). In addition to its functional role as a cancer-specific dependency, BRD9 also plays a pivotal role in immune cells as a regulator of regulatory T cells (Tregs) through transcriptional regulation of Foxp3 target genes (BioRxiv, 10.1101 / 2020.02.26.964981).

[0005] Due to the role of BRD9 in cancer growth, there has been interest in developing BRD9 inhibitors for the treatment of cancer, including those described in WO 2014 / 114721, WO 2016 / 077375, WO 2016 / 077378, WO 2016 / 139361, WO 2019 / 152440, Martin LJ et al., "Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor," Journal of Medicinal Chemistry, 2016, 59, 4462-4475, Theodoulou NH et al., "Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain-Containing Protein 9 Inhibition," Journal of Medicinal Chemistry, 2015, 59, 1425-1439, and Clack A 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 cellular degradation machinery to induce the degradation of specific disease-causing proteins. Compared to other drug modalities (e.g., small-molecule inhibitors, antibody- and protein-based drugs, antisense oligonucleotides, and related knockdown approaches), the TPD approach offers many advantages, including enhanced pharmacological effects due to the removal of catalytic proteins from within cells, the ability to inhibit multiple functions of a specific drug target, including scaffolding functions, through targeted knockdown, the opportunity for systemic administration due to favorable biodistribution, potent in vivo efficacy due to a long duration of action limited only by catalytic activity and de novo protein resynthesis, and facile chemical synthesis and formulation due to the application of small-molecule processes.

[0007] Physiological post-translational regulation of protein levels and the removal of damaged, misfolded, or excess proteins is largely mediated by the ubiquitin proteasome system (UPS). The UPS can be repurposed as a therapeutic agent to degrade specific proteins using bifunctional chemical molecules, which act by inducing proximity of desired substrates with UPS proteins, initiating a cascade of events that ultimately leads to the degradation of the desired target by the proteasome and its removal from the cell.

[0008] Protein degradation targeting chimeras (PROTACs) constitute one such class of bifunctional degraders that induce the proximity of target proteins to the UPS by recruiting specific ubiquitin E3 ligases. PROTACs consist of two ligands connected by a linker: one ligand that engages the desired target protein and the other ligand that recruits the ubiquitin E3 ligase.

[0009] The most frequently 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 their close analogs, that functions as a warhead. Other ligases, including mdm2 and the IAP family, have also shown utility in PROTAC design.

[0010] However, these approaches have various limitations that limit their usefulness in treating a wide range of diseases. For example, limitations of current PROTAC approaches include the inability to efficiently degrade some targets, low activity of PROTACs in many specific cell types due to low and variable expression of E3 ligases and other proteins required for efficient degradation, chemical properties that make it difficult to prepare degraders with suitable drug-like properties, including favorable drug metabolism and pharmacokinetic profiles, and high susceptibility to induced resistance mechanisms in tumors.

[0011] Due to these limitations, there remains a need to identify novel degradation mechanisms and warheads that can provide new bifunctional degradant molecules that exhibit efficient degradation against a variety of targets and cellular systems and / or have improved profiles suitable for drug development.

[0012] Further bifunctional decomposition inducer molecules are described in WO2019 / 238886, WO2019 / 238817, WO2019 / 238816 and WO2022 / 129925.

[0013] Proteolytic compounds having an E3 ligase-binding moiety and a BRD9-binding moiety (the BRD9-binding ligand binds to BRD9 and delivers it to the ligase, which ultimately degrades it via the proteasome) have been described by Ciulli et al. (J. Med. Chem. 2019, 62, 2, 699-726), WO2017 / 223452, WO2019 / 152440, and WO2 019 / 246423, WO2019 / 246430, WO2020 / 051235, WO2020 / 106915, WO2020 / 160192, WO2020 / 160193, WO2020 / 160196, WO2021 / 022163, WO2021 / 178920, WO2020 / 160198 and WO2020 / 160196.

[0014] Most known BRD9 inhibitors have poor efficacy. Because BRD9 plays an important role in cancer, there remains a need to identify bifunctional degrader molecules that efficiently degrade BRD9 across various cellular systems and / or have improved profiles suitable for drug development. Summary of the Invention

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

[0016] Removal and / or reduction of BRD9 from a cell or subject in need thereof by a targeted proteolytic mechanism may find particular application in therapy, e.g., the treatment of cancer. Accordingly, the present disclosure further relates to methods of treating cancer comprising selective and / or targeted degradation of BRD9, as well as bifunctional molecules and pharmaceutical compositions for use in such methods.

[0017] The bifunctional molecules described herein are [ka] where TBL is a target protein-binding ligand that binds to BRD9, and L is a linker. The "Z" portion ("warhead") regulates, promotes, and / or enhances proteasomal degradation of the target protein BRD9, and is sometimes referred to as a regulator, promoter, and / or promoter of proteasomal degradation. For example, in use, the TBL portion of the bifunctional molecule binds to BRD9. The Z portion (the portion that is bound or connected to TBL via the linker) then regulates, promotes, and / or enhances degradation of the BRD9 protein, for example, by acting to bring the BRD9 protein into proximity with the proteasome and / or otherwise labeling the BRD9 protein for proteasomal degradation within the cell.

[0018] Thus, a bifunctional molecule described in the present disclosure can be considered to include a target protein binding ligand (TBL) that binds to BRD9 (i.e., a ligand that can bind (e.g., specifically bind) to BRD9), a warhead or degradation tag (Z) (e.g., a Z portion that acts to regulate, promote and / or enhance the degradation of this target protein), and a linker (e.g., a chemical linker) that joins, bonds, or connects the TBL and Z.

[0019] The bifunctional molecules described herein have been shown to be effective inducers of BRD9 degradation. Without being bound by theory, it is hypothesized that the Z moieties of the bifunctional molecules described herein do not bind to the specific E3 ligases typically relied upon in the classical PROTAC approaches discussed above (such as CRBN and VHL). Thus, it is believed that the bifunctional molecules described herein regulate, promote, and / or enhance proteasomal degradation through alternative mechanisms. Thus, this class of bifunctional molecules of the present invention may be useful for a broader range of diseases, including those that are resistant to many PROTAC degradation inducers.

[0020] The bifunctional molecules described herein can provide degraders with one or more properties (e.g., one or more drug-like properties) that facilitate, enhance, and / or promote their use in vivo. Specifically, bifunctional molecules comprising warhead Z can provide improved levels of bioavailability (e.g., oral bioavailability) over many classic PROTAC degraders. Additionally or alternatively, bifunctional molecules comprising warhead Z can provide improved levels of CNS (central nervous system) penetration (as opposed to many other degrader molecules currently known in the art).

[0021] The bifunctional molecules described in the present disclosure are specifically designed to degrade BRD9. In particular, the inventors have shown that attaching a BRD9-binding ligand to a linker that is itself attached to a warhead results in the formation of a bifunctional molecule capable of degrading BRD9. Furthermore, the inventors have shown that these bifunctional molecules can be used to specifically and selectively degrade BRD9 over other types of BRD proteins (e.g., BRD4 and / or BRD7), while maintaining good degradation levels.

[0022] According to a first aspect of the present disclosure, a compound of the general formula: [ka] wherein TBL is a target protein binding ligand that binds to BRD9; L is a linker, Z comprises a structure according to formula (I): [ka] During the ceremony, R 1is selected from C1-C6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S, and / or with a carbocyclic or heterocyclic group; A does not exist or CR 2 R 2’ and B is selected from aryl, heteroaryl, substituted aryl, and substituted heteroaryl; R 2 and R 2’ are each independently selected from H and C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from N, O, S or halo, or R 2 and R 2’ taken together form an optionally substituted 3-, 4-, 5-, 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-C6 alkyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from N, O or S; Or, R 1 and R 4 taken together form an optionally substituted 5-, 6-, or 7-membered heterocyclic ring; Or, A is CR 2 R 2’ If R 1 and R2 taken together form an optionally substituted 5-, 6- or 7-membered heterocyclic ring, or R 2 and R 4 taken together form an optionally substituted 5-, 6-, or 7-membered heterocyclic or carbocyclic ring; L represents the attachment point of the linker, Or, Z is a group of the formula (WZI): [ka] including a structure according to During the ceremony, 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 optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; R 2A is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R y is an optionally substituted C 1-6 alkyl or H, 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; L represents the attachment point of the linker, Or, Z is a group represented by the formula (WI): [ka] including a structure according to In the formula, R 1A is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; R 2A is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; 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; X 1 is CH2, X2 and X 3 are each independently CH2, or O and NR x and R is a heteroatom selected from x is H or C1-C6 alkyl, and n is 0, 1, 2 or 3; L represents the attachment point of the linker, Or, Z is a group represented by the formula (A): [ka] wherein the linker is a carbonyl carbon C 1 binds to In particular, Z is a group of formula (A1): [ka] consisting of or consisting essentially of a structure according to During the ceremony, 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; wherein the linker is the carbonyl carbon C 1 The present invention provides a bifunctional molecule that binds to

[0023] In some embodiments, the BRD9 conjugate has formula 1a: [ka] It is of During the ceremony, Z 1 is N or CR A and Z 2 is N or CR B and Z 3 is N or CR D and Z 4 is N or CR E and In the formula, Z 1 , Z 2 , Z 3 and Z 4 Of these, three or fewer are N, R A and R E are each independently -H, -OC 1-3 Alkyl, and -C 1-3 is selected from the group consisting of alkyl, R B and R D are each independently -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, 4- to 7-membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2, -N(C 1-3 alkyl)2, -NH-R F is selected from the group consisting of R F is -SO2-C 1-3 Alkyl and -C 1-3 alkyl, wherein -C 1-3 The alkyl is optionally substituted with a 5- to 6-membered heteroaryl; Or, R A and R B together to form a benzene ring, Or, RC and Z 2 , or RC and Z 3 together (for example, R C and R B , or R C and R D together with the carbon atom to which they are attached) optionally -C 1-3 forming a 5- to 7-membered heterocycloalkyl substituted with alkyl; R C -H, -YR G , -NH2, -C 1-3 is selected from the group consisting of alkyl, and 4- to 7-membered heterocycloalkyl; Y is absent or -CR H R I -, -SO2-, and -CO-; R H and R I are each independently -H or -C 1-3 alkyl, or R H and R I Together -C 3-4 forming a cycloalkyl, R G -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ), -OR L , aryl, and 5- to 6-membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more halogens, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, and these monocyclic or bicyclic heterocycloalkyls may optionally be substituted with suitable substituents, such as halogen, -OH, -NH, -C, 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl, and -CH2-R M1 and optionally substituted with one or more groups independently selected from R M1-NH2, -OH, halogen, -CN, -C 1-3 Alkyl or -OC 1-3 selected from 5-10 membered mono- or bicyclic aryl or heteroaryl optionally substituted with alkyl; R J is -H or -C 1-3 is alkyl, R K -C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 alkyl)2, -C 2-3 Alkyl-NHC 1-3 alkyl, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is optionally selected from the group consisting of -C 1-3 substituted with suitable substituents such as alkyl; R L -C 1-3 alkyl or 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally C 1-3 is substituted with alkyl, where R C YR G If R B and R D are each independently -H, -OH, halogen, -NH2, -CN, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, and -C 1-3 Alkyl-OC 1-3 alkyl, where R A ~R E at least one of the substituents is not hydrogen; and, A 2 is represented by formula 1b or formula 1c: [ka] is selected from In the formula, the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom located ortho to R M is an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, C 2-6 selected from the group consisting of alkynyl, and H; Z 5 is N or CR O and Z 6 is N or CR P and Z 7 is N or CR N and where Z 5 , Z 6 and Z 7 and exactly one of them is N, Z 8 is CR W or N, R N is a halogen, optionally substituted -C 1-6 Alkyl, -H, C(O)C 1-5 Alkyl, -NH2, optionally substituted amino, -OH, cyano, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, and thiol; R O is H, halogen, cyano, optionally substituted 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 selected from the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino; R P is H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl and optionally substituted C 6-10 aryl; Or, R N and Z 5 are bonded together and optionally substituted C 6-10 arene or optionally substituted C 2-9 forming a heteroarene, optionally R N and R O are bonded together with the carbon atom to which they are attached, and optionally substituted C 6-10 arene or optionally substituted C 2-9 forming a heteroarene, R S is H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl and optionally substituted C 3-10 carbocyclyl; R T is H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, optionally substituted sulfone, and optionally substituted sulfonamido; or R T and R U are optionally substituted C, together with the atom to which each is attached. 2-9 forming a heterocyclyl, R U and R V are each independently H, halogen, hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, thiol, optionally substituted sulfone, and optionally substituted amino; Or, R T and R U are optionally substituted C, together with the atom to which each is attached. 2-9 forming a heterocyclyl, R W is H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 aryl, or optionally substituted C 2-9 heteroaryl; and, The BRD9 conjugate is attached to the linker at any suitable position.

[0024] In some embodiments of Formula 1a above, R C The group may be H and the linker may be attached at this position. In other words, the linker (L) is R C The groups may be substituted. Such examples are sometimes designated as formula 1a''.

[0025] In some embodiments, the bifunctional molecule is [ka] not, or [ka] isn't it.

[0026] Target Protein Binding Ligands (TBLs) As used herein, a "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 may 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 it were not bound to the bifunctional molecule.

[0027] The target protein binding ligand may comprise or be derived from a small molecule (or analogue or fragment thereof) already known to act as a regulator, promoter, and / or inhibitor of BRD9 protein function. By way of example, the target protein binding ligand may comprise or be derived from a small molecule known to inhibit the activity of the BRD9 target protein.

[0028] By way of example, the bifunctional molecules disclosed herein can include a target protein-binding ligand that binds to BRD9 with sufficient binding affinity such that BRD9 is selectively degraded. In particular, when the bifunctional molecules described herein contact BRD9, the observed DCs 50 The value (for degradation of BRD9) can be about 15 μM or less, about 10 μM or less, 1000 nM or less, 500 nM or less, 100 nM or less, or 25 nM or less, 10 nM or less, 5 nM or less, 1.25 nM or less, 1 nM or less, or 0.5 nM or less.

[0029] As a further example, a target protein-binding ligand that binds (e.g., specifically binds) to BRD9 may bind to BRD9 with a dissociation constant of about 10 μM or less, about 5 μM or less, or about 3 μM or less. In some examples, a target protein-binding ligand that binds (e.g., specifically binds) to BRD9 may bind to BRD9 with a dissociation constant of 1000 nM or less, 500 nM or less, 100 nM or less, 50 nM or less, or 20 nM or less. In some examples, the ligand may bind to BRD9 with a dissociation constant of about 0.001 nM to about 10 μM, e.g., 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 may bind to BRD9 with a dissociation constant of about 0.01 nM to about 10 μM, for example, 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.

[0030] In some examples, the ligand may bind to BRD9 with a dissociation constant of about 0.1 nM to about 10 μM, e.g., 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 may bind to BRD9 with a dissociation constant of about 1 nM to about 10 μM, e.g., 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.

[0031] For the avoidance of doubt, a dissociation constant is a measure of the tendency of two components bound together to separate (dissociate) into the two components. As used herein, a dissociation constant refers to a measure of the tendency of a complex formed by binding a target protein-binding ligand to a target protein to dissociate into its individual components, i.e., the tendency of a target protein-binding ligand to dissociate from the target protein.

[0032] The bond between the BRD9 protein and the target protein-binding ligand may comprise one or more binding interactions, such as one or more of the group consisting of a hydrogen bond, a dipole-dipole bond, an ion-dipole bond, an ion-induced dipole bond, an ionic bond, and a covalent bond. For example, the bond between the BRD9 protein and the target protein-binding ligand may comprise a salt bridge (a combination of a hydrogen bond and an ionic bond).

[0033] In some examples, the bifunctional molecules of the present disclosure may be selective degradation inducers of BRD9 protein, e.g., the bifunctional molecules may selectively degrade BRD9 over other proteins, such as other BRD proteins (e.g., BRD7 or BRD4). In more specific examples, the bifunctional molecules may be selective degradation inducers of a specific type of BRD9 protein. For example, the molecules of the present disclosure may have a greater binding affinity for a specific BRD9 mutant than for other types of proteins, such as other types of BRD9 proteins (e.g., wild-type BRD9).

[0034] Representative examples targeting BRD9 have been developed over the years and include those described in the following publications: WO 2014 / 114721, WO 2016 / 077375, WO 2016 / 077378, WO 2016 / 139361, WO 2019 / 152440, "Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor" by Martin LJ et al. (Journal of Medicinal Chemistry, 2016, 59, 4462-4475), "Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain-Containing Protein 9 Inhibition" by Theodoulou NH et al. (Journal of Medicinal Chemistry, 2015, 59, 1425-1439), and "Angewandte" by Clack P. et al. Chemie, 2015, 127, 6315-6319).

[0035] Such BRD9 binding molecules (mentioned in the paragraph above) can be incorporated into the bifunctional molecules of the present disclosure as target protein binding ligands (TBLs).

[0036] As noted above, the BRD9 conjugates of the present disclosure have the formula 1a: [ka] It is of In the formula, A 2 , Z 1 , Z 2 , Z 3 , Z 4 and R C is as defined above.

[0037] In some embodiments, Z in Formula 1a 1 , Z 2 , Z 3and Z 4 At most one of these is N. In some cases, Z 1 is CR A , Z 2 is CR B , Z 3 is N or CR D , Z 4 is CR E That is, Z 3 may be N. In such embodiments, the BRD9 conjugate has formula 1a': [ka] It is of During the ceremony, R A、 R B , R C , R E , Z 3 and A 2 is as defined above and herein. A 2 is represented by formula 1b or formula 1c: [ka] is selected from In the formula, the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom ortho to Z 5 , Z 6 , Z 7 , Z 8 , R M , R S , R T , R U and R V is as defined above and herein.

[0038] Z 7 is N or CR N and Z 5 is N or CR O In some embodiments, R N(including the carbon to which it is attached) and Z 5 are bonded together and optionally substituted C 6-10 arene or optionally substituted C 2-9 For the avoidance of doubt, Z 5 is N and R N (including the carbon to which it is attached) and Z 5 are bonded together and optionally substituted C 6-10 arene or optionally substituted C 2-9 When forming a heteroarene, R N (including the carbon to which it is attached) and Z 5 NC optionally substituted together 2-4 Forms heteroarenes. For example, Z 5 If N, then R N and N are joined to form an optionally substituted N-C as shown below: 2-4 A heteroaryl may be formed: [ka] In the formula, the wavy line represents A 2 and R A and R E The bond between the carbon atom ortho to the Z 6 and R M is as defined above, and 1B is optionally substituted NC 2-4 It is a heteroarene, for example, an optionally substituted 5-membered heteroarene, such as any one selected from the group consisting of optionally substituted pyrrole, imidazole, pyrazole, and triazole (including 1,2,3-triazole and 1,2,4-triazole).

[0039] In some embodiments, Z 5 is CR O and Z 7 is CR N If R N and R Oare bonded together with the carbon to which they are attached, and optionally substituted C 6-10 arene or optionally substituted C 2-9 Heteroarenes may be formed: [ka] In the formula, the wavy line represents A 2 and R A and R E The bond between the carbon atom ortho to Z 6 and R M is as defined above, and as previously mentioned, Ring 1C is optionally substituted C 6-10 arene or optionally substituted C 2-9 For example, ring 1C may be an optionally substituted benzene or a 5- or 6-membered heteroarene, such as any one selected from the group consisting of optionally substituted benzene, pyridine, pyrrole, imidazole, pyrimidine, thiophene, and pyrazole.

[0040] In some embodiments, R N (including the carbon atom to which it is attached) and Z 5 may be joined together to form a benzene ring or a 5- or 6-membered heteroarene ring (for example, Ring 1C may be a benzene ring or a 5- or 6-membered heteroarene ring), and these rings may each optionally independently be selected from the group consisting of halogen, —OH, —NH, —NH—C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, 1d, C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, where -C 1-5The alkyl group can be optionally substituted with a 5- to 6-membered heteroaryl or phenyl, where 1d is [ka] wherein: Y 2 is NR R or O, Y 1 is S(O) a or NR R and Each R R are independently H or C 1-4 is alkyl, Each R Q is C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and -C(O)C 1-3 independently selected from the group consisting of alkyl, a is 0 to 2; r is 0 to 3.

[0041] In some embodiments, Z 7 is CR N That is, A 2 is Equation 1b': [ka] is selected from In the formula, the wavy line represents A 2 and R A and R E and Z 5 , Z 6 , R M and R N is as defined above and herein.

[0042] As mentioned above, R M is an optionally substituted C 1-6 Alkyl, optionally substituted C2-6 Alkenyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, C 2-6 In some embodiments, R M is an optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl and H. For example, R M is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 In some embodiments, R M is C 1-5 Alkyl, etc., -C 1-5 Alkyl, -cyclopropyl, -C 1-4 In some embodiments, R is selected from the group consisting of haloalkyl and H. M is C 1-3 It is alkyl.

[0043] As mentioned above, R N is a halogen, optionally substituted -C 1-6 Alkyl, -H, C(O)C 1-5 Alkyl, -NH2, optionally substituted amino, -OH, cyano, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 In some embodiments, R may be selected from the group consisting of heteroalkenyl and thiol. N is a halogen, optionally substituted C 1-6 Alkyl, H, C(O)C 1-5 Alkyl, -NH2, -NHC1-3 In some embodiments, R N is a halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 alkyl, and —OH. For example, R N is C 1-5 It may be alkyl or halogen.

[0044] As mentioned above, Z 5 is N or CR O and R O is H, halogen, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 is selected from the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino. For example, R O is H or C 1-3 Optionally substituted C such as alkyl 1-6 In some embodiments, R O is H or -C 1-3 It may also be alkyl.

[0045] In some embodiments, R N -C 1-5 alkyl or halogen, or R N and Z 5are joined together to form an optionally substituted 5- or 6-membered heteroarene or benzene ring. In some embodiments, the optionally substituted 5- or 6-membered heteroarene 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- or 6-membered heteroarene ring may be an N-heteroarene or an S-heteroarene. In some embodiments, the optionally substituted 5- or 6-membered heteroarene ring is any one selected from the optionally substituted group consisting of pyridine, pyrrole, imidazole, pyrimidine, thiophene, and pyrazole.

[0046] For the avoidance of doubt, the optional substituents are halogen, -OH, -NH, -NH-C 1-3 Alkyl, -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, 1d, C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, where -C 1-5 The alkyl group can be optionally substituted with a 5- to 6-membered heteroaryl or phenyl, where 1d is [ka] wherein: Y 2 is NR R or O, Y 1 is S(O) a or NR R and Each R R are independently H or C 1-4 is alkyl, Each R Q is C 1-4 Alkyl, C 1-4Haloalkyl, halogen, and -C(O)C 1-3 independently selected from the group consisting of alkyl, a is 0 to 2; r is 0 to 3.

[0047] For example, optional substituents include halogen, —OH, —NH, —NH—C 1-3 Alkyl, -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, and C 1-4 Optionally, the optional substituents may be independently selected from the group consisting of C1-C4 alkyl, allyl, crotyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 Haloalkyl, C 3-5 In some embodiments, R N and Z 5 together with optionally substituted C 6-10 Aryl or optionally substituted C 2-9 When forming a heteroaryl, the C 6-10 Aryl or C 2-9 The heteroaryl is unsubstituted.

[0048] As mentioned above, Z 6 is N or CR P and R P is H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl and optionally substituted C 6-10 aryl. For example, R P is H or C 1-6 H or optionally substituted C, such as alkyl 1-6 In some embodiments, R P is H or -C 1-3Alkyl, i.e., Z 6 is N, CH, or CC 1-3 It is an alkyl group. For example, Z 6 is CH or CC 1-3 It may also be alkyl.

[0049] In some particular embodiments, A 2 is selected from formula 1b', where formula 1b' is [ka] It is of In the formula, the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom located ortho to R M -C 1-5 Alkyl, -cyclopropyl, -C 1-4 haloalkyl, and H; R N is a halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 is selected from the group consisting of alkyl, and -OH; Z 5 is N or CR O and Z 6 is N or CR P and Z 5 and Z 6 Only one of may be N, R O is H or -C 1-3 is alkyl, R P is H or -C 1-3 is alkyl, R O and R P Only one of them is -C 1-3 may be alkyl, Or, R Nand Z 5 are united to form a benzene ring or a 5- or 6-membered heteroarene ring, and each ring is not substituted with halogen, -OH, -NH2, -NH-C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, 1d, C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, where -C 1-5 The alkyl group can be optionally substituted with a 5- to 6-membered heteroaryl or phenyl; Here, 1d is [ka] wherein: Y 2 is NR R or O, Y 1 is S(O) a or NR R and Each R R are independently H or C 1-4 is alkyl, Each R Q is C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and -C(O)C 1-3 independently selected from the group consisting of alkyl, a is 0 to 2; r is 0 to 3.

[0050] As previously mentioned, the BRD9 conjugate may be attached to the linker at any suitable position (provided it has the correct valence and / or is chemically appropriate). For example, the linker may be attached to an atom on the linker and an R C , R A , R B, R D or R E Alternatively, the linker may be attached to the BRD9 conjugate by a covalent bond between an atom that is part of R C , R A , R B , R D and / or R E may be directly attached to the ring to which R is attached, i.e., the linker C , R A , R B , R D or R E In some embodiments, the linker may be substituted with an atom on the linker and R C or by a covalent bond between atoms that form part of R C is attached to the BRD9 conjugate by a covalent bond between an atom on the linker and the atom to which it would otherwise be attached, i.e., the linker is R C Replace with.

[0051] Or, R C and Z 2 , or R C and Z 3 together (for example, R C and R B or R C and R D together with the carbon atom to which they are attached) optionally -C 1-3 When forming a 5- to 7-membered heterocycloalkyl substituted with alkyl, the linker may be attached to the BRD9 conjugate by a covalent bond between an atom on the linker and an atom forming part of the 5- to 7-membered heterocycloalkyl.

[0052] In some embodiments, the BRD9 conjugate has formula 1a 1 , Equation 1a 2 , Equation 1a 3 : [ka] It is of wherein the wavy line crosses the bond between the BRD9 binder and the linker; A 2 , Z 1 , Z 2 , Z 3 and Z 4 is as defined above and herein; R C is absent or is as defined above and herein; Ring 1A is optionally -C 1-3 It is a 5- to 7-membered heterocycloalkane substituted with alkyl.

[0053] Ring 1A may contain one or two heteroatoms independently selected from the list consisting of N, S, and O. For example, ring 1A may be selected from the list consisting of pyrrolidine, piperidine, piperazine, morpholine, oxolane, oxane, tetrahydrothiophene, and thiane. In some cases, ring 1A may be an N-heterocycloalkane such as pyrrolidine, piperidine, or piperazine. In a particular example, ring 1A is pyrrolidine.

[0054] For the avoidance of doubt, the linker may be a bond between an atom on the linker and a feature on the BRD9 binder (e.g., R C When attached to a BRD9 conjugate by a covalent bond between an atom forming part of a BRD9 conjugate, the linker replaces a chemical group or feature with a valence of one (e.g., a hydrogen atom) to satisfy the valence. For example, if the feature on the BRD9 conjugate is dimethylamide (-C(O)N(CH)) or dimethylaminomethylene (-CHN(CH)), the linker can replace a methyl group or a hydrogen atom on that feature.

[0055] Alternatively, the linker can be a bond between the atoms on the linker and A 2 Atoms that form part of, for example, R M , R N , R O , R P , R S , R T , R U , RV or R W or the linker may be attached to the BRD9 conjugate by a covalent bond between R M , R N , R O , R P , R S , R T , R U , R V or R W Alternatively, R N and Z 5 are bonded together and optionally substituted C 6-10 arene or optionally substituted C 2-9 When forming a heteroarene, optionally R N and R O together with the carbon atom to which they are attached, 6-10 arene or optionally substituted C 2-9 When forming a heteroarene, the linker may be a C optionally substituted with an atom on the linker. 6-10 arene or optionally substituted C 2-9 It may be attached to the BRD9 binder by a covalent bond between atoms that form part of the heteroarene.

[0056] R N and Z 5 In one exemplary BRD9 conjugate in which the linkers are linked together to form an optionally substituted thiophene, the linker may be attached to the BRD9 conjugate as shown in the following structure: [ka] In the formula, the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom ortho to R M and Z 6 is as defined above and herein.

[0057] The linker may be attached to an atom that forms part of a substituent attached at the same position as shown above. For example, the linker may be attached to an atom that forms part of substituent 1d that is attached at the same position as shown above. This is because R N and Z 5 are linked together to form an optionally substituted thiophene, the wavy line indicating A 2 and R A and R E and crosses the bond between the carbon atom ortho to Y. 2 is O and Y 1 is N and R R is H and R Q and r is as defined above: [ka]

[0058] As mentioned above, the Z of the BRD9 binder 1 , Z 2 , Z 3 , Z 4 and R C is defined as follows: Z 1 is N or CR A and Z 2 is N or CR B and Z 3 is N or CR D and Z 4 is N or CR E and In the formula, Z 1 , Z 2 , Z 3 and Z 4 Of these, three or fewer are N, R A and R E are each independently -H, -OC 1-3 Alkyl, and -C 1-3 is selected from the group consisting of alkyl, R B and R D are each independently -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, 4- to 7-membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2, -N(C 1-3 alkyl)2, -NH-R F is selected from the group consisting of R F is -SO2-C 1-3 Alkyl and -C 1-3 alkyl, wherein -C 1-3 The alkyl is optionally substituted with a 5- to 6-membered heteroaryl; Or, R A and R B together form a benzene ring, or R C and Z 2 , or R C and Z 3 together (for example, R C and R B or R C and R D together with the carbon atom to which they are attached) optionally -C 1-3 forming a 5- to 7-membered heterocycloalkyl substituted with alkyl; R C -H, -YR G , -NH2, -C 1-3 is selected from the group consisting of alkyl, and 4- to 7-membered heterocycloalkyl; Y is absent or -CR H R I -, -SO2-, and -CO-; R H and R Iare each independently -H or -C 1-3 alkyl, or R H and R I Together -C 3-4 forming a cycloalkyl, R G -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ), -OR L , aryl, and 5- to 6-membered heteroaryl, wherein the aryl and heteroaryl are optionally and independently substituted with one or more halogens, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is optionally substituted with one or more halogens, —OH, —NH, —C 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl and -CH2-R M1 and substituted with any suitable substituents, such as one or more groups independently selected from R M1 -NH2, -OH, halogen, -CN, -C 1-3 Alkyl or -OC 1-3 selected from 5-10 membered mono- or bicyclic aryl or heteroaryl optionally substituted with alkyl; R J is -H or -C 1-3 is alkyl, R K -C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3 alkyl)2, -C 2-3 Alkyl-NHC 1-3 alkyl, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is optionally selected from the group consisting of -C 1-3substituted with any suitable substituent, such as alkyl; R L -C 1-3 alkyl or 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally C 1-3 is substituted with alkyl, where R C YR G If R B and R D are each independently -H, -OH, halogen, -NH2, -CN, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl and -C 1-3 Alkyl-OC 1-3 alkyl, wherein the substituent R A ~R E At least one of them is not hydrogen.

[0059] In the above alternative example, R G and R K The list of groups may be replaced by: R G -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ), -OR L , aryl, and 5- to 6-membered heteroaryl, wherein the aryl and heteroaryl are optionally and independently substituted with one or more halogen, 4- to 7-membered heterocycloalkyl, and the heterocycloalkyl is optionally substituted with one or more halogen, —OH, —NH, —C 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl and -CH2-R M1 and is substituted with one or more groups independently selected from R K -C 1-3 Alkyl, -C 2-3 Alkyl-N(C 1-3alkyl)2, -C 2-3 Alkyl-NHC 1-3 alkyl and 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally selected from the group consisting of -C 1-3 is substituted with alkyl, R J , R L , R M1 is as defined above.

[0060] In some embodiments of the BRD9 binding ligands described herein (unless otherwise specified): (i)R A , R B , R D and R E are each independently -OC 1-3 Alkyl, -H, halogen, -OC 1-3 Haloalkyl, -OH, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2 and -N(C 1-3 alkyl)2; or (ii)R A , R D and R E are each independently -OC 1-3 Alkyl, -H, halogen, -OC 1-3 Haloalkyl, -OH, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2 and -N(C 1-3 alkyl)2, and R B and R C together, optionally -C 1-3 Forms a 5- to 7-membered heterocycloalkyl substituted with alkyl.

[0061] In such embodiments, the 5- to 7-membered heterocycloalkyl may be as defined above for Ring 1A.

[0062] In some embodiments, R A , R B , R D and R E independently, -OC 1-3 Alkyl, -H, halogen, -OC 1-3 Haloalkyl, -OH, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2 and -N(C 1-3 For example, R A , R B , R D and R E independently, -OC 1-3 Alkyl, -H, halogen and -OC 1-3 It may be selected from the group consisting of haloalkyl.

[0063] In some cases, R A , R B , R D and R E At least one of R may be -H. For example, A and R B At least one of R may be -H. A , R B , R D and R E At least two of the are -H.

[0064] In some embodiments, R A , R B , R D and R E At least one of them is -OC 1-3 Alkyl, halogen, -OC 1-3 haloalkyl. B and R E-OC 1-3 Alkyl, halogen and -OC 1-3 haloalkyl.

[0065] In some embodiments, R C is -H or -YR G Y is -CR H R I - or -CO-, where R H and R I is as defined above. R H and R I may each be -H, or R H and R I Together -C 3-4 It may also form a cycloalkyl.

[0066] R G may be as defined above, or may be —NH, —OH, —C 1-3 Alkyl, -N(R J R K ), -OR L , optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein R J , R K , R L and the optional substituents of the 4- to 7-membered monocyclic heterocycloalkyl and the 7- to 12-membered bicyclic heterocycloalkyl are as defined above. R J is -H or -C 1-3 alkyl, and R K Ha-C 1-3 R may be selected from alkyl, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl. L -C 1-3 It may also be alkyl.

[0067] R G or R Kis an optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, the optionally substituted 4- to 7-membered monocyclic heterocycloalkyl can be a 5- to 7-membered monocyclic heterocycloalkyl containing 1 to 3 ring heteroatoms selected from N, O, and S. In some examples, the optionally substituted 4- to 7-membered monocyclic heterocycloalkyl can be a 5- to 7-membered monocyclic heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N. In some examples, the optionally substituted 4- to 7-membered monocyclic heterocycloalkyl can be piperazinyl, piperidinyl, or diazepanyl (each of which can optionally contain 1 to 3 substituents as described herein).

[0068] R G or R K When is an optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may be a bridged bicyclic ring or a spirocyclic bicyclic ring (i.e., it may contain two rings joined at a spiro center). By way of example only, the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may be a bridged piperazinyl or a bridged piperidinyl. In other examples, the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl may contain one to three ring heteroatoms selected from N, O, and S (e.g., one to two ring heteroatoms selected from N), and may be an optionally substituted spirocyclic bicyclic heterocycloalkyl. In some examples, the optionally substituted 7- to 12-membered bicyclic heterocycloalkyl is spirocyclic and includes a five- or six-membered first ring and a three- to six-membered second ring.

[0069] In some embodiments, R C may be any one selected from the following: [ka] In the formula, Y is CR H R I (e.g. CH2), R G1 and R G2 are each independently selected from H or C1-C3 alkyl; R J is as defined above and herein, and L indicates the point of attachment of the linker.

[0070] In the above structure, the Y and L groups may both be attached to the heterocycle(s) via covalent bonds between atoms on the Y and L groups and atoms of the heterocycle. These groups may be attached at any chemically suitable position as long as valences are satisfied (e.g., by replacing an H atom).

[0071] Further, by way of example only, R C may be any one selected from the following: [ka] In the formula, Y is CR H R I (e.g., CH2), and L indicates the point of attachment of the linker.

[0072] In certain embodiments, R C teeth, [ka] -CH2N(C 1-3 alkyl)2, -C(O)N(C 1-3 alkyl)2, -C(CH2CH2)N(C 1-3 alkyl)2, and CH2OCH3, wherein the wavy line represents R C and the rest of the BRD9 conjugate, and R C and the linker.

[0073] In some embodiments, the BRD9 conjugate is of formula 1e, 1f, or 1g: [ka] wherein the wavy line crosses the bond between the BRD9 binder and the linker; R A , R B , R E , R M , R N , Z 3 , Z 5 and Z 6 is as defined above, R C is not present or is not R C is as defined for Ring 1A is optionally -C 1-3 a 5- to 7-membered heterocycloalkane substituted with alkyl, and Ring 1D is an optionally substituted C 6-10 arene or optionally substituted C 2-9 It is a heteroarene.

[0074] In some embodiments, Ring 1D is an optionally substituted benzene or an optionally substituted 5- to 6-membered heteroarene. The 5- to 6-membered heteroarene is selected from the group consisting of S, N, and O. It may contain one or more heteroatoms, such as S. In some cases, Ring 1D is a 5- to 6-membered N- or S-heteroarene, such as any one selected from the group consisting of thiophene, pyrazole, imidazole, pyrrole, pyrimidine, and pyridine. In certain embodiments, Ring 1D is a thiophene fused to the remainder of the BRD9 conjugate at the 2' and 3' positions, and in more particular embodiments, is attached to the linker by a covalent bond between an atom on the linker and the carbon atom at the 5' position of the thiophene. In certain such embodiments, the BRD9 conjugate has the formula 1g': [ka] It is of where the wavy line crosses the bond between the BRD9 binder and the linker, and R A , R B , R C , R E , R M , Z 3 , and Z 6 is as defined above.

[0075] In some embodiments, ring 1A is pyrrolidine. In some embodiments, ring 1A is pyrrolidine. In particular examples, ring 1A is pyrrolidine and is fused to the remainder of the BRD9 conjugate at the 3' and 4' positions, and in more particular embodiments, is attached to the linker by a covalent bond between an atom on the linker and the nitrogen atom of the pyrrolidine. In certain such embodiments, the BRD9 conjugate may be of formula 1f', as follows: [ka] where the wavy line crosses the bond between the BRD9 binder and the linker, and where R A , R E , R M , R N , Z 3 , Z 5 and Z 6 is as defined above and herein.

[0076] In some embodiments, the BRD9 conjugate is of formula 1e, 1f', or 1g'.

[0077] In certain embodiments, the BRD9 conjugate is any one of formulas 1ea-1eh, 1fa-1fh, and 1ga: [ka] wherein the wavy line crosses the bond between the BRD9 binder and the linker; R A , R B , R E , R M , Z 3 and Z 6 is as defined above and herein; R C is absent or is as defined above and herein; R N is as defined above and herein, for example, halogen, —C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 selected from the group consisting of alkyl and -OH; R O is as defined above and herein, for example, —H or —C 1-3 is alkyl, Each R X is R N and Z 5 Optionally substituted C 6-10 Aryl or optionally substituted C 2-9 as defined as optional substituents of heteroaryl, e.g., each R X are each independently a halogen, -OH, -NH2, or -NH-C 1-3 Alkyl, -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy and C 1-4 haloalkoxy; n is 0 to 3 (e.g., 0), o is 0 to 2 (e.g., 0), p is 0 or 1 (e.g., 0), and q is 0 to 4 (for example, 0).

[0078] Each of n, o, p, and q may be 0.

[0079] In some embodiments, the BRD9 conjugate has formula 1ea': [ka] This is due to wherein the wavy line crosses the bond between the BRD9 binder and the linker; R A and R E are as defined above and herein, for example, each independently H or —OC 1-3 alkyl, R B and R D are as defined above and herein, for example, each independently represents -OC 1-3 Alkyl, -H, -halo, -C 1-3 Alkyl or -OC 1-3 haloalkyl; R C does not exist or -YR G and Y is -CR H R I - and -CO-, R H and R I are each independently -H or -C 1-3 alkyl, or R H and R I Together -C 3-4 forming a cycloalkyl, R G is -N(R J R K ) (e.g., -N(C 1-3 alkyl)-, -N(C 1-3 alkyl)(optionally substituted 4- to 7-membered monocyclic heterocycloalkylene), or —N(C 1-3alkyl)(optionally substituted 7- to 12-membered bicyclic heterocycloalkylene)), -O-, optionally substituted 4- to 7-membered monocyclic heterocycloalkylene, and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene; R J and R K is as defined above and herein; R M is as defined above and herein, for example, -C 1-3 alkyl, and R N , R O and R P are each as defined above and herein, for example, each independently -halo, -C 1-3 Alkyl, and -C 1-3 haloalkyl.

[0080] In more particular embodiments, the BRD9 conjugates have formulas 1h-1z and 2a-2g: [ka] TIFF2025531881000034.tif144170 One of the following: In the formula, R C is not present or -YR G and Y is -CR H R I - and -CO-, R H and R I are -H or R, respectively H and R I Together -C 3-4 forming a cycloalkyl, R G is -N(R J R K ) (e.g., -N(C 1-3 alkyl)-, -N(C 1-3alkyl)(optionally substituted 4- to 7-membered monocyclic heterocycloalkylene), or —N(C 1-3 alkyl) (optionally substituted 7- to 12-membered bicyclic heterocycloalkylene), -O-, optionally substituted 4- to 7-membered monocyclic heterocycloalkylene containing 1 or 2 N ring atoms, and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing 1 or 2 N ring atoms; R J and R K is as defined above and herein; where the wavy line crosses the bond between the BRD9 binder and the linker.

[0081] In certain examples of any of the above formulas (e.g., any one of formulas 1e, 1g, 1g', 1ea-1eh, 1ea', 1h-1z, and 2a-2g unless otherwise specified), R G is -N(C 1-3 alkyl)-, -O- or [ka] is.

[0082] In some examples of any of the above formulas (e.g., any one of formulas 1e, 1g, 1g', 1ea-1eh, 1ea', 1h-1z, and 2a-2g unless otherwise specified), R C teeth, [ka] It may be any one selected from In the formula, Y is CR H R I (e.g., CH2) or -CO-, R H and R I is as defined above and herein, and L indicates the point of attachment of the linker.

[0083] In particular, in each of the structures shown above, Y may be CH2.

[0084] In some examples of any of the above formulas (e.g., any one of formulas 1e, 1g, 1g', 1ea-1eh, 1ea', 1h-1z, and 2a-2g unless otherwise specified), R C may be absent, and a linker may be attached (i.e., covalently attached) to the parent structure at this position. Such examples are designated " and may be referred to herein as formulas 1e", 1g", 1g'", 1ea"-1eh", 1ea", 1h"-1z", and 2a"-2g", respectively.

[0085] In some embodiments, the BRD9 conjugate has formula 1h, 1i, 1j, 1m, 1t, 2c, or 2e: [ka] One of the following: In the formula, R C is not present or -YR G and Y is -CR H R I - and -CO-, R H and R I are -H or R, respectively H and R I Together -C 3-4 forming a cycloalkyl, R G is -N(R J R K ) (e.g., -N(C 1-3 alkyl)-, -N(C 1-3 alkyl)(optionally substituted 4- to 7-membered monocyclic heterocycloalkylene), or —N(C 1-3alkyl) (optionally substituted 7- to 12-membered bicyclic heterocycloalkylene), -O-, optionally substituted 4- to 7-membered monocyclic heterocycloalkylene containing 1 or 2 N ring atoms, and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing 1 or 2 N ring atoms; R J and R K is as defined above and herein; where the wavy line crosses the bond between the BRD9 binder and the linker.

[0086] In certain instances of any of the above formulas, R G -N(C 1-3 alkyl)-, -O- or [ka] is.

[0087] In some examples of any of the above formulas, R C teeth, [ka] may be any one selected from In the formula, Y is CR H R I (e.g., CH2) or -CO-, R H and R I is as defined above and herein, and L indicates the point of attachment of the linker.

[0088] In particular, in each of the structures shown above, Y may be CH2.

[0089] In some examples of any of the above formulas, R Cmay be absent, and a linker may be attached (i.e., covalently attached) to the parent structure at this position. Such examples are designated "", and may be referred to herein as formula 1h", 1i", 1j", 1m", 1t", 2c", or 2e", respectively.

[0090] In some embodiments, the BRD9 binder is [ka] is selected from where the wavy line crosses the bond between the BRD9 binder and the linker.

[0091] In some cases, the BRD9 binder may not be: [ka] where the wavy line crosses the bond between the BRD9 binder and the linker.

[0092] Warhead (Z) Z comprises a structure according to formula (I) or formula (WI).

[0093] As shown in formulas (I) and (WI), there is a double bond at Z. The stereochemistry of this double bond is either E or Z, as indicated by the wavy bond in formulas (I) and (WI) (as well as other formulas and structures disclosed herein). Whether this moiety is designated as E or Z is determined by the R 3 group or R 3AThe stereochemistry of the double bond and the moiety attached thereto may depend on the identity of the group. In some examples, Z may include a mixture of E and Z stereoisomers. Thus, the present disclosure includes within its scope the use of each individual E and Z stereoisomer (e.g., in substantially stereochemically pure form) of any of the disclosed Z moieties according to any of Formulas (I) and (WI) and other formulas described herein, as well as the use of mixtures of these E and Z isomers. In some cases, the stereochemistry of the double bond and the moiety attached thereto is Z, i.e., the Z stereoisomer. In other examples, the stereochemistry of the double bond and the moiety attached thereto is E, i.e., the E stereoisomer.

[0094] For the avoidance of doubt, when the Z double bond of formula (I) or (WI) is shown in the structures herein to be a particular stereoisomer (E or Z) in any of the specific examples of this disclosure, it does not necessarily have to be that particular stereoisomer. In other words, both the E and Z stereoisomers and mixtures of the two are included within the scope of the structure, regardless of whether a specific stereoisomer is shown.

[0095] As noted above, in some embodiments, formula (I) is as follows: [ka] In the formula, R 1 , R 3 , R 4 , A, B and L are as defined above.

[0096] On ring B, the group R 4 and A may be held in adjacent positions on the aryl, heteroaryl, substituted aryl, or substituted heteroaryl ring. 4 The A and R groups may be in a 1,2 substitution pattern or may be separated from each other by three bonds. For the avoidance of doubt, when B is heteroaryl or substituted heteroaryl, the heteroatoms contained within ring B may be A or R 4 can be directly bonded to

[0097] As shown in formula (I) above, the linker is attached to moiety Z through ring B. The linker may be attached to moiety Z by 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 may be attached to ring B at any position on the optionally substituted aromatic or heteroaromatic ring, provided it has the correct valence and / or is chemically suitable. For example, the linker may replace a hydrogen atom at any position on the aromatic or heteroaromatic ring.

[0098] In other examples, Z may comprise the structure shown in formula (I) above, wherein: A, B, X, and R 4 is as defined above, R 1 is selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl; R 2 and R 2’ are each independently selected from H or optionally substituted C1-C6 alkyl, or R 2 and R 2’ taken together form a 3-, 4-, 5- or 6-membered optionally substituted carbocyclic or heterocyclic ring; R 3 is selected from optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl.

[0099] R 1 and R 4 When taken together to form an optionally substituted 5-, 6- or 7-membered heterocyclic ring, Z may be represented by formula (Ia): [ka] In the formula, A, B, R 3 and L is as defined for formula (I); n is 1, 2 or 3; W is CR W1 R W2 , O, N.R. W3 and S, and R W1 , R W2 and R W3 are each independently selected from H and C1-C6 alkyl; When n is 2 or 3, each W is a CR W1 R W2 , O, N.R. W3 and S.

[0100] R 1 and R 2 When taken together to form an optionally substituted 5-, 6- or 7-membered heterocyclic ring, Z may be represented as formula (Ib): [ka] In the formula, B, R 2’ , R 3 , R 4 and L is as defined for formula (I), m is 3, 4 or 5; Each T is independently T1 R T2 , O, N.R. T3 and S, and R T1 , R T2 and R T3 are each independently selected from H or C1-C6 alkyl.

[0101] R 2 and R 4 When taken together to form an optionally substituted 5-, 6- or 7-membered heterocyclic or carbocyclic ring, Z may be represented as formula (Ic): [ka] In the formula, B, R 1 , R 2’ , R 3 and L is as defined for formula (I), p is 2, 3 or 4; Each U can independently U1 R U2 , O, N.R. U3 and S, and R U1 , R U2 and R U3 are each independently selected from H and C1-C6 alkyl.

[0102] With respect to the various structures of Z defined by the formulas described herein, R 1 may be C1-C6 alkyl, such as C1-C4 alkyl. For example, R 1 may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl.

[0103] As described above for formula (I), A is absent or CR 2 R 2’ In some cases, A is either 2 R 2’ If R 2 and R 2’ are each independently selected from H and C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more halo atoms (such as F, Cl, or Br). 2 R 2’ If R 2 and R 2’ are each independently selected from H and C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, and n-butyl). 2 and R 2’ One of the groups is hydrogen and the other is C1-C6 alkyl. For example, R2 may be methyl, ethyl, n-propyl or isopropyl, R 2’ may be H. In other embodiments, R 2 and R 2’ are both independently selected from C1-C6 alkyl (e.g., R 2 and R 2’ and may both be methyl). In some embodiments, R 2 and R 2’ are each independently selected from H and C1-C3 alkyl substituted with one or more halo atoms (such as trifluoromethyl).

[0104] 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, the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S. In some embodiments, R 3 is selected from C1-C6 alkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl, where the C1-C6 alkyl is optionally substituted with one or more heteroatoms selected from halo, N, O, and S, and / or with a carbocyclic or heterocyclic group. For example, R 3 may be selected from heteroaryl, substituted heteroaryl, substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C3-C6 heterocycloalkyl, C1-C6 alkyl substituted with a heterocyclic group, aryl, and substituted aryl.

[0105] Suitable R 3Representative examples of groups include, but are not limited to, thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydropyranyl, oxetanyl, cyclobutanyl, cyclopropanyl, tert-butyl, imidazolyl, oxazolyl, thiophenyl, imidazo(1,2-a)pyridinyl, N-C1-C6 alkylenemorpholine, and 4,5,6,7-tetrahydro-1,3-benzothiazolyl, such as thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydropyranyl, oxetanyl, cyclobutanyl, cyclopropanyl, and tert-butyl.

[0106] In either case, these R 3 Groups may be substituted, such as, for example, substituted thiazolyl, substituted pyridinyl, substituted benzothiazolyl, substituted phenyl, substituted pyrazolyl, substituted isoxazolyl, substituted isothiazolyl, substituted tetrahydropyranyl, substituted oxetanyl, substituted cyclobutanyl, substituted cyclopropanyl, and substituted tert-butyl. R 3 When R is a substituted heteroaryl or aryl group, there may be one or more substituents on the aromatic ring, and R may be, for example, mono-, di-, or tri-substituted. 3 When is an optionally substituted pyrazolyl or imidazolyl, the nitrogen atom of the pyrazolyl or imidazolyl ring may be substituted with C1-C6 alkyl, such as methyl.

[0107] Suitable R 3 Examples of groups are shown below: [ka] In the formula, the dotted lines on the structure represent the respective R 3 Indicates the position where each of the groups is attached to the structure shown in the formulas described herein. If the dotted line is not directly connected to an atom, R 3Groups may be attached to the structure shown in the formula via a covalent bond to an atom at any position on the aromatic ring (provided that they have the correct valence and / or are chemically feasible). For example, R 3 A hydrogen at any position on the group may be replaced with a bond to the parent structure shown in the formulas described herein.

[0108] R 5 may be any substituent described herein or may be absent. In some examples, R 5 may be selected from halo (e.g., F, Cl, Br, I), CF, -CHF, -OCF, -OCHF, -OCHF, -CHF, C-C alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SOMe, -NH, -NHMe, -NMe, COMe, -NO, CHO, and COMe. As noted above, there may be one or more substituents on the aromatic ring (e.g., n may be 0-5, e.g., 0-4, 0-3, or 0-2). When multiple substituents are present, each substituent may be selected from the R groups described above. 5 may be independently selected from the group

[0109] R 6 may be, for example, a C1-C6 alkyl such as methyl.

[0110] G may be selected from CH2, O, and NH.

[0111] Q may be, for example, a C1-C6 alkylene such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0112] Suitable R 3 Further examples of groups are shown below: [ka] In the formula, the dotted lines on the structure represent the respective R 3Indicates the position where each of the groups is attached to the structure shown in the formulas described herein. If the dotted line is not directly connected to an atom, R 3 Groups may be attached to the structure shown in the formula via a covalent bond to an atom at any position on the aromatic ring (provided that they have the correct valence and / or are chemically feasible). For example, R 3 A hydrogen at any position on the group may be replaced with a bond to the parent structure shown in the formulas described herein.

[0113] R 5 may be any substituent described herein or may be absent. In some examples, R 5 may be selected from halo (e.g., F, Cl, Br, I), CHOH, CF, -CHF, -OCF, -OCHF, -OCHF, -CHF, C-C alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SOMe, -NH, -NHMe, -NMe, COMe, -NO, CHO, and COMe. As noted above, there may be one or more substituents on the aromatic ring (e.g., n may be 0-5, e.g., 0-4, 0-3, or 0-2). When multiple substituents are present, each substituent may be selected from the R groups described above. 5 may be independently selected from the group

[0114] R 6 may be, for example, a C1-C6 alkyl such as methyl.

[0115] G may be selected from CH2, O, and NH.

[0116] Q may be, for example, a C1-C6 alkylene such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0117] In a further embodiment, R 3 teeth, [ka] is selected from the group consisting of In the formula, the dotted lines represent the respective R 3 Indicates the position at which each of the groups is attached to the formula structures described herein.

[0118] As a further example, R 5 may be selected from C1-C6 alkyl (e.g., methyl) and halo (e.g., F). As noted above, one or more substituents may be present on the aromatic ring. When two or more substituents are present, each substituent may be selected from the R groups described above. 5 Similarly, when present and unless otherwise indicated, R 5 may be attached to any position of the aryl or heteroaryl ring (provided it has the correct valence and / or is chemically feasible).

[0119] As a further example, suitable R 3 The group may be selected from: [ka] where the dotted lines in these structures represent the respective R 3 indicates the position at which each of the groups may be attached to the structure shown in formulas (I) to (Ic), and R 5 , R 6 , n and G are as defined above.

[0120] Suitable R 3 Further examples of groups are shown below: [ka] In the formula, the dotted lines on the structure represent the respective R 3 Indicates the position where each of the groups is attached to the structure shown in the formulas described herein. If the dotted line is not directly connected to an atom, R 3Groups may be attached to the structure shown in the formula via a covalent bond to an atom at any position on the aromatic ring (provided that they have the correct valence and / or are chemically feasible). For example, R 3 A hydrogen at any position on the group may be replaced with a bond to the parent structure shown in the formulas described herein.

[0121] R 5 may be any substituent described herein or may be absent. In some examples, R 5 may be selected from halo (e.g., F, Cl, Br, I), CHOH, CF, -CHF, -OCF, -OCHF, -OCHF, -CHF, C-C alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SOMe, -NH, -NHMe, -NMe, COMe, -NO, CHO, and COMe. As noted above, there may be one or more substituents on the aromatic ring (e.g., n may be 0-5, e.g., 0-4, 0-3, or 0-2). When multiple substituents are present, each substituent may be selected from the R groups described above. 5 may be independently selected from the group

[0122] R 6 may be, for example, a C1-C6 alkyl such as methyl.

[0123] G may be selected from CH2, O, and NH.

[0124] Q may be, for example, a C1-C6 alkylene such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0125] As a further example, suitable R 3 The base is [ka] JPEG2025531881000052.jpg184123 may be selected from In the formula, the dotted lines on the structure represent the respective R 3 Each of the groups indicates a position at which it may be attached to the structure shown in formulas (I)-(Ic).

[0126] In certain examples, Z comprises a structure according to formula (II): [ka] During the ceremony, R 1 is selected from C1-C6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S, and / or with a carbocyclyl or heterocyclyl group; R 2 and R 2’ are each independently selected from H and C1-C6 alkyl; R 3 is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S, and / or with a carbocyclyl or heterocyclyl group; R 4 is H, C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from N, O or S; Or, R 1 and R 4 taken together form a 5-, 6- or 7-membered heterocyclic ring; Or, R 1 and R 2 taken together form a 5-, 6- or 7-membered heterocyclic ring; Or, R 2 and R 4together form a 5-, 6- or 7-membered heterocyclic or carbocyclic ring; L indicates the linker binding position.

[0127] As shown in formula (II) above, the linker is attached to the moiety Z via the aromatic ring. Specifically, the linker is attached to the moiety Z by a covalent bond between an atom on the linker and a carbon atom of the aryl ring system. The linker can be attached to the aromatic ring at any position (provided 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.

[0128] Representative examples of compounds according to formula (II) include, but are not limited to: [ka] In the formula, R 3 and L is as defined for formulas (I) and (II) herein; R 1 is selected from C1-C6 alkyl; R 2 is selected from C1 to C6 alkyl.

[0129] In some cases, R 1 is methyl and R 2 is n-propyl.

[0130] In one particular example, R 1 and R 4 When taken together to form a 5-, 6-, or 7-membered heterocyclic ring, Z may be represented as formula (IIaa): [ka] In the formula, A, R 3 and L are as defined for formulas (I) and (II) herein; n is 1, 2, or 3; W is CR W1 R W2 , O, N.R. W3 and S, R W1 , R W2 and R W3 are each independently selected from H and an optionally selected C1-C6 alkyl; When n is 2 or 3, each W is a CR W1 R W2 , O, N.R. W3 and S.

[0131] In some cases, each W is a CR W1 R W2 is.

[0132] Representative examples of compounds according to formula (IIaa) include, but are not limited to: [ka] In the formula, R 3 and L is as defined herein for formula (I) above; R 2 may be selected from C1-C6 alkyl optionally substituted with one or more heteroatoms selected from H or halo (such as methyl, ethyl, isopropyl, or trifluoromethyl), and R 2’ may be C1-C6 alkyl (e.g., methyl), R W1 may be selected from C1-C6 alkyl (such as methyl or ethyl).

[0133] Representative examples of compounds according to formula (IIaa) include, but are not limited to: [ka] In the formula, R 3and L is as defined herein for formula (I) above; R 2 may be selected from one or more heteroatoms selected from H, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with C1-C4 alkoxy, or halo (such as cyclopropyl, methyl, ethyl, n-propyl, isopropyl, methylmethoxy, difluoromethyl, or trifluoromethyl), and R 2’ may be C1-C6 alkyl (such as methyl) or C1-C4 alkoxy (such as methoxy), R W1 may be selected from C1-C6 alkyl (such as methyl or ethyl).

[0134] As a further example, R 1 and R 4 When taken together to form a 5-, 6-, or 7-membered heterocyclic ring, Z may be represented as formula (IIa): [ka] R 2 , R 2’ , R 3 and L is as defined above, for example, with respect to formula (II), n is 1, 2, or 3; W is CR W1 R W2 , O, N.R. W3 and S, R W1 , R W2 and R W3 are each independently selected from H or C1-C6 alkyl; When n is 2 or 3, each W is a CR W1 R W2 , O, N.R. W3 and S.

[0135] In some cases, each W is CH2.

[0136] In some embodiments, Z is (IIa'): [ka] may be expressed as In the formula, R 3 and L is as defined above, R 2 is C1-C3 alkyl, and R 2’ is H, n is 2, and each W is CH2.

[0137] As yet another example, Z has the following structure: [ka] may be selected from one of In the formula, R 3 and L is as defined above and herein.

[0138] Alternatively, Z has the following structure: [ka] may be selected from one of In the formula, R 3 and L is as defined above and herein.

[0139] The present invention also relates to a compound having the following structure: [ka] For any compound comprising a moiety selected from one of In the formula, R 3 is as defined above and herein.

[0140] The present invention also relates to a compound having the following structure: [ka] and a compound selected from one of In the formula, R 3 is as defined above and herein.

[0141] The group G is configured to allow the compound to be attached to another chemical structure (such as a linker moiety or a linker-target protein binding ligand moiety) via the formation of a new covalent bond, after which the group G can form part of a linker as defined herein.

[0142] In some embodiments, G can include a functional group that can facilitate the formation of a new covalent bond between Z and another moiety, for example, through the formation of an amide, ester, thioester, keto, urethane, amine, or ether bond, or through the formation of a new carbon-carbon bond or a new carbon-nitrogen bond.

[0143] By way of example only, G may be represented as shown below: [ka] In the formula, R G is absent or is C1-C6 alkyl, optionally substituted with one or more heteroatoms selected from N, O, and S; X G -COH, -(CO)-N-hydroxysuccinimide and -(CO)-pentafluorophenol ester, -CHO, -COR G1 , -OH, -NH2, -NHR G2, halo (e.g., iodo and bromo), O-leaving groups (such as -OTs (tosylates), OMs (mesylates), -OTf (triflates)), alkynyl, azido, dienyl, aminooxy, tetrazinyl, (E)-cyclooctenyl, cyclooctynyl, norbornyl, boronic acid, boronic ester, alkylborane, or organometallic groups (e.g., organotin, zinc, or other suitable reagents); R G1 and R G2 are each independently selected from C1 to C6 alkyl.

[0144] In this structure, a wavy line is shown over the bond that forms the bond with the aromatic portion of the compound.

[0145] G is R G It is attached to the aromatic part of the compound through the R group. G If there is no group X G is directly attached to the aromatic portion of the compound.

[0146] Representative examples of suitable G moieties are: [ka] As shown in.

[0147] R 1 and R 2 When taken together to form a 5-, 6-, or 7-membered heterocyclic ring, Z may be represented as formula (IIb): [ka] In the formula, R 2’ , R 3 and L is as defined above, for example, with respect to formula (II), m is 3, 4 or 5; Each T is a CR T1 R T2 , O, N.R. T3 and S are independently selected, R T1 , R T2 and R T3 are each independently selected from H and C1-C6 alkyl.

[0148] For example, in some cases, each T is CH2.

[0149] R 2 and R 4 When taken together to form a 5-, 6-, or 7-membered heterocyclic or carbocyclic ring, Z may be represented as formula (IIc): [ka] In the formula, R 1 , R 2’ , R 3 and L is as defined above, for example, with respect to formula (II), p is 2, 3 or 4; Each U is a CR U1 R U2 , O, N.R. U3 and S are independently selected, R U1 , R U2 and R U3 are each independently selected from H and C1-C6 alkyl.

[0150] For example, in some cases, each T is CH2.

[0151] Representative examples of Z are shown below: [ka]

[0152] A more representative example of Z is [ka] TIFF2025531881000070.tif228170TIFF2025531881000071.tif231170TIFF2025531881000072.tif229170TIFF2025531881000073.tif157170 As shown in

[0153] The dotted line in the above structure indicates that the linker can be attached to the Z moiety at any position on the aromatic ring (provided 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. As a further example, when B is a phenyl ring, the linker can be attached in a para-substitution pattern to the pendant amide group, as shown in formula (IId) below. [ka]

[0154] Alternatively, while formulas (I)-(IId) show that the linker is attached to the Z moiety via ring B (which may optionally be an aromatic ring), it should be noted that the present disclosure also extends to instances where the linker is attached at any other position on the Z moiety (provided it has the correct valence and / or is chemically suitable). For example, the linker may replace a hydrogen atom at any position within the Z moiety. Thus, in some examples, Z may be represented as shown in formula (III): [ka] In the formula, R 1 , A, R 3 , R 4 , B and L are as defined for formula (I) (or any of formulas (Ia)-(IId)).

[0155] The dotted line shown through the square brackets in formula (III) indicates that the linker may be attached via a covalent bond to any atom on the Z moiety, provided that it has the correct valence, is chemically suitable, and / or that attachment of the linker at this alternative position does not interfere with the function of the Z moiety in promoting and / or facilitating proteasomal degradation.

[0156] In some embodiments, the Zi moiety is [ka] It doesn't have to be.

[0157] In some embodiments, the Z moiety can be of formula (Ia), (Ib), (IIaa), (IIa), or (IIb), for example.

[0158] 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, e.g., other BRD proteins such as BRD4.

[0159] As noted above, Z may comprise a structure according to formula (I), formula (WZI), or formula (WI).

[0160] The formula (WZI) is [ka] It is of During the ceremony, Ring A 2Ais an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; R 2A is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R y is an optionally substituted C 1-6 alkyl or H, 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; L represents the attachment point of the linker, Formula (WI) is [ka] It is of In the formula, R 1A is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; R 2Ais absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R 3A is selected from C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x and R is a heteroatom selected from x is H or C1-C6 alkyl, n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0161] In some embodiments, when Z is of formula (WZI) or formula (WI) or any subformula described below, it is [ka] It doesn't have to be.

[0162] In embodiments of formula (WI), R 1A and R 2A At least one of the following is present.

[0163] As shown in formula (WZI) above, the linker is R 2A In such instances, the linker may be attached to the Z moiety via a linker atom and an R 2A The linker may be attached to the Z moiety by a covalent bond between an atom in the ring system of the aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl of the group. Alternatively, the linker may be NR yor by a covalent bond to the benzylic carbon atom of -CH(aryl)- or -CH(substituted aryl)-, for example by a covalent bond to the benzylic carbon atom of -CH(aryl)- or -CH(substituted aryl)-.

[0164] As noted above, in some embodiments of Formula (WZI) or Formula (WI), R 2A In such an example, the linker may be connected to an atom on the linker and a heterocyclic ring (e.g., ring A 2A ) may be attached to the Z moiety by a covalent bond between the

[0165] In all instances, the linker may be attached at any suitable position, e.g., with the correct valence and / or chemically suitable. For example, the linker may be R 2A The groups aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , -CH(aryl)- or -CH(substituted aryl)-, or at any position on the heterocyclic ring shown, for example, in formula (WZI) or formula (WI).

[0166] 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 optionally containing 1 or 2 ring heteroatoms selected from N, O, and S (such as N and O).

[0167] Ring A 2A When is bicyclic or tricyclic, unless otherwise specified, it may include bonded rings, fused rings, bridged rings, and / or rings joined through spiro centers.

[0168] Ring A 2AWhen is bicyclic, it may be a bridged bicyclic (i.e., it may contain two rings that share three or more atoms) or it may be a spirocyclic bicyclic (i.e., it may contain two rings that share one atom, e.g., the two rings may be joined at a spiro center).

[0169] Ring A 2A When ring A is a bridged bicyclic ring, it may be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl, optionally containing 1 or 2 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, optionally containing 1 or 2 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, optionally containing one ring atom selected from N.

[0170] Ring A 2A When is a spirocyclic bicyclic ring, it may be an optionally substituted 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S. In some embodiments, ring A 2A is a 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S. Optionally, ring A 2A is bicyclic and includes a first 5- to 7-membered ring and a second 3- to 7-membered ring. For example, ring A 2A may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, optionally containing one or two additional ring heteroatoms selected from N, O, and S. In some embodiments, ring A 2A may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, optionally containing one additional ring heteroatom selected from N.

[0171] In some embodiments, Z is (WZIa): [ka] including a structure according to During the ceremony, 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-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 1-3 Bridged, optionally substituted C 3-5 cycloalkyl or an optionally substituted 5- to 7-membered heterocycloalkyl (e.g., a 5- to 7-membered N-heterocycloalkyl), optionally including C 3-5 Cycloalkyl or 5- to 7-membered heterocycloalkyl is a spiro center in ring A. A Connected to R 2A is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R y is an optionally substituted C 1-6 alkyl or H, 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; X 1 is CH2, X 2 , X 3 and X 4 are each independently CH, O or NR x and R x is H or C1-C6 alkyl, or one R 1A group and one R x The group is bonded to an optionally substituted C 1-3 Forming a crosslink, n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; L indicates the point of attachment of the linker.

[0172] In some embodiments, when n is 1, 2, or 3 (i.e., X 4 When one, two or three groups are present, the X adjacent to (or directly attached to) the N of the heterocyclic ring shown in formula (WZIa) 4 The group is CH2.

[0173] In some embodiments, Z is of formula (WZIb): [ka] including a structure according to During the ceremony, R 1Ais absent (i.e., when m is 0) or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 1-3 Bridged, optionally substituted C 3-5 cycloalkyl or an optionally substituted 5- to 7-membered heterocycloalkyl (e.g., a 5- to 7-membered N-heterocycloalkyl), optionally including C 3-5 Cycloalkyl or 5- to 7-membered heterocycloalkyl is a spiro center in ring A. A Connected to R 2A is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R y is an optionally substituted C 1-6 alkyl or H, 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; X 1 and X 4 are CH2, respectively, X 2 and X 3 are each independently CH, O or NR x where X 2and X 3 provided that none or only one of is O, R x is H or C1-C6 alkyl, or one R 1A group and one R x The group is bonded to an optionally substituted C 1-3 Forming a crosslink, n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; L indicates the point of attachment of the linker.

[0174] In some embodiments, Z has the formula (WZIb'): [ka] including a structure according to During the ceremony, 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).

[0175] In some embodiments, Z is of the formula (WZIb″): [ka] including a structure according to During the ceremony, R 2A , R 3A , X 1 , X 2 , X 3 , X 4 , n and L are as defined above for formulae (WZIa) and (WZIb).

[0176] As noted above, in some embodiments of formulas (WZIa), (WZIb), (WZIb') and (WZIb'') (and other formulas described herein), optionally substituted C 1-3 The bridge is made up of two R 1A group, or optionally one R 1A group and one R x It may be formed by a C group. 1-3 The bridge may be a C1-C3 alkylene bridging group, such as methylene, ethylene, or propylene. In some embodiments, the C1-C3 bridge may be methylene or ethylene. 1-3 When the bridge is substituted, it may contain 1 to 3 (e.g., 1 or 2) substituents (selected from any suitable substituents described herein). For example, a C1-C3 alkylene bridge may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0177] In a further embodiment, Z has the formula (WI): [ka] may include a structure according to In the formula, R 1A is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; R 2A is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; In the formula, R y is H or C1-C6 alkyl, R 3Ais selected from C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x where R is a heteroatom selected from x is H or C1-C6 alkyl, n is 0, 1, 2 or 3; L represents the attachment point of the linker, Furthermore, Z is [ka] isn't it.

[0178] In an alternative example of formula (WI), the R 3A The list of alternatives may be replaced with 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 C1-C6 alkyl substituted with one or more heteroatoms selected from halo, N, O, and S.

[0179] In some embodiments, R 2A 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)-.

[0180] In some embodiments of formula (WI), R 1A or R2A At least one of the following is present.

[0181] For example, R 1A If does not exist, R 2A is present and is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -NR y , -CH(aryl)-, -CH(substituted aryl)-, -CH(heteroaryl)-, and -CH(substituted heteroaryl)-. For example, R 1 If does not exist, R 2 may be present and is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-.

[0182] As a further example, R 2A If does not exist, R 1A is present and may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl. 2A If there is no R, then there is at least one R 1A may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 1-3 Bridged, optionally substituted C 3-6 cycloalkyl, or optionally substituted 5- to 7-membered N-heterocycloalkyl, optionally 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl is a spiro center in ring A. A Concatenate to.

[0183] In some embodiments of formula (WI), R 1A and R 2A For example, in some cases, R 2A exists and at least one R 1A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 1-3 Bridged, optionally substituted C 3-6 cycloalkyl, or an optionally substituted 5- to 7-membered N-heterocycloalkyl.

[0184] In the compounds of formula (WZI) and formula (WI) (and subformulas thereof), R 1A and / or R 2A can be attached to a heterocyclic ring (e.g., ring A) at any suitable position, e.g., with the correct valence and / or as long as it is chemically feasible. 2A or ring A A ) may be covalently bonded to, for example, R 1A and / or R 2A may replace a hydrogen atom at any position on the heterocyclic core, for example, at the position shown in formula (WI).

[0185] R 1A and R 2A When both are present, they may be attached to a heterocyclic ring (e.g., ring A) at the same or different positions. 2A or ring A A ) may be covalently attached to R 1A and R 2A may be covalently attached to the heterocyclic core through different carbon atoms. 1A and R 2A may be covalently attached to the heterocyclic core via the same carbon atom.

[0186] As a further example, Z may be represented as either formula (WIa) or (WIb): [ka] In the formula, 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 subformulas thereof shown below.

[0187] As a further example, Z can be (WIc'): [ka] may be expressed as During the ceremony, R 1A is absent (i.e., m is 0) or is selected from the group consisting of aryl having 6 to 10 carbon ring atoms optionally substituted with 1 to 3 substituents; heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents; C3-C8 cycloalkyl optionally substituted with 1 to 3 substituents; heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 ring heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents; C1-C6 alkyl optionally substituted with 1 to 3 substituents; and / or two R 1A The group is bonded to a C optionally substituted with 1 to 3 substituents. 1-3 Bridged, C optionally substituted with 1 to 3 substituents 3-5 cycloalkyl, or 5- to 7-membered N-heterocycloalkyl optionally substituted with 1 to 3 substituents (e.g., C 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl is a spiro center in ring A. A ) and R 2Ais absent or is an aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents; a heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents; a heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents; -NR y -CH(aryl)-, where aryl has 6 to 10 carbon ring atoms and is optionally substituted with 1 to 3 substituents; and -CH(heteroaryl)-, where heteroaryl has 5 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O, and S; and heteroaryl is optionally substituted with 1 to 3 substituents; In the formula, R y is H or C1-C6 alkyl, R 3A is selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 3 substituents, C3-C8 cycloalkyl optionally substituted with 1 to 3 substituents, heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents, aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents, and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x and R is a heteroatom selected from x is H or C1-C6 alkyl, or one R 1A group and one R x The group is optionally substituted with 1 to 3 substituents. 1-3 Forms a bridge, provided that X2 and X 3 are not heteroatoms or only one or two are heteroatoms; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0188] As a further example, Z may be of the formula (WIc): [ka] may be expressed as During the ceremony, R 1A is absent or is selected from the group consisting of aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents, heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents, C3-C8 cycloalkyl, C1-C6 alkyl optionally substituted with 1 to 3 substituents; R 2A is absent or is an aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents; a heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents; a heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents; -NR y -CH(aryl)-, where aryl has 6 to 10 carbon ring atoms and is optionally substituted with 1 to 3 substituents; and -CH(heteroaryl)-, where heteroaryl has 5 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O, and S; and heteroaryl is optionally substituted with 1 to 3 substituents; In the formula, R yis H or C1-C6 alkyl, R 3A is selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 3 substituents, C3-C8 cycloalkyl optionally substituted with 1 to 3 substituents, heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents, aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents, and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x where R is a heteroatom selected from x is a heteroatom that is H or C1-C6 alkyl, provided that X 2 and X 3 are not heteroatoms, or only one or two are heteroatoms; and n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0189] As a further example, Z may be of the formula (WId'): [ka] may be expressed as During the ceremony, R 1Ais absent (i.e., when m is 0) or is selected from the group consisting of phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 ring heteroatoms each independently selected from N, O, and S; C3-C8 cycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl; and / or two R's 1A The group is bonded to C 1-3 Crosslinked, C 3-5 Cycloalkyl, or 5- to 7-membered N-heterocycloalkyl (e.g., C 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl is a spiro center in ring A. A ) and R 2A is absent or phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; -NR y-CH(phenyl)- (phenyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy), and -CH(heteroaryl) (heteroaryl having 5-6 ring atoms and containing 1-3 heteroatoms each independently selected from N, O, and S, heteroaryl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy); In the formula, R y is H or C1-C6 alkyl, R 3A is selected from the group consisting of C1-C6 alkyl (optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group), C3-C6 cycloalkyl (optionally wherein the C3-C6 cycloalkyl is substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy), phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x and R is a heteroatom selected from x is H or C1-C6 alkyl, or one R 1A group and one R x is combined with C 1-3 bridges, provided that X 2 and X 3is a heteroatom, provided that none or only one of m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0190] As a further example, Z may be of the formula (WId): [ka] may be expressed as During the ceremony, R 1A is absent or is selected from the group consisting of phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; C3-C8 cycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl; R 2A is absent or phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; heterocycloalkyl having 5 to 7 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; -NR y-CH(phenyl)- (phenyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy), and -CH(heteroaryl) (heteroaryl having 5-6 ring atoms and containing 1-3 heteroatoms each independently selected from N, O, and S, heteroaryl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy); In the formula, R y is H or C1-C6 alkyl, R 3A is selected from the group consisting of C1-C6 alkyl (optionally, the C1-C6 alkyl is substituted with a heterocycloalkyl group), C3-C8 cycloalkyl optionally substituted with 1 to 3 substituents, heterocycloalkyl having 3 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents, phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; X 1 is CH2, X 2 and X 3 are each independently CH2, or O and NR x and R is a heteroatom selected from x is H or C1-C6 alkyl, provided that X 2 and X 3 is a heteroatom, provided that none or only one of n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0191] As a further example, Z may be of the formula (WIe′): [ka] may be expressed as During the ceremony, 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 and containing 1 or 2 heteroatoms each independently selected from N, O, and S, C3-C7 cycloalkyl, heterocycloalkyl having 5 to 7 ring atoms and containing 1 or 2 heteroatoms each independently selected from N, O, and S, C1-C6 alkyl, and C1-C6 haloalkyl, wherein phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy, and / or two R 1A The group is bonded to C 1-3 Crosslinked, C 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl (e.g., C 3-5 Cycloalkyl or 5- to 7-membered N-heterocycloalkyl is a spiro center in ring A. A ) and R 2A is absent or is selected from 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 heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O, and S, and wherein phenyl, heteroaryl, heterocycloalkyl, -CH(phenyl)-, and -CH(heteroaryl)- are each optionally substituted with one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; In the formula, R y is H or C1-C6 alkyl, R 3A is selected from the group consisting of C1-C6 alkyl (optionally substituted with a heterocycloalkyl group, wherein the heterocycloalkyl has 5 to 7 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O, and S), C3-C6 cycloalkyl, phenyl, and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, wherein the C3-C6 cycloalkyl, phenyl, and heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, m is 0, 1, 2 or 3; n is 1, 2, or 3; L indicates the point of attachment of the linker.

[0192] As a further example, Z may be of the formula (WIe): [ka] may be expressed as During the ceremony, R 1A 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, C3-C7 cycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl, wherein phenyl or heteroaryl is optionally substituted with one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; R 2A is absent or is selected from 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 heteroaryl has 5 to 6 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O, and S, and wherein phenyl, heteroaryl, heterocycloalkyl, -CH(phenyl)-, and -CH(heteroaryl)- are each optionally substituted with one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; In the formula, R y is H or C1-C6 alkyl, R 3Ais selected from the group consisting of C1-C6 alkyl (optionally substituted with a heterocycloalkyl group, wherein the heterocycloalkyl has 5 to 7 ring atoms and contains 1 or 2 heteroatoms each independently selected from N, O, and S), C3-C6 cycloalkyl, phenyl, and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, wherein the C3-C6 cycloalkyl, phenyl, and heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, and n is 1, 2, or 3; L indicates the point of attachment of the linker.

[0193] In a further embodiment, Z is of formula (WZII): [ka] including a structure according to In the formula, R 2A is absent or as described in any one of the embodiments disclosed herein; R 3A is as described in any one of the embodiments disclosed herein; X 5 is CR b 2. NR b , O, or a 5- to 7-membered heterocycloalkyl (e.g., a 5- to 7-membered heterocycloalkyl); Each R 1Aare independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 1-3 Bridged or optionally substituted C 3-5 Cycloalkyl (optionally C 3-5 The cycloalkyl forms a spiro center that connects to the heterocyclic ring shown in formula (WZII), R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 3; m is 0, 1 or 2; L indicates the point of attachment of the linker.

[0194] In yet other embodiments, Z comprises a structure according to any one of formulas (WZIIa)-(WZIIe): [ka] During the ceremony, R 2A is as described in any one of the embodiments disclosed herein; R 3A is as described in any one of the embodiments disclosed herein; Each R 1A are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 3-5 Cycloalkyl (optionally C 3-5 The cycloalkyl forms a spiro center that is connected to the heterocyclic ring of formula (ZIIa), X5 is C(R b )2, NR b or O, R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 3; n' is 1 or 2; m is 0, 1 or 2; L indicates the point of attachment of the linker.

[0195] For example, Z may include structures according to formulae (WZIIIa)-(WZIIIh): [ka] During the ceremony, R 2A is as described in any one of the embodiments disclosed herein; R 3A is as described in any one of the embodiments disclosed herein; Each R 1A are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; X 5 CH2, NR b or O, R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, or 2; n' is 1 or 2; m is 0, 1 or 2; L indicates the point of attachment of the linker.

[0196] In yet another embodiment, Z comprises a structure according to formula (WZIVa)-(WZIVj): [ka] During the ceremony, R 2A is absent or as described in any one of the embodiments disclosed herein; R 3A is as described in any one of the embodiments disclosed herein; Each R 1A are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; n1 is 0, 1, or 2; n' is 1 or 2; m is 0, 1 or 2; L indicates the point of attachment of the linker.

[0197] In a further example, Z has the formula (WIf): [ka] including a structure according to In the formula, R 1A is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; R 2A is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, -CH(aryl)- and -CH(substituted aryl)-; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted C1-C6 alkyl, substituted aryl, and substituted heteroaryl; R 1A and R 2A At least one of n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0198] In some embodiments, R of formula (WIf) 1A , R 2A and R 3A may be selected from the groups defined above for any one or more of formulae (WIc'), (WIc), (WId'), (WId), (WIe') or (WIe).

[0199] In some embodiments of formulas (WZI), (WI) and various subgeneric formulas described above and herein, n may be 1, 2, or 3, and / or n1 may be 0, 1, or 2.

[0200] R 1A is not present, Z is a group represented by formula (WII): [ka] may be represented by In the formula, R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0201] R 1A is not present, Z is a group represented by formula (WIIa): [ka] wherein R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0202] As a particular example, in formula (WII) or (WIIa), n may be 1 or 2.

[0203] As a further example, Z may be of formula (WIIb): [ka] may be represented by In the formula, R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3provided that none or only one of is O, n is 1 or 2, L indicates the point of attachment of the linker.

[0204] As a further example, Z may be of formula (WIIc): [ka] may be represented by In the formula, R 2A is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 1 or 2, L indicates the point of attachment of the linker.

[0205] In some cases, Z is a group represented by formula (WIId): [ka] wherein R 2A is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; n is 1 or 2, L indicates the point of attachment of the linker.

[0206] In other embodiments, Z is a group of formula (WIIe): [ka] wherein R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; n is 1 or 2, L indicates the point of attachment of the linker.

[0207] In other embodiments, Z has the formula (WIIf): [ka] wherein R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker.

[0208] R 2A is not present, Z is a group represented by formula (WIII): [ka] wherein R 1Ais selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0209] In some embodiments, n may be 1 or 2.

[0210] In some embodiments, when n is 2, Z is (WIIIa): [ka] wherein R 1A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker.

[0211] In some embodiments, when n is 1, Z is (WIIIb): [ka] wherein R 1A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3Ais selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker.

[0212] As illustrated above, bifunctional molecules of formula (WIIIb) contain at least two stereocenters and therefore exist in several diastereomeric (and enantiomeric) forms. In some embodiments, R 1A The R and L groups may be in a trans relationship (e.g., the groups are held and / or oriented on opposite sides of the heterocyclic core). 1A The groups L and L may be in a cis relationship (e.g., the groups are held and / or oriented on the same side of the heterocyclic core). As a further example, a bifunctional molecule of Formula (WIIIb) can include at least the following diastereomeric forms: [ka]

[0213] R 1A does not exist and R 2A is selected from —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-, Z is a group of formula (WIV): [ka] wherein R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; R 4A is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker.

[0214] In some embodiments, Z is (WIVa): [ka] wherein R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; R 4A is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; L indicates the point of attachment of the linker.

[0215] In either formula (WIV) or (WIVa), R 4A may be selected from aryl or substituted aryl.

[0216] With respect to the various structures of Z defined by formulas (WI)-(WIV) (and subformulas thereof) herein (unless otherwise stated), R 1A may be selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0217] In some embodiments, R 1A is optionally substituted aryl or optionally substituted heteroaryl. R 1A When is a substituted aryl or substituted heteroaryl, the aryl or heteroaryl may contain one or more substituents selected from the group consisting of C1-C6 alkyl (e.g., methyl), C1-C6 alkoxy (e.g., methoxy), C1-C6 haloalkyl, and halo.

[0218] As a further example, R 1AAs yet another example, R may be phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. 1A may be heteroaryl, C3-C8 cycloalkyl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0219] Suitable R 1A Representative examples of groups include, but are not limited to, phenyl, substituted phenyl, pyrazolyl, and substituted pyrazolyl.

[0220] In some embodiments, R 1A is cycloalkyl, such as C3-C7 cycloalkyl or C3-C6 cycloalkyl.

[0221] In some embodiments, R 1A is C1-C6 alkyl, for example C1-C3 alkyl optionally substituted with 1 to 3 substituents as defined herein.

[0222] Suitable R 1A Further non-limiting examples of groups are shown below: [ka]

[0223] Suitable R 1A Further non-limiting examples of groups are shown below: [ka]

[0224] Suitable R 1A Further non-limiting examples of groups are shown below: [ka]

[0225] In the above structure, the wavy intersecting lines represent the exemplary R 1A group and R in the parent structure of Z 1A represents a covalent bond between a carbon atom on the heterocycloalkyl core that is bonded to the group (represented by the various formulas (WI)-(WIV) (and subgeneric formulas) described herein). While specific substitution patterns are depicted in the exemplary aryl and heteroaryl structures above, it will be understood that other substitution patterns are encompassed within the scope of the present disclosure.

[0226] As a further example, for example, with respect to formula (WZII), two R 1A The group is bonded to C 1-3 Crosslinked or C 3-5 For example, two R 1A The group is bonded to C 3-5 In such cases, C 3-5 A cycloalkyl may be attached to the heterocyclic ring of the parent structure at a spiro center.

[0227] With respect to the various structures of Z defined by formulae (WZI)-(WZIV), (WI)-(WIV) (and subformulas) described herein (unless otherwise stated), R 2A is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl) and —CH(substituted heteroaryl), R y is an optionally substituted C 1-6 It is alkyl (such as methyl) or H.

[0228] In some embodiments, R 2Ais present as a divalent group within Z (and / or the bifunctional molecules described herein). In other words, as shown in formulas (WI)-(WIVa) (unless otherwise specified), R 2A The various groups defined for are covalently bonded to atoms of the heterocyclic core of Z and may also be covalently bonded to atoms of the linker. Thus, these groups can be considered divalent radical species.

[0229] R 2A When R is selected from optionally substituted aryl or optionally substituted heteroaryl, 2A may be selected from aryl having 6 to 10 carbon ring atoms and optionally substituted with 1 to 3 substituents, and heteroaryl having 5 to 10 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, and optionally substituted with 1 to 3 substituents. 2A may be selected from H, phenyl optionally substituted with 1-3 substituents selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy, and heteroaryl having 5-6 ring atoms, containing 1 or 2 N atoms, and optionally substituted with 1-3 substituents selected from C1-C6 alkyl (e.g., C1-C3 alkyl), halo (e.g., F), C1-C6 haloalkyl (e.g., C1-C3 haloalkyl), and C1-C6 alkoxy (e.g., C1-C3 alkoxy). 2A Suitable examples of include, but are not limited to, optionally substituted phenyl and optionally substituted pyrazolyl.

[0230] R 2AWhen is selected from optionally substituted heterocycloalkyl, the heterocycloalkyl has 3 to 10 ring atoms and contains 1 to 3 heteroatoms each independently selected from N, O, and S, and the heterocycloalkyl can be optionally substituted with 1 to 3 substituents. In some examples, the heterocycloalkyl can have 5 to 8 ring atoms (e.g., 6 ring atoms) and can include 1 or 2 N atoms. In some cases, suitable examples include, but are not limited to, optionally substituted piperidinyl and optionally substituted piperazinyl.

[0231] Suitable R 2A Further examples of groups are shown below: [ka] In the structure shown above, R 6A may be selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy. 6A may be selected from H and C1-C6 alkyl.

[0232] Suitable R 2A Further examples of groups are shown below: [ka] R 6A is selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy. 6A may be selected from H and C1-C6 alkyl.

[0233] In the structure shown above, the wavy lines and intersecting lines represent the exemplary R 2A group and R in the parent structure of Z 2Arepresents a covalent bond between a carbon atom on the heterocycloalkyl core that is bonded to the group (represented by the various formulas (WI)-(WIV) (and subgeneric formulas thereof) described herein unless otherwise noted). While particular substitution patterns are shown in the exemplary structures above, it will be understood that other substitution patterns are also encompassed within the scope of the present disclosure.

[0234] Additionally, the bond to L indicates the point of attachment to the linker. In the exemplary aryl structures above, it will be understood that the linker may replace a hydrogen atom at any suitable position on the aryl ring (e.g., if it is chemically appropriate and has the correct valence).

[0235] With respect to the various structures of Z defined by the various formulas (WI)-(WIV) (and sub-formulas thereof) 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, the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S. In some embodiments, R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted C1-C6 alkyl, substituted aryl, and substituted heteroaryl.

[0236] In some embodiments, R 3Amay be selected from the group consisting of C1-C6 alkyl optionally 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, 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 with 1 or 2 substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. By way of further example, in some cases, the aryl and heteroaryl may be optionally substituted with 1 or 2 substituents selected from halo (e.g., F) and C1-C3 alkyl (e.g., methyl).

[0237] Suitable R 3A Representative examples of groups include, but are not limited to, thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, oxetanyl, cyclobutanyl, cyclopropanyl, tert-butyl, imidazolyl, oxazolyl, thiophenyl, imidazo(1,2-a)pyridinyl, N-C1-C6 alkylenemorpholine, and 4,5,6,7-tetrahydro-1,3-benzothiazolyl, such as, for example, thiazolyl, pyridinyl, benzothiazolyl, phenyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, cyclobutanyl, cyclopropanyl, and tert-butyl.

[0238] In either case, these R 3A The group may be substituted, such as substituted thiazolyl, substituted pyridinyl, substituted benzothiazolyl, substituted phenyl, substituted pyrazolyl, substituted isoxazolyl, substituted isothiazolyl, substituted tetrahydropyranyl, substituted tetrahydrofuranyl, substituted oxetanyl, substituted cyclobutanyl, substituted cyclopropanyl, and substituted tert-butyl. R 3AWhen R is a substituted heteroaryl or aryl group, there may be one or more substituents on the aromatic ring, and R may be, for example, mono-, di-, or tri-substituted. 3A When is an optionally substituted pyrazolyl or imidazolyl, the nitrogen atom of the pyrazolyl or imidazolyl ring may be substituted with C1-C6 alkyl, such as methyl.

[0239] 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 including morpholino substituents, optionally substituted benzothiazolyl, and optionally substituted pyridinyl. 3A When is a substituted aryl or heteroaryl group, there may be one or more substituents on the aromatic ring, which may be, for example, mono-, di-, or tri-substituted.

[0240] 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 including morpholino substituents, optionally substituted benzothiazolyl, and optionally substituted pyridinyl.

[0241] Suitable R 3A Further examples of groups are shown below: [ka] It is of In the formula, the dotted lines on the structure represent the respective R 3A Indicates the position at which each of the groups may be attached to the structures depicted in the formulas described herein. If the dotted line is not directly connected to an atom, R 3AGroups may be connected to the structure shown in the formula by a covalent bond to an atom anywhere on the aromatic ring (provided they have the correct valence and / or are chemically feasible). For example, R 3A A hydrogen at any position on the group may be replaced with a bond to the parent structure shown in the formulas described herein.

[0242] R 5A may be any substituent described herein or may be absent. In some examples, R 5A may be selected from halo (e.g., F, Cl, Br, I), CF, -CHF, -CHF, OCF, -OCHF, -OCHF, C-C alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SOMe, -NH, -NHMe, -NMe, COMe, -NO, CHO, and COMe. As noted above, there may be one or more substituents on the aromatic ring (e.g., n may be 0-5, e.g., 0-4, 0-3, or 0-2). When multiple substituents are present, each substituent may be selected from the group consisting of ... -CF, -CHF, -OCHF, C-C alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SOMe, -NH, -NHMe, -NMe, COMe, -NO, CHO, and COMe. 5A may be independently selected from the group

[0243] R 6 may be a C1-C6 alkyl such as methyl.

[0244] G may be selected from CH2, O, and NH.

[0245] Q may be, for example, a C1-C6 alkylene such as dimethylmethylene (-C(CH3)2-) or dimethylethylene (-C(CH3)2CH2-).

[0246] In a further embodiment, R 3 is selected from the group consisting of: [ka] It is of In the formula, the dotted lines represent the respective R 3Each of the groups indicates the point at which it is attached to the formula structures described herein.

[0247] As a further example, R 5A may be selected from C1-C6 alkyl (e.g., methyl) and halo (e.g., F). As noted above, one or more substituents may be present on the aromatic ring. When two or more substituents are present, each substituent may be selected from the R groups described above. 5A Also, when present, unless otherwise specified, R 5A may be attached to the aryl or heteroaryl ring at any position (provided it has the correct valence and / or is chemically feasible).

[0248] In the structure shown above, the wavy lines and intersecting lines represent the exemplary R 3A represents a covalent bond between a group and a carbon atom of the parent structure of Z (represented by the various formulae (WZI)-(WZV), (WI)-(WIV) (and their sub-formulae) described herein). 3A When R is an aryl or heteroaryl group, the covalent bond (as exemplified by the various formulas described herein) may be formed at any position on the aromatic ring (provided it has the correct valence and / or is chemically feasible). For example, 3A A hydrogen at any position on the group may be replaced with a bond to the structure shown in formula (I).

[0249] As a further example, suitable R 3A The group may be selected from: [ka] where the dotted lines in these structures represent the respective R 3A Each of the groups indicates a position at which it may be attached to the structure shown in the formulas described herein, and R 5A , R 6A , n and G are as defined above.

[0250] In other embodiments, a suitable R 3A The group may be selected from: [ka] where the dashed crossed lines represent the exemplary R 3A represents a covalent bond between a group and a carbon atom of the parent structure of Z (as illustrated by the various formulas described herein), R 5A is as defined above.

[0251] In other embodiments, a suitable R 3A The group may be selected from: [ka] where the dashed crossed lines represent the exemplary R 3A represents a covalent bond between a group and a carbon atom of the parent structure of Z (as illustrated by the various formulas described herein), R 5A is as defined above.

[0252] As a further example, suitable R 3A The group may be selected from: [ka]

[0253] Also, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 3A represents a covalent bond between the group and a carbon atom of the parent structure of Z (represented by the various formulae (WZI)-(WZV), (WI)-(WIV) (and their subformulae) described herein).

[0254] As a further example, suitable R 3A The group may be selected from: [ka]

[0255] Also, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 3A represents a covalent bond between the group and a carbon atom of the parent structure of Z (represented by the various formulae (WZI)-(WZV), (WI)-(WIV) (and their subformulae) described herein).

[0256] Another example is R 3A The base is [ka] may be.

[0257] Also, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 3A represents a covalent bond between the group and a carbon atom of the parent structure of Z (represented by the various formulae (WZI)-(WZV), (WI)-(WIV) (and their subformulae) described herein).

[0258] As mentioned above, R 4A may be selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In some embodiments, R 4A may be selected from aryl having 6 to 10 carbon ring atoms and heteroaryl having 5 to 10 ring atoms and 1 to 3 heteroatoms each independently selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. 4A may be an optionally substituted phenyl.

[0259] As a further example, suitable R 4A The group may be selected from: [ka] R 7A may be any substituent described herein or may be absent. In some examples, R 7A may be selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy. 6A may be C1-C6 alkyl or C1-C3 alkyl (e.g., methyl). As noted above, one or more substituents may be present on the aromatic ring. When two or more substituents are present, each substituent may be a ... 7A Also, when present, unless otherwise indicated, R 7A may be covalently attached to the aryl or heteroaryl ring at any position (provided it has the correct valence and / or is chemically feasible).

[0260] By way of further example, representative examples of Z are shown below: [ka] TIFF2025531881000126.tif113170TIFF2025531881000127.tif220170TIFF2025531881000128.tif202170

[0261] By way of further example, representative examples of Z are shown below: [ka]

[0262] In the exemplary structure shown above, R 3A is the R 3A In some cases, in the exemplary structures shown above, R 3A may be selected from the group consisting of: [ka] TIFF2025531881000131.tif212170

[0263] In the exemplary structure shown above, R 3A is the R 3A In some cases, in the exemplary structures shown above, R 3A teeth, [ka] may be.

[0264] In certain embodiments, Z has the formula: [ka] wherein R 3A is as defined above.

[0265] For example, Z is [ka] It may be any one of the structures shown in

[0266] In certain embodiments, Z has the formula: [ka] where R 3A is as defined above.

[0267] For example, Z is [ka] It may be any one of the structures shown in

[0268] For example, Z is [ka] It may be one of the structures shown in

[0269] Alternatively, the various formulas (WZI)-(WZV), and (WI)-(WIV) (and their subgeneric formulae) described herein may be any formula wherein the linker is connected via the heterocyclic core (directly or indirectly to R 2A It is noted that although shown attached to the Z moiety (via a group), the present disclosure extends to instances where the linker is attached to any other position on the Z moiety (provided it has the correct valence and / or is chemically feasible). For example, the linker may replace a hydrogen atom at any position within the Z moiety. Thus, in some examples, Z is a group of formula (WZV) or (WV): [ka] may be represented as shown in In the formula, ring A 2A , R 1A , R 2A , R 3A , X 1 , X 2 , X 3 , n, and L are as defined for any of the embodiments of formula (W) or a subformula thereof (e.g., formula (WZI) or (WI) (or any one or more of formulas (WZIa)-(WZIV) or (WIa)-(WIVa)).

[0270] The dotted line shown through the square brackets in formulas (WZV) and (WV) indicates that the linker may be covalently attached to any atom of the Z moiety, provided that this atom has the correct valence and is chemically feasible, and / or provided that attachment of the linker at this alternative position does not impair the function of the Z moiety to enhance and / or promote proteasomal degradation.

[0271] As noted above, in some embodiments, Z is a group represented by formula (A): [ka] may include a structure according to wherein the linker is the carbonyl carbon C 1 binds to In particular, in some embodiments, Z is a group of formula (A1): [ka] consisting of or consisting essentially of a structure according to In the formula, R 1A1 can be any suitable chemical group.

[0272] For example, R 1A1 is alkyl (e.g., C1-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., CH -ppyridyl), substituted alkylheteroaryl, alkylamino (e.g., (CH2)2NMe2), alkylamido (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-C6 alkyl) is substituted with one or more heteroatoms selected from halo, N, O, and S; wherein the linker is the carbonyl carbon C 1 Combine with.

[0273] In embodiments of the present invention defined by Formula (A1) or any formula 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 includes monocyclic, bicyclic, and tricyclic ring systems, wherein the additional ring is attached by a covalent bond at a fused ring junction, a spirocyclic junction, or by a bridged ring system, or any combination thereof.

[0274] In embodiments, 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 the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S, and / or is substituted with a carbocyclic or heterocyclic group.

[0275] In embodiments, R 1A1is 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.

[0276] In embodiments, R 1A1 is selected from the group consisting of: [ka] In the formula, the dotted lines represent the respective R 1 The dotted lines indicate the positions at which each of the groups is attached to the structure shown in formula (I), or, if no dotted line is attached to an atom, the dotted line indicates the position at which each of the R 1A1 indicates that each of the groups is attached to the structure via any position on the aromatic or heteroaromatic ring; Each R 3A1 may be independently selected from halo, CF, —CHF, —CHF, —OCF, —OCHF, —OCHF, C-C alkyl, —CN, —OH, —OMe, —SMe, —SOMe, —SOMe, —NH, —NHMe, —NMe, COMe, —NO, CHO, and COMe; n is 0 to 3, R 4A1 is a C1-C6 alkyl; G is CH, O or NH; Q is a C1-C6 alkylene.

[0277] In a further embodiment, R 1A1 teeth, [ka] is selected from the group consisting of In the formula, R 3A1 and n is as defined above.

[0278] In a further embodiment, R 1A1is selected from the group consisting of: [ka] In the formula, the dotted lines represent the respective R 1A1 Each of the groups indicates the position at which it is attached to the structure depicted in the formulas described herein.

[0279] As another example, a suitable R 1A1 The group may be selected from: [ka]

[0280] Also, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 1A1 represents a covalent bond between the group and a carbon atom of the parent structure of Z (represented by the various formulae (A1)-(A3) (and their sub-formulae) described herein).

[0281] As another example, a suitable R 1A1 The group may be selected from: [ka]

[0282] Also, in the structure shown above, the lines intersecting the wavy lines represent the exemplary R 1A1 represents a covalent bond between the group and a carbon atom of the parent structure of Z (represented by the various formulae (A1)-(A3) (and their sub-formulae) described herein).

[0283] In the above embodiment, C 1 The atom directly bonded to is preferably N.

[0284] In embodiments, the bifunctional molecule has the formula (A2): [ka] including a structure according to During the ceremony, C 1 and R 1A1 is defined for formula (A1), R 2A1 is selected from H, C1-C6 alkyl, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, where the C1-C6 alkyl is optionally substituted with one or more heteroatoms selected from halo, N, O, and S, and / or with a carbocyclic or heterocyclic group.

[0285] In embodiments, the bifunctional molecule has the formula (A2a): [ka] including a structure according to During the ceremony, C 1 and R 1A1 is as defined in formula (A1), A is CR ’ R ’’ and R ’ and R ’’ are each independently selected from H and C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from N, O or S, or R ’ and R ’’ together form a 3-, 4-, 5- or 6-membered carbocyclic or heterocyclic ring; q is 1 to 3.

[0286] In embodiments of Formulas A2 and A2a, R 2A1 is selected from H, C1-C6 alkyl. In other embodiments, R 2A1 is not H.

[0287] In an alternative embodiment, the bifunctional molecule has formula (A3): [ka] including a structure according to During the ceremony, C 1 and R 1A1 is as defined in formula (A1), Ring A A3 is an optionally substituted monocyclic, bicyclic, or tricyclic N-heterocycle, optionally containing 1 to 4 additional ring heteroatoms selected from N, O, and S.

[0288] In embodiments, the bifunctional molecule comprises a structure according to formula (A3), wherein: Ring A A3 is an optionally substituted 4- to 9-membered (e.g., 5- to 6-membered) monocyclic N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; or Ring A A3 is an optionally substituted 6- to 12-membered (e.g., 7- to 8-membered) bridged N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; or Ring A A3 is an optionally substituted bicyclic N-heterocycloalkyl comprising a first ring and a second ring, wherein the first ring is an optionally substituted 3- to 7-membered N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S, and the second ring is an optionally substituted 3- to 7-membered cycloalkyl or N-heterocycloalkyl, optionally containing 1 or 2 ring heteroatoms selected from N, O, and S, and the first and second rings are joined at a spiro center; or Ring A A3is an optionally substituted fused bicyclic N-heterocycloalkyl comprising a first ring and a second ring, wherein the first ring is an optionally substituted 4-9 membered N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S, and the second ring is an optionally substituted 4-9 membered cycloalkyl or heterocycloalkyl ring, optionally containing 1 or 2 ring heteroatoms selected from N, O, and S; or Ring A A3 is an optionally substituted fused bicyclic N-heterocycloalkyl comprising a first ring and a second ring, wherein the first ring is an optionally substituted 4-9 membered N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S, and the second ring is a 6-10 membered aryl, heteroaryl, substituted aryl, or substituted heteroaryl.

[0289] In embodiments, the bifunctional molecule is [ka] and In the formula, C 1 and R 1A1 is as defined in formula (A1).

[0290] In embodiments, the bifunctional molecule is [ka] and In the formula, C 1 and R 1A1 is as defined in formula (A1).

[0291] In embodiments, the bifunctional molecule is [ka] and In the formula, C 1 and R 1A1 is as defined in formula (A1).

[0292] In embodiments, the bifunctional molecule is [ka] The structure comprises a structure selected from the group consisting of:

[0293] Linker (L) As described herein, TBL is attached or linked to the Z moiety via a linker, L. The linker may be a chemical linker (e.g., a chemical linker moiety), and may be, for example, a covalent linker, meaning that the linker is attached to Z and / or TBL by a covalent bond.

[0294] The linker acts to link the target protein-binding ligand and the Z moiety to one another while allowing both of these moieties to bind to their respective targets and / or perform their intended functions. In particular, the linker can act to link the target protein-binding ligand to Z while mitigating the possibility that the Z moiety will interfere with, interfere, and / or inhibit the binding of the target protein-binding ligand to the target protein. Additionally or alternatively, the linker can serve to link Z to the target protein-binding ligand while mitigating the possibility that the target protein-binding ligand will interfere with, or inhibit the intracellular interaction of Z (e.g., the function of regulating, promoting, and / or promoting proteasomal degradation of the target protein).

[0295] In other words, by making each end of the bifunctional molecule available for binding to various components of the cellular environment (or other types of cellular interactions), the linker can function to facilitate targeted protein degradation. For example, the linker can be configured to allow the binding of a target protein-binding ligand to the target protein without interference, obstruction, and / or inhibition from the Z moiety of the bifunctional molecule. Additionally or alternatively, the linker can be configured to allow the Z moiety to interact with various components in the cellular environment to regulate, promote, and / or enhance the proteasomal degradation of the target protein without interference, obstruction, and / or inhibition from the target protein-binding ligand of the bifunctional molecule.

[0296] In many cases, a wide range of linkers are acceptable, and the choice of linker can depend on the protein targeted for degradation (target protein) and / or the particular target protein-binding ligand that binds to BRD9.

[0297] The linker may be selected to provide a particular length and / or flexibility, for example, to hold the target protein-binding ligand and the Z moiety within a particular distance and / or shape. As will be understood by those skilled in the art, the length and / or flexibility of the linker can vary depending on the structure and / or properties of the target protein-binding ligand.

[0298] In some embodiments, TBL is directly connected to the Z moiety by a covalent bond, i.e., the linker is a covalent bond. Such direct bonds are also encompassed by the term "linker" within the context of the present disclosure (unless otherwise specified).

[0299] By way of example only, a linker may include 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 include any number of atoms in a single linear chain between 1 and 200, between 1 and 100, between 1 and 50, between 1 and 30, or between 1 and 10. In some embodiments of the present disclosure, a linker may include any number of atoms in a single linear chain 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).

[0300] The degree of flexibility of a linker can depend on the number of rotatable bonds present in the linker. A rotatable bond is defined as a single acyclic bond attached to a non-terminal heavy atom (e.g., an atom other than hydrogen). As described herein, amide (C-N) bonds are not considered rotatable due to their high rotational energy barrier. In some cases, the linker may contain one or more moieties selected from a ring, a double bond, and an amide, thereby reducing the flexibility of the linker. In other cases, the linker may contain a greater number and / or a higher proportion of single bonds (e.g., primarily a single acyclic bond), thereby increasing the flexibility of the linker. It may also be understood that the length of the linker can affect the degree of flexibility. For example, a shorter linker containing fewer bonds may reduce the flexibility of the linker.

[0301] In some embodiments, the number of rotatable bonds present in a linker can be any number between 1 and 20, between 1 and 15, between 1 and 10, or between 1 and 8. In some embodiments, the number of rotatable bonds present in a linker can be any number between 2 and 9, between 2 and 8, or between 3 and 6.

[0302] In some embodiments, the linker may contain any number of atoms in a single linear chain between 10 and 20, and / or the number of rotatable bonds present in the linker may be any number between 1 and 8.

[0303] The structure of the linker (L) is (L x ) q It may be expressed as In the formula, each L x represents a subunit of L, q is an integer of 1 or greater.

[0304] For example, q may be any integer between 1 and 30, between 1 and 20, or between 1 and 5.

[0305] For example, if q is 1, the linker has one L x It may contain only subunits and be represented as L1. When q is 2, the linker is made up of two L x The linker comprises subunits, which are covalently bonded to one another and can be represented as L1-L2. As another example, if q is 3, the linker is composed of three L x It comprises subunits, which are covalently bonded to one another and can be represented as L1-L2-L3. For higher integer values ​​of q, L can be L1, L2, L3, L4...L q It can contain up to 10 subunits.

[0306] Each L x is CR L1 R L2 , O, C=O, S, S=O, SO2, NR L3 ,SONR L4 ,SONR L5 C=O, CONR L6 , N.R. L7 CO, C(R L8 )=C(R L9 ), C≡C, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl groups.

[0307] R L1 , R L2 , R L3 , R L4 , R L5 , R L6 , R L7 , R L8 and R L9 may each be independently selected from H, halo, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —NO2, —CN, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —S(O)OC1-C6 alkyl, —C(O)OC1-C6 alkyl, and —CO(C1-C6 alkyl). In some embodiments, R L1 , R L2 , R L3 , R L4 , R L5 , R L6 , R L7 , R L8 and R L9 may each be independently selected from H and C1-C6 alkyl.

[0308] Terminal L x The subunits can link or couple linker moieties to the TBL and Z moieties of the bifunctional molecule. For example, x The subunits are L1 and L q When specified as q can attach a linker to the Z moiety. When q is 1, one L x A subunit (eg, L1) provides a link between the TBL and Z portions of the bifunctional molecule.

[0309] The TBL and Z moieties can be covalently attached to L through any group that is compatible with the linker chemistry and is stable. By way of example only, the linker may be covalently attached to the TBL moiety through a carbon-carbon bond, a keto, amino, amido, ester, or ether bond. Similarly, the linker may be covalently attached to the Z moiety through a carbon-carbon bond, a carbon-nitrogen bond, a keto, amino, amido, ester, or ether bond.

[0310] In some cases, L at each end x Subunits (e.g., L1 and L q ) is O, C=O, CR L1 R L2 , N.R. L3 ,CONR L6 , N.R. L7 It may be independently selected from CO, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocyclyl, substituted carbocyclyl, heterocyclyl and substituted heterocyclyl groups.

[0311] In some embodiments, L x At least one of comprises a ring structure and is selected from, for example, a heterocyclyl, heteroaryl, carbocyclyl, or aryl group.

[0312] In alternative embodiments, the linker may be or may include an alkyl linker comprising repeating -CH2- subunits, where the number of repeats is 1 to 50, e.g., 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, and 1 to 2.

[0313] In other embodiments, the linker may be or include a polyalkylene glycol. By way of example only, the linker may be or include a polyethylene glycol (PEG) comprising repeating ethylene glycol (CHO) subunits, e.g., having about 1-50 ethylene glycol subunits, e.g., 1-100 repeats, e.g., 1-50, 1-40, 1-30, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, or 1-5 repeats.

[0314] In some examples described herein, the structure of the linker (L) has the formula (L1a): [ka] The structure may be, or may include, the structure shown in In the formula, L 1A does not exist or C 1 -C6 alkylene (e.g., ethylene), C1-C6 alkoxy (e.g., —O(CH2)—, —O(CH2)2—, —O(CH2)5—, —CH2OCH2—), and C1-C6 alkylamino (e.g., —NR L2A (CH2)-, -R L2A (CH2)2-, -R L2A (CH2)5-, -CH2R L2A CH2-), L 2A is -NR L2A C=O- or -C=ONR L2A - and L 3A is C1-C3 alkylene (e.g., ethylene), C1-C6 alkoxy (e.g., —(CH2)O—, —(CH2)2O—, —(CH2)5O—, —CH2OCH2—), and C1-C6 alkylamino (e.g., —(CH2)NR L2A -, -(CH2)2NR L2A -, -(CH2)5NR L2A -, -CH2NR L2A CH2-), R L2A is H or C1-C6 alkyl (for example, C1-C3 alkyl).

[0315] In a further embodiment, the structure of the linker (L) may be or include a structure as shown in formula (L1b), as follows: [ka] In the formula, L 1B is absent or is selected from C1 to C3 alkylene (e.g., ethylene), C1 to C6 alkoxy (e.g., -O(CH2)-, -O(CH2)2-, -O(CH2)5-, -CH2OCH2-), and C1 to C6 alkylamino (e.g., -NR L2A (CH2)-, -NR L2A (CH2)2-, -R L2A (CH2)5-, -CH 2 R L2A CH2-), L 2B is -NR L2A C=O- or -C=ONR L2A - and L 3B is C1~C 15 Alkylene, -[(CH2)2O] 1-6 (CH2)2-, L 4B is -NR L2A C=O- or -C=ONR L2A - and R L2A is H or C1-C6 alkyl (e.g., C 1- C3 alkyl), L 5B is C1-C3 alkylene (e.g., ethylene), C1-C6 alkoxy (e.g., —(CH2)O—, —(CH2)2O—(CH2)5O—, —CH2OCH2—), and C1-C6 alkylamino (e.g., —(CH2)NR L2A -, -NR L2A (CH2)2-, -(CH2)5NR L2A -, -CH2NR L2ACH2-), R L2A is H or C1-C6 alkyl (for example, C1-C3 alkyl).

[0316] In some examples described herein, the structure of the linker (L) may be or include a structure as shown in formula (L1c), as follows: [ka] In the formula, 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 optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; L 2C is absent or is selected from C1 to C3 alkylene (e.g., ethylene), C1 to C6 alkoxy (e.g., —(CH2)O—, —(CH2)2O—, —(CH2)5O—, —CH2OCH2—) and C1 to C6 alkylamino (e.g., —(CH2)NR L2A -, -(CH2)2NR L2A -, -(CH2)5NR L2A -, -CH2NR L2A CH2-), L 3C -R L2B C=O- or -(C=O)R L2B - and L 4C is C1-C3 alkylene (e.g., ethylene), C1-C6 alkoxy (e.g., —(CH2)O—, —(CH2)2O—, —(CH2)5O—, —CH2OCH2—), and C1-C6 alkylamino (e.g., —(CH2)NR L2A -, (CH2)2NR L2A -, -(CH2)5NR L2A -, -CH2NR L2A CH2-), During the ceremony, R L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl), and R L2B is 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 optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S.

[0317] In an embodiment of the linker (L) represented by formula L1c, L 1C and L 2C In such an embodiment, L 3C R in L2B is an N-linked optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S, and L 3C is R L2B The terminal subunit of the appropriate covalently linked linker is attached to the TBL via

[0318] In some embodiments described herein, the structure of the linker (L) may be or include a structure as shown in formula (L1d), as follows: [ka] In the formula, L 1D is absent or is selected from C1-C3 alkylene, CO, C1-C3 alkylene (N(C1-C3 alkyl), L 2D is NR L2Aor an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; R L2A is H or C1-C6 alkyl (e.g., C1-C3 alkyl), L 3D is absent or selected from C1-C3 alkylene, —O—, —N(C1-C3 alkyl)-, and CO.

[0319] In a further embodiment, the structure of the linker (L) may be or include a structure as shown in formula (L1e): [ka] In the formula, L 1E is C1-C3 alkylene (e.g., methylene) or CO, L 2E is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; L 3E is selected from C1 to C3 alkylene (eg, methylene).

[0320] In some embodiments, L 1A , L 1B , L 1C , L 1D , or L 1E is the terminal subunit of the linker structure and is attached (i.e., covalently attached) to the W moiety, and L 3A , L 5B , L 4C , L 3D , L 3Eis the terminal subunit of the linker structure and is attached (ie, covalently bound) to the TBL moiety.

[0321] L 1A , L 1B , or L 1D If either of these is not present, L 2A , L 2B , or L 2D is directly bonded (i.e., covalently bonded) to the W moiety. 3D If there is no L 2D is directly attached (ie, covalently attached) to the TBL moiety.

[0322] As mentioned above, L 1C , L 2D , L 2E , R L2B Linker moieties, such as the example: may be bicyclic or tricyclic, and unless otherwise specified, these moieties may include bonded rings, fused rings, bridged rings, and / or rings joined at spiro centers.

[0323] L 1C , L 2D , L 2E , R L2B When any one of the examples is bicyclic, it may be a bridged bicyclic ring (i.e., it may comprise two rings which share three or more atoms) or a spirocyclic bicyclic ring (i.e., it may comprise two rings which share one atom, e.g., the two rings may be joined at a spiro center).

[0324] L 1C , L 2D , L 2E , R L2B When any one of the examples of is a bridged bicyclic ring, it may also be an optionally substituted 7- to 12-membered bridged bicyclic N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S. In some cases, L 1C , L 2D , L 2E , and R L2BExamples of L may be 7- or 8-membered bridged bicyclic N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S. In some cases, L 1C , L 2D , L 2E , and R L2B Examples of are 7- or 8-membered bridged bicyclic N-heterocycloalkyls, optionally containing one additional ring atom selected from N.

[0325] L 1C , L 2D , L 2E , and R L2B When any one of the examples of is a spirocyclic bicyclic ring, it may be an optionally substituted 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl, optionally containing 1 or 2 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 7- to 12-membered spirocyclic bicyclic N-heterocycloalkyl, optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S. 1C , L 2D , L 2E , and R L2B Examples of L may be bicyclic and include a first 5- to 7-membered ring and a second 3- to 7-membered ring. 1C , L 2D , L 2E , and R L2B Examples of L may be spirocyclic bicyclic N-heterocycloalkyls comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, optionally containing one or two additional ring heteroatoms selected from N, O, and S. In some embodiments, L 1C , L 2D , L 2E , and R L2BAn example of may be a spirocyclic bicyclic N-heterocycloalkyl comprising a first 5- or 6-membered ring and a second 3- to 6-membered ring, optionally containing one additional ring heteroatom selected from N.

[0326] In some embodiments, L 1C , L 2D , L 2E , and R L2B The example structure is [ka] It may be any one selected from where L 1A and L 3A is as defined above, X 5 is C(R b )2, NR b or O, R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 3; n' is 1 or 2; m is 0, 1, or 2.

[0327] The dotted lines on the structures above indicate that a linker may be attached to the structure shown at any position shown (provided it has the correct valence and / or is chemically feasible).

[0328] In some embodiments, L 1C , L 2D , L 2E , and R L2B An example of is any one of the following: [ka]

[0329] The dotted lines on the structures above indicate that a linker may be attached to the structure shown at any position shown (provided it has the correct valence and / or is chemically feasible).

[0330] As mentioned above, L 1D is absent or is selected from C1-C3 alkylene, —O—, —N(C1-C3 alkyl)-, and CO. In some embodiments, L 3D is selected from C1 to C3 alkylene (for example, methylene).

[0331] In some examples described herein, the linker (L) has the formula (Llf): L 1F It may be or include the structure shown in (L1f), In the formula, L 1F is C1-C3 alkylene, CO and C1-C3 alkylene (NR L1C ) and R L1C is H or C1-C3 alkyl.

[0332] In some embodiments, L 1F is selected from C1 to C3 alkylene (for example, methylene).

[0333] In any of the embodiments described herein, the linker is or includes one or more of the following: [ka] In the formula, q1 is an arbitrary integer between 1 and 20, or between 1 and 10 (for example, between 1 and 5).

[0334] Alternatively, in any of the embodiments described herein, the linker is or comprises one or more of the following: [ka] JPEG2025531881000162.jpg152123TIFF2025531881000163.tif110170 In the formula, q2 is any integer between 1 and 20, or between 1 and 10 (for example, 3, 4, 6, or 10).

[0335] Alternatively or additionally, in any of the embodiments described herein, the linker may be or include one or more of the following: [ka] TIFF2025531881000165.tif56170 In the formula, q1 is any integer between 1 and 20, or between 1 and 10 (e.g., between 1 and 5), and q2 is any integer between 1 and 20, or between 1 and 10 (e.g., 3, 4, 5, 6, or 10).

[0336] In certain embodiments, the linker is or includes one or more of the following structures: [ka] JPEG2025531881000167.jpg69123

[0337] In yet another alternative, in any of the embodiments described herein, the linker is or includes one or more of the following: [ka] In the formula, q3 is 1 to 8, for example, 1 to 5, and q4 is 1 to 12, for example, 1 to 10. [ka]

[0338] In certain embodiments, the linker is or includes one or more of the following structures: [ka] TIFF2025531881000171.tif196170TIFF2025531881000172.tif221170TIFF202 5531881000173.tif236170TIFF2025531881000174.tif216170TIFF20255318810 00175.tif233170TIFF2025531881000176.tif229170TIFF2025531881000177.t if203170TIFF2025531881000178.tif238170TIFF2025531881000179.tif193170

[0339] In some cases, the structures shown above represent the entire linker. In other examples, the linker of the bifunctional molecule may include multiple structures shown above.

[0340] In these structures, wavy lines are shown on the bond(s) that form the linkages with the TBL and Z moieties, respectively.

[0341] In some examples, the bond(s) forming the linkage to the TBL and / or Z moieties are attached to a ring structure. On many of the structures described herein, this bond is shown attached at a specific position on the ring structure. However, the present disclosure also encompasses linking or coupling to the TBL and Z moieties at any chemically suitable position on these ring structures.

[0342] The present disclosure encompasses the use of any of the linkers disclosed herein in combination with any of the Z and TBL moieties described herein.

[0343] In certain embodiments, the linker is [ka] It doesn't have to be.

[0344] In a more particular embodiment, the bifunctional molecule is [ka] It may not include.

[0345] In other cases, the linker is [ka] It doesn't have to be.

[0346] In some embodiments, the bifunctional molecule comprising the general formula TBL-LZ is [ka] TIFF2025531881000184.tif238170TIFF2025531881000185.tif224170TIFF2025531881000186.tif23717 0TIFF2025531881000187.tif234170TIFF2025531881000188.tif163170TIFF2025531881000189.tif89170 may be selected from any of wherein Z and TBL are as defined above and herein.

[0347] In some embodiments, the bifunctional molecule comprising the general formula TBL-LZ has the following structure: [ka] including one of In the formula, R 2 and R3 is as defined above and herein, and the bond indicates the attachment to the remainder of the bifunctional molecule.

[0348] Exemplary Bifunctional Molecules It will be understood that the bifunctional molecules of the present disclosure can exist in different stereoisomeric forms. The present disclosure includes within its scope the use of all stereoisomeric forms or mixtures of stereoisomers of the bifunctional molecules. By way of example, if the bifunctional molecule contains one or more chiral centers, the present disclosure encompasses each individual enantiomer of the bifunctional molecule as well as mixtures of enantiomers, including racemic mixtures of such enantiomers. As a further example, if the bifunctional molecule contains two or more chiral centers, the present disclosure encompasses each individual diastereomer of the bifunctional molecule as well as mixtures of various diastereomers.

[0349] Unless otherwise specified, the various structures depicted herein encompass all isomeric (e.g., enantiomeric, diastereomeric, geometric (or conformational) isomeric) forms. For example, the present disclosure encompasses R and S configurations at each asymmetric center, as well as Z and E double bond isomers. Accordingly, single 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 present disclosure. Additionally, unless otherwise specified, all tautomeric forms of the bifunctional molecules described herein, when present, are understood to be included within the scope of the present disclosure.

[0350] As used herein, the expression "bifunctional molecule" may further include pharmaceutically acceptable salts thereof.

[0351] For the avoidance of doubt, a bifunctional molecule may comprise any combination of target binding protein (TBL), linker (L), and warhead (Z), provided that it has the correct valence and is chemically suitable. For example, a bifunctional compound may comprise Z of formula (I), (II), or (III) (corresponding subgeneric formulas defined herein, such as (Ia), (Ib), (Ic), (IIaa), (IIb), (IIc), and (IId)), L of any formula or subgeneric formula defined herein, and L of formula 1a, 1a', 1b, 1c, 1b', 1a 1 , 1a 2 , 1a 3 , 1e, 1f, 1g, 1f', 1g', 1ea-1eh, 1fa-1fh, 1ga, 1ea', 1h-1z, or 2a-2g. In other examples, the bifunctional compound may include any combination of Z, (A), (A1)-(A3), of formula (WZI)-(WZV), (WI), (WII), (WIII), (WIV), or (WV) (corresponding subgeneric formulas defined herein such as (WIa)-(WIf), (WIIa)-(WIIf), (WIIIa), (WIIIb), and (WIVa)), L, and TBL of any formula or subgeneric formula defined herein.

[0352] In some embodiments, (i) Z is represented by formula (I), (Ia), (Ib), (Ic), (IIaa), (IIa) or (IIb) as defined above; (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[0353] In other embodiments, (i) Z is represented by formula (Ia), (IIaa), or (IIa) as defined above; (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[0354] In certain embodiments, (i) Z is represented by formula (Ia), (IIaa), or (IIa) as defined above; (ii) TBL is represented by formula (1h), (1i) or (1j) as defined above.

[0355] In other particular embodiments, (i) Z is represented by formula (Ib) or (IIb) as defined above; (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[0356] In a more particular embodiment, (i) Z is represented by formula (Ib) or (IIb) as defined above; TBL is represented by formula (1h), (1i) or (1j) as defined above.

[0357] In certain embodiments, (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; (ii) TBL is represented by formula 1a″ as defined above. In certain of these embodiments, L may be represented by formula L1a or L1b.

[0358] In yet another embodiment, (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; (ii) TBL is represented by any one of formulas 1e'', 1g'', 1g''', 1ea''-1eh'', 1ea'', 1h''-1z'', and 2a''-2g'', as defined above; (iii) L is represented by formula L1a or L1b as defined above.

[0359] In a more particular embodiment, (i) Z is represented by formula (WI), (WII), (WIIa), (WIIb), (WIIc), (WIId), (WIIe), (WIIf), (WIII), (WIIIa), (WIIIb), (WIV) or (WIVa) as defined above; (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above.

[0360] In some embodiments: (i) Z is represented by formula (WI), (WII), (WIIa), (WIIb), (WIIc), (WIId), (WIIe), (WIIf), (WIII), (WIIIa), (WIIIb), (WIV) or (WIVa) as defined above; Z is [ka] Instead, (ii) TBL is a target protein-binding ligand that binds to BRD9, and TBL is [ka] isn't it.

[0361] In some embodiments, (i) Z is represented by any one of formulas (WZI), (WZII), (WZIIa) to (WZIIe), (WZIIIa) to (WZIIIh), or (WZIVa) to (WZIVj) defined above; (ii) TBL is represented by formula 1a″ as defined above, (iii) L is represented by the formula L1c defined above.

[0362] In some embodiments, (i) Z is represented by any one of formulas (WZI), (WZII), (WZIIa) to (WZIIe), (WZIIIa) to (WZIIIh), or (WZIVa) to (WZIVj) defined above; (ii) TBL is represented by any one of formulas 1e'', 1g'', 1g''', 1ea''-1eh'', 1ea'', 1h''-1z'', and 2a''-2g'', as defined above; (iii) L is represented by the formula L1c defined above.

[0363] In some cases, the bifunctional molecule is [ka] isn't it.

[0364] In some more specific examples, the bifunctional molecule is selected from the group consisting of formulae A2-A76, BRD9a-BRD9ac, B1-B84, B86, B88-B96, B98-B104, B106-B127, B130-B149, B152-B156, B158-B162, B164, B165, B169, B173-B175, B180-B215, and C1-C1 07, or any one of any combinations of TBL, L, and Z represented by 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. [Table 1] JPEG2025531881000195.jpg95123 JPEG2025531881000196.jpg110141 JPEG2025531881000197.jpg109142 JPEG2025531881000198.jpg110141 JPEG2025531881000199.jpg110141 JPEG2025531881000200.jpg110141 JPEG2025531881000201.jpg110142 JPEG2025531881000202.jpg110141 JPEG2025531881000203.jpg110141 JPEG2025531881000204.jpg109141 JPEG2025531881000205.jpg110141 JPEG2025531881000206.jpg110141 JPEG2025531881000207.jpg109141 JPEG2025531881000208.jpg109141 JPEG2025531881000209.jpg109141 JPEG2025531881000210.jpg109141 JPEG2025531881000211.jpg110141 JPEG2025531881000212.jpg110141 JPEG2025531881000213.jpg110141 JPEG2025531881000214.jpg109141 JPEG2025531881000215.jpg110141 JPEG2025531881000216.jpg109141 JPEG2025531881000217.jpg109141 JPEG2025531881000218.jpg109141 JPEG2025531881000219.jpg110141 JPEG2025531881000220.jpg110141 JPEG2025531881000221.jpg110141 JPEG2025531881000222.jpg110141 JPEG2025531881000223.jpg110142 JPEG2025531881000224.jpg110140 JPEG2025531881000225.jpg110141 JPEG2025531881000226.jpg109141 JPEG2025531881000227.jpg110141 JPEG2025531881000228.jpg110142 JPEG2025531881000229.jpg109141 JPEG2025531881000230.jpg110141 JPEG2025531881000231.jpg110142 JPEG2025531881000232.jpg109141 JPEG2025531881000233.jpg109141 JPEG2025531881000234.jpg11085

[0365] Table 1 shows the structures of exemplary bifunctional molecules A2-A76, BRD9a-BRD9ac, B1-B84, B86, B88-B96, B98-B104, B106-B127, B130-B149, B152-B156, B158-B162, B164, B165, B169, B173-B175, B180-B215, and C1-C107.

[0366] Table 1 shows representative structures of the illustrated examples. Absolute stereochemistry and double bond geometry have been arbitrarily assigned where necessary unless otherwise indicated herein, e.g., in the detailed experimental section.

[0367] In some more specific examples, the bifunctional molecule is any one of formulas B202, C6, C35, and C77.

[0368] isotope labeled compounds The present disclosure also encompasses various deuterated forms of compounds of any of the formulas disclosed herein, including Formulas (I), (II), (III), (WZI)-(WZV), (WI), (WII), (WIII), (WIV), (WV), (A), (A1)-(A3), 1T, 2T, 3T, 4T, 5T, 6T, 7T, 8T, 9T, 11T, 12T, 13T, 14T (including the corresponding subgeneric formulas defined herein), or pharmaceutically acceptable salts and / or corresponding tautomeric forms (including the subgeneric formulas defined above) of the present disclosure. Each available hydrogen atom bonded to a carbon atom may be independently replaced with a deuterium atom. One of ordinary skill in the art would know how to synthesize deuterated forms of any of the compounds of the formulas disclosed herein, including those mentioned above. Deuterated materials, such as alkyl groups, can be prepared by conventional techniques (see, for example, methyl-d3-amine available from Aldrich Chemical Co., Milwaukee, Wis., Cat. No. 489,689-2).

[0369] The present disclosure also relates to compounds of formula (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 Also included are isotopically labeled compounds identical to those set forth in any of the formulas disclosed herein, including 1e, 1f, 1g, 1f', 1g', 1ea-1eh, 1fa-1fh, 1ga, 1ea', 1h-1z, or 2a-2g (including the corresponding subgeneric formulas defined herein), or a pharmaceutically acceptable salt and / or corresponding tautomeric form thereof of the present disclosure (including the subgeneric formulas defined above), but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 18 F, 123 I or 125 I. Compounds of the present disclosure and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and / or isotopes of other atoms are included within the scope of the present disclosure. Isotopically labeled compounds of the present disclosure, such as 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).

[0370] Degradation activity Degradation can be determined by measuring the amount of BRD9 target protein in the presence of a bifunctional molecule described herein and / or comparing it to the amount of BRD9 target protein observed in the absence of the bifunctional molecule. For example, the amount of BRD9 target protein in cells contacted and / or treated with a bifunctional molecule described herein can be determined. This amount can be compared to the amount of BRD9 target protein in cells not contacted and / or treated with the bifunctional molecule. If the amount of BRD9 target protein in cells contacted and / or treated with the bifunctional molecule is reduced, the bifunctional molecule can be considered to promote and / or enhance the degradation and / or proteolysis of the BRD9 target protein.

[0371] The amount of BRD9 target protein can be determined using methods known in the art, for example, by performing immunoblotting assays, Western blot analysis and / or ELISA using cells contacted and / or treated with the bifunctional molecule.

[0372] Selective degradation and / or increased proteolysis may be considered to have occurred if at least a 10% decrease, e.g., a 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease, in the amount of BRD9 target protein is observed following administration of the bifunctional molecule to cells.

[0373] For example, selective degradation and / or increased proteolysis may be considered to have occurred if at least a 10% decrease (e.g., at least a 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease) in the amount of BRD9 target protein is observed within 4 hours or more (e.g., 4 hours, 8 hours, 12 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 ​​hours, 54 hours, 60 hours, 66 hours, and 72 hours) after administration of the bifunctional molecule to the cells. In particular examples, selective degradation and / or increased proteolysis may be considered to have occurred if at least a 40% decrease in the amount of BRD9 target protein is observed. The bifunctional molecule may be administered at any concentration, e.g., 0.01 nM to 10 μM, e.g., 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM, and 10 μM. In some cases, after administration of the bifunctional molecule at a concentration of about 100 nM (e.g., after an incubation period of about 8 hours), an increase in degradation of the BRD9 target protein of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100% is observed.

[0374] One measure of the degrader activity of a bifunctional molecule is the DC 50 As used herein, DC 50 is the concentration required to achieve 50% of maximal degradation of the BRD9 target protein. The bifunctional molecules described herein have DC values ​​of 10,000 nM or less, 1,000 nM or less, 500 nM or less, 100 nM or less, or 75 nM or less. 50 In some cases, the bifunctional molecule may comprise a DC of 50 nM or less, 25 nM or less, 10 nM or less, 5 nM or less, 1.5 nM or less, 1 nM or less, or 0.5 nM or less. 50 In some cases, the bifunctional molecules of the invention have a DC of less than 1.25 nM in any of the BRD9 degradation assays described below. 50 Includes.

[0375] Another measure of the decomposition inducer activity of bifunctional molecules is the D max As used herein, D maxrepresents the maximum percentage of BRD9 target protein degradation. The bifunctional molecules described herein may achieve a D of 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%. max In certain embodiments, the bifunctional molecule may comprise at least 40% D max In some cases, the bifunctional molecules of the invention have a DC of less than 1.25 nM in any of the BRD9 degradation assays described below. 50 and 75% or more of D max may include:

[0376] In some cases, the bifunctional molecules of the invention exhibit a D of 75% or greater in any of the BRD9 degradation assays described below. max may include:

[0377] Yet another measure of the effectiveness of the described bifunctional molecules is cell viability and / or their IC 50 For example, the antiproliferative effects of the bifunctional molecules described herein can be assessed in cell viability assays to determine IC 50 As used herein, IC 50 Values ​​represent the concentration at which 50% cell viability was observed in a cell viability assay (following administration of the bifunctional molecules described herein). In terms of cell viability, the bifunctional molecules described herein have an IC of less than 1000 nM, less than 500 nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 20 nM, or less than 10 nM. 50 In some cases, the bifunctional molecules described herein may have an IC of less than 5 nM. 50 It may contain a value.

[0378] Bioavailability The bifunctional molecules described herein may provide decomposition inducers with improved levels of bioavailability, such as improved levels of oral bioavailability.

[0379] As used herein, bioavailability is the rate or fraction of an administered active agent (e.g., a bifunctional molecule described herein) that reaches the systemic circulation in a subject. As used herein, oral bioavailability is the rate or fraction of an orally administered active agent that reaches the systemic circulation in a subject.

[0380] Oral bioavailability is calculated by comparing the area under the curve (AUC) for intravenous administration of a particular active agent to the AUC for oral administration of that active agent. The AUC value is the explicit integral of the curve showing the fluctuation of the active agent concentration in plasma as a function of time. As used herein, AUC 0-INF is the area under the curve extrapolated from time zero to infinity and represents the total active agent exposure over time.

[0381] Oral bioavailability (F) can be calculated using the following formula:

number

[0382] 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 approximately 28%.

[0383] Pharmaceutical Compositions The present disclosure provides pharmaceutical compositions comprising the bifunctional molecules described herein.In such compositions, the bifunctional molecules can be suitably formulated so that they can be introduced into the cellular environment by a means that allows a sufficient portion of the molecules to enter the cell and induce the degradation of BRD9 target protein.

[0384] Accordingly, provided is a pharmaceutical composition comprising a bifunctional molecule described herein together with a pharmaceutically acceptable carrier.

[0385] Pharmaceutically acceptable carriers are known to those skilled in the art and include, but are not limited to, phosphate buffer and / or saline. Pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions (including saline and buffered media). Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils. Preservatives and other additives may also be present, such as antibacterial agents, antioxidants, chelating agents, and inert gases.

[0386] In addition to the aforementioned carrier components, the pharmaceutical compositions may alternatively or additionally contain one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), as well as substances included to render the formulation isotonic with the blood of the intended recipient.

[0387] The pharmaceutical composition may be in any formulation that is typical for administering a pharmaceutical compound to a subject.Representative examples of typical formulations include, but are not limited to, capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants, etc.

[0388] A pharmaceutical composition is formulated to be compatible with its intended route of administration, which includes parenteral, e.g., intravenous, intradermal, subcutaneous, oral, transdermal, topical, transmucosal, vaginal, and rectal administration.

[0389] Pharmaceutical compositions can include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), topical (including cutaneous, buccal, and sublingual), rectal, nasal, and pulmonary administration, for example, by inhalation. The compositions may, where appropriate, be conveniently presented in individual unit dosage forms and may be prepared by any of the methods well known to those skilled in the art of pharmacy. Methods typically include the step of bringing the active compound into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0390] Pharmaceutical compositions suitable for oral administration in which the carrier is solid are most preferably presented as unit dose formulations such as boluses, capsules, or tablets, each containing a predetermined amount of active compound. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersant, in a suitable machine. Molded tablets can be made by molding the active compound with an inert liquid diluent. Tablets can be optionally coated, or, if uncoated, can be optionally scored. Capsules can be prepared by filling the active compound, alone or in admixture with one or more accessory ingredients, into capsule shells, which are then sealed in the usual manner. Cachets are similar to capsules, in that the active compound, along with any accessory ingredients, is sealed in a rice paper envelope. The bifunctional molecule can also be formulated as dispersible granules, which can be suspended in water or sprinkled on food before administration, for example. The granules can be packaged, for example, in sachets. Compositions suitable for oral administration in which the carrier is a liquid can be presented as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion. Compositions for oral administration include controlled-release dosage forms, for example, tablets in which the active compound is formulated in a suitable release-controlling matrix or coated with a suitable release-controlling film.

[0391] Pharmaceutical compositions suitable for parenteral administration include sterile solutions or suspensions of active compounds in aqueous or oily vehicles.Injection preparations can be adapted for bolus injection or continuous infusion.Such preparations are conveniently presented in unit-dose or multi-dose containers, and are sealed after the introduction of the preparation until required for use.Alternatively, bifunctional molecules can be in powder form, which is combined with suitable vehicles such as sterile pyrogen-free water before use.

[0392] The pharmaceutical compositions may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implant, for example, subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion exchange resins.

[0393] Pharmaceutical compositions suitable for topical formulation may be provided, for example, as a gel, cream, or ointment.

[0394] The bifunctional molecules described herein may be present in the pharmaceutical composition as pharmaceutically and / or physiologically acceptable salts, solvates, or derivatives.

[0395] 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.

[0396] Pharmaceutically and / or physiologically functional derivatives of the compounds of the present invention are derivatives that can be converted into the parent compound in the body. Such pharmaceutical and / or physiologically functional derivatives may also be referred to as "prodrugs" or "bioprecursors." Pharmaceutically and / or physiologically functional derivatives of the compounds of the present disclosure may include in vivo hydrolyzable esters or amides, particularly esters.

[0397] It may be convenient or desirable to prepare, purify, and / or handle corresponding pharmaceutically and / or physiologically acceptable solvates of the bifunctional molecules described herein, which may be used in any one of the described uses / methods. The term solvate is used herein to refer to a complex of a solute and a solvent, such as a compound or a salt of the compound. When the solvent is water, the solvate may be referred to as a hydrate, for example, a monohydrate, a dihydrate, a trihydrate, etc., depending on the number of water molecules present per molecule of substrate.

[0398] Use of Part Z As described herein, moiety Z forms part of a bifunctional molecule intended for use in methods of targeted protein degradation, wherein moiety Z acts to regulate, promote and / or enhance proteasomal degradation of a BRD9 target protein.

[0399] Thus, according to a further aspect of the present disclosure, there is provided the use of moiety Z or a compound comprising moiety Z (e.g., as defined by any one of formulas (I)-(III)) in a method for BRD9 degradation (e.g., an in vitro or in vivo method of targeted protein degradation). For example, moiety Z may find particular use as a promoter or facilitator of BRD9 degradation.

[0400] Also provided is the use of moiety Z or a compound comprising moiety Z (e.g., as defined by any one of formulas (I) to (III)) in the preparation of a bifunctional molecule suitable for degrading BRD9.

[0401] Therapeutic Methods and Uses The bifunctional molecules of the present disclosure can regulate, promote, and / or enhance the proteasomal degradation of BRD9 target proteins. Accordingly, a method for selectively degrading and / or increasing the proteolytic degradation of a BRD9 target protein in a cell is provided, comprising contacting and / or treating the cell with a bifunctional molecule described herein. The method can be performed in vivo or in vitro.

[0402] Specifically, provided is a method for 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.

[0403] Therefore, the bifunctional molecules of the present disclosure can find applications in medicine and / or therapy. Specifically, the bifunctional molecules of the present disclosure can find use in the treatment and / or prevention of any disease or condition regulated through a BRD9 target protein. For example, the bifunctional molecules of the present disclosure can be useful in treating any disease regulated through a BRD9 target protein by reducing the level of that protein in a cell, e.g., a subject's cell.

[0404] Further provided is the use of a bifunctional molecule described herein in the manufacture of a medicament for the treatment and / or prevention of any disease or condition regulated through a BRD9 target protein. Additionally provided is the use of a Z moiety (e.g., as defined in any one of formulas (I)-(III)) in the manufacture of a medicament for the treatment and / or prevention of any disease or condition regulated through a BRD9 target protein.

[0405] Diseases and / or conditions that may be treated and / or prevented by the molecules of the present disclosure include any disease associated with and / or caused by abnormal levels of BRD9 protein activity.

[0406] Such diseases and conditions include those whose pathology is associated, at least in part, with abnormal (e.g., elevated) levels of BRD9 protein and / or overexpression of BRD9 protein. For example, the bifunctional molecules may find use in the treatment and / or prevention of diseases in which elevated levels of BRD9 protein are observed in subjects suffering from the disease. In other examples, the diseases and / or conditions may be those whose pathology is associated, at least in part, with inappropriate BRD9 protein expression (e.g., expression at the wrong time and / or in the wrong cells) or excessive BRD9 protein expression.

[0407] Accordingly, provided are methods for treating and / or preventing diseases or conditions associated with and / or caused by abnormal levels of BRD9 protein activity, comprising administering a therapeutically effective amount of a bifunctional compound described herein.

[0408] Representative examples of diseases and / or conditions that can be treated and / or prevented by use of the described bifunctional compounds include, but are not limited to, cancer.

[0409] A recent review article summarized the potential mechanisms of action of BRD9 in carcinogenesis and described various strategies for targeting BRD9 for use as a cancer therapeutic (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, suggesting that it could be a therapeutic target for these cancers (Xiaofeng Wang et al., Nature Communications, 2019, 10(1881)). Recent studies have also highlighted the role of BRD9 in leukemia proliferation: BRD9 was shown to be required for the proliferation of acute myeloid leukemia (AML) cells (Nature Chemical Biology, 2016, 101038 / nchembio.2115). In addition to its role as a functional dependency in certain cancers, BRD9 also plays a pivotal role in immune cells as a regulator of regulatory T cells (Tregs) through transcriptional regulation of Foxp3 target genes (BioRxiv, 10.1101 / 2020.02.26.964981).

[0410] Representative examples of cancers that can be treated and / or prevented using the described bifunctional molecules include: (i) Brain tumors, for example, astrocytomas such as acoustic neuroma, pilocytic astrocytoma, fibrillary astrocytoma, protoplasmic astrocytoma, mastocytic astrocytoma, anaplastic astrocytoma, and glioblastoma, brain lymphoma, brain metastasis, pituitary tumors such as prolactinoma, HGH (human growth hormone)-producing tumors and ACTH (adrenocorticotropic hormone)-producing tumors, craniopharyngioma, medulloblastoma, meningioma, and oligodendroglioma, etc. (ii) Neural tumors (tumor formations), for example, tumors of the vegetative nervous system such as sympathetic neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma, pheochromocytoma), and carotid glomus tumor; tumors of the peripheral nervous system such as amputation neuroma, neurofibroma, neurilemmoma (neurinoma, schwannoma), and malignant neurinoma; and tumors of the central nervous system such as brain tumors and bone marrow tumors; (iii) intestinal cancers, such as rectal cancer, colon cancer, colorectal cancer, anal cancer, carcinoma of the large intestine, tumors of the small intestine and duodenum, etc. (iv) eyelid tumors, such as basal cell tumors or basal cell carcinomas; (v) pancreatic cancer or carcinoma of the pancreas; (vi) bladder cancer or carcinoma of the bladder, (vii) lung cancer (bronchial carcinoma), such as small cell bronchial carcinoma (oat cell carcinoma) and non-small cell bronchial carcinoma (NSCLC), such as squamous cell carcinoma, adenocarcinoma, and large cell bronchial carcinoma; (viii) breast cancer, such as invasive ductal carcinoma, colloid carcinoma, lobular carcinoma, tubular carcinoma, adenocystic carcinoma, and papillary carcinoma; (ix) Non-Hodgkin's lymphoma (NHL), such as Burkitt's lymphoma, low-grade non-Hodgkin's lymphoma (NHL), and mucosal fungoides; (x) uterine cancer, endometrial cancer, or uterine cancer; (xi) CUP syndrome (cancer of unknown primary origin), (xii) ovarian cancer, such as ovarian cancer or mucinous cancer, endometrial cancer or serous cancer; (xiii) gallbladder cancer, (xiv) Cholangiocarcinoma, such as Clarkin tumor, (xv) testicular cancer, including seminoma and nonseminoma; (xvi) Lymphomas (lymphosarcoma), such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (NHL), such as chronic lymphocytic leukemia, leukemic reticuloendotheliosis, immunocytoma, plasmacytoma (multiple myeloma (MM)), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large cell anaplastic lymphoblastoma, and lymphoblastoma, etc. (xvii) Laryngeal cancer, such as tumors of the vocal cords, supraglottic tumors, glottic tumors, and subglottic tumors; (xviii) Bone cancers, such as osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant osteocytoma, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulum cell sarcoma, plasmacytoma, fibrous dysplasia, juvenile bone cyst, and aneurysmal bone cyst, etc. (xix) Head and neck tumors, such as tumors of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, pharynx, nasal cavity, paranasal sinuses, larynx, and middle ear. (xx) liver cancer, such as hepatocellular carcinoma or hepatocellular carcinoma (HCC); (xxi) Leukemia, for example, acute leukemia (acute lymphocytic / lymphoblastic leukemia (ALL) etc.), acute myeloid leukemia (AML), chronic leukemia (chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML) etc.), (xxii) Gastric cancer or lymphocytic infiltration gastric cancer, such as papillary adenocarcinoma, tubular adenocarcinoma and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small cell carcinoma and undifferentiated carcinoma, (xxiii) melanoma, such as superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma; (xxiv) renal cancer, such as renal cell carcinoma, adrenal tumor, or Grawitz tumor; (xxv) esophageal cancer or carcinoma of the esophagus, (xxvi) Penile cancer, (xxvii) prostate cancer, (xxviii) Pharyngeal cancer or carcinoma of the pharynx, such as nasopharyngeal carcinoma, oropharyngeal carcinoma, and hypopharyngeal carcinoma. (xxix) retinoblastoma, such as vaginal or vaginal carcinoma, (xxx) squamous cell carcinoma, adenocarcinoma, carcinoma in situ, malignant melanoma and sarcoma; (xxxi) Thyroid cancer, such as papillary carcinoma, follicular carcinoma, and medullary thyroid carcinoma, and undifferentiated carcinoma, (xxxii) squamous cell carcinoma, epidermoid carcinoma and squamous cell tumor of the skin; (xxxiii) Cancers include, but are not limited to, thymoma, urethral cancer, and vulvar cancer.

[0411] In certain embodiments, the cancer is any 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).

[0412] Other specific examples of cancers that can be treated by targeted proteolysis of BRD9 include cancers associated with SMARCB1 abnormalities, e.g., SMARCB1-deficient cancers such as malignant rhabdoid tumors and some specific types of sarcomas, and leukemias such as acute myeloid leukemia (AML).

[0413] As used herein, the term "patient" or "subject" is used to refer to an animal, e.g., a mammal (e.g., a human or livestock), that is provided treatment, including prophylactic treatment, with a composition according to the present disclosure. With respect to treatment of those infections, conditions, or disease states specific to a particular animal, such as 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, cows, sheep, etc. Generally, in the present invention, the term patient refers to a human patient, unless otherwise stated or implied from the context of the use of the term.

[0414] Assay The present disclosure also encompasses methods for screening bifunctional molecules to identify suitable BRD9-binding ligands and linkers for use in the bifunctional molecules described herein, e.g., bifunctional molecules that can effectively regulate, promote, and / or enhance proteolysis of BRD9 target proteins. This method may be useful for identifying suitable linkers for specific BRD9 binding partners so that levels of degradation can be further optimized.

[0415] This method is a. (i) a first ligand comprising the structure according to Z (e.g., as defined by any one of the formulas defined herein, including (I), (II), (III), (WI), (WII), (WIII), (WIV), (WV) and any subgeneric formula); (ii) a second ligand that binds to the BRD9 target protein (e.g., a compound represented by Formula 1a, 1a', 1b, 1c, 1b', 1a 1 , 1a 2 , 1a 3, 1e, 1f, 1g, 1f', 1g', 1ea-1eh, 1fa-1fh, 1ga, 1ea', 1h-1z, 2a-2g and any subgeneric formula), and (iii) a linker covalently linking the first and second ligands; b. contacting the cell with a bifunctional molecule; c. detecting degradation of the BRD9 target protein in the cell.

[0416] This method is d. detecting degradation of the BRD9 target protein in the cell in the absence of the bifunctional molecule; e. comparing the level of degradation of the BRD9 target protein in the cells contacted with the bifunctional molecule with the level of degradation of the BRD9 target protein in the absence of the bifunctional molecule; An increase in the level of degradation of the BRD9 target protein in cells contacted with the bifunctional molecule indicates that the bifunctional molecule promotes and / or enhances the degradation of the BRD9 target protein.

[0417] In such methods, detecting degradation of the BRD9 target protein can include detecting a change in the level of BRD9 protein in the cell. For example, a decrease in the level of BRD9 protein indicates degradation of the BRD9 protein. An increased decrease in the level of BRD9 protein in cells contacted with the bifunctional molecule (compared to any decrease in the level of BRD9 protein observed in the cells in the absence of the bifunctional molecule) indicates that the bifunctional molecule has promoted and / or enhanced degradation of the BRD9 target protein.

[0418] The method may further include providing a plurality of linkers, each used to covalently link a first and a second ligand together to form a plurality of bifunctional molecules. The degradation levels provided by each of the plurality of bifunctional molecules may 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.

[0419] The method can be carried out in vivo or in vitro.

[0420] Compound Library The present disclosure also provides a library of bifunctional molecules, the library comprising a plurality of bifunctional molecules, the plurality of bifunctional molecules comprising a plurality of Z moieties that covalently bind to a selected BRD9 protein partner.

[0421] Thus, the BRD9 binding partner may be pre-selected and the Z moiety may not be predetermined. The library can be used to determine the activity of candidate Z moieties of bifunctional molecules in regulating, enhancing, and / or promoting selective proteolysis of the BRD9 protein.

[0422] The present disclosure also includes libraries of bifunctional molecules, the libraries comprising a plurality of bifunctional molecules, the plurality of bifunctional molecules comprising a plurality of BRD9 protein-binding ligands and selected Z moieties. Thus, the Z moieties of the bifunctional molecules may be pre-selected, and the BRD9 target protein may not be pre-determined. The libraries can be used to determine the activity of putative BRD9 protein-binding ligands and their value as binders of the BRD9 protein to enhance BRD9 degradation.

[0423] Manufacturing method According to a further aspect of the present disclosure, there is provided a method of making the bifunctional molecules described herein.

[0424] The method for making a bifunctional molecule comprises: (a) providing a first ligand or moiety comprising the structure according to Z (e.g., as defined by any one of the formulas defined herein, including (I), (II), (III), (WI), (WII), (WIII), (WIV), (WV) and any subgeneric formula); (b) a second ligand or moiety that binds to the BRD9 protein (e.g., a ligand of Formula 1a, 1a', 1b, 1c, 1b', 1a 1 , 1a 2 , 1a 3 providing a BRD9-binding ligand defined by any one of the formulas defined herein, including any one of: 1e, 1f, 1g, 1f', 1g', 1ea-1eh, 1fa-1fh, 1ga, 1ea', 1h-1z, 2a-2g, and any subgeneric formula; (c) linking (e.g., covalently linking) the first and second ligands or moieties using a linker as defined herein.

[0425] In another embodiment, a method for making a bifunctional molecule comprises: (a) a BRD9 protein-binding ligand (e.g., a compound of Formula 1a, 1a', 1b, 1c, 1b', 1a 1 , 1a 2 , 1a 3 providing a BRD9-binding ligand defined by any one of the formulas defined herein, including any one of: 1e, 1f, 1g, 1f', 1g', 1ea-1eh, 1fa-1fh, 1ga, 1ea', 1h-1z, 2a-2g, and any subgeneric formula; (b) attaching (e.g., covalently attaching) a linker (defined herein) to the BRD9 protein binding ligand to provide a BRD9 protein binding ligand-linker conjugate (TBL-L); (c) further reacting the linker portion of the conjugate to add and / or form a structure according to Z (e.g., as defined by any one of the formulae defined herein, including (I), (II), (III), (WI), (WII), (WIII), (WIV), (WV) and any subgeneric formulas) to provide a bifunctional molecule having the general formula TBL-LZ.

[0426] Parts Kit According to a further aspect of the present disclosure, there is provided a kit of individual parts from which bifunctional molecules as defined herein can be prepared, for example according to the manufacturing methods described above.

[0427] The parts kit is (i) a first ligand comprising a structure according to Z defined above (e.g., defined by any one of the formulas defined herein, including (I), (II), (III), (WI), (WII), (WIII), (WIV), (WV) and any subgeneric formula); (ii) a second ligand that binds to BRD9 as defined above (e.g., a compound represented by formula 1a, 1a', 1b, 1c, 1b', 1a 1 , 1a 2 , 1a 3 , 1e, 1f, 1g, 1f', 1g', 1ea-1eh, 1fa-1fh, 1ga, 1ea', 1h-1z, 2a-2g, and any subgeneric formula), and (iii) a linker covalently linking the first and second ligands as defined above.

[0428] In some cases, each of the first ligand, the second ligand, and the linker are separate from one another.

[0429] Terms The present disclosure may also be defined by reference to the following series of clauses: 1. General formula: [ka] wherein TBL is a target protein binding ligand that binds to BRD9; L is a linker, Z comprises a structure according to formula (I): [ka] During the ceremony, R 1 is selected from C1-C6 alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl, optionally wherein the C1-C6 alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S, and / or with a carbocyclic or heterocyclic group; A does not exist or CR 2 R 2’ and B is selected from aryl, heteroaryl, substituted aryl, and substituted heteroaryl; R 2 and R 2’ are each independently selected from H and C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from N, O, or S, or R 2 and R 2’ together form a 3-, 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; R 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 4is H, C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more heteroatoms selected from N, O or S; Or, R 1 and R 4 taken together form a 5-, 6- or 7-membered heterocyclic ring; Or, A is CR 2 R 2’ If R 1 and R 2 taken together form a 5-, 6-, or 7-membered heterocyclic ring, or R 2 and R 4 taken together form a 5-, 6-, or 7-membered heterocyclic or carbocyclic ring; L represents the attachment point of the linker, Or, Z is a group of the formula (WZI): [ka] including a structure according to During the ceremony, 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 optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; R 2A is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R y is an optionally substituted C 1-6 alkyl or H, 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; L represents the attachment point of the linker, Or, Z is a group represented by the formula (WI): [ka] including a structure according to In the formula, R 1A is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl; R 2A is absent or is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; 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; X 1 is CH2, X2 and X 3 are each independently CH2, or O and NR x and R is a heteroatom selected from x is H or C1-C6 alkyl, n is 0, 1, 2 or 3; L represents the attachment point of the linker, Or, Z is a group represented by the formula (A1): [ka] consisting of or consisting essentially of a structure according to During the ceremony, 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; wherein the linker is the carbonyl carbon C 1 binds to Furthermore, The BRD9 conjugate has the formula 1a: [ka] It is of During the ceremony, Z 1 is N or CR A and Z 2 is N or CR B and Z 3 is N or CR D and Z 4 is N or CRE and In the formula, Z 1 , Z 2 , Z 3 and Z 4 Of these, three or fewer are N, R A and R E are each independently -H, -OC 1-3 Alkyl, and -C 1-3 is selected from the group consisting of alkyl, R B and R D are each independently -OC 1-3 Alkyl, -H, -OH, halogen, -NH2, -C 1-3 Alkyl, -OC 1-3 Haloalkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, 4- to 7-membered heterocycloalkyl, -C 1-3 Alkyl-SO2-C 1-3 Alkyl, -C 1-3 Alkyl-NH2, -C 1-3 Alkyl-N(-C 1-3 alkyl)2, -N(C 1-3 alkyl)2, -NH-R F is selected from the group consisting of R F is -SO2-C 1-3 Alkyl and -C 1-3 alkyl, wherein -C 1-3 The alkyl is optionally substituted with a 5- to 6-membered heteroaryl; Or, R A and R B together to form a benzene ring, Or, R C and Z 2 , or RC and Z 3 together (for example, R C and R B , or R C and R D together with the carbon atom to which they are attached) optionally -C 1-3 forming a 5- to 7-membered heterocycloalkyl substituted with alkyl; RC -H, -YR G , -NH2, -C 1-3 is selected from the group consisting of alkyl, and 4- to 7-membered heterocycloalkyl; Y is absent or -CR H R I -, -SO2-, and -CO-; R H and R I are each independently -H or -C 1-3 alkyl, or R H and R I Together -C 3-4 forming a cycloalkyl, R G -NH2, -OH, -C 1-3 Alkyl, -N(R J R K ), -ORL, aryl, and 5- to 6-membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more halogens, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, and these monocyclic or bicyclic heterocycloalkyls may optionally be substituted with suitable substituents, such as halogens, -OH, -NH, -C, 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -OC 1-3 Alkyl, and -CH2-R M1 and optionally substituted with one or more groups independently selected from R M1 -NH2, -OH, halogen, -CN, -C 1-3 Alkyl or -OC 1-3 selected from 5-10 membered mono- or bicyclic aryl or heteroaryl optionally substituted with alkyl; R J is -H or -C 1-3 is alkyl, R K -C 1-3 Alkyl, -C2-3 Alkyl-N(C 1-3 alkyl)2, -C 2-3 Alkyl-NHC 1-3 alkyl, and optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is optionally selected from the group consisting of -C 1-3 substituted with any suitable substituent, such as alkyl; R L -C 1-3 alkyl or 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally C 1-3 is substituted with alkyl, where R C YR G If R B and R D are each independently -H, -OH, halogen, -NH2, -CN, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, and -C 1-3 Alkyl-OC 1-3 alkyl, where R A ~R E at least one of the substituents is not hydrogen; and, A 2 is represented by formula 1b or formula 1c: [ka] is selected from In the formula, the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom located ortho to R M is an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, C 2-6 selected from the group consisting of alkynyl, and H; Z 5 is N or CR O and Z 6 is N or CR P and Z 7 is N or CR N and where Z 5 , Z 6 and Z 7 and exactly one of them is N, Z 8 is CR W or N, R N is a halogen, optionally substituted -C 1-6 Alkyl, -H, C(O)C 1-5 Alkyl, -NH2, optionally substituted amino, -OH, cyano, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, and thiol; R O is H, halogen, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino; R P is H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl and optionally substituted C 6-10 aryl; Or, R N and Z 5 are bonded together and optionally substituted C 6-10 arene or optionally substituted C 2-9 forming a heteroarene, optionally R N and R O are bonded together with the carbon atom to which they are attached, and optionally substituted C 6-10 arene or optionally substituted C 2-9 forming a heteroarene, R S is H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl and optionally substituted C 3-10 carbocyclyl; R T is H, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, optionally substituted sulfone, and optionally substituted sulfonamido; or R Tand R U are optionally substituted C, together with the atom to which each is attached. 2-9 forming a heterocyclyl, R U and R V are each independently H, halogen, hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 Heteroaryl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 selected from the group consisting of heteroalkenyl, thiol, optionally substituted sulfone, and optionally substituted amino; Or, R T and R U are optionally substituted C, together with the atom to which each is attached. 2-9 forming a heterocyclyl, R W is H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Carbocyclyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 aryl, or optionally substituted C 2-9 heteroaryl; and, The BRD9 conjugate is attached to the linker at any suitable position. 2. The bifunctional molecule of clause 1, wherein Z 1 , Z 2 , Z 3 and Z 4 At most one of them is N. 3. The bifunctional molecule of clause 1 or clause 2, wherein the BRD9 conjugate has the formula 1a': [ka] It is of During the ceremony, R A , R B , R C , R E , Z 3 and A 2 is as defined in clause 1 or 2. 4. The bifunctional molecule of any one of clauses 1 to 3, wherein A 2 is selected from formula 1b', where formula 1b' is [ka] It is of In the formula, the wavy line represents A 2 and R A and R E crosses the bond between the carbon atom located ortho to R M -C 1-5 Alkyl, -cyclopropyl, -C 1-4 haloalkyl, and H; R N is a halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 is selected from the group consisting of alkyl, and -OH; Z 5 is N or CR O and Z 6 is N or CR P where Z 5 and Z 6 Only one of may be N, R O is H or -C 1-3 is alkyl, R P is H or -C 1-3is alkyl, R O and R P Only one of them is -C 1-3 may be alkyl, Or, R N and Z 5 are taken together to form a benzene ring or a 5- to 6-membered heteroarene ring, each ring optionally and independently containing a halogen, —OH, —NH, —NH—C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, formula 1d (shown below), C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, and -C 1-5 The alkyl group may be optionally substituted with a 5- to 6-membered heteroaryl or phenyl; [ka] During the ceremony, Y 2 is NR R or O, Y 1 is S(O) a or NR R and Each R R are independently H or C 1-4 is alkyl, Each R Q is C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and -C(O)C 1-3 independently selected from the group consisting of alkyl, a is 0 to 2; r is 0 to 3. 5. The bifunctional molecule of any one of clauses 1 to 4, wherein the BRD9 conjugate is of formula 1e, 1f, or 1g: [ka] where the wavy line crosses the bond between the BRD9 conjugate and the linker, and R A , R B , R C , R E , R M , R N , Z 3 , Z 5 and Z 6 is as defined in any one of clauses 1 to 4; R C’ does not exist or in any one of clauses 1 to 4, R C as defined for Ring 1A is optionally -C 1-3 an alkyl-substituted 5- to 7-membered heterocycloalkane; and Ring 1D is an optionally substituted C 6-10 arene or optionally substituted C 2-9 It is a heteroarene. 6. The bifunctional molecule of clause 5, wherein ring 1A contains one or two heteroatoms independently selected from the list consisting of N, S, and O. 7. The bifunctional molecule of clause 5, wherein ring 1A is selected from the list consisting of pyrrolidine, piperidine, piperazine, morpholine, oxolane, oxane, tetrahydrothiophene, and thiane. 8. The bifunctional molecule of any one of clauses 1-5, wherein the BRD9 conjugate has formula 1e, 1f', or 1g': [ka] It is of where the wavy line crosses the bond between the BRD9 conjugate and the linker, and R A , R B , R C , R E , R M , R N , Z 3 , Z5 and Z 6 is as defined in any one of clauses 1 to 4. 9. The bifunctional molecule of any one of clauses 1 to 8, wherein R A , R B , R C , R D and R E -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. 10. The bifunctional molecule of any one of clauses 1 to 9, wherein R A , R B , R D and R E At least two of the are -H. 11. The bifunctional molecule of any one of clauses 1 to 10, wherein R A , R B , R D and R E At least one of the 1-3 Alkyl, -H, halogen and -OC 1-3 haloalkyl. 12. The bifunctional molecule of any one of clauses 1 to 11, wherein R M Ha-C 1-5 It is alkyl. 13. The bifunctional molecule of any one of clauses 1 to 12, wherein R N -C 1-5 alkyl or halogen, or R N and Z 5 taken together form an optionally substituted 5- to 6-membered heteroarene or benzene ring. 14. The bifunctional molecule of clause 13, wherein the optionally substituted 5- to 6-membered heteroarene ring contains one or more heteroatoms selected from the group consisting of N, S, and O. 15. The bifunctional molecule of clause 13, wherein the optionally substituted 5- to 6-membered heteroarene ring is an N- or S-heteroarene. 16. The bifunctional molecule of clause 13, wherein the optionally substituted 5- to 6-membered heteroarene ring is any one selected from the optionally substituted group consisting of pyridine, pyrrole, imidazole, pyrimidine, thiophene, and pyrazole. 17. The bifunctional molecule of any one of clauses 1 to 16, wherein the BRD9 conjugate is any one of formulas 1ea to 1eh, 1fa to 1fi, and 1ga: [ka] wherein the wavy line crosses the bond between the BRD9 binder and the linker; R A , R B , R E , R M , Z 3 and Z 6 is as defined in any one of clauses 1 to 11; R C does not exist or is as defined in any one of clauses 1 to 11, R N is a halogen, -C 1-5 Alkyl, -C 1-3 Haloalkyl, -H, C(O)C 1-5 Alkyl, -NH2, -NHC 1-3 is selected from the group consisting of alkyl, and -OH; R O is H or -C 1-3 is alkyl, Each R X are halogens, -OH, -NH2, -NH-C 1-3 Alkyl, -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy and C 1-4 independently selected from the group consisting of haloalkoxy; n is 0 to 3, o is 0 to 2; p is 0 or 1; q is 0 to 4. 18. The bifunctional molecule of any one of clauses 1 to 17, wherein the BRD9 conjugate is 1ea': [ka] This is due to wherein the wavy line crosses the bond between the BRD9 binder and the linker; R A and R E -H and -OC 1-3 are each independently selected from alkyl, R B and R D -OC 1-3 Alkyl, -H, -halo, -C 1-3 Alkyl and -OC 1-3 haloalkyl; R C does not exist or -YR G and Y is -CR H R I - and -CO-, R H and R I are each independently -H or -C 1-3 alkyl, or R H and R I Together -C 3-4 forming a cycloalkyl, R G is -N(R J R K ) (e.g., -N(C 1-3 alkyl)-, -N(C 1-3 alkyl)(optionally substituted 4- to 7-membered monocyclic heterocycloalkylene), or —N(C 1-3alkyl)(optionally substituted 7- to 12-membered bicyclic heterocycloalkylene)), -O-, optionally substituted 4- to 7-membered monocyclic heterocycloalkylene, and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene; R J and R K is as defined in clause 1; R M is C 1-3 is alkyl, R N , R O and R P Ha, halo, -OC 1-3 Alkyl and -C 1-3 haloalkyl. 19. The bifunctional molecule of any one of clauses 1 to 18, wherein the BRD9 conjugate has the formula 1h to 1z and 2a to 2g: [ka] TIFF2025531881000251.tif142170 One of the following: In the formula, R C is not present or -YR G and Y is -CR H R I - and -CO-, R H and R I are -H or R, respectively H and R I Together -C 3-4 forming a cycloalkyl, R G is -N(R J R K ) (e.g., -N(C 1-3 alkyl)-, -N(C 1-3 alkyl)(optionally substituted 4- to 7-membered monocyclic heterocycloalkylene), or —N(C 1-3alkyl)(optionally substituted 7- to 12-membered bicyclic heterocycloalkylene)), -O-, optionally substituted 4- to 7-membered monocyclic heterocycloalkylene containing 1 or 2 N ring atoms, and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing 1 or 2 N ring atoms; R J and R K is as defined in clause 1; where the wavy line crosses the bond between the BRD9 binder and the linker. 20. The bifunctional molecule of any one of clauses 1 to 19, wherein R C exists, [ka] One of the following is selected from In the formula, Y is CR H R I (e.g. CH2), R G1 and R G2 are each independently selected from H or C1-C3 alkyl; R J is as defined in claim 1, L indicates the point of attachment of the linker. 21. The bifunctional molecule of any one of clauses 1 to 20, (i)R 1 and R 4 taken together to form a 5-, 6-, or 7-membered heterocyclic ring, Z is represented by formula (Ia): [ka] In the formula, A, B, R 3 and L is as defined for formula (I); n is 1, 2 or 3; W is CR W1 R W2 , O, N.R. W3and S, R W1 , R W2 and R W3 are each independently selected from H and C1-C6 alkyl, and when n is 2 or 3, each W is CR W1 R W2 , O, N.R. W3 and S are independently selected, (ii)R 1 and R 2 are taken together to form a 5-, 6-, or 7-membered heterocyclic ring, Z is represented by formula (Ib): [ka] In the formula, B, R 2’ , R 3 , R 4 and L is as defined for formula (I), m is 3, 4 or 5; Each T is a CR T1 R T2 , O, N.R. T3 and S are independently selected, R T1 , R T2 and R T3 are each independently selected from H or C1-C6 alkyl, or (iii)R 2 and R 4 are taken together to form a 5-, 6-, or 7-membered heterocyclic or carbocyclic ring, Z is represented by formula (Ic): [ka] In the formula, B, R 1 , R 2’ , R 3 and L is as defined for formula (I), p is 2, 3 or 4; Each U is a CR U1 R U2 , O, N.R. U3and S are independently selected, R U1 , R U2 and R U3 are each independently selected from H or C1-C6 alkyl. 22. The 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 with a heterocyclic group, aryl, and substituted aryl; Optionally, R 3 teeth, [ka] The dotted lines represent the respective R 3 indicates the position at which each of the R groups is attached to the structure shown in formulas (I)-(Ic), or, if the dotted line is not attached to an atom, the dotted line indicates the attachment of each R group to the structure shown in formulas (I)-(Ic) through any position on the aromatic or heteroaromatic ring. 3 indicates that each of the groups is attached to the structure via any position on the aromatic or heteroaromatic ring; Each R 5 are independently selected from the group consisting of halo, CF, -CHF, -CHF, -OCF, -OCHF, -OCHF, C-C alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SOMe, -NH, -NHMe, -NMe, COMe, -NO, CHO, and COMe; n is 0 to 3, R 6 is a C1-C6 alkyl; G is CH, O and NH; Q is a C1-C6 alkylene. 23. The bifunctional molecule according to any one of the preceding clauses, wherein A is CR 2 R 2’ and optionally, (i) R 2 and R 2’is hydrogen and the other is C1-C6 alkyl, optionally C1-C6 alkyl substituted with one or more halo atoms, or (ii) R 2 and R 2’ are both selected from C1-C6 alkyl. 24. The bifunctional molecule according to any one of the preceding clauses, wherein B is a phenyl group. 25. The bifunctional molecule according to any one of the preceding clauses, wherein Z is represented by formula (IIaa): [ka] In the formula, A, R 3 and L is as defined for formula (I); n is 1, 2, or 3; W is CR W1 R W2 , O, N.R. W3 and S, R W1 , R W2 and R W3 are each independently selected from H or C1-C6 alkyl; When n is 2 or 3, each W is a CR W1 R W2 , O, N.R. W3 and S. 26. The bifunctional molecule according to any one of the preceding clauses, wherein Z is represented by formula (IIa): [ka] In the formula, R 2 , R 2’ , R 3 and L is as defined in any one of the preceding clauses; n is 1, 2, or 3; W is CR W1 R W2 , O, N.R. W3 and S, R W1, R W2 and R W3 are each independently selected from H or C1-C6 alkyl; When n is 2 or 3, each W is a CR W1 R W2 , O, N.R. W3 and S. 27. The bifunctional molecule according to any one of the preceding clauses, wherein Z is represented by formula (IIb): [ka] In the formula, R 2’ , R 3 and L is as defined in any one of the preceding clauses; m is 3, 4 or 5; Each T is a CR T1 R T2 , O, N.R. T3 and S are independently selected, R T1 , R T2 and R T3 are each independently selected from H and C1-C6 alkyl; 28. The bifunctional molecule of any one of clauses 1 to 25, wherein Z is represented by formula (Ia) or (IIaa). 29. The bifunctional molecule of any one of clauses 1 to 20, wherein Z is (WZIa): [ka] is expressed as During the ceremony, 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-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 1-3Bridged, optionally substituted C 3-5 cycloalkyl or an optionally substituted 5- to 7-membered heterocycloalkyl (e.g., a 5- to 7-membered N-heterocycloalkyl), optionally including C 3-5 Cycloalkyl or 5- to 7-membered heterocycloalkyl is a spiro center in ring A. A Connected to R 2A is absent or is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NR y , —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R y is an optionally substituted C 1-6 alkyl or H, 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; X 1 is CH2, X 2 , X 3 and X 4 are each independently CH, O or NR x and R x is H or C1-C6 alkyl, or one R 1A group and one R x The group is bonded to an optionally substituted C 1-3 Forming a crosslink, n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; L indicates the point of attachment of the linker. 30. The bifunctional molecule of any one of clauses 1 to 20, wherein Z is a group represented by formula (WZII): [ka] is expressed as In the formula, R 2A does not exist or is as described in clause 1 or 29, R 3A is as set out in clause 1 or 29, X 5 is CR b 2. NR b , O, or a 5- to 7-membered heterocycloalkyl (e.g., a 5- to 7-membered heterocycloalkyl); Each R 1A are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 1-3 Bridged or optionally substituted C 3-5 Cycloalkyl (optionally C 3-5 The cycloalkyl forms a spiro center that connects to the heterocyclic ring shown in formula (WZII), R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 3; m is 0, 1 or 2; L indicates the point of attachment of the linker. 31. The bifunctional molecule of any one of clauses 1 to 20, wherein Z is represented by formula (WZIIa) to (WZIIe): [ka] During the ceremony, R2A is as set out in clause 1 or 29, R 3A is as set out in clause 1 or 29, Each R 1A are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, C1-C6 alkyl, and substituted C1-C6 alkyl, and / or two R 1A The group is bonded to an optionally substituted C 3-5 Cycloalkyl (optionally C 3-5 The cycloalkyl forms a spiro center that is connected to the heterocyclic ring of formula (ZIIa), X 5 is C(R b )2, NR b or O, R b is H or optionally substituted C 1-3 is alkyl, n1 is 0, 1, 2 or 3; n' is 1 or 2; m is 0, 1 or 2; L indicates the point of attachment of the linker. 32. The bifunctional molecule of any one of clauses 1 to 20, wherein Z is Formula (WII): [ka] is expressed as In the formula, R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R 3Ais selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 0, 1, 2 or 3; L indicates the point of attachment of the linker. 33. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIIa): [ka] is expressed as In the formula, R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)-, and —CH(substituted heteroaryl)-; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker. 34. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIIb): [ka] is expressed as In the formula, R 2Ais selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 1 or 2, L indicates the point of attachment of the linker. 35. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIIc): [ka] is expressed as In the formula, R 2A is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; X 1 is CH2, X 2 and X 3 are each independently CH2 or O, provided that X 2 and X 3 provided that none or only one of is O, n is 1 or 2, L indicates the point of attachment of the linker. 36. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIId): [ka] is expressed as In the formula, R 2A is selected from heterocycloalkyl and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; n is 1 or 2, L indicates the point of attachment of the linker. 37. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIIe): [ka] is expressed as In the formula, R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; n is 1 or 2, L indicates the point of attachment of the linker. 38. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by the formula (WIIf): [ka] is expressed as In the formula, R 2A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; R 3Ais selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker. 39. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIII): [ka] is expressed as In the formula, R 1A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker. 40. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIIIa): [ka] is expressed as In the formula, R 1A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker. 41. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is (WIIIb): [ka] is expressed as In the formula, R 1A is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, and C1-C6 alkyl; R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; L indicates the point of attachment of the linker. 42. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIV): [ka] is expressed as In the formula, R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; R 4A is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; n is 0, 1, 2 or 3; L indicates the point of attachment of the linker. 43. The bifunctional molecule of any one of clauses 1 to 19, wherein Z is a group represented by formula (WIVa): [ka] is expressed as In the formula, R 3A is selected from C1-C6 alkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl, optionally wherein the C1-C6 alkyl is substituted with a heterocycloalkyl group; R 4A is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; L indicates the point of attachment of the linker. 44. The bifunctional molecule of any one of the preceding clauses, wherein n is 1 or 2. 45. The bifunctional molecule of any one of clauses 35 to 37, wherein R 1A teeth, (i) selected from the group consisting of phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, and heteroaryl having 5 to 6 ring atoms and containing 1 to 3 heteroatoms each independently selected from N, O, and S, optionally substituted with 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, and C3-C8 cycloalkyl; or (ii) is selected from the group consisting of phenyl, substituted phenyl, pyrazolyl, and substituted pyrazolyl. 46. ​​The bifunctional molecule of any one of clauses 35 to 37, wherein R 1A is C3-C7 cycloalkyl or C1-C3 alkyl. 47. The bifunctional molecule of any one of clauses 35 to 37, wherein R 1A has the following structure: [ka] is selected from one of the following. 48. The bifunctional molecule of any one of clauses 28 to 34, wherein R 2A teeth, (i) selected from H, phenyl optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy, and heteroaryl having 5 to 6 ring atoms and containing 1 or 2 N atoms, optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; (ii) optionally substituted phenyl and optionally substituted pyrazolyl; or (iii) a structure: [ka] is selected from one of the following: In the formula, R 6 is selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy. 49. The bifunctional molecule of any one of clauses 28 to 34, wherein R 2A teeth, (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; (ii) optionally substituted piperidinyl and optionally substituted piperazinyl; or (iii) a structure: [ka] is selected from one of the following: In the formula, R 6 is selected from H, C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy. 50. The bifunctional molecule of any one of clauses 28 to 45, wherein R 3A teeth, (i) selected from C1-C6 alkyl optionally 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, an aryl having 6 to 10 carbon ring atoms, and a 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 with 1 or 2 substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; or (ii) selected from optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, tert-butyl, C1-C6 alkyl containing a morpholino substituent, optionally substituted benzothiazolyl, and optionally substituted pyridinyl. 51. The bifunctional molecule of any one of clauses 28 to 45, wherein R 3A has the following structure: [ka] is selected from one of the following: R 5A is absent or selected from halo (e.g., F, Cl, Br, I), CF, —CHF, —CHF, OCF, —OCHF, —OCHF, C-C alkyl, —CN, —OH, —OMe, —SMe, —SOMe, —SOMe, —NH, —NHMe, —NMe, COMe, —NO, CHO, and COMe. 52. The bifunctional molecule of any one of clauses 28 to 45, wherein R 3A has the following structure: [ka] is selected from one of the following. 53. The bifunctional molecule of any one of clauses 38-40 and 46-48, wherein R4A teeth, (i) 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 heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; or (ii) optionally substituted phenyl. 54. The bifunctional molecule of clause 1, wherein Z has the following structure: [ka] TIFF2025531881000281.tif231170TIFF2025531881000282.tif245170TIFF2025531881000283.tif78170 wherein R in each of the above structures 3A teeth, [ka] It contains one of the following structures: 55. A bifunctional molecule according to any one of the preceding clauses, wherein the linker comprises 1 to 25 or 1 to 18 atoms in a single linear chain. 56. The bifunctional molecule according to any one of the preceding clauses, wherein the linker comprises 1 to 10 or 1 to 8 rotatable bonds. 57. A 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: (L x ) q where each Lx is a CR L1 R L2 , O, C=O, S, SO, SO2, NR L3 ,SONR L4 ,SONR L5 C=O, CONRL6 , N.R. L7 CO, C(R L8 )=C(R L9 ), C≡C, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl groups; 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-C6 alkyl, C1-C6 haloalkyl, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NO2, -CN, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -SO2(C1-C6 alkyl), -CO2(C1-C6 alkyl), and -CO(C1-C6 alkyl); q is an integer of 1 to 30. 58. The bifunctional molecule according to any one of the preceding clauses, wherein the bifunctional molecule comprises: [ka] not, or [ka] not, or BRD9 conjugates are [ka] not, or [ka] where the wavy line crosses the bond between the BRD9 binder and the linker. 59. A bifunctional molecule according to clause 1, (i) Z is represented by formula (I), (Ia), (Ib), (Ic), (IIaa), (IIa) or (IIb) as defined above; (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above. 60. A bifunctional molecule according to clause 1, (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above. 61. A bifunctional molecule according to clause 1, (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; (ii) TBL is represented by formula (1h), (1i) or (1j) as defined above. 62. A bifunctional molecule according to clause 1, (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; (ii) TBL is represented by formula 1a″ as defined above, (iii) L is represented by formula L1a or L1b. 63. A bifunctional molecule according to clause 1, (i) Z is represented by formula (Ia), (IIaa) or (IIa) as defined above; (ii) TBL is represented by any one of formulas 1e'', 1g'', 1g''', 1ea''-1eh'', 1ea'', 1h''-1z'', and 2a''-2g'', as defined above; (iii) L is represented by formula L1a or L1b as defined above. 64. A bifunctional molecule according to clause 1, (i) Z is represented by formula (Ib) or (IIb) as defined above; (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above. 65. A bifunctional molecule according to clause 1, (i) Z is represented by formula (Ib) or (IIb) as defined above; (ii) TBL is represented by formula (1h), (1i) or (1j) as defined above. 66. A bifunctional molecule according to clause 1, (i) Z is represented by formula (WI), (WII), (WIIa), (WIIb), (WIIc), (WIId), (WIIe), (WIIf), (WIII), (WIIIa), (WIIIb), (WIV) or (WIVa) as defined above; (ii) TBL is represented by formula (1e), (1f) or (1f') as defined above. 67. A bifunctional molecule according to clause 1, (i) Z is represented by any one of formulas (WZI), (WZII), (WZIIa) to (WZIIe), (WZIIIa) to (WZIIIh), or (WZIVa) to (WZIVj) as defined herein; (ii) TBL is represented by formula 1a″ as defined herein; (iii) L is represented by formula L1c as defined herein. 68. A bifunctional molecule according to clause 1, (i) Z is represented by any one of formulas (WZI), (WZII), (WZIIa) to (WZIIe), (WZIIIa) to (WZIIIh), or (WZIVa) to (WZIVj) as defined herein; (ii) TBL is represented by any one of formulas 1e'', 1g'', 1g''', 1ea''-1eh'', 1ea'', 1h''-1z'', and 2a''-2g'', as defined herein; (iii) L is represented by formula L1c as defined herein. 69. A bifunctional molecule according to clause 1, (i) Z is represented by formula (WI), (WII), (WIIa), (WIIb), (WIIc), (WIId), (WIIe), (WIIf), (WIII), (WIIIa), (WIIIb), (WIV) or (WIVa) as defined above; Z is [ka] Instead, (ii) TBL is a target protein-binding ligand that binds to BRD9, and TBL is [ka] isn't it. 70. The bifunctional molecule of any one of the preceding clauses, wherein the bifunctional molecule has a structure as shown in Table 1. 71. A pharmaceutical composition comprising a bifunctional molecule according to any one of the preceding clauses together with a pharmaceutically acceptable carrier, optionally wherein the bifunctional molecule is present in the composition as a pharmaceutically acceptable salt, solvate, or derivative. 72. A bifunctional molecule according to any one of clauses 1 to 70, or a pharmaceutical composition according to clause 71, for use in medicine. 73. A bifunctional molecule or pharmaceutical composition for use according to clause 72, the use comprising the treatment and / or prevention of any disease or condition associated with and / or caused by an abnormal level of BRD9 activity. 74. A bifunctional molecule or pharmaceutical composition for use according to clause 72 or 73, wherein the disease or condition is cancer. 75. A method for treating and / or preventing any disease or condition associated with and / or caused by an abnormal level 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 of clause 71. 76. The method of clause 75, wherein the disease or condition is cancer. 77. A method for selectively degrading and / or increasing proteolysis of BRD9 in a cell, the method comprising contacting and / or treating a cell with a bifunctional molecule as defined in any one of clauses 1 to 70 or a pharmaceutical composition as defined in clause 71. 78. Use of a bifunctional molecule as defined in any one of clauses 1 to 70 in a method for targeted BRD9 degradation. 79. A method for producing a bifunctional molecule as defined in any one of clauses 1 to 70. 80. A method for screening a bifunctional molecule according to any one of clauses 1 to 70, comprising: a. (i) a first ligand comprising a structure according to Z as defined in any one of clauses 1 and 21 to 54; (ii) a second ligand that binds to BRD9 as defined in any one of clauses 1 to 20; and (iii) a linker covalently linking the first and second ligands as defined in any one of clauses 1 and 55-57; b. contacting the cell with a bifunctional molecule; c. Detecting degradation of BRD9 in cells; d. Detecting degradation of BRD9 in the cell in the absence of the bifunctional molecule; e. comparing the level of BRD9 degradation in the cells contacted with the bifunctional molecule with the level of BRD9 degradation in the absence of the bifunctional molecule; an increase in the level of BRD9 degradation in cells contacted with the bifunctional molecule indicates that the bifunctional molecule promotes and / or facilitates the degradation of BRD9; Optionally, detecting degradation of BRD9 includes detecting a change in the level of a target protein in the cell. 81. A compound library comprising a plurality of bifunctional molecules according to any one of clauses 1 to 70. 82. A kit of parts, (i) a first ligand comprising a structure according to Z as defined in any one of clauses 1 and 21 to 54; (ii) a second ligand that binds to BRD9 as defined in any one of clauses 1 to 20; and (iii) a linker covalently linking the first and second ligands as defined in any one of clauses 1 and 55-57.

[0430] definition In this disclosure, reference will be made to a number of terms that will be understood to have the meanings set forth below, unless the context indicates otherwise. The nomenclature used to define compounds, particularly those described herein, is intended to conform to the rules of the International Union of Pure and Applied Chemistry (IUPAC), particularly the "IUPAC Compendium of Chemical Terminology (Gold Book)" (see AD Jenkins et al., Pure & Appl. Chem., 68, 2287-2311 (1996)). For the avoidance of doubt, in the event that an IUPAC rule contradicts a definition set forth herein, the definition set forth herein shall prevail.

[0431] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group. The chain may be saturated or unsaturated, e.g., in some cases the chain may contain one or more double or triple bonds.

[0432] As used herein, "C1-C n"Alkyl" may be selected from straight or branched chain hydrocarbyl groups containing 1 to n carbon atoms. For example, "C1-C6 alkyl" may be selected from straight or branched chain hydrocarbyl groups containing 1 to 6 carbon atoms, and C1-C3 alkyl may be selected from straight or branched chain hydrocarbyl groups containing 1 to 3 carbon atoms. Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, neohexyl, and the like. When a C1-C6 alkyl group is substituted, any hydrogen atom(s), CH3, CH2, or CH group(s) may be replaced with substituent(s), provided valences are satisfied. When a C1-6 alkyl group includes a divalent hydrocarbon radical (containing 1 to 6 carbon atoms), the moiety is sometimes referred to herein as a C1-C6 alkylene.

[0433] The term "cycloalkyl" defines any monovalent group derived from a cycloalkane by removing one hydrogen atom from a ring carbon atom. The term "cycloalkane" refers to a group having the general formula C n H 2n where n is an integer of 3 or greater. As used herein, "cycloalkyl" generally refers to a ring containing 3 to 10 carbon atoms, optionally 3 to 8, or optionally 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 or triple bonds. As used herein, C n ~C n’ Cycloalkyl is a cycloalkyl containing n to n' carbon atoms in the ring, where n and n' are integers.

[0434] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic ring having at least one heteroatom selected from O, N, and S (e.g., 1 to 5 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 contain one or more double bonds, as long as they are not fully aromatized. One or more rings of a heterocycloalkyl may contain 3 to 10 atoms, and in some cases, 3 to 8 atoms. One or more rings may be aliphatic. One or more rings may be saturated or unsaturated; for example, in some cases, one or more rings may contain one or more double or triple bonds. Any N heteroatom present in a heterocycloalkyl group may be replaced with a C1-C6 alkyl. In some cases, a heterocycloalkyl is a monocyclic or bicyclic ring, and in some cases, a monocyclic ring. C n ~C n’ Heterocycloalkyl is a heterocycloalkyl containing n to n' carbon atoms in the ring, where 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, diazaspirondecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, and the like. As used herein, "substituted heterocycloalkyl" refers to a heterocycloalkyl group, as defined herein, containing one or more substituents on the heterocycloalkyl ring.

[0435] The term "heterocyclyl" refers to a monovalent radical derived from a heterocycle, which is a cyclic compound (a compound containing one or more rings of linked atoms) having at least two different elements (e.g., carbon and nitrogen) as ring members.

[0436] As used herein, a "halo" group can be F, Cl, Br, or I, typically F.

[0437] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced with a halo atom (such as fluoro, chloro, or bromo, often fluoro). By way of example, a C1-C6 haloalkyl refers to an alkyl group containing 1 to 6 carbon atoms in which at least one hydrogen atom is replaced with a halo atom. Trifluoromethyl and 1,1-difluoroethyl are examples of haloalkyl.

[0438] 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, and the term "alkene" has the general formula CH 2n where n is an integer of 2 or greater. Examples of alkenyl groups include ethenyl, n-propylenyl, isopropylenyl, n-butylenyl, sec-butylenyl, isobutylenyl, and tert-butylenyl. When an alkenyl group is substituted, any hydrogen atom(s) can be replaced by a substituent(s), provided that valence is satisfied. When alkenyl includes a divalent hydrocarbon group, the moiety is sometimes referred to herein as alkenylene.

[0439] The term "alkynyl" is well recognized in the art and defines a monovalent group derived from an alkyne by removing a hydrogen atom from any carbon atom, and the term "alkyne" has the general formula CH 2n-2where n is an integer of 2 or greater. Examples of alkynyl groups include ethynyl, n-propylinyl, isopropylinyl, n-butylinyl, sec-butylinyl, isobutylinyl, and tert-butylinyl. When an alkynyl group is substituted, any hydrogen atom(s) can be replaced by a substituent(s), provided that valence is satisfied. When alkynyl includes a divalent hydrocarbon group, the moiety is sometimes referred to herein as alkynylene.

[0440] As used herein, "benzyl" refers to the group -CHPh. As used herein, "substituted benzyl" refers to a benzyl group, as defined herein, bearing one or more substituents on the CH and / or aromatic ring. When a benzyl group is substituted, any hydrogen atom(s) may be replaced with a substituent(s), provided that valences are satisfied.

[0441] As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon system having 6 to 14 carbon atoms, and 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, containing one or more substituents on the aromatic ring. When an aryl group is substituted, any hydrogen atom(s) may be replaced with a substituent(s), provided that valences are satisfied.

[0442] As used herein, "heteroaryl" may be a single ring system or a fused ring system having one or more aromatic rings, optionally containing 1 to 3, optionally 1 to 2, and optionally a single, O, N, and / or S heteroatom(s). The term "heteroaryl" may refer to a monocyclic or polycyclic heteroaromatic system having 5 to 10 ring atoms. n ~Cn’ Heteroaryl is a heteroaryl containing n to n' carbon atoms in the ring, where n and n' are integers. Representative examples of heteroaryl groups may include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, and the like. As used herein, "substituted heteroaryl" refers to a heteroaryl group as defined herein containing one or more substituents on the heteroaromatic ring.

[0443] As used herein, a "carbocyclic ring" is a ring containing 3 to 10 carbon atoms, and optionally 3 to 8 carbon atoms, or 5 to 6 carbon atoms. The ring may be aliphatic. Thus, as used herein, references to "carbocyclyl" and "substituted carbocyclyl" groups may refer to aliphatic carbocyclyl groups and aliphatic substituted carbocyclyl groups. The ring may be saturated or unsaturated; for example, the ring may optionally contain one or more double or triple bonds. C n ~C n’ A carbocyclic ring is a carbocyclic ring containing n to n' carbon atoms in the ring, where n and n' are integers. Representative examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctyne, and the like. As used herein, "substituted carbocyclyl" refers to a carbocyclyl group, as defined herein, containing one or more substituents on the carbocyclic ring. When a carbocyclyl group is substituted, any hydrogen atom(s) may be replaced with a substituent(s), provided that valences are satisfied.

[0444] As used herein, a "heterocyclic ring" (or heterocyclic) can contain at least one heteroatom selected from O, N, and S. A heterocyclic ring can be monocyclic or polycyclic, with each ring containing 3 to 10 atoms, and in some cases 3 to 8 atoms. One or more rings can be aliphatic. Thus, as used herein, references to "heterocyclyl" and "substituted heterocyclyl" groups can refer to aliphatic heterocyclyl groups and aliphatic-substituted heterocyclyl groups. One or more rings can be saturated or unsaturated; for example, in some cases, one or more rings can contain one or more double or triple bonds. C n ~C n’ A heterocyclic ring is a heterocyclic ring containing n to n' carbon atoms in the ring, where n and n' are integers. Any N heteroatom present in the heterocyclic group may be substituted with a C1-C6 alkyl. In some cases, the heterocyclyl is monocyclic or bicyclic, e.g., monocyclic. In other examples, the heterocyclyl may be a bicyclic ring, or may be an optionally fused ring. Representative examples of heterocyclyl 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, diazaspirondecane, diazaspiroheptane, azaspiroheptane, diazaspirodecane, octahydropyrrolopyrrole, pyrrolididinyl, thiophenyl, etc. As used herein, "substituted heterocyclyl" refers to a heterocyclyl group, as defined herein, containing one or more substituents on the heterocyclic ring.

[0445] As used herein, the term "optionally substituted" means that the moiety may include one or more substituents.

[0446] As used herein, "substituents" include hydroxy, thiol, carboxyl, cyano (CN), nitro (NO), halo, haloalkyl (e.g., C1-C6 haloalkyl or C1-C4 haloalkyl), alkyl group (e.g., C1-C 10 or C1-C6, which may themselves be unsubstituted or substituted, for example, with one or more selected from the group consisting of aryl, halo, and hydroxy), alkenyl groups (for example, C2-C6), alkynyl groups (for example, C2-C6), aryl (for example, phenyl and substituted phenyl, for example, benzyl or benzoyl), morpholino, NC 1-6 alkylenylmorpholine, alkoxy groups (e.g., C1-C6 alkoxy or C1-C4 alkoxy), haloalkoxy (e.g., C1-C4 haloalkoxy), aryloxy (e.g., phenoxy and substituted phenoxy), hydroxyalkynyl (e.g., C2-C6), thioether (e.g., C1-C6 alkyl or aryl thioether), alkylthio (e.g., C1-C6 alkylthio), cyanoalkyl (e.g., C1-C6), oxo, keto (e.g., C1-C6 keto), ester (e.g., C1-C6 alkyl or aryl ester which may be present on a substituent moiety as an oxyester or carbonyl ester), thioester (e.g., C1-C6 alkyl or aryl ester which may be present on a substituent moiety as an oxyester or carbonyl ester), For example, C1-C6 alkyl or aryl thioesters), alkylene esters (where the attachment is on the alkylene group rather than the ester functionality which is optionally substituted with a C1-C6 alkyl or aryl group), amines (including monoalkylamino, dialkylamino, 5- or 6-membered cyclic alkyleneamines optionally substituted with one or more halo, further including C1-C6 alkylamines or C1-C6 dialkylamines where the alkyl group may be substituted with one or two hydroxy groups, also including alkylphenylamino or alkylphenyl(alkyl)amino groups), amides (-C(O)NH, -C(O)NH(alkyl), e.g., -C(O)NH(C 1-4 alkyl), -C(O)N(alkyl), for example -C(O)N(C 1-3 alkyl)2, -NHC(O)alkyl, e.g., -NHC(O)C 1-4Alkyl, -NHC(O)(phenyl), -N(alkyl)C(O)(alkyl), e.g., -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -N(alkyl)C(O)(phenyl), e.g., -N(C 1-4 alkyl)C(O)(phenyl), NC 1-6 alkylenylamino, etc.), amide (e.g., optionally substituted with one or two C1-C6 alkyl groups (including carboxamide optionally substituted with one or two C1-C6 alkyl groups), aminoalkyl (e.g., C1-C4 aminoalkyl), alkanol (e.g., C1-C6 alkyl, C1-C4 alkyl, or arylalkanol), or carboxylic acid (e.g., C1-C6 alkyl or arylcarboxylic acid), sulfoxide, sulfone, sulfinimide, sulfonamide, and urethane (e.g., —OC(O)—NR2 or —N(R)—C(O)—OR, where each R in this context is independently selected from C1-C6 alkyl or aryl), heteroaryl (which itself may be, for example, a halogen, —OH, —NH2, —NH—C 1-3 Alkyl and -C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-4 Haloalkoxy, 1d (defined above), C 3-5 Azacycloalkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 cycloalkyl, and -C 1-5 The alkyl group may be a 5- to 6-membered heteroaryl or phenyl, which may be optionally substituted, heterocyclyl, arylalkyl (aryl C 1-4 alkyl, heteroaryl alkyl (heteroaryl C 1-4 alkyl, etc.), -OC 1-4 Alkylphenyl, -C(O) alkyl (-C(O)(C 1-4 alkyl), -C(O) alkylphenyl (C(O)(C 1-4 alkylphenyl), -C(O)haloalkyl (-C(O)(C 1-4haloalkyl), -SO2(alkyl) (-SO2(C 1-4 alkyl), -SO2(phenyl), -SO2 haloalkyl (OSO2(C 1-4 haloalkyl), -SO2NH2, -SO2NH(alkyl) (-SO2NH(C 1-4 alkyl), -SO2NH(phenyl), -NHSO2(alkyl) (-NHSO2(C 1-4 alkyl), -NHSO2(phenyl), -NHSO2(haloalkyl) (-NHSO2(C 1-4 haloalkyl), -SC 1-3 Haloalkyl, -CHC(O)N(R C )2, -C 3-4 Alkynyl (NR C )2, deuterated C 2-4 Alkynyl, (C 1-3 Alkoxy) Halo C 1-3 Alkyl-, C 3-6 Cycloalkyl (C 3-6 Cycloalkyl is halo or C 1-3 (optionally substituted with alkyl), azido, sulfonyl, HC(O)-, -COR C , or -CO2N(R C )2(R C is hydrogen or C 1-3 alkyl).

[0447] As used herein, the term "analog" refers to a compound or moiety that is structurally similar to a specified compound or moiety. Despite the similar structure, an analog may exhibit different chemical and / or biological properties. An analog may have about 90% similarity to a specified compound or moiety, i.e., an analog may share about 90% of its structure with a specified compound or moiety. In some examples, an analog may have about 92%, 94%, 96%, or 98% similarity to a specified compound or moiety.

[0448] As used herein, when a group containing carbon atoms is defined as "saturated," only single bonds connect the carbon atoms to one another. When a group containing carbon atoms is defined as "unsaturated," at least two carbon atoms are joined by double or triple bonds. For the avoidance of doubt, unsaturated compounds may contain any number of double and / or triple bonds.

[0449] The term "spiro" is used to refer to a moiety containing two or more ring systems, at least two of which are linked by only one atom (typically a quaternary carbon atom).

[0450] As used herein, "monocyclic" refers to a moiety containing one ring of atoms. As used herein, "bicyclic" is used to refer to a moiety characterized by two linked rings of atoms. As used herein, "tricyclic" refers to a moiety characterized by three linked rings of atoms. As used herein, "polycyclic" refers to a moiety containing two or more linked rings of atoms. Unless the context indicates otherwise, bicyclic and polycyclic systems may include fused ring systems (at least two rings share a covalent bond). In other examples, two or more rings may be joined by a bond between each atom of the two or more rings. In other examples, bicyclic systems may include a spiro center (see definition above).

[0451] As used herein, the term "bridged" refers to a cyclic moiety or ring that includes two bridgehead atoms (usually two carbon atoms of a cyclic compound or ring) that are connected by one or more atoms located outside the ring (such as 1 to 3 atoms located outside the ring). A bridged ring includes two rings that share three or more atoms. In some embodiments, the bridgehead atoms are separated by at least one carbon atom within the ring. In some embodiments, rings may be bridged by between 1 and 3 bridging atoms located outside the ring to form a bridging group (optionally, the bridging atoms are selected from C, N, O, and S). As used herein, "C" refers to a cyclic moiety or ring that includes two bridgehead atoms (usually two carbon atoms of a cyclic compound or ring) that are connected by one or more atoms located outside the ring (such as 1 to 3 atoms located outside the ring). 1-3A "bridge" is a bridging group containing 1 to 3 carbon bridging atoms. The bridging group may contain 1 to 3 atoms located outside the ring, of which 1, 2, or 3 are carbon. In some cases, the bridging group may further contain atoms other than carbon (e.g., heteroatoms selected from N, O, and S). By way of example, as used herein, "C 1-3 "Bridge" refers to a bridging group containing 1 to 3 atoms, of which 1, 2, or 3 are carbon, and the remaining atoms (if present) are selected from N, O, and S. The bridging group may be a C1-C3 alkylene (e.g., methylene, ethylene, propylene). A C1-C3 alkylene bridging group may be optionally substituted with any suitable substituent described herein. For example, a C1-C3 alkylene bridging group may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0452] The term "fused" is used to refer to moieties containing two or more ring systems, at least two of which are joined by a [1,2] ring junction, i.e., moieties containing two or more ring systems, where two or more of the rings present share a bond in each ring structure.

[0453] The term "aliphatic" refers to acyclic or cyclic, saturated or unsaturated moieties, excluding aromatic moieties, and "aromatic" defines a cyclic conjugated molecular entity whose stability (due to delocalization) is significantly greater than that of a hypothetical localized structure. Hückel's rule is often used to assess aromaticity and describes a monocyclic planar (or nearly planar) system of tri- (or sometimes bi-) hybridized atoms containing (4n + 2) π electrons, where n is an integer greater than or equal to 0. This rule is usually limited to n = 0 to 5.

[0454] The term "hydrocarbyl" refers to a monovalent radical derived from a hydrocarbon by removing a hydrogen atom. A hydrocarbon is any molecule containing only the elements carbon and hydrogen. Hydrocarbons may be aliphatic, aromatic, unsaturated, or saturated.

[0455] As used herein, alkoxy refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group (-O-). As used herein, C1-C6 alkoxy refers to a C1-C6 alkyl group (defined above) appended to the parent molecular moiety through an oxy group -O-, and C1-C4 alkoxy refers to a C1-C4 alkyl group (defined above) appended to the parent molecular moiety through an oxy group -O-. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0456] The term "alkoxyalkyl" is used herein to refer to a moiety derived from an alkyl moiety in which a hydrogen atom at any position of the alkyl moiety is replaced with an alkoxy moiety. Examples of alkoxyalkyl groups include methoxyethyl, methoxypropyl, ethoxymethyl, and the like.

[0457] As used herein, the term "alkylamino" refers to a moiety derived from an amino (NH) moiety in which one or both hydrogen atoms of the amino are replaced by one or two alkyl moieties. Examples of alkylamino groups include dimethylamino, diethylamino, and the like.

[0458] The term "alkylaminoalkyl" is used herein to refer to a moiety derived from an alkyl moiety in which a hydrogen atom at any position of the alkyl is replaced with an alkylamino moiety. Examples of alkylaminoalkyl groups include dimethylaminomethyl, dimethylaminoethyl, and the like.

[0459] As used herein, the term "alkoxyalkylene" refers to a moiety derived from an alkylene moiety in which a hydrogen atom at any position of the alkylene is replaced with an alkoxy moiety. Examples of alkoxyalkylene groups include methoxyethylene, methoxymethylene, and the like.

[0460] As used herein, the term "haloalkylene" refers to a moiety derived from an alkylene moiety in which one or more hydrogen atom(s) at any position(s) of the alkylene has been replaced with one or more halo groups. Examples of haloalkylene groups include fluoroethylene, difluoromethoxymethylene, dichloroethylene, and the like.

[0461] As used herein, the term "hydroxyalkylene" refers to a moiety derived from an alkylene moiety in which a hydrogen atom at any position of the alkylene is replaced with a hydroxy moiety. Examples of hydroxyalkylene groups include hydroxyethylene, hydroxymethylene, and the like.

[0462] In some embodiments, unless otherwise indicated by context, "substituents" include, but are not limited to, halo, C-C alkyl, NH, NH(C-C alkyl), N(C-C alkyl)OH, O(C-C alkyl), NO, CN, C-C haloalkyl, CONH, CONH(C-C alkyl), CON(C-C alkyl), C(O)OC-C alkyl, CO(C-C alkyl), S(C-C alkyl), S(O)(OC-C alkyl), and SO(C-C alkyl).

[0463] As used herein, an electron-withdrawing group may refer to any group that attracts electron density from adjacent atoms and toward itself. Typically, an electron-withdrawing group attracts electron density from adjacent atoms and toward itself more strongly than a hydrogen substituent. Representative examples of suitable electron-withdrawing groups include, but are not limited to, -CN, halo, -NO, -CONH, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl), -SO(C1-C6 alkyl), -CO(C1-C6 alkyl), -CO(C1-C6 alkyl), and C1-C6 haloalkyl.

[0464] It should be understood that throughout this specification, the terms "comprise," "comprising," and / or "comprises" are used to indicate that aspects, embodiments, and examples of the present disclosure "comprise" specified feature(s). It should be understood that this / these terms can also encompass aspects, embodiments, and / or examples that "consist essentially of" or "consist of" the relevant feature(s). DETAILED DESCRIPTION OF THE INVENTION

[0465] The invention will now be described in detail with reference to the following non-limiting examples. List of abbreviations: μL = microliter μM = micromolar NMR=nuclear magnetic resonance ACN = acetonitrile AcOH or HOAc = acetic acid BINAP = (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) Boc = tert-butoxycarbonyl bs = broad singlet ℃ = degrees Celsius d = doublet δ = chemical shift DCM = dichloromethane dba = dibenzylideneacetone DIPEA = N,N-diisopropylethylamine or Hunig's base DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide dppf = 1,1'-ferrocenediyl-bis(diphenylphosphine) EtOAc = ethyl acetate g or G = grams h or H = hour(s) HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC = High-Performance Liquid Chromatography Hz = Hertz J = coupling constant (expressed in Hz unless otherwise specified) LCMS = Liquid Chromatography Mass Spectrometry m=multiplet M = moles M+H + = H in the parent peak of the mass spectrum + plus mg = milligram min=minutes mL = milliliters mM = millimolar mmol = millimolar MS = mass spectrum MsCl = methanesulfonyl chloride MTBE = methyl tert-butyl ether nM = nanomolar NMP = N-methyl-2-pyrrolidone pTsOH = p-toluenesulfonic acid q=Quartet RT or rt = room temperature STAB = sodium triacetoxyborohydride t = triplet TBAF = tetra-n-butylammonium fluoride TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0466] Chemistry - Materials and Methods Unless otherwise stated, all chemicals were commercially available and used without further purification, solvents were anhydrous, and reactions were carried out under a positive pressure of nitrogen or argon.

[0467] Flash column chromatography (FCC) was performed using a Teledyne Isco Combiflash Rf or Rf200i. Prepacked RediSep Rf normal phase disposable columns were used.

[0468] NMR data were acquired on a Bruker Avance Neo Nano Bay 400 MHz NMR spectrometer. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or other solvents as specified in the NMR spectral data. A small amount (1–5 mg) of sample was dissolved in an appropriate deuterated solvent (0.6 ml).

[0469] Preparative HPLC was performed on a Gilson preparative HPLC system equipped with a Waters X-Bridge C18 column (100 mm × 19 mm; 5 μm particle size) and a gradient of 5% to 95% acetonitrile in water for 10 min at a flow rate of 25 mL / min with 0.1% formic acid in the aqueous phase.

[0470] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent InfinityLab Single Quadrupole LC / MSD equipped with a Waters XBridge® C18 3.5 μm column (2.1 mm × 50 mm) using a 3-minute linear gradient of HO + MeCN (5–95%) + 0.1% HCOH or HO + MeCN (20–95%) + 0.1% HCOH as eluent, followed by positive ion electrospray ionization (ESI). +Alternatively, a Shimadzu LC: Prominence-I series instrument was used with the following settings:

number

number

[0471] Part A - Synthesis Method Below are provided examples of various synthetic methods and general procedure outlines that may be used to provide compounds of the present disclosure.

[0472] Reductive Amination - General Procedure 1 [ka] A solution of amine (I) (1 equiv.) and aldehyde (II) (1 equiv.) in DCM (0.05 M) was treated with EtN (1.5 equiv.). The reaction mixture was stirred for 1 h and then treated with NaBH(OAc) (2.0 equiv.) or MP-CNBH (5.0 equiv.) (or alternative reducing agent as described in the procedure). The reaction mixture was stirred at room temperature until the reaction was complete by LCMS. The reaction was quenched by the addition of H2O and extracted with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. Purification by silica gel column chromatography afforded the desired product.

[0473] Reductive Amination - General Procedure 14 [ka] A solution of amine (I) (1 equivalent) and aldehyde (II) (1 equivalent) in a solvent (see below, 0.05 M) was treated with either: a) Acetic acid (catalytic amount), solvent = MeOH (Procedure 14) b) Sodium acetate (2 equiv.), solvent = DCM:MeOH (1:1) (Procedure 14a) c) Sodium acetate (2 equivalents) and acetic acid (catalytic amount), solvent = DCM:MeOH (Procedure 14b = 30)

[0474] The reaction mixture was stirred for 1 h and then treated with NaBH(OAc) (2.0 equiv.) or MP-CNBH (w / w) (or alternative reducing agent as described in the procedure). The reaction mixture was heated at 70 °C overnight. Completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated in vacuo, quenched by the addition of H O, and extracted with DCM. The combined organic layers were washed with water and brine, dried over MgSO, and concentrated in vacuo. Purification by silica gel column chromatography afforded the desired product.

[0475] Boc Deprotection - General Procedure 2 [ka] A solution of Boc-protected amine (I) (1.0 equiv.) in DCM (Procedure 2) or 1,4-dioxane (Procedure 2a) (0.05 M) was treated with HCl (4 M in dioxane, 50 equiv.), and the mixture was stirred for 2 h. Volatiles were evaporated in vacuo to give the corresponding amine hydrochloride (II).

[0476] Acetylation Boc Deprotection - General Procedure 13 [ka] A solution of Boc-protected amine (I) (1.0 equiv.) in DCM (5 mL) was added with TFA (2 equiv.) at 0° C. and stirred at room temperature for 3 h. The reaction was monitored by TLC, and upon completion, the reaction mixture was concentrated under reduced pressure. The crude material was purified by medium-pressure liquid chromatography to give the corresponding amine trifluoroacetate (II).

[0477] Amine Acylation - General Procedure 3 [ka] of amine (I) (1.0 equivalent), a) A suspension in 1,4-dioxane (0.05 M) was treated with EtN (3 equiv.) (Procedure 3) or DIPEA (3 equiv.) (Procedure 3a), or b) A suspension in MeCN (0.05 M) was treated with EtN (3 equiv.) (step 3b), 3-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile (1.1 equiv.) was added and the mixture was heated to 80° C. (Procedure 3 / 3a) or 55° C. (Procedure 3b) for 16 h. The volatiles were concentrated in vacuo and purified by flash chromatography to give the corresponding cyanoacetamide (II).

[0478] Cyano-Knoevenagel Condensation - General Procedure 4 [ka] A solution of cyanoacetamide (I) (1.0 equiv.) in THF (Procedure 4) (0.1 M) or EtOH (Procedure 4a) was treated with aldehyde (II) (2.5 equiv.) and piperidine (0.5 equiv.), and the mixture was stirred at room temperature or heated to reflux for 72 h until the reaction was complete. The volatiles were concentrated in vacuo and purified by silica gel column chromatography to give the corresponding cyanoacrylamide (III).

[0479] Cyano-Knoevenagel Condensation - General Procedure 17a [ka] A solution of cyanoacetamide (I) (1.0 equiv.) in DCM / DMF (0.1 M) was treated with pyrrolidine (5 equiv.) and TMS-Cl (4 equiv.), followed by the addition of aldehyde (II) (5 equiv.), and the mixture was stirred or heated at 55° C. for 16 h until the reaction was complete at room temperature. Volatiles were concentrated in vacuo (at reduced temperature, if appropriate) and purified by silica gel column chromatography to give the corresponding cyanoacrylamide (III).

[0480] Cyano-Knoevenagel Condensation - General Procedure 17b [ka] A solution of cyanoacetamide (I) (1.0 equiv.) and aldehyde (II) (4 equiv.) in ethanol:water (2:1, 0.064 M) was treated with beta-alanine (16.0 equiv.), and the mixture was stirred at RT for 16 h. The volatiles were concentrated in vacuo and purified by silica gel column chromatography to give the corresponding cyanoacrylamide (III).

[0481] Cyano-Knoevenagel Condensation - General Procedure 17c [ka] To a solution of cyanoa...

Claims

1. General formula: 【Chemical 1】 wherein TBL is a target protein binding ligand that binds to BRD9; L is a linker, Z comprises a structure according to formula (I): 【Chemistry 2】 During the ceremony, R １ is C １ ~C ６ alkyl, benzyl, substituted benzyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl, and optionally １ ~C ６ the alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S, and / or with a carbocyclic or heterocyclic group; A does not exist or CR ２ R ２’ and B is selected from aryl, heteroaryl, substituted aryl, and substituted heteroaryl; R ２ and R ２’ is H and C １ ~C ６ alkyl, and optionally, １ ~C ６ The alkyl is substituted with one or more heteroatoms selected from halo, N, O, or S, or R ２ and R ２’ together form a 3-, 4-, 5- or 6-membered carbocyclic or heterocyclic ring, R ３ is C １ ~C ６ is selected from 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, and optionally, １ ~C ６ The alkyl is substituted with one or more heteroatoms selected from halo, N, O, and S; R ４ is H, C １ ~C ６ alkyl, and optionally, １ ~C ６ The alkyl is substituted with one or more heteroatoms selected from N, O, or S; Or, R １ and R ４ taken together form a 5-, 6- or 7-membered heterocyclic ring; Or, A is CR ２ R ２’ If R １ and R ２ taken together form a 5-, 6- or 7-membered heterocyclic ring, or R ２ and R ４ together form a 5-, 6- or 7-membered heterocyclic or carbocyclic ring; L represents the attachment point of the linker; and, The BRD9 binder (TBL) has the formula 1a: 【Chemistry 3】 It is of During the ceremony, Z １ is N or CR Ａ and Z ２ is N or CR Ｂ and Z ３ is N or CR Ｄ and Z ４ is N or CR Ｅ and Z １ , Z ２ , Z ３ and Z ４ 3 or less of the R Ａ and R Ｅ is -H, -O-C １－３ Alkyl and -C １－３ alkyl, R Ｂ and R Ｄ is -O-C １－３ Alkyl, -H, -OH, halogen, -NH ２ , -C １－３ Alkyl, —O—C １－３ Haloalkyl, —C １－３ Alkyl-O-C １－３ alkyl, 4- to 7-membered heterocycloalkyl, —C １－３ Alkyl-SO ２ -C １－３ Alkyl, -C １－３ Alkyl-NH ２ , -C １－３ Alkyl-N(-C １－３ alkyl) ２ , -N(C １－３ alkyl) ２ , -NH-R Ｆ are each independently selected from the group consisting of: R Ｆ is -SO ２ -C １－３ Alkyl and -C １－３ alkyl, —C １－３ The alkyl is optionally substituted with a 5- to 6-membered heteroaryl; Alternatively, R Ａ and R Ｂ are taken together to form a benzene ring, alternatively, R Ｃ and Z ２ or R Ｃ and Z ３ Together, -C １－３ forming a 5- to 7-membered heterocycloalkyl optionally substituted with alkyl; R Ｃ is -H, -Y-R Ｇ , -NH ２ , -C １－３ selected from the group consisting of alkyl and 4- to 7-membered heterocycloalkyl; Y is absent or -CR Ｈ R Ｉ -, -SO ２ - and -CO-; R Ｈ and R Ｉ is -H or -C １－３ alkyl, or R Ｈ and R Ｉ Let's get together -C ３－４ forming a cycloalkyl, R Ｇ is -NH ２ , —OH, —C １－３ Alkyl, —N(R Ｊ R Ｋ ), -O-R Ｌ , aryl, and 5- to 6-membered heteroaryl, wherein said aryl and heteroaryl are optionally and independently substituted with one or more halogens, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein said monocyclic or bicyclic heterocycloalkyl is optionally substituted with one or more halogens, —OH, —NH ２ , -C １－３ Alkyl, -NHC １－３ Alkyl, —N(C １－３ alkyl) ２ , —O—C １－３ Alkyl and -CH ２ -R Ｍ１ and is substituted with one or more groups independently selected from R Ｍ１ is -NH ２ , —OH, halogen, —CN, —C １－３ Alkyl, —O—C １－３ selected from 5-10 membered mono- or bicyclic aryl or heteroaryl optionally substituted with alkyl; R Ｊ is -H or -C １－３ is alkyl, R Ｋ is -C １－３ Alkyl, -C ２－３ Alkyl-N(C １－３ alkyl) ２ , -C ２－３ Alkyl-NHC １－３ alkyl, optionally substituted 4- to 7-membered monocyclic heterocycloalkyl, and optionally substituted 7- to 12-membered bicyclic heterocycloalkyl, wherein the monocyclic or bicyclic heterocycloalkyl is optionally selected from the group consisting of -C １－３ is substituted with alkyl, R Ｌ is -C １－３ alkyl or 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally C １－３ is substituted with alkyl, R Ｃ Y-R Ｇ If R Ｂ and R Ｄ is -H, -OH, halogen, -NH ２ , -CN, -C １－３ Alkyl, -C １－３ Haloalkyl, —O—C １－３ Alkyl, —O—C １－３ Haloalkyl and —C １－３ Alkyl-O-C １－３ alkyl; R Ａ ~R Ｅ at least one of the substituents is not hydrogen; and, A ２ is represented by formula 1b or 1c 【Chemistry 4】 is selected from In the formula, the wavy line represents A ２ And, R Ａ and R Ｅ crosses the bond between the carbon atom located ortho to R Ｍ is an optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ３－１０ Carbocyclyl, C ２－６ selected from the group consisting of alkynyl and H; Z ５ is N or CR Ｏ and Z ６ is N or CR Ｐ and Z ７ is N or CR Ｎ and Z ５ , Z ６ and Z ７ is N, and Z ８ is CR Ｗ or N, R Ｎ is halogen, optionally substituted —C １－６ Alkyl, —H, C(O)C １－５ Alkyl, —NH ２ , optionally substituted amino, —OH, cyano, optionally substituted C １－６ Heteroalkyl, optionally substituted C ３－１０ Carbocyclyl, optionally substituted C ２－９ Heterocyclyl, optionally substituted C ６－１０ Aryl, optionally substituted C ２－９ Heteroaryl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ selected from the group consisting of heteroalkenyl and thiol; R Ｏ is H, halogen, cyano, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ３－１０ Carbocyclyl, optionally substituted C ２－９ Heterocyclyl, optionally substituted C ６－１０ Aryl, optionally substituted C ２－９ Heteroaryl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ selected from the group consisting of heteroalkenyl, hydroxy, thiol, and optionally substituted amino; R Ｐ is H, halogen, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ３－１０ Carbocyclyl and optionally substituted C ６－１０ aryl; Alternatively, R Ｎ and Z ５ are bonded together and optionally substituted C ６－１０ arene or optionally substituted C ２－９ forming a heteroarene, R Ｎ and R Ｏ are bonded together with the carbon atoms to which they are attached, and optionally substituted C ６－１０ arene or optionally substituted C ２－９ forming a heteroarene, R Ｓ is H, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl and optionally substituted C ３－１０ carbocyclyl; R Ｔ is H, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ３－１０ Carbocyclyl, optionally substituted C ２－９ Heterocyclyl, optionally substituted C ６－１０ Aryl, optionally substituted C ２－９ Heteroaryl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ is selected from the group consisting of heteroalkenyl, optionally substituted sulfone, and optionally substituted sulfonamido, or R Ｔ and R Ｕ Each of them, together with the atom to which it is attached, represents an optionally substituted C ２－９ forming a heterocyclyl, R Ｕ and R Ｖ is H, halogen, hydroxyl, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ３－１０ Carbocyclyl, optionally substituted C ２－９ Heterocyclyl, optionally substituted C ６－１０ Aryl, optionally substituted C ２－９ Heteroaryl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ each independently selected from the group consisting of heteroalkenyl, thiol, optionally substituted sulfone, and optionally substituted amino; Alternatively, R Ｔ and R Ｕ Each of them, together with the atom to which it is attached, represents an optionally substituted C ２－９ forming a heterocyclyl, R Ｗ is H, halogen, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C ３－１０ Carbocyclyl, optionally substituted C ２－９ Heterocyclyl, optionally substituted C ６－１０ aryl, or optionally substituted C ２－９ heteroaryl; and, the BRD9 conjugate is attached to the linker at any suitable position; (iii) the bifunctional molecule is 【Chemistry 5】 Not a bifunctional molecule.

2. Z １ , Z ２ , Z ３ and Z ４ 10. The bifunctional molecule of claim 1, wherein at most one of

3. The BRD9 conjugate has the formula 1a': 【Chemistry 6】 It is of During the ceremony, R Ａ , R Ｂ , R Ｃ , R Ｅ , Z ３ and A ２ is as defined in claim 1 or 2.

4. A ２ is selected from formula 1b', where formula 1b' is 【Chemistry 7】 and In the formula, the wavy line represents A ２ And, R Ａ and R Ｅ crosses the bond between the carbon atom located ortho to R Ｍ is -C １－５ Alkyl, -cyclopropyl, -C １－４ selected from the group consisting of haloalkyl and H; R Ｎ is a halogen, -C １－５ Alkyl, -C １－３ Haloalkyl, —H, C(O)C １－５ Alkyl, —NH ２ , -NHC １－３ selected from the group consisting of alkyl and —OH; Z ５ is N or CR Ｏ and Z ６ is N or CR Ｐ and Z ５ and Z ６ may be N, R Ｏ is H or -C １－３ is alkyl, R Ｐ is H or -C １－３ is alkyl, R Ｏ and R Ｐ Only one of them is -C １－３ may be alkyl, Alternatively, R Ｎ and Z ５ are taken together to form a benzene ring or a 5- to 6-membered heteroarene ring, each ring optionally and independently containing a halogen, —OH, —NH ２ , —NH—C １－３ Alkyl and -C １－５ Alkyl, C １－５ Haloalkyl, C １－５ Alkoxy, C １－４ Haloalkoxy, 1d,C ３－５ Azacycloalkyl, C ２－５ Alkenyl, C ２－５ Alkynyl, C ３－５ cycloalkyl, and the —C １－５ The alkyl group may be optionally substituted with a 5- to 6-membered heteroaryl or phenyl; 【Chemistry 8】 During the ceremony, Y ２ is NR Ｒ or O, Y １ is S(O) ａ or NR Ｒ and Each R Ｒ are independently H or C １－４ is alkyl, Each R Ｑ is C １－４ Alkyl, C １－４ Haloalkyl, halogen and —C(O)C １－３ independently selected from the group consisting of alkyl, a is 0 to 2; The bifunctional molecule according to any one of claims 1 to 3, wherein r is 0 to 3.

5. The BRD9 conjugate is of formula 1e, 1f or 1g: 【Chemistry 9】 wherein the wavy line crosses the bond between the BRD9 binder and the linker, and R Ａ , R Ｂ , R Ｃ , R Ｅ , R Ｍ , R Ｎ , Z ３ , Z ５ and Z ６ is as defined in any one of claims 1 to 4, R Ｃ’ is absent or R according to any one of claims 1 to 4 Ｃ as defined for Ring 1A is -C １－３ a 5- to 7-membered heterocycloalkane optionally substituted with alkyl; Ring 1D is an optionally substituted C ６－１０ Aryl or optionally substituted C ２－９ The bifunctional molecule of any one of claims 1 to 4, which is heteroaryl.

6. Ring 1A is (i) contains 1 or 2 heteroatoms independently selected from the list consisting of N, S, and O; or (ii) The bifunctional molecule of claim 5, selected from the list consisting of pyrrolidine, piperidine, piperazine, morpholine, oxolane, oxane, tetrahydrothiophene, and thiane.

7. The BRD9 conjugate has the formula 1e, 1f' or 1g' 【Chemistry 10】 It is of wherein the wavy line crosses the bond between the BRD9 binder and the linker, and R Ａ , R Ｂ , R Ｃ , R Ｅ , R Ｍ , R Ｎ , Z ３ , Z ５ and Z ６ is as defined in any one of claims 1 to 4. The bifunctional molecule according to any one of claims 1 to 5.

8. R Ａ , R Ｂ , R Ｃ , R Ｄ and R Ｅ is -O-C １－３ Alkyl, —H, halogen, —O—C １－３ Haloalkyl, —OH, —NH ２ , -C １－３ Alkyl, -C １－３ Alkyl-NH ２ , -C １－３ Alkyl-N(-C １－３ alkyl) ２ and -N(C １－３ alkyl) ２ The bifunctional molecule of any one of claims 1 to 7, independently selected from:

9. (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 the groups is —O—C １－３ Alkyl, —H, halogen and —O—C １－３ The bifunctional molecule of any one of claims 1 to 8, selected from the group consisting of haloalkyl.

10. R Ｍ Ha-C １－５ The bifunctional molecule of any one of claims 1 to 9, which is alkyl.

11. R Ｎ is -C １－５ alkyl or halogen, or R Ｎ and Z ５ taken together form an optionally substituted 5- to 6-membered heteroarene or benzene ring; (i) the optionally substituted 5- to 6-membered heteroarene 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 bifunctional molecule according to any one of claims 1 to 10, wherein the optionally substituted 5- to 6-membered heteroarene ring is any one selected from the optionally substituted group consisting of pyridine, pyrrole, imidazole, pyrimidine, thiophene, and pyrazole.

12. The BRD9 conjugates have the formula 1ea-1eh, 1fa-1fi and 1ga: 【Chemistry 11】 and wherein the wavy line crosses the bond between the BRD9 binder and the linker; R Ａ , R Ｂ , R Ｅ , R Ｍ , Z ３ and Z ６ is as defined in any one of claims 1 to 11, R Ｃ is absent or as defined in any one of claims 1 to 11, R Ｎ is a halogen, -C １－５ Alkyl, -C １－３ Haloalkyl, —H, C(O)C １－５ Alkyl, —NH ２ , -NHC １－３ selected from the group consisting of alkyl and —OH; R Ｏ is H or -C １－３ is alkyl, Each R Ｘ is a halogen, -OH, -NH ２ , —NH—C １－３ Alkyl, -C １－５ Alkyl, C １－５ Haloalkyl, C １－５ Alkoxy and C １－４ independently selected from the group consisting of haloalkoxy; n is 0 to 3; o is 0 to 2; p is 0 or 1; The bifunctional molecule according to any one of claims 1 to 11, wherein q is 0 to 4.

13. The BRD9 conjugate has the formula 1ea': 【Chemistry 12】 This is due to wherein the wavy line crosses the bond between the BRD9 binder and the linker; R Ａ and R Ｅ is H and —O—C １－３ are each independently selected from alkyl, R Ｂ and R Ｄ is -O-C １－３ Alkyl, -H, -halo, -C １－３ Alkyl and —O—C １－３ haloalkyl; R Ｃ is absent or -Y-R Ｇ and Y is -CR Ｈ R Ｉ - and -CO-; R Ｈ and R Ｉ is -H or -C １－３ alkyl, or R Ｈ and R Ｉ Let's get together -C ３－４ forming a cycloalkyl, R Ｇ is -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 is as defined in claim 1, R Ｍ is C １－３ is alkyl, R Ｎ , R Ｏ and R Ｐ is halo, -C １－３ Alkyl and -C １－３ The bifunctional molecule of any one of claims 1 to 12, wherein each independently is selected from the group consisting of haloalkyl.

14. The BRD9 conjugates have formulas 1h-1z and 2a-2g: 【Chemistry 13】 【change】 and In the formula, R Ｃ is absent or -Y-R Ｇ and Y is -CR Ｈ R Ｉ - and -CO-; R Ｈ and R Ｉ are each —H or R Ｈ and R Ｉ Let's get together -C ３－４ forming a cycloalkyl, R Ｇ is -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 1 or 2 N ring atoms, and optionally substituted 7- to 12-membered bicyclic heterocycloalkylene containing 1 or 2 N ring atoms; R Ｊ and R Ｋ is as defined in claim 1, 13. The bifunctional molecule of claim 1, wherein the wavy line crosses the bond between the BRD9 binder and the linker.

15. R Ｃ exists, 【Chemistry 14】 is one selected from In the formula, Y is CR Ｈ R Ｉ and R Ｇ１ and R Ｇ２ is H and C １ ~C ３ are each independently selected from alkyl, R Ｊ is as defined in claim 1, The bifunctional molecule according to any one of claims 1 to 14, wherein L represents the point of attachment of the linker.

16. (i) R １ and R ４ taken together to form a 5-, 6- or 7-membered heterocyclic ring, Z is represented by formula (Ia): 【Chemistry 15】 In the formula, A, B, R ３ and L is as defined for formula (I), n is 1, 2 or 3; W is CR Ｗ１ R Ｗ２ , O., N.R. Ｗ３ and S; R Ｗ１ , R Ｗ２ and R Ｗ３ is H and C １ ~C ６ alkyl, and when n is 2 or 3, each W is independently selected from CR Ｗ１ R Ｗ２ , O., N.R. Ｗ３ and S, (ii) R １ and R ２ are taken together to form a 5-, 6- or 7-membered heterocyclic ring, Z is represented by formula (Ib): 【Chemistry 16】 In the formula, B, R ２’ , R ３ , R ４ and L is as defined for formula (I), m is 3, 4 or 5; Each T is a CR Ｔ１ R Ｔ２ , O., N.R. Ｔ３ and S, R Ｔ１ , R Ｔ２ and R Ｔ３ is H and C １ ~C ６ alkyl; or (iii) R ２ and R ４ are taken together to form a 5-, 6- or 7-membered heterocyclic or carbocyclic ring, Z is represented by formula (Ic): 【Chemistry 17】 In the formula, B, R １ , R ２’ , R ３ and L is as defined for formula (I), p is 2, 3 or 4; Each U is a CR Ｕ１ R Ｕ２ , O., N.R. Ｕ３ and S, R Ｕ１ , R Ｕ２ and R Ｕ３ is H and C １ ~C ６ The bifunctional molecule of any one of claims 1 to 15, wherein each of the bifunctional molecules is independently selected from alkyl.

17. R ３ is heteroaryl, substituted heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloheteroalkyl, C substituted with heterocyclic groups １ ~C ６ selected from the group consisting of alkyl, aryl, and substituted aryl; Optionally, R ３ teeth, 【Chemistry 18】 The dotted lines represent the respective R ３ indicates the position where each of the R groups is attached to the structure shown in formulas (I)-(Ic), or if the dotted line is not attached to an atom, the dotted line ... ３ indicates that each of the groups is attached to the structure via any position on the aromatic or heteroaromatic ring; Each R ５ Ha, Halo, CH ２ OH, CF ３ , -CH ２ F, -CHF ２ , OCF ３ , -OCH ２ F, -OCHF ２ , C １ ~C ６ Alkyl, -CN, -OH, -OMe, -SMe, -SOMe, -SO ２ Me, -NH ２ , -NHMe, -NMe ２ , CO ２ Me, -NO ２ , CHO, and COMe; n is 0 to 3; R ６ is C １ ~C ６ is alkyl, G is CH ２ , O and NH, Q is C １ ~C ６ 10. The bifunctional molecule of any one of the preceding claims, which is alkylene.

18. A is CR ２ R ２’ and optionally, (i) R ２ and R ２’ One of them is hydrogen and the other is C １ ~C ６ alkyl, and optionally, １ ~C ６ alkyl is substituted with one or more halo atoms, or (ii) R ２ and R ２’ Both are C １ ~C ６ 10. The bifunctional molecule of any one of the preceding claims, selected from alkyl.

19. Z is represented by formula (IIaa): 【Chemistry 19】 In the formula, A, R ３ and L is as defined for formula (I), n is 1, 2 or 3; W is CR Ｗ１ R Ｗ２ , O., N.R. Ｗ３ and S; R Ｗ１ , R Ｗ２ and R Ｗ３ is H and C １ ~C ６ are each independently selected from alkyl, When n is 2 or 3, each W is a CR Ｗ１ R Ｗ２ , O., N.R. Ｗ３ and S, Optionally, (i) Z is represented by formula (IIa): 【Chemistry 20】 In the formula, R ２ , R ２’ , R ３ and L is as defined in any one of the preceding claims, n is 1, 2 or 3; W is CR Ｗ１ R Ｗ２ , O., N.R. Ｗ３ and S; R Ｗ１ , R Ｗ２ and R Ｗ３ is H and C １ ~C ６ are each independently selected from alkyl, When n is 2 or 3, each W is a CR Ｗ１ R Ｗ２ , O., N.R. Ｗ３ and S.

20. 10. The bifunctional molecule of any one of the preceding claims, wherein the linker comprises 1 to 25 or 1 to 18 atoms in a single linear chain.

21. 10. The bifunctional molecule of any one of the preceding claims, wherein the linker comprises 1 to 10 or 1 to 8 rotatable bonds.

22. The linker (L) is a covalent bond, or the structure of the linker (L) is (L ｘ ) ｑ where each Lx is CR Ｌ１ R Ｌ２ ,O,C=O,S,SO,SO ２ , N.R. Ｌ３ , SONR Ｌ４ , SONR Ｌ５ C=O, CONR Ｌ６ , N.R. Ｌ７ CO, C(R Ｌ８ ) = C(R Ｌ９ ), subunits of L independently selected from C≡C, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl groups; R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ５ , R Ｌ６ , R Ｌ７ , R Ｌ８ and R Ｌ９ is H, halo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, —OH, —O(C １ ~C ６ alkyl), -NH ２ , —NH(C １ ~C ６ alkyl), -NO ２ , -CN, -CONH ２ , -CONH(C １ ~C ６ alkyl), -CON(C １ ~C ６ alkyl) ２ , -SO ２ (C １ ~C ６ alkyl), —CO ２ (C １ ~C ６ alkyl), and —CO(C １ ~C ６ alkyl), 10. The bifunctional molecule of any one of the preceding claims, wherein q is an integer from 1 to 30.

23. The linker (L) has the formula (L1a): 【Chemical 21】 wherein L １Ａ does not exist or C １ ~C ６ Alkylene, C １ ~C ６ Alkoxy and C １ ~C ６ alkylamino; L ２Ａ is -NR Ｌ２Ａ C=O- or -C=ONR Ｌ２Ａ - and L ３Ａ is C １ ~C ３ Alkylene, C １ ~C ６ Alkoxy and C １ ~C ６ alkylamino; R Ｌ２Ａ is H or C １ ~C ６ Is it alkyl? Alternatively, the structure of the linker (L) is represented by formula (L1b): 【Chemical 22】 wherein L １Ｂ does not exist or C １ ~C ３ Alkylene, C １ ~C ６ Alkoxy and C １ ~C ６ alkylamino; L ２Ｂ is -NR Ｌ２Ａ C=O- or -C=ONR Ｌ２Ａ - and L ３Ｂ is C １ ~C １５ Alkylene, -[(CH ２ ) ２ O] １－６ (CH ２ ) ２ - is selected from, L ４Ｂ is -NR Ｌ２Ａ C=O- or -C=ONR Ｌ２Ａ - and R Ｌ２Ａ is H or C １ ~C ６ is alkyl, L ５Ｂ is C １ ~C ３ Alkylene, C １ ~C ６ Alkoxy and C １ ~C ６ alkylamino; R Ｌ２Ａ is H or C １ ~C ６ Is it alkyl? Alternatively, the structure of the linker (L) is represented by formula (L1c): 【Chemical 23】 wherein L １Ｃ is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; L ２Ｃ does not exist or C １ ~C ３ Alkylene, C １ ~C ６ Alkoxy and C １ ~C ６ alkylamino; L ３Ｃ is -R Ｌ２Ｂ C=O- or -(C=O)R Ｌ２Ｂ - and L ４Ｃ is C １ ~C ３ Alkylene, C １ ~C ６ Alkoxy and C １ ~C ６ alkylamino; R Ｌ２Ａ is H or C １ ~C ６ is alkyl, R Ｌ２Ｂ is NR Ｌ２Ａ or an N-linked optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; Alternatively, the structure of the linker (L) is represented by formula (L1d): 【Chemistry 24】 wherein L １Ｄ does not exist or C １ ~C ３ Alkylene, CO, C １ ~C ３ Alkylene (N(C １ ~C ３ alkyl), L ２Ｄ is NR Ｌ２Ａ or an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, or an optionally substituted 8- to 18-membered tricyclic N-heterocycloalkyl, each optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; R Ｌ２Ａ is H or C １ ~C ６ is alkyl, L ３Ｄ does not exist or C １ ~C ３ Alkylene, —O—, —N(C １ ~C ３ alkyl)- and CO; Alternatively, the structure of the linker (L) is represented by formula (L1e): 【Chemistry 25】 wherein L １Ｅ is C １ ~C ３ alkylene or CO; L ２Ｅ is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl, an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each optionally containing 1 or 2 additional ring heteroatoms selected from N, O, and S; L ３Ｅ is C １ ~C ３ alkylene; Alternatively, the linker (L) has the formula (L1f): L １Ｆ L1f) wherein L １Ｆ is C １ ~C ３ Alkylene, CO and C １ ~C ３ Alkylene (NR Ｌ１Ｃ ) and R Ｌ１Ｃ is H or C １ ~C ３ The bifunctional molecule of any one of claims 1 to 22, which is alkyl.

24. 10. The bifunctional molecule of any one of the preceding claims, wherein the bifunctional molecule has the structure shown in Table 1.

25. 10. A pharmaceutical composition comprising a bifunctional molecule according to any one of the preceding claims together with a pharmaceutically acceptable carrier, optionally wherein the bifunctional molecule is present in the composition as a pharmaceutically acceptable salt, solvate or derivative.

26. A bifunctional molecule according to any one of claims 1 to 24, or a pharmaceutical composition according to claim 25, for use in medicine.

27. 27. The bifunctional molecule or pharmaceutical composition for use according to claim 26, wherein said use comprises the treatment and / or prevention of any disease or condition associated with and / or caused by an abnormal level of BRD9 activity.

28. 28. The bifunctional molecule or pharmaceutical composition for use according to claim 26 or 27, wherein the disease or condition is cancer.

29. 26. A method for selectively degrading BRD9 in a cell and / or increasing its proteolysis, comprising contacting and / or treating 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.

30. A method for making a bifunctional molecule as defined in any one of claims 1 to 24.

31. A method for screening bifunctional molecules as defined in any one of claims 1 to 24, comprising: a. (i) a first ligand comprising a structure according to 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 covalently linking a first ligand and a second ligand as defined in any one of claims 1 and 20 to 23; and b. contacting a cell with the bifunctional molecule; c. Detecting degradation of BRD9 in said cells; d. detecting degradation of BRD9 in the cell in the absence of the bifunctional molecule; e. comparing the level of BRD9 degradation in the cells contacted with the bifunctional molecule with the level of BRD9 degradation in the absence of the bifunctional molecule; an increase in the level of degradation of BRD9 in the cells contacted with the bifunctional molecule indicates that the bifunctional molecule has promoted and / or facilitated the degradation of BRD9; Optionally, the method, wherein detecting degradation of BRD9 comprises detecting a change in the level of the target protein in the 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 of any one of claims 1 to 24.

Images