Albumin binder conjugated protac degraders and uses thereof

Abstract

The present disclosure relates generally to albumin binder conjugated PROTAC degraders, compositions thereof, and methods of using said conjugates and compositions thereof. More specifically, the present disclosure relates to conjugates for use for treating cancer.

Description

WSGR Docket No. 68195-704.601ALBUMIN BINDER CONJUGATED PROTAC DEGRADERS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 737,372, filed on December 20, 2024, U. S. Provisional Application No. 63 / 737,374, filed on December 20, 2024, U. S. Provisional Application No. 63 / 827,486, filed on June 20, 2025, and U. S.Provisional Application No. 63 / 827,492, filed on June 20, 2025, each of which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Proteolysis-targeting chimeras (PROTACs) are versatile small molecular therapeutic agents for cancer treatment via inducing the selective degradation of cancer-associated proteins. They have a heterobifunctional molecular structure where a ligand for the protein of interest (POI) and E3 ubiquitin ligase (E3) recruiter are chemically conjugated with each other. When PROTACs are internalized to cancer cells, they induce the polyubiquitination of POIs through concurrently binding to E3s and POIs, and polyubiquitinated POIs are degraded into oligomeric peptides by proteasomes. After the dissociation, PROTACs can be further recycled to participate in the degradation of other POIs. Due to their unique mode of action, PROTACs can silence POIs in more catalytic, irreversible, and long-lasting manners, successfully overcoming the tumor drug resistance caused by the re-activation and mutation of proteins. Furthermore, PROTACs are effective even in the treatment of ‘undruggable’ proteins since they are not required to access active sites of POIs. However, PROTACs have some issues in their biodistribution and cell permeation properties due to their hydrophobic and small molecular structures, which greatly diminishes their efficacy in anticancer therapy. To improve the pharmacokinetic and pharmacodynamic properties of PROTACs, nanomaterials including micelles, liposomes, and nanoparticles have been recently evaluated as their carriers. The use of nanomaterials was found to be somewhat effective in resolving the poor water solubility and short circulation time of PROTACs in vivo. These nanomaterials, however, often have limited drug loading capacity and may generate carrier-associated toxicity or immune reaction.Moreover, the complex structural and compositional heterogeneity of nanomaterials makes it hard not only to estimate their pharmacokinetic properties but also to control their quality in mass production for clinical application. Although active targeting modalities including antibodies, aptamers, and ligands have also been explored as PROTAC carriers, most of them are costly and have limited drug loading amounts due to their bulky structures. In addition, the delivery efficiency of nanomaterials or active targeting modalities to target tissues does notWSGR Docket No. 68195-704.601exceed 1-2%, and the remains would be accumulated in off-target tissues to induce carrier-attributed toxicides. Therefore, there is a need for a novel method different from traditional drug carriers for the efficient delivery of PROTACs.BRIEF SUMMARY OF THE INVENTION

[0003] Albumin is a major plasma protein that plays an important role in the transport of nutrient sources. Including its high biocompatibility and biodegradability, albumin has several favorable characteristics allowing itself to be used as a drug carrier. As drugs are loaded to albumin, their poor pharmacokinetic properties can be modulated, thereby extending their circulation time. Furthermore, albumin tends to selectively accumulate in tumor tissues utilizing both passive and active targeting pathways. The highly permeable vasculature and lack of lymphatic drainage in tumor microenvironments contribute to the prolonged retention of albumin, and cancer cells under stress conditions actively uptake the accumulated albumins to utilize them as nutrition sources. In addition to the non-specific pinocytosis of albumin, several tumor-overexpressing receptors including glycoprotein 60 (GP60) and secreted protein acidic and rich in cysteine (SPARC) were reported to be involved in the intense albumin uptake and catabolism of cancer cells. Various approaches have been conducted to exploit albumins as drug carriers, and among them, the in situ covalent binding of drugs to the unpaired thiol of the 34th cysteine residue (cys34) in albumin is considered the most effective. The introduction of maleimide moieties to drug molecules enables their immediate and site-specific binding to cys34 of albumins via the thiol-maleimide (Thiol-Mal) click reaction. Since the Thiol-Mal click reaction is feasible even under physiological conditions, the maleimide-conjugated drug molecules can conveniently ‘hitchhike’ native albumins without damaging their structures.

[0004] The tumor microenvironment (TME) represents a highly intricate system composed of a heterogeneous mix of cancer cells, associated stromal cells, and the extracellular matrix (ECM). The ECM offers structural support within the extracellular space and orchestrates various cellular signaling pathways in tumor tissues. As a pivotal component of the TME, the tumor stroma actively facilitates cancer cell proliferation, angiogenesis, invasion, metastasis, immune evasion, and resistance to therapy. The functions of stromal cells and their interactions with cancer cells are modulated by the production and secretion of numerous signaling molecules, including growth factors, chemokines, cytokines, and proteolytic enzymes.

[0005] While the role of proteases was once believed to be limited to ECM degradation, recent insights reveal their significantly more complex and essential involvement in tumor biology. Besides cancer cells, stromal cells, such as fibroblasts, endothelial cells, and infiltrating immune cells, contribute various proteases — including matrix metalloproteinases (MMPs), cysteineWSGR Docket No. 68195-704.601cathepsins, and serine proteases — to the tumor milieu. These proteases participate in proteolytic networks that remodel the ECM, regulate growth factor and cytokine signaling, and modulate inflammatory responses and immunosuppressive effects. Depending on the cellular context, the activity and interactions of these proteases can either promote or suppress tumor growth.

[0006] Among these, serine proteases, constituting about one-third of human proteases, are crucial in carcinomas. The dysregulated expression and activity of several proteases derived from stromal cells have been closely linked to tumor progression and metastasis.

[0007] Protease-activated prodrugs are commonly employed to enhance the therapeutic index of anticancer agents. Dysregulated proteolysis, a hallmark of many cancers, plays a vital role in tumor growth and metastasis. These prodrugs exploit the differential proteolytic activity between tumor and normal tissues to achieve targeted therapy. TME-associated proteases — such as fibroblast activation protein (FAP), cathepsins, matriptase, and urokinase-type plasminogen activator (uPA) — are attractive targets for this approach, given their consistent involvement in tumor progression across various cancers. Their minimal proteolytic activity in normal tissues, due to low expression levels and the presence of endogenous inhibitors, further enhances their suitability as therapeutic targets.

[0008] In some embodiments, the PROTACs is conjugated to an albumin binder, solving the PK issue while delivering the drug to solid tumors.

[0009] Described herein are albumin conjugated PROTAC degraders that are useful in treating cancer.

[0010] Disclosed herein is a conjugate of Formula (I):D— S1— L— S2-ABFormula (I);wherein:D is a degrader;51is absent or is a spacer;L is a cleavable linker;52is absent or is a spacer; andAB is an albumin binder;or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0011] Disclosed herein is a conjugate of Formula (la):D-S1— L— S2-ABFormula (la);WSGR Docket No. 68195-704.601wherein:D is a degrader;51is absent or is a spacer;L is a cleavable linker;52is a spacer; andAB is a non-covalent albumin binder;or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0012] Disclosed herein is a conjugate of Formula (lb):D-S1— L— S2-ABFormula (lb);wherein:D is a degrader;51is absent or is a spacer;L is a cleavable linker;52is a spacer; andAB is a covalent albumin binder;or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0013] Also disclosed herein is a pharmaceutical composition comprising a conjugate disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0014] Also disclosed herein is a method of treating cancer in a subject, comprising administering to the subject a conjugate disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.INCORPORATION BY REFERENCE

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0016] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout theWSGR Docket No. 68195-704.601specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0017] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0018] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0019] “ Oxo” refers to =0.

[0020] “Amino” refers to -NH2.

[0021] “Hydroxy” refers to -OH.

[0022] “Carboxyl” refers to -COOH.

[0023] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-1 -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl. In some embodiments, the alkyl is a Ci-Ce alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo,WSGR Docket No. 68195-704.601halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0024] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s), and should be understood to include both isomers.Examples include, but are not limited to ethenyl (-CH=CH2), 1 -propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0025] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionallyWSGR Docket No. 68195-704.601substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0026] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0027] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0028] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenal enyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0029] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, theWSGR Docket No. 68195-704.601cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cisdecalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[l.l.l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0030] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0031] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0032] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.WSGR Docket No. 68195-704.601

[0033] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0034] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0035] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0036] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.WSGR Docket No. 68195-704.601

[0037] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran- 1 -yl, 3 -oxo- 1,3 -dihydroisobenzofuran- 1 -yl, methyl-2-oxo- 1,3 -dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and theWSGR Docket No. 68195-704.601oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0038] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.WSGR Docket No. 68195-704.601In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0039] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0040] “Where bivalent substituent groups (such as L and S in Formula (I)) are specified herein by their conventional chemical formulae, written from left to right, they are intended toWSGR Docket No. 68195-704.601encompass the regioisomer that would result from writing the structure from right to left, e.g.,Ois also intended to encompassO OF cr i O A^is also intended to encompassH0 0H

[0041] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.

[0042] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The terms “treat,” “treated,” “treatment,” or “treating” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level ofWSGR Docket No. 68195-704.601treatment of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.

[0043] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a conjugate disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a conjugate disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.Conjugates

[0044] Described herein are albumin conjugated PROTAC degraders that are useful in treating cancer.

[0045] Disclosed herein is a conjugate of Formula (I):D-S1— L— S2-ABFormula (I);wherein:D is a degrader;51is absent or a spacer;L is a cleavable linker;52is absent or is a spacer; andAB is an albumin binder;or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, AB is a covalent albumin binder. In some embodiments, AB is a non-covalent albumin binder.

[0047] In some embodiments, the conjugate of Formula (I) is a conjugate of Formula (la):D-S1— L— S2-ABFormula (la);wherein:D is a degrader;S1is absent or is a spacer;WSGR Docket No. 68195-704.601L is a cleavable linker;S2is a spacer; andAB is a non-covalent albumin binder;or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the conjugate of Formula (I) is a conjugate of Formula (lb):D-S1— L— S2-ABFormula (lb);wherein:D is a degrader;51is absent or is a spacer;L is a cleavable linker;52is a spacer; andAB is a covalent albumin binder;or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments of a conjugate of Formula (I), D is a small molecule degrader. In some embodiments, the small molecule degrader comprises a warhead (W), a protac linker (Lp), and an E3 ligase ligand (E3RL).

[0050] In some embodiments of a conjugate of Formula (I), D is a heterobifunctional proteolysis-targeting chimera (PROTAC) compound of Formula (D-l):W - LP - E3RLFormula (D-l),wherein,W a warhead that binds to a target protein;Lpis a linker;E3RL is an E3 ligase ligand.

[0051] In some embodiments, the warhead (W) comprises a bromodomain-containing protein 4 (BRD4) ligand, an estrogen receptor (ER) ligand, a fibroblast growth factor receptor 2 (FGFR2) ligand, a Myc ligand, or a receptor-interacting protein kinase 2 (RIPK2) ligand. In some embodiments, the warhead (W) comprises a bromodomain-containing protein 4 (BRD4) ligand, an estrogen receptor (ER) ligand, a fibroblast growth factor receptor 2 (FGFR2) ligand, or a Myc ligand. In some embodiments, the warhead comprises a bromodomain-containing protein 4 (BRD4) ligand. In some embodiments, the warhead comprises an estrogen receptor (ER) ligand. In some embodiments, the warhead comprises a fibroblast growth factor receptor 2 (FGFR2)WSGR Docket No. 68195-704.601ligand. In some embodiments, the warhead comprises a Myc ligand. In some embodiments, the warhead comprises a receptor-interacting protein kinase 2 (RIPK2) ligand.

[0052] In some embodiments of a conjugate of Formula (I), D comprises:DegraderStructurePayload J Xf \ IiX— 'OHAH H^x O^Q^NHClo '\ S )=N o. OHZ ZEHoB / =< H » JCl 71 IIX Q? \ _ S / =N OHoCHAHX 0Qz — %**’DWSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0053] In some embodiments of a conjugate of Formula (I), D is a bromodomain-containing protein 4 (BRD4) degrader.

[0054] In some embodiments of a conjugate of Formula (I), D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to BRD4. In some embodiments, W is a moiety that binds to BRD4 having the following structure:R22Formula (D-2),wherein,R21is phenyl, Cs-Cecycloalkyl, or 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionallyWSGR Docket No. 68195-704.601substituted with 1, 2, or 3 substituents independently selected from halo, Ci-C4alkyl, Ci-C4haloalkyl, C3-C6 cycloalkyl, hydroxyl, Ci-C4alkoxy, or cyano;R22and each R23are independently halo, Ci-C4alkyl, Ci-C4haloalkyl, C3-C6cycloalkyl, hydroxyl, Ci-C4alkoxy, or cyano; and n is 0, 1, 2, 3, or 4.

[0055] In some embodiments, W is a moiety that binds to BRD4 having the following structure:

[0056] In some embodiments of a conjugate of Formula (I), D comprises ARV-771, ARV-825, BETd-246, BETd-260, dBETl, dBET6, dBET23, QCA276, or QCA570. In some embodiments of a conjugate of Formula (I), D comprises ARV-771. In some embodiments of a conjugate of Formula (I), D comprises ARV-825. In some embodiments of a conjugate of Formula (I), D comprises dBET6. In some embodiments, D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to BRD4 comprising:S. In some embodiments, D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds toBRD4 comprising:

[0057] In some embodiments of a conjugate of Formula (I), D comprisesWSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0058] In some embodiments of a conjugate of Formula (I), D comprises

[0059] In some embodiments, D comprisesWSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601\ or

[0060] In some embodiments, D comprises

[0061] In some embodiments, D comprisesWSGR Docket No. 68195-704.601

[0062] In some embodiments of a conjugate of Formula (I), D is an estrogen receptor (ER) degrader.

[0063] In some embodiments of a conjugate of Formula (I), D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to the estrogen receptor (ER). In some embodiments, W is a moiety that binds to ER having the following structure:WSGR Docket No. 68195-704.601

[0064] In some embodiments of a conjugate of Formula (I), D comprisesWSGR Docket No. 68195-704.601

[0065] In some embodiments of a conjugate of Formula (I), D is a fibroblast growth factor receptor 2 (FGFR2) degrader.

[0066] In some embodiments of a conjugate of Formula (I), D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to FGFR2. In some embodiments, W is a moiety that binds to FGFR2 having the following structure:wherein, each R24is independently hydrogen, Ci-C4alkyl, Ci-C4haloalkyl, or C3-C6 cycloalkyl, cyano; or both R24are taken together with the N atom to which they are attached to form a 4 to 6 membered heterocycloalkyl.

[0067] In some embodiments, W is a moiety that binds to FGFR2 having the following

[0068] In some embodiments of a conjugate of Formula (I), D comprises

[0069] In some embodiments of a conjugate of Formula (I), D is a Myc degrader.

[0070] In some embodiments of a conjugate of Formula (I), D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to Myc. In some embodiments, W is a moiety that binds to Myc having the following structure:WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0072] In some embodiments of a conjugate of Formula (I), D comprises

[0073] In some embodiments of a conjugate of Formula (I), D is a receptor-interacting protein kinase 2 (RIPK2) degrader.

[0074] In some embodiments of a conjugate of Formula (I), D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to RIPK2.

[0075] In some embodiments, D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to receptor-interacting protein kinase 2(RIPK2) comprising:

[0076] In some embodiments, W is a moiety that binds to RIPK2 having the followingstructure:

[0077] In some embodiments, the conjugate of Formula (I) does not comprise a conjugate described in WO 2024 / 237414 Al, Biomaterials 295 (2023) 122038, or Molecules 2023, 28, 3223.

[0078] In some embodiments, the E3 ligase is the von Hippel-Lindau (VHL) tumor suppressor protein, Cereblon (CRBN), Mouse Double Minute 2 homologue (MDM2), Cellular Inhibitor of Apoptosis (cIAP), X-linked IAP (XIAP), Kelch-like ECH-associated protein 1 (KEAP1), KLHDC2, AhR, RNF2, RNF114, DDB1 and CUL4 Associated Factor 1 (DCAF1), DDB1 and CUL4 Associated Factor 11 (DCAF11), orDDBl and CUL4 associated factor 15 (DCAF15). InWSGR Docket No. 68195-704.601some embodiments, the E3 ligase is the von Hippel-Lindau (VHL) tumor suppressor protein, Cereblon (CRBN), Mouse Double Minute 2 homologue (MDM2), Cellular Inhibitor of Apoptosis (cIAP), RNF2, or DDB 1 and CUL4 associated factor 15 (DCAF15).

[0079] In some embodiments, the E3 ligase is VHL or cereblon. In some embodiments, the E3 ligase is VHL. In some embodiments, the E3 ligase is cereblon.

[0080] In some embodiments, E3RL is a von Hippel-Lindau (VHL) binder, Cereblon binder, or Inhibitor of Apoptosis (IAP) binder.

[0081] In some embodiments, E3RL is an IAP binder. In some embodiments, E3RL comprisesWSGR Docket No. 68195-704.601

[0082] In some embodiments, E3RL is an IAP binder comprising

[0083] In some embodiments, E3RL is a Cereblon binder. In some embodiments, E3Bcomprises a glutarimide. In some embodiments, E3B comprises

[0084] In some embodiment, E3B comprises a cereblon binder described in: S. Norris, et al., J. Med. Chem. 2023, 66, 23, 16388-16409; J. Min, et al., Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs, Angewandte Chemie International Edition, November 2021, 60(51); Steinebach C, et al., Leveraging Ligand Affinity and Properties:Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs. J MedWSGR Docket No. 68195-704.601Chem. 2023 Nov 9;66(21):14513-14543; Vicente, A. T. S., Moura, S. P. S. P. & Salvador, J. A. R. Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs. Commun Chem 8, 218 (2025).

[0085] In some embodiments, the E3 ligase is VHL and the (E3RL) has the following structure of Formula (E):Rb— L1O R3R1R5KM X\JHL JIR1a*^s^R2\4R1 aRFormula (E),wherein,R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -Ci-C6alkyl-CN, Ci-C6heteroalkyl, Ci- Ceheterofluoroalkyl, Ci-Ceheteroalkyl-CN, Ci-Ceheterofluoroalkyl-CN, -OH, -Ci-Cealkyl- OH, -Ci-C6haloalkyl-OH, -Ci-C6alkyl-O-L2-Ra, -Ci-C6haloalkyl-O-L2-Ra, -N(R13)2, -Ci- C6alkyl-N(R13)2, -O-Ci-C6alkyl-N(R13)2, or -O-(CH2CH2O)n-R13;L2is absent or -Ci-C6alkyl-N(R14)-;or R1is Rla;each Rlais independently hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehaloalkoxy, or Ci-Cealkoxy;X is N, -CR1-, or -CRla-;n is 1, 2, or 3;R2is hydrogen, halogen, -CN, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, - N(Ci-C4alkyl)2, Cs-Cecycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci- C4haloalkoxy, Cs-Cecycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl is optionally and independently substituted with one or more R;or R2is;R3is hydrogen, Ci-Cealkyl, Ci-Cealkyl-OH, Ci-C6alkyl-ORa, Ci-Cehaloalkyl, -Ci-Cehaloalkyl- OH, -Ci-C6alkyl-N(R13)2, -Ci-C6alkyl-N(Ra)(R14), C3-C6cycloalkyl, -Ci-C6alkyl-C3- Cecycloalkyl, -Ci-C6alkyl-(3-6 membered heterocycloalkyl optionally and independently substituted with one or more R)-Ra, -OP(=O)(OH)2, or -Ci-C6alkyl-OP(=O)(OH)2;R4is hydrogen or Ra;WSGR Docket No. 68195-704.601R5is hydrogen, Ci-Cealkyl, or Ci-C4haloalkyl;L1is -C(=O)(NR12)- or a 5-membered heteroarylene, wherein the 5-membered heteroarylene comprises at least one nitrogen atom and wherein -C(=O)(NR12)- is linked to Rbvia the C atom;Rais -S1-L-S2-AB, and Formula (E) comprises only one Rawhen -Lp- and W do not comprise Ra, or Formula (E) does not comprise a Ragroup when -Lp- or W comprise the Ramoiety; Rbis -Lp-W;each R13is independently hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3- Cecycloalkyl or 3-6 membered heterocycloalkyl, wherein Ci-Cealkyl, Ci-Cefluoroalkyl, Ci- Ceheteroalkyl, Cs-Cecycloalkyl, and 3-6 membered heterocycloalkyl is optionally and independently substituted with one or more R;R14is hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, Cs-Cecycloalkyl, or 3-6 membered heterocycloalkyl, wherein Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3- Cecycloalkyl, and 3-6 membered heterocycloalkyl is optionally and independently substituted with one or more R;each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C4alkyl, - S(=O)2NH2, -S(=O)2NHCi-C4alkyl, -S(=O)2N(Ci-C4alkyl)2, -S(=O)2H, -NH2, -NHCi-C4alkyl, -N(Ci-C4alkyl)2, -C(=O)Ci-C4alkyl, -C(=O)OH, -C(=O)OCi-C4alkyl, -C(=O)NH2, - C(=O)NHCi-C4alkyl, -C(=O)N(Ci-C4alkyl)2, Ci-C4alkyl, Ci-C3alkoxy, Ci-C4haloalkyl, Ci- C4haloalkoxy, Ci-Cshydroxyalkyl, Ci-C4aminoalkyl, Ci-C4heteroalkyl, Cs-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl;or two R on the same carbon atom form an oxo;wherein Formula (E) comprises only one Ra.

[0086] In some embodiments, the E3 ligase is VHL and the (E3RL) has the following structure of Formula (E):Rb— L1Formula (E),wherein,R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -Ci-C6alkyl-CN, Ci-C6heteroalkyl, Ci- Ceheterofluoroalkyl, Ci-Ceheteroalkyl-CN, Ci-Ceheterofluoroalkyl-CN, -OH, -Ci-Cealkyl- OH, -Ci-C6haloalkyl-OH, -Ci-C6alkyl-O-L2-Ra, -Ci-C6haloalkyl-O-L2-Ra, -N(R13)2, -Ci- C6alkyl-N(R13)2, -O-Ci-C6alkyl-N(R13)2, or -O-(CH2CH2O)n-R13;WSGR Docket No. 68195-704.601L2is absent or -Ci-C6alkyl-N(R14)-;or R1is Rla;each Rlais independently hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehaloalkoxy, or Ci-Cealkoxy;X is N, -CR1-, or -CRla-;n is 1, 2, or 3;R2is hydrogen, halogen, -CN, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, - N(Ci-C4alkyl)2, Cs-Cecycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci- C4haloalkoxy, Cs-Cecycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl is optionally and independently substituted with one or more R;or R2is;R3is hydrogen, Ci-Cealkyl, Ci-Cealkyl-OH, Ci-C6alkyl-ORa, Ci-Cehaloalkyl, -Ci-Cehaloalkyl- OH, -Ci-C6alkyl-N(R13)2, -Ci-C6alkyl-N(Ra)(R14), C3-C6cycloalkyl, -Ci-C6alkyl-C3- Cecycloalkyl, -Ci-C6alkyl-(3-6 membered heterocycloalkyl optionally and independently substituted with one or more R)-Ra, -0P(=0)(0H)2, or -Ci-C6alkyl-OP(=O)(OH)2;R4is hydrogen or Ra;R5is hydrogen, Ci-Cealkyl, or Ci-C4haloalkyl;L1is -C(=O)(NR12)- or a 5-membered heteroarylene, wherein the 5-membered heteroarylene comprises at least one nitrogen atom and wherein -C(=O)(NR12)- is linked to Rbvia the C atom;Rais -S^L-S^AB;Rbis -Lp-W;R12is hydrogen, Ci-Cealkyl, or Ci-C4haloalkyl;each R13is independently hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3- Cecycloalkyl or 3-6 membered heterocycloalkyl, wherein Ci-Cealkyl, Ci-Cefluoroalkyl, Ci- Ceheteroalkyl, C3-C6cycloalkyl, and 3-6 membered heterocycloalkyl is optionally and independently substituted with one or more R;R14is hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3-C6cycloalkyl, or 3-6 membered heterocycloalkyl, wherein Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3- Cecycloalkyl, and 3-6 membered heterocycloalkyl is optionally and independently substituted with one or more R;WSGR Docket No. 68195-704.601each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C4alkyl, - S(=O)2NH2, -S(=O)2NHCi-C4alkyl, -S(=O)2N(Ci-C4alkyl)2, -S(=O)2H, -NH2, -NHCi-C4alkyl, -N(Ci-C4alkyl)2, -C(=O)Ci-C4alkyl, -C(=O)OH, -C(=O)OCi-C4alkyl, -C(=O)NH2, - C(=O)NHCi-C4alkyl, -C(=O)N(Ci-C4alkyl)2, Ci-C4alkyl, Ci-C3alkoxy, Ci-C4haloalkyl, Ci- C4haloalkoxy, Ci-Cshydroxyalkyl, Ci-C4aminoalkyl, Ci-C4heteroalkyl, Cs-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl;or two R on the same carbon atom form an oxo;wherein Formula (E) comprises only one Ra.

[0087] In some embodiments, and Formula (E) comprises only one Rawhen -Lp- and W do not comprise Ra, or Formula (E) does not comprise a Ragroup when -Lp- or W comprise the Ramoiety;

[0088] In some embodiments, one of R1, R2, R3, or R4comprises the Ramoiety. In some embodiments, one of R1comprises the Ramoiety. In some embodiments, one of R2comprises the Ramoiety. In some embodiments, one of R3comprises the Ramoiety. In some embodiments, one of R4comprises the Ramoiety. In some embodiments, one of R1, R2, R3, or R4comprises the Ramoiety when -Lp- or W do not comprise Ra. In some embodiments, -Lp- comprises Ra. In some embodiments, W comprises Ra. In some embodiments, -Lp- or W comprise Ra, and each of R1, R2, R3, and R4do not comprise Ra.

[0089] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure ofO R3R1ANA^HFormula (E-l): Formula (E-l).

[0090] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure ofO R3R1ANX^HFormula (E-l a): Formula (E-l a).WSGR Docket No. 68195-704.601

[0091] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure of Rb— L1O R3Formula (E-lb):RFormula (E-lb).

[0092] In some embodiments, X is N, or -CRla-, and R1comprises a Ragroup.

[0093] In some embodiments, X is N, or -CRla-, and R1is -L2-Ra, -O-L2-Ra, or -N(Ra)(R13).

[0094] In some embodiments, X is N, or -CRla-, and R1is -O-L2-Ra, -N(Ra)(R13), -CH2-N(Ra)(R14), -CH2CH2-N(Ra)(R14),

[0095] In some embodiments, X is N or -C(H)-. In some embodiments, X is N. In some embodiments, X is -C(Rla). In some embodiments, X is -C(R1). In some embodiments, X is -C(H)-.

[0096] In some embodiments, each Rlais independently hydrogen, -F, -Cl, -I, -CN, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2F, -OCH3, -OCHF2, or -OCF3. In some embodiments, each Rlais independently hydrogen, -F, -Cl, -I, -CN, -CH3, -CF3, -OCH3, or -OCF3. In some embodiments, each Rlais independently hydrogen, -F, -Cl, -CN, -CH3, or -OCH3. In some embodiments, each Rlais hydrogen.

[0097] In some embodiments, R2is hydrogen, halogen, -CN, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, -N(Ci-C4alkyl)2, C3-C6cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein R2is optionally substituted.2

[0098] In some embodiments, R2is hydrogen, -F, -Cl, -CN,I,, ^^-OH'Y';or. In some embodiments, R2is. In some embodiments, R3is - CH3; and R5is -C(CH3)3

[0099] In some embodiments, R4is hydrogen.

[0100] In some embodiments, R5is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R5is -CH(CH3)2, or -C(CH3)3.WSGR Docket No. 68195-704.601X^N / >szNXv O XC S In some embodiments, L1is ‘•A 5! ^ ^ oIn some embodiments,L1is In some embodiments, L1is

[0101] In some embodiments, R1is -L2-Raor -O-L2-Ra; L2is absent or -Ci-C6alkyl-N(R14)-; R4is hydrogen; and Rais -S^L-S^AB.

[0102] In some embodiments, R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -Ci-Cealkyl-CN, Ci- Ceheteroalkyl, -OH, -Ci-Cealkyl-OH, -Ci-Cehaloalkyl-OH, -Ci-C6alkyl-O-Ra, -Ci-Cehaloalkyl-O-Ra, -N(R13)2, -Ci-C6alkyl-N(R13)2, -O-Ci-C6alkyl-N(R13)2, or -O-(CH2CH2O)n-R13; L2is absent or -Ci-C6alkyl-N(R14)-; or R1is Rla.

[0103] In some embodiments, R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -OH, or -Ci-Cealkyl-O- L2-Ra; L2is absent or -Ci-C6alkyl-N(R14)-; or R1is Rla. In some embodiments, R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -OH, or -Ci-C2alkyl-O- L2-Ra; L2is absent or -Ci-C2alkyl-N(R14)-; or R1is Rla

[0104] In some embodiments, R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -Ci-C2alkyl-CN, Ci-Ceheteroalkyl, -OH, -Ci-C2alkyl-OH, -Ci-C2haloalkyl-OH, -Ci-C2alkyl-O-Ra, -Ci-C2haloalkyl-O-Ra, -N(R13)2, -Ci-C2alkyl-N(R13)2, -O-Ci-C2alkyl-N(R13)2, or -O-(CH2CH2O)n-R13; L2is absent or -Ci-C2alkyl-N(R14)-; or R1is Rla.

[0105] In some embodiments, R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R13), -CH2-CN, -CH2CH2-CN, Ci-C6heteroalkyl, -OH, -CH2-OH, -CH2CH2-OH, -Ci-C2haloalkyl-OH, -CH2-ORa, -CH2CH2-ORa, -Ci-C2haloalkyl-ORa, -N(R13)2, -N(R13)2, -CH2-N(R13)2, -CH2CH2-N(R13)2, -O-CH2CH2-N(R13)2, or -O-(CH2CH2O)n-R13; L2is absent, -CH2-N(R14)-,or -CH2CH2-N(R14)-; or R1is Rla

[0106] In some embodiments, R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -Ci-C6alkyl-O-Ra, or -Ci-C6haloalkyl-O-Ra; L2is absent or -Ci-C6alkyl-N(R14)-; or R1is Rla. In some embodiments, R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -Ci-C2alkyl-O-Ra, or -Ci-C2haloalkyl-O-Ra; L2is absent or -Ci-C2alkyl-N(R14)-; or R1is Rla. In some embodiments, R1is -L2-Ra, -O-L2-Ra, -Ci-C2alkyl-O-Ra, or -Ci-C2haloalkyl-O-Ra; L2is absent or -Ci-C2alkyl-N(R14)-; or R1is Rla.

[0107] In some embodiments, R1is -L2-Ra, -O-L2-Ra, or -N(Ra)(R14); L2is absent, -CH2-N(R14)-, or -CH2CH2-N(R14)-; or R1is Rla. In some embodiments, R1is -L2-Ra, or -O-L2-Ra; L2is absent, -CH2-N(R14)-, or -CH2CH2-N(R14)-; or R1is Rla

[0108] In some embodiments, R1is -Ra, -ORa, -CH2N(Ra)(R14), -CH2CH2-N(Ra)(R14), -OCH2-N(Ra)(R14), -OCH2CH2-N(Ra)(R14), or -N(Ra)(R14); or R1is Rla. In some embodiments, R1is -ORa, -CH2N(Ra)(R14), -CH2CH2-N(Ra)(R14), -OCH2-N(Ra)(R14), -OCH2CH2-N(Ra)(R14), or -WSGR Docket No. 68195-704.601N(Ra)(R14); or R1is Rla. In some embodiments, R1is -ORa, -CH2N(Ra)(R14), -CH2CH2-N(Ra)(R14), -OCH2CH2-N(Ra)(R14), or -N(Ra)(R14); or R1is Rla

[0109] In some embodiments, R1is -Ra, -ORa, -CH2N(Ra)(R14), -CH2CH2-N(Ra)(R14), -OCH2-N(Ra)(R14), or -OCH2CH2-N(Ra)(R14); or R1is Rla. In some embodiments, R1is -ORa, -CH2N(Ra)(R14), -CH2CH2-N(Ra)(R14), -OCH2-N(Ra)(R14), or -OCH2CH2-N(Ra)(R14); or R1is Rla. In some embodiments, R1is -ORa, -CH2N(Ra)(R14), -CH2CH2-N(Ra)(R14), or -OCH2CH2-N(Ra)(R14); or R1is Rla. In some embodiments, R1is -ORa, -CH2N(Ra)(R14), or -OCH2CH2-N(Ra)(R14); or R1is Rla. In some embodiments, R1is -CH2N(Ra)(R14), or -OCH2CH2-N(Ra)(R14); or R1is Rla. In some embodiments, R1is -ORa, or -OCH2CH2-N(Ra)(R14); or R1is Rla

[0110] In some embodiments, L2is absent or -Ci-C2alkyl-N(R14)-. In some embodiments, L2is absent. In some embodiments, L2is -Ci-C2alkyl-N(R14)-.

[0111] In some embodiments, L2is absent, -CH2-N(R14)-, or -CH2CH2-N(R14)-.

[0112] In some embodiments, L2is -CH2-N(R14)-, or -CH2CH2-N(R14)-.

[0113] In some embodiments, L2is -CH2-N(R14)-. In some embodiments, L2is -CH2CH2-N(R14)-.

[0114] In some embodiments, L2is absent or -CH2-N(R14)-. In some embodiments, L2is absent or -CH2CH2-N(R14)-.

[0115] In some embodiments, R1is hydrogen, Ci-Cealkyl, or Ci-Cealkoxy; or R1is hydrogen, halogen, -CN, -Ci-Cealkyl-CN, Ci-Cehaloalkyl, Ci-Cehaloalkoxy, Ci-Ceheteroalkyl, -OH, -Ci-C6alkyl-OH, -Ci-C6haloalkyl-OH, -O-L2-Ra, -OCH2CH2-NHR14, -OCH2CH2-N(R14)2, or -O-(CH2CH2O)n-R13; L2is absent or -CH2CH2-N(R14)-.

[0116] In some embodiments, R1is hydrogen, Ci-C4alkyl, or Ci-C4alkoxy; or R1is hydrogen, halogen, -CN, -Ci-C4alkyl-CN, Ci-C4haloalkyl, Ci-C4haloalkoxy, Ci-Ceheteroalkyl, -OH, -Ci-C4alkyl-OH, -Ci-C4haloalkyl-OH, -O-L2-Ra, -OCH2CH2-NHR14, -OCH2CH2-N(R14)2, or -O-(CH2CH2O)n-R13; L2is absent or -CH2CH2-N(R14)-.

[0117] In some embodiments, R1is hydrogen, Ci-C4alkyl, or Ci-C4alkoxy; or R1is hydrogen, halogen, -CN, -Ci-C4alkyl-CN, Ci-C4haloalkyl, Ci-C4haloalkoxy, Ci-Ceheteroalkyl, -OH, -Ci-C4alkyl-OH, -O-L2-Ra, -OCH2CH2-NHR14, -OCH2CH2-N(R14)2, or -O-(CH2CH2O)n-R13; L2is absent or -CH2CH2-N(R14)-.

[0118] In some embodiments, R1is hydrogen, Ci-C4alkyl, or Ci-C4alkoxy; or R1is hydrogen, -OH, -O-L2-Ra, -OCH2CH2-NHR14, or -OCH2CH2-N(R14)2; L2is absent or -CH2CH2-N(R14)-.

[0119] In some embodiments, L2is -CH2CH2-N(R14)-.

[0120] In some embodiments, L2is absent.WSGR Docket No. 68195-704.601

[0121] In some embodiments, R1is hydrogen, Ci-Cealkyl, or Ci-Cealkoxy; or R1is hydrogen, halogen, -CN, Ci-Cealkyl-CN, Ci-Cehaloalkyl, Ci-Cehaloalkoxy, Ci-Ceheteroalkyl, -OH, -O-Ra, -N(R13)2, -N(Ra)(R13), -N(R13)2, -O-(CH2CH2O)n-R13, -OCH2CH2-NHR14, or -OCH2CH2-N(Ra)(R14).

[0122] In some embodiments, R1is -O-L2-Ra.

[0123] In some embodiments, R1is -O-Ra, -N(Ra)(R13), -CH2-NHR14, -CH2-N(Ra)(R14), -OCH2CH2-NHR14, or -OCH2CH2-N(Ra)(R14).

[0124] In some embodiments, R1is -O-Ra, -CH2-N(Ra)(R14), or -OCH2CH2-N(Ra)(R14). In some embodiments, R1is -O-Raor -OCH2CH2-N(Ra)(R14). In some embodiments, R1is -OCH2CH2-N(Ra)(R14).

[0125] In some embodiments,R1is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CF3, -CHF2, -CH2F, -CN, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -OCHF2, -OCF3,or R1is -OH, -NH2, -NH(CH3), -N(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2OCH3,- CH2CH2OCH2CH3, -CH2CH2OCH2CF3, -CH2CH2OCH2CHF2, -CH2CH2OCH2CH2F, - CH2CH2OCH2CH2OH, -OCH2CH2NHCH3, -OCH2CH2NHCH2CH3, -OCH2CH2NHCH2CF3, -OCH2CH2NHCH2CHF2, -OCH2CH2NHCH2CH2F, -OCH2CH2NHCH2CN, - OCH2CH2NHCH2CH2OH, -OCH2CH2NHCH2OCH2CH3, -OCH2CH2NHCH2OCH2CHF2, or -OCH2CH2NHCH2CH2OCF3;orR1is -ORa, -NHRa, -NRa(CH3), -OCH2CH2N(Ra)CH3, -OCH2CH2N(Ra)CH2CH3, - OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CF3, -OCH2CH2N(Ra)CH2CHF2, - OCH2CH2N(Ra)CH2CH2F, -OCH2CH2N(Ra)CH2CN, -OCH2CH2N(Ra)CH2CH2OH, - OCH2CH2N(Ra)CH2OCH2CH3, -OCH2CH2N(Ra)CH2OCH2CHF2, or - OCH2CH2N(Ra)CH2CH2OCF3.

[0126] In some embodiments,R1is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CF3, -CHF2, -CH2F, -CN, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OC(CH3)3-OCHF2, -OCF3,or R1is -OH, -NH2, -NH(CH3), -N(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2OCH3,- CH2CH2OCH2CH3, -CH2CH2OCH2CF3, -CH2CH2OCH2CHF2, -CH2CH2OCH2CH2F, - OCH2CH2OCH2CH2OH, -OCH2CH2NHCH3, -OCH2CH2NHCH2CH3, - OCH2CH2NHCH2CF3, -OCH2CH2NHCH2CHF2, -OCH2CH2NHCH2CH2F, - OCH2CH2NHCH2CN, -OCH2CH2NHCH2CH2OH, -OCH2CH2NHCH2OCH2CH3, - OCH2CH2NHCH2OCH2CHF2, or -OCH2CH2NHCH2CH2OCF3;WSGR Docket No. 68195-704.601orR1is -ORa, -OCH2CH2N(Ra)CH3, -OCH2CH2N(Ra)CH2CH3, -OCH2CH2N(Ra)CH2CH2OH, - OCH2CH2N(Ra)CH2CF3, -OCH2CH2N(Ra)CH2CHF2, -OCH2CH2N(Ra)CH2CH2F, - OCH2CH2N(Ra)CH2CN, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2OCH2CH3, - OCH2CH2N(Ra)CH2OCH2CHF2, or -OCH2CH2N(Ra)CH2CH2OCF3.

[0127] In some embodiments,R1is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -OCH3, -OCH2CH3, -CH2CH2CH3, -OCH(CH3)2, or - OC(CH3)3;or R1is -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -OCHF2, -OCF3, -CH2OH, -CH2CH2OH -CH2OCH3,-CH2OCH2CH3, -CH2OCH2CF3, -CH2OCH2CHF2, - CH2OCH2CH2F, -CH2OCH2CH2OH, -CH2NHCH3, -CH2NHCH2CH3, -CH2NHCH2CF3, - CH2NHCH2CHF2, -CH2NHCH2CH2F, -CH2NHCH2CH2CN, -CH2NHCH2CH2OH, - CH2NHCH2CH2OCH2CH3, -CH2NHCH2CH2OCH2CHF2, -CH2NHCH2CH2OCF3, - OCH2CH2OCH3,-OCH2CH2OCH2CH3, -OCH2CH2OCH2CF3, -OCH2CH2OCH2CHF2, - OCH2CH2OCH2CH2F, -OCH2CH2OCH2CH2OH, -OCH2CH2NHCH3, - OCH2CH2NHCH2CH3, -OCH2CH2NHCH2CF3, -OCH2CH2NHCH2CHF2, - OCH2CH2NHCH2CH2F, -OCH2CH2NHCH2CH2CN, -OCH2CH2NHCH2CH2OH, - OCH2CH2NH CH2CH2OCH2CH3, -OCH2CH2NHCH2CH2OCH2CHF2, or - OCH2CH2NHCH2CH2OCF3.

[0128] In some embodiments, R1is -ORa, -OCH2CH2NH(Ra), -OCH2CH2N(Ra)CH3, -OCH2CH2N(Ra)CH2CH3, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CF3, -OCH2CH2N(Ra)CH2CHF2, -OCH2CH2N(Ra)CH2CH2F, -OCH2CH2N(Ra)CH2CH2CN, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CH2OCH2CH3, -OCH2CH2N(Ra)CH2CH2OCH2CHF2, -OCH2CH2N(Ra)CH2CH2OCF3.

[0129] In some embodiments, R1is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -OCH3, -OCH2CH3, -CH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -CH2OH, or -CH2CH2OH.

[0130] In some embodiments, R1is -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -OCHF2, -OCF3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CF3, -CH2CH2OCH2CHF2, -CH2CH2OCH2CH2F, -CH2CH2OCH2CH2OH, -OCH2CH2NHCH3, -OCH2CH2NHCH2CH3, -OCH2CH2NHCH2CF3, -OCH2CH2NHCH2CHF2, -OCH2CH2NHCH2CH2F, -OCH2CH2NHCH2CH2CN, -OCH2CH2NHCH2CH2OH, -OCH2CH2NHCH2CH2OCH2CH3, -OCH2CH2NHCH2CH2OCH2CHF2, or -OCH2CH2NHCH2CH2OCF3.WSGR Docket No. 68195-704.601

[0131] In some embodiments, R1is -ORa, -NHRa, -NRa(CH3), -OCH2CH2NH(Ra), -OCH2CH2N(Ra)CH3, -OCH2CH2N(Ra)CH2CH3, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CF3, -OCH2CH2N(Ra)CH2CHF2, -OCH2CH2N(Ra)CH2CH2F, -OCH2CH2N(Ra)CH2CH2CN, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CH2OCH2CH3, -OCH2CH2N(Ra)CH2CH2OCH2CHF2, or -OCH2CH2N(Ra)CH2CH2OCF3.

[0132] In some embodiments, R1is -ORa, -OCH2CH2NH(Ra), -OCH2CH2N(Ra)CH3, -OCH2CH2N(Ra)CH2CH3, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CF3, -OCH2CH2N(Ra)CH2CHF2, -OCH2CH2N(Ra)CH2CH2F, -OCH2CH2N(Ra)CH2CH2CN, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra) CH2CH2OCH2CH3, -OCH2CH2N(Ra)CH2CH2OCH2CHF2, or -OCH2CH2N(Ra)CH2CH2OCF3.

[0133] In some embodiments, R1is -CH2NH(Ra), -CH2N(Ra)CH3, -CH2N(Ra)CH2CH3, -CH2N(Ra)CH2CH2OH, -CH2N(Ra)CH2CF3, -CH2N(Ra)CH2CHF2, -CH2N(Ra)CH2CH2F, -CH2N(Ra)CH2CH2CN, -CH2N(Ra)CH2CH2OH, -CH2N(Ra)CH2CH2OCH2CH3, -CH2N(Ra)CH2CH2OCH2CHF2, or -CH2N(Ra)CH2CH2OCF3.

[0134] In some embodiments, R3is hydrogen, Ci-C4alkyl, Ci-C4alkyl-OH, Ci-C4alkyl-ORa, Ci-C4haloalkyl, -Ci-C4haloalkyl-OH, -Ci-C4alkyl-NH2, -Ci-C4alkyl-NH(Ci-C4alkyl), -Ci-C4alkyl-N(Ci-C4alkyl)2, -Ci-C4alkyl-N(Ra)(R14), C3-C6cycloalkyl, or -Ci-C4alkyl-C3-C6cycloalkyl.

[0135] In some embodiments, R3is hydrogen, Ci-C4alkyl, Ci-C2alkyl-OH, Ci-C2alkyl-ORa, Ci-C2haloalkyl, -Ci-C2alkyl-NH2, -Ci-C2alkyl-NH(Ci-C4alkyl), -Ci-C2alkyl-N(Ci-C4alkyl)2, -Ci-C2alkyl-N(Ra)(R14), C3-C6cycloalkyl, or -Ci-C2alkyl-C3-C6cycloalkyl.

[0136] In some embodiments, R3is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, - CH2OH, -CF3, -CHF2, -CH2F, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R3is -CH2ORa, -CH2NH(Ra), or -CH2N(Ra)(CH3).

[0137] In some embodiments, R3is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OH, -CF3, -CHF2, -CH2F, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R3is -CH2ORa, -CH2NH(Ra), -CH2N(Ra)(CH3), -CH2N(Ra)(CH2F), -CH2N(Ra)(CHF2), -CH2N(Ra)(CHF3), -CH2N(Ra)(CH2CH2F), -CH2N(Ra)(CH2CHF2), -CH2N(Ra)(CH2CHF3).

[0138] In some embodiments, R3is hydrogen, -CH3, -CH2OH, -CF3, -CHF2, -CH2F, -CH2NH2, or -CH2NH(CH3); or R3is -CH2ORa, -CH2NH(Ra), -CH2N(Ra)(CH3), -CH2N(Ra)(CH2F), -CH2N(Ra)(CHF2), -CH2N(Ra)(CHF3), -CH2N(Ra)(CH2CH2F), -CH2N(Ra)(CH2CHF2), -CH2N(Ra)(CH2CHF3).

[0139] In some embodiments, R3is hydrogen, -CH3, -CH2OH, -CF3, -CHF2, -CH2F, -CH2NH2, or -CH2NH(CH3).

[0140] In some embodiments, R3is -CH2ORa, -CH2NH(Ra), -CH2N(Ra)(CH3), -WSGR Docket No. 68195-704.601CH2N(Ra)(CH2F), -CH2N(Ra)(CHF2), -CH2N(Ra)(CHF3), -CH2N(Ra)(CH2CH2F), -CH2N(Ra)(CH2CHF2), -CH2N(Ra)(CH2CHF3).

[0141] In some embodiments,R1is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -OCH3, -OCH2CH3, -CH2CH2CH3, -OCH(CH3)2, or- OC(CH3)3;or R1is -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -OCHF2, -OCF3, -CH2OH, or -CH2CH2OH -CH2CH2OCH3,-CH2CH2OCH2CH3, -CH2CH2OCH2CF3, - CH2CH2OCH2CHF2, -CH2CH2OCH2CH2F, -CH2CH2OCH2CH2OH, -OCH2CH2NHCH3, - OCH2CH2NHCH2CH3, -OCH2CH2NHCH2CF3, -OCH2CH2NHCH2CHF2, - OCH2CH2NHCH2CH2F, -OCH2CH2NHCH2CN, -OCH2CH2NHCH2CH2OH, - OCH2CH2NHCH2OCH2CH3, -OCH2CH2NHCH2OCH2CHF2, or - OCH2CH2NHCH2CH2OCF3;R3is -CH2ORa, -CH2NH(Ra), or -CH2N(Ra)(CH3).

[0142] In some embodiments, R1is -ORa, -NHRa, -NRa(CH3), -OCH2CH2N(Ra)CH3, -OCH2CH2N(Ra)CH2CH3, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CF3, -OCH2CH2N(Ra)CH2CHF2, -OCH2CH2N(Ra)CH2CH2F, -OCH2CH2N(Ra)CH2CN, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2OCH2CH3, -OCH2CH2N(Ra)CH2OCH2CHF2, or -OCH2CH2N(Ra)CH2CH2OCF3; R3is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OH, -CF3, -CHF2, -CH2F, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0143] In some embodiments, R1is -ORa, -CH2N(Ra)CH3, -CH2N(Ra)CH2CH3, -CH2N(Ra)CH2CH2OH, -CH2N(Ra)CH2CF3, -CH2N(Ra)CH2CHF2, -CH2N(Ra)CH2CH2F, -CH2N(Ra)CH2CN, -CH2N(Ra)CH2CH2OH, -CH2N(Ra)CH2OCH2CH3, -CH2N(Ra)CH2OCH2CHF2, -CH2N(Ra)CH2CH2OCF3, -OCH2CH2N(Ra)CH3, -OCH2CH2N(Ra)CH2CH3, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CF3, -OCH2CH2N(Ra)CH2CHF2, -OCH2CH2N(Ra)CH2CH2F, -OCH2CH2N(Ra)CH2CN, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2OCH2CH3, -OCH2CH2N(Ra)CH2OCH2CHF2, or -OCH2CH2N(Ra)CH2CH2OCF3; R3is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OH, -CF3, -CHF2, -CH2F, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0144] In some embodiments, R1is -ORa, -OCH2CH2N(Ra)CH3, -OCH2CH2N(Ra)CH2CH3, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2CF3, -OCH2CH2N(Ra)CH2CHF2, -OCH2CH2N(Ra)CH2CH2F, -OCH2CH2N(Ra)CH2CN, -OCH2CH2N(Ra)CH2CH2OH, -OCH2CH2N(Ra)CH2OCH2CH3, -OCH2CH2N(Ra)CH2OCH2CHF2, or -WSGR Docket No. 68195-704.601OCH2CH2N(Ra)CH2CH2OCF3; R3is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OH, -CF3, -CHF2, -CH2F, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R12is hydrogen, Ci-Cealkyl, or Ci-C4haloalkyl. In some embodiments, R12is hydrogen or -CH3. In some embodiments, R12is hydrogen.

[0145] In some embodiments, each R13is independently hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3-C6cycloalkyl or 3-6 membered heterocycloalkyl, wherein each R13is independently optionally substituted.

[0146] In some embodiments, each R13is independently hydrogen, Ci-Cealkyl, or Ci-Cefluoroalkyl, wherein Ci-Cealkyl, and Ci-Cefluoroalkyl is optionally substituted with one or more R.

[0147] In some embodiments, each R13is independently hydrogen, -CH3, -CF3, -CHF2, -CH2F, -CH2CH3, -CH2CF3, -CH2CHF2, -CH2CH2F, or -CH2CH2R. In some embodiments, each R13is independently hydrogen, -CH3, -CF3, -CHF2, -CH2F, -CH2CH3, -CH2CF3, -CH2CHF2, -CH2CH2F, or -CH2CH2R.

[0148] In some embodiments, each R13is independently hydrogen, -CH3, -CF3, -CHF2, -CH2F, -CH2CH3, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2CN, -CH2CH2OH, -CH2CH2OCH2CH3, -CH2CH2OCH(CH3)2, -CH2CH2OCH2CH2F, -CH2CH2OCH2CHF2, or -CH2CH2OCF3. In some embodiments, each R13is independently hydrogen, -CH3, -CHF2, -CH2F, -CH2CH3, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2CN, -CH2CH2OH, -CH2CH2OCH2CH3, -CH2CH2OCH(CH3)2, -CH2CH2OCH2CH2F, -CH2CH2OCH2CHF2, or -CH2CH2OCF3. In some embodiments, each R13is independently hydrogen, -CH3, -CHF2, -CH2F, -CH2CH3, -CH2CF3, -CH2CHF2, or -CH2CH2F. In some embodiments, each R13is independently hydrogen, -CH3, or -CH2CH3. In some embodiments, each R13is independently hydrogen, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, or -CH2CH2F.

[0149] In some embodiments, R14is hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3-C6cycloalkyl, or 3-6 membered heterocycloalkyl, wherein Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3-C6cycloalkyl, and 3-6 membered heterocycloalkyl is optionally and independently substituted with one or more R.

[0150] In some embodiments, R14is hydrogen, Ci-Cealkyl, or Ci-Cefluoroalkyl, wherein Ci-Cealkyl, and Ci-Cefluoroalkyl is optionally substituted with one or more R.

[0151] In some embodiments, R14is Ci-Cefluoroalkyl.

[0152] In some embodiments, each R is independently halogen, -CN, -OH, -NH2, -NHCi-C4alkyl, -N(Ci-C4alkyl)2, Ci-C4alkoxy, Ci-C4haloalkyl, or Ci-C4haloalkoxy. In some embodiments, each R is independently halogen, -CN, -OH, Ci-C4alkoxy, or Ci-C4haloalkoxy. InWSGR Docket No. 68195-704.601some embodiments, each R is independently F, -CN, -OH, -OCH3, -OCH2CH3, -CH2CH2CH3, -OCH(CH3)2, -0CF3, -0CHF2, -0CH2F, -OCH2CF3, -OCH2CHF2, or -OCH2CH2F.

[0153] In some embodiments, R14is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2OH, -CH2CH2OCH3,-CH2CH2OCH2CH3, -CH2CH2OCF3, -CH2CH2OCHF2, -CH2CH2OCH2F, -CH2CH2OCH2CF3, -CH2CH2OCH2CHF2, -CH2CH2OCH2CH2F, -CH2CH2OCH2CH2OH, -CH2CH2NHCH3, -CH2CH2NHCH2CH3, -CH2CH2NHCH2CF3, -CH2CH2NHCH2CHF2, -CH2CH2NHCH2CH2F, -CH2CH2NHCH2CN, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, -CH2CH2NHCH2CH2OH, -CH2CH2NHCH2OCH2CH3, -CH2CH2NHCH2OCH2CHF2, or -CH2CH2NHCH2CH2OCF3.

[0154] In some embodiments, R14is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2OH, -CH2CH2OCH3,-CH2CH2OCH2CH3, -CH2CH2OCF3, -CH2CH2OCHF2, -CH2CH2OCH2F, -CH2CH2OCH2CF3, -CH2CH2OCH2CHF2, -CH2CH2OCH2CH2F, -CH2CH2OCH2CH2OH, -CH2CH2NHCH3, -CH2CH2NHCH2CH3, -CH2CH2NHCH2CF3, -CH2CH2NHCH2CHF2, -CH2CH2NHCH2CH2F, -CH2CH2NHCH2CN, -CH2CN, -CH2CH2CN, or -CH2CH2CH2CN.

[0155] In some embodiments, R14is hydrogen, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2OH, -CH2CH2OCH3,-CH2CH2OCH2CH3, -CH2CH2OCH2CF3, -CH2CH2OCH2CHF2, -CH2CH2OCH2CH2F, -CH2CN, -CH2CH2CN, or -CH2CH2CH2CN.

[0156] In some embodiments, R14is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, or -CH2CH2CN.

[0157] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-2):Rb— L1L2-S1-LC-S2O R3O'H I ||R2Formula (E-2).

[0158] In some embodiments of Formula (E-2), L2is absent or -CH2CH2-N(R14)-. In some embodiments of Formula (E-2), L2is absent. In some embodiments of Formula (E-2), L2is -CH2CH2-N(R14)-.

[0159] In some embodiments of Formula (E-2), L2is -CH2CH2-N(R14)-, and Formula (E-2) has the following structure of Formula (E-2a):WSGR Docket No. 68195-704.601R14'N-S1-LC-S2-ABFormula (E-2a).

[0160] In some embodiments of Formula (E-2), L2is absent, and Formula (E-2) has the following structure of Formula (E-2b):O R3O'HRFormula (E-2b).

[0161] In some embodiments of Formula (E-2), Formula (E-2a), or Formula (E-2b), X is N or -C(H)-. In some embodiments of Formula (E-2), Formula (E-2a), or Formula (E-2b), X is N. In some embodiments of Formula (E-2), Formula (E-2a), or Formula (E-2b), X is -C(H)-.

[0162] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-3):O R3I2-S1-LC-S2-ABM.0^HR2Formula (E-3).

[0163] In some embodiments of Formula (E-3), L2is absent or -CH2CH2-N(R14)-. In some embodiments of Formula (E-3), L2is absent. In some embodiments of Formula (E-3), L2is -CH2CH2-N(R14)-.

[0164] In some embodiments of Formula (E-3), L2is -CH2CH2-N(R14)-, and Formula (E-3) has the following structure of Formula (E-3a):R14XN-S i_Lc-S2— ABO R3HR2Formula (E-3 a).

[0165] In some embodiments of Formula (E-3), L2is absent, and Formula (E-3) has the following structure of Formula (E-3b):WSGR Docket No. 68195-704.601S1-Lc-S2— ABFormula (E-3b).

[0166] In some embodiments of Formula (E-3), Formula (E-3a), or Formula (E-3b), X is N or -C(H)-. In some embodiments of Formula (E-3), Formula (E-3a), or Formula (E-3b), X is N. In some embodiments of Formula (E-3), Formula (E-3a), or Formula (E-3b), X is -C(H)-.

[0167] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-4):N HR2Formula (E-4).

[0168] In some embodiments of Formula (E-4), X is N or -C(H)-. In some embodiments of Formula (E-4), X is N. In some embodiments of Formula (E-4), X is -C(H)-.

[0169] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-5):o R3H, SFormula (E-5).

[0170] In some embodiments of Formula (E-5), X is N or -C(H)-. In some embodiments of Formula (E-5), X is N. In some embodiments of Formula (E-5), X is -C(H)-.

[0171] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-3):Rb— L1O R3L2-S1-LC-S2-ABH I 1R2Formula (E-6).WSGR Docket No. 68195-704.601

[0172] In some embodiments of Formula (E-6), L2is -CH2-N(R14)- or -CH2CH2-N(R14)-. In some embodiments of Formula (E-6), L2is -CH2-N(R14)-. In some embodiments of Formula (E-6), L2is -CH2CH2-N(R14)-.

[0173] In some embodiments of Formula (E-6), L2is -CH2-N(R14)-, and Formula (E-6) has the following structure of Formula (E-6a):Formula (E-6a).

[0174] In some embodiments, the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-7):Rb— L1Formula (E-7).

[0175] In some embodiments of Formula (E-7), L2is -CH2-N(R14)- or -CH2CH2-N(R14)-. In some embodiments of Formula (E-7), L2is -CH2-N(R14)-. In some embodiments of Formula (E- 7), L2is -CH2CH2-N(R14)-.

[0176] In some embodiments of Formula (E-7), L2is -CH2-N(R14)-, and Formula (E-7) has the following structure of Formula (E-7a):Formula (E-7a).

[0177] In some embodiments, the E3 ligase is VHL and (E3RL) has one of the following structures:WSGR Docket No. 68195-704.601

[0178] In some embodiments, the E3 ligase is VHL and (E3RL) is

[0179] In some embodiments, L1is -C(=O)(NR12)-.

[0180] In some embodiments, E3RL is a VHL binder. In some embodiments, E3B comprisesWSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601embodiments, E3B comprisesWSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0181] In some embodiments, W-LP-E3RL is:wWSGR Docket No. 68195-704.601w E3RL-, wherein W-LP-E3RL is connected to S1-L-S2-AB at W, E3RL, or

[0182] In some embodiments, Lpis absent. In some embodiments, Lpis flexible. In some embodiments, Lpis rigid. In some embodiments, the Lpcomprises a linear structure. In some embodiments, Lpcomprises a non-linear structure. In some embodiments, Lpcomprises a branched structure. In some embodiments, Lplinker comprises a cyclic structure. In some embodiments, Lpcomprises one or more linear structures, one or more non-linear structures, one or more branched structures, one or more cyclic structures, one or more flexible moieties, one or more rigid moieties, or combinations thereof. In some embodiments, Lphas 1 to 100 atoms, 1 to 50 atoms, 1 to 30 atoms, 1 to 20 atoms, 1 to 15 atoms, 1 to 10 atoms, or 1 to 5 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length. In some embodiments, the linker has 1 to 20 atoms in length.,, I — ( A ) — (Lqn— f A J — I

[0183] In some embodiments, Lpis absent, -La-Lb-, -Lb-La-, or ' « •Lais unsubstituted or substituted Ci-Cioalkylene, unsubstituted or substituted Ci-Cioheteroalkylene, or C4-C2opolyethylene glycol;Lbis absent, -NR4C(=O)-(CH2)m-, -(CH2)m-NR4C(=O)-, -(CH2)q-(CH2CH2O)m-(CH2)q-, -C(=O)-(CH2CH2O)m-(CH2)q-, -C(=O)NR4-(CH2CH2O)m-(CH2)q-, -(CH2CH2O)m-(CH2)q-C(=O)NR4-, -(CH2CH2O)m-(CH2)q-NR4C(=O)-, or -NR4C(=O)-(CH2CH2O)m-(CH2)q-; each q is independently 0, 1, or 2; each m is independently 1, 2, 3, 4, 5, 6, 7, or 8;each A is independently absent, substituted or unsubstituted monocyclic Cs-Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2as r>j each Lqis independently absent,X •o^°-oeach x is independently 1, 2, 3, 4, 5, 6, 7, or 8;each R2ais independently hydrogen or Ci-Cealkyl.

[0184] In some embodiments, Lpis absent. In some embodiments, Lpis -La-Lb-. In some h I - ( & ) - (L embodiments, Lpis -L -La-. In some embodiments, Lpis1 q)n—( &WSGR Docket No. 68195-704.601

[0186] In some embodiments, each A is independently absent,each x is independently 1, 2, 3, 4, 5, 6, 7, or 8;each Rais independently hydrogen or substituted or unsubstituted Ci-Cealkyl.

[0187] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n isWSGR Docket No. 68195-704.601

[0188] In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6.

[0189] In some embodiments, Rais hydrogen. In some embodiments, each Rais independently substituted or unsubstituted Ci-Cealkyl. In some embodiments, each Rais independently hydrogen, methyl, ethyl, propyl, or iso-propyl. In some embodiments, each Rais independently hydrogen or methyl.

[0190] In some embodiments, (Lq)nis absent,

[0191] In some embodiments of a conjugate of Formula (I), LpisH

[0192] In some embodiments of a conjugate of Formula (I), Lpis

[0193] In some embodiments of a conjugate of Formula (I), Lpis

[0194] In some embodiments of a conjugate of Formula (I), Lpiso, or. Strategies for the design of protac linkers can also be found in: Yawen Dong, et al., Characteristic roadmap of linkerWSGR Docket No. 68195-704.601governs the rational design ofPROTACs, Acta Pharmaceutica SinicaB, Volume 14, Issue 10, 2024, Pages 4266-4295; Troup RI, et al., Current strategies for the design of PROTAC linkers: a critical review. Explor Target Antitumor Ther. 2020;1(5):273-312; N. A. Zografou-Barredo, et al,, A beginner’s guide to current synthetic linker strategies towards VHL-recruiting PROTACs, Bioorganic & Medicinal Chemistry, Volumes 88-89, 2023, 117334; Zagidullin A, et al., Novel approaches for the rational design of PROTAC linkers. Explor Target Antitumor Ther.2020;1:381-90.

[0195] In some embodiments of a conjugate of Formula (I), S1is absent.

[0196] In some embodiments of a conjugate of Formula (I), D comprises a nucleophilic moiety capable of reacting with an electrophilic moiety of L. In some embodiments of a conjugate of Formula (I), D comprises a nucleophilic moiety capable of reacting with an electrophilic moiety of L, wherein D comprises an E3 Ligase binder and the E3 Ligase ligand comprises a nucleophilic moiety capable of reacting with an electrophilic moiety of L. In some embodiments of a conjugate of Formula (I), D comprises a nucleophilic moiety capable of reacting with an electrophilic moiety of L, wherein the nucleophilic moiety is an amine (e.g., -NH-). In some embodiments of a conjugate of Formula (I), D comprises a moiety capable of forming a covalent bond with L. In some embodiments of a conjugate of Formula (I), D comprises a moiety capable of forming a covalent bond with L, wherein D comprises an E3 Ligase ligand and the E3 Ligase ligand comprises a moiety capable of forming a covalent bond with L. In some embodiments of a conjugate of Formula (I), D comprises a moiety capable of forming a covalent bond with L, wherein the moiety is an amine (e.g., -NH-). In some embodiments of a conjugate of Formula (I), D comprises an E3 Ligase ligand and -L-S2-AB is covalently attached to the E3 Ligase ligand. In some embodiments of a conjugate of Formula (I), D comprises an E3 Ligase ligand and -L-S2-AB is covalently attached to an amine (e.g., -NH-) of the E3 Ligase ligand.

[0197] In some embodiments of a conjugate of Formula (I), S1is a spacer. In some embodiments of a conjugate of Formula (I), D comprises a nucleophilic moiety capable of reacting with an electrophilic moiety of S1. In some embodiments of a conjugate of Formula (I), D comprises a nucleophilic moiety capable of reacting an electrophilic moiety of S1, wherein D comprises an E3 Ligase binder and the E3 Ligase ligand comprises a nucleophilic moiety capable of reacting with an electrophilic moiety of S1. In some embodiments of a conjugate of Formula (I), D comprises a nucleophilic moiety capable of reacting with an electrophilic moiety of S1, wherein the nucleophilic moiety is -OH or -NH2. In some embodiments of a conjugate of Formula (I), D comprises a nucleophilic moiety capable of reacting with an electrophilic moiety of S1, wherein the nucleophilic moiety is -OH. In some embodiments of a conjugate of Formula (I), D comprises a moiety capable of forming a covalent bond with S1. In some embodiments ofWSGR Docket No. 68195-704.601a conjugate of Formula (I), D comprises a moiety capable of forming a covalent bond with S1, wherein D comprises an E3 Ligase ligand and the E3 Ligase ligand comprises a moiety capable of forming a covalent bond with S1. In some embodiments of a conjugate of Formula (I), D comprises a moiety capable of forming a covalent bond with S1, wherein the moiety is -OH or NH2. In some embodiments of a conjugate of Formula (I), D comprises a moiety capable of forming a covalent bond with S1, wherein the moiety is -OH. In some embodiments of a conjugate of Formula (I), D comprises an E3 Ligase ligand and -S1-L-S2-AB is covalently attached to the E3 Ligase ligand. In some embodiments of a conjugate of Formula (I), D comprises an E3 Ligase ligand and -S1-L-S2-AB is covalently attached to a -OH or -NH2 of the E3 Ligase ligand. In some embodiments of a conjugate of Formula (I), D comprises an E3 Ligase ligand and -S1-L-S2-AB is covalently attached to a -OH of the E3 Ligase ligand. In some embodiments of a conjugate of Formula (I), S1allows for the conjugation of an OH containing degrader via a carbamate to the cleavable linker. In some embodiments, a carbamate linkage allows for aqueous stability.

[0198] In some embodiments of a conjugate of Formula (I), S1comprises an alkylene spacer. In some embodiments of a conjugate of Formula (I), S1comprises a Ci-Cealkylene spacer. In some embodiments of a conjugate of Formula (I), S1comprises a -CH2- spacer.

[0199] In some embodiments of a conjugate of Formula (I), S1comprises an amide moiety. Insome embodiments of a conjugate of Formula (I), S1comprisesN, or. In some embodiments of a conjugate of Formula (I), S1'N comprises. In some embodiments of a conjugate of Formula (I), S1comprisesN, or. In some embodiments, S1written from leftWSGR Docket No. 68195-704.601to right is also intended to encompass the regioisomer that would result from writing the structure from right to left.

[0200] In some embodiments of a conjugate of Formula (I), L comprises an acid cleavable linker.

[0201] In some embodiments of a conjugate of Formula (I), L comprises an N-acyl hydrazone linkage, a carbonate linker, or an ester linkage. In some embodiments of a conjugate of Formula (I), L comprises an N-acyl hydrazone linkage. In some embodiments of a conjugate of Formula (I), L comprises a carbonate linker. In some embodiments of a conjugate of Formula (I), L comprises an ester linkage.

[0202] In some embodiments of a conjugate of Formula (I), L comprises. In some embodiments, L written from left to right is also intended to encompass the regioisomer that would result from writing the structure from right to left.O

[0203] In some embodiments of a conjugate of Formula (I), L comprises.0 ih'S'

[0204] In some embodiments of a conjugate of Formula (I), L comprises°. In some embodiments, L written from left to right is also intended to encompass the regioisomer that would result from writing the structure from right to left.

[0205] In some embodiments of a conjugate of Formula (I), L comprises a disulfide linker. In some embodiments of a conjugate of Formula (I), L comprises a sterically hindered disulfide linker.

[0206] In some embodiments of a conjugate of Formula (I), L comprises an enzyme cleavable linker. In some embodiments, L is an enzyme cleavable linker, wherein the enzyme is overexpressed in tumors as compared to healthy tissues, the enzyme is expressed in tumors but not present in human plasma, or the enzyme is more active in tumor tissues as compared to healthy tissues or human plasma.

[0207] In some embodiments, L is an enzyme cleavable linker that is stable in plasma. In some embodiments, L is an enzyme cleavable linker that is stable in human plasma.

[0208] In some embodiments, L is a cleavable linker, wherein L facilitates release of D in a cell. In some embodiments, L comprises an acid-cleavable linker (e.g., a hydrazone), a glutathione (GSH)-cleavable linker (e.g., a disulfide), or an enzyme-cleavable linker (e.g., a dipeptide).WSGR Docket No. 68195-704.601

[0209] In some embodiments, L comprises an acid cleavable linker, for example, L comprises a hydrazone group, a carbonate group, or an ester group. In some embodiments, L comprises a pH sensitive group.

[0210] In some embodiments, L comprises a glutathione (GSH)-cleavable linker, for example, L comprises a disulfide group. In some embodiments, L comprises a reducible linker.In some embodiments, L comprises an enzyme cleavable linker, wherein L comprises a protease cleavable linker, a glycosidase cleavable linker (e.g., a P-glucuronidase-cleavable linker), a P-galactosidase-cleavable linker, or a phosphatase cleavable linker.

[0211] In some embodiments of a conjugate of Formula (I), L comprises a protease cleavable linker.

[0212] In some embodiments of a conjugate of Formula (I), L comprises a glycosidase cleavable linker.

[0213] In some embodiments of a conjugate of Formula (I), L comprises a P-glucuronidase-cleavable linker.

[0214] In some embodiments of a conjugate of Formula (I), L comprises a galactosidase cleavable linker.

[0215] In some embodiments of a conjugate of Formula (I), L comprises a P-galactosidase-cleavable linker.

[0216] In some embodiments of a conjugate of Formula (I), L comprisesCOOH. In some embodiments, L written from left to right is also intended to encompass the regioisomer that would result from writing the structure from right to left.

[0217] In some embodiments of a conjugate of Formula (I), L comprisesOH OHO^NOHWSGR Docket No. 68195-704.601COOHembodiments of a conjugate of Formula (I), L comprisesembodiments of a conjugate of Formula (I), L comprisessome embodiments of a conjugate of Formula (I), L compriseswherein R1is hydrogen, Ci-Cealkyl, or Ci- C6alkyleneN(Ci-C6alkyl)2. In some embodiments of a conjugate of Formula (I), L comprises OHOH In some embodiments of a conjugate of Formula (I), L comprises OH HO HOOH. In some embodiments of a conjugate of Formula (I), Lcompriseswherein R1is hydrogen, Ci-Cealkyl, or Ci- C6alkyleneN(Ci-C6alkyl)2. In some embodiments, R1is hydrogen. In some embodiments, R1is methyl or ethyl. In some embodiments, R1is -CH2CH2N(CH3)2.WSGR Docket No. 68195-704.601

[0218] In some embodiments of a conjugate of Formula (I), L comprises

[0219] In some embodiments, L written from left to right is also intended to encompass the regioisomer that would result from writing the structure from right to left.

[0220] In some embodiments of a conjugate of Formula (I), L comprises a phosphatase cleavable linker.O

[0221] In some embodiments of a conjugate of Formula (I), L comprisesorO O O TXT \ I \ IOHOH. In some embodiments of a conjugate of Formula (I), L comprises0H. In O Of \ Isome embodiments of a conjugate of Formula (I), L comprisesOH jn someembodiments, L written from left to right is also intended to encompass the regioisomer that would result from writing the structure from right to left.WSGR Docket No. 68195-704.601

[0222] In some embodiments of a conjugate of Formula (I), L comprises a peptide. In some embodiments of a conjugate of Formula (I), L comprises a dipeptide. In some embodiments of a conjugate of Formula (I), L comprises a tripeptide. In some embodiments of a conjugate of Formula (I), L comprises a tetrapeptide.

[0223] In some embodiments, peptide sequences that are incorporated in the cleavable linker include: Arg, Arg-Arg, Phe-Arg, Phe-Cit, Ile-Pro Lys, Lys-Lys, Arg-Lys, Ala-Leu-Ala-Leu, Phe-Lys, Phe-Lys-Ala, Val-Cit, Val-Arg, Ala-Phe-Lys, D-Ala-Phe-Lys, Met, Met-Met, Phe-Met, Tyr-Met, Ala-Met, Ala-Phe-Met, Phe- Ala-Met, Ala-Tyr-Met, Phe-Tyr-Met, Ser-Ser-Tyr-Tyr-Ser-Arg, Phe-Pro-Lys-Phe-Phe-Ser-Arg-Gln, Lys-Pro-Ile-Glu-Phe-Nph-Arg-Leu, Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln, Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln, Gly-Pro-Gln-Gly-Ile-Trp-Gly-Gln, Asn-Asn, Ala-Ala-Asn, Leu-Ser-Gly-Lys, Gly-Pro, Val-Cit, Gly-Phe-Leu-Gly, Glu-Val-Cit, Ala-Leu- Ala-Leu, Phe-Lys, Val-Cit, Ser-Val-Cit, cBu-Cit, cBu-Val-Cit, Vai-Ala, Phe-Lys, Gly-Phe-Leu-Gly, or Ala-Leu-Ala-Leu.

[0224] In some embodiments, peptide sequences that are incorporated in the cleavable linker include: valine-citrulline (val-cit), N-methyl-valine-citrulline (Me-val-cit), valine-arginine (val-arg), valine-lysine (val-lys), valine-alanine (val-ala), (Gly-Phe-Leu-Gly), alanine-phenylalanine (ala-phe), phenylalanine-lysine (phe-lys), glycine-valine-citrulline (gly-val-cit), glycine-glycine-glycine (gly-gly-gly), glycine-phenylalanine-leucine-glycine (Gly-Phe-Leu-Gly), alanine-leucine-alanine-leucine (Ala-Leu-Ala-Leu), Asn-Asn, Ala-Ala-Asn, Leu-Ser-Gly-Lys, Glu-Val-Cit, Ser-Val-Cit, cBu-Cit, cBu-Val-Cit, Gly-Phe-Leu-Gly, or Ala-Leu- Ala-Leu.

[0225] In some embodiments, peptide sequences that are incorporated in the cleavable linker include: -Asn-Asn-, -Ala-Ala-Asn-, -Leu-Ser-Gly-Lys-, -Gly-Pro-, -Val-Cit-, -Gly-Phe-Leu-Gly-, Glu-Val-Cit-, -Ala-Leu-Ala-Leu-, -Phe-Lys-, -Val-Cit-, -Ser-Val-Cit-, -cBu-Cit-, -cBu-Val-Cit-, Vai-Ala-, -Gly-Phe-Leu-Gly-, -Ala-Leu-Ala-Leu-, -Asn-Ala-, Gln-Asn-, -Gln-Val-, TyrTrp, -Asn-Ala-, -Gln-Asn-, -Gln-Val-, -Tyr-Trp-, or -Asn-Aib-.

[0226] In some embodiments, L is valine-citrulline (val-cit), N-methyl-valine-citrulline (Me-val-cit), valine-arginine (val-arg), valine-lysine (val-lys), valine-alanine (val-ala), (Gly-Phe-Leu-Gly), alanine-phenylalanine (ala-phe), phenylalanine-lysine (phe-lys), glycine-valine-citrulline (gly-val-cit), glycine-glycine-glycine (gly-gly-gly), glycine-phenylalanine-leucine-glycine (Gly-Phe-Leu-Gly), alanine-leucine-alanine-leucine (Ala-Leu-Ala-Leu), Asn-Asn, Ala-Ala-Asn, Leu-Ser-Gly-Lys, Glu-Val-Cit, Ser-Val-Cit, cBu-Cit, cBu-Val-Cit, Gly-Phe-Leu-Gly, or Ala-Leu-Ala-Leu.

[0227] In some embodiments, L is Asn-Asn. In some embodiments, L is Ala-Ala-Asn. In some embodiments, L is Leu-Ser-Gly-Lys. In some embodiments, L is Gly-Pro. In some embodiments, L is Val-Cit. In some embodiments, L is Gly-Phe-Leu-Gly. In someWSGR Docket No. 68195-704.601embodiments, L is Glu-Val-Cit. In some embodiments, L is Ala-Leu-Ala-Leu. In some embodiments, L is Phe-Lys. In some embodiments, L is Val-Cit. In some embodiments, L is Ser-Val-Cit. In some embodiments, L is cBu-Cit. In some embodiments, L is cBu-Val-Cit. In some embodiments, L is Vai-Ala. In some embodiments, L is Phe-Lys. In some embodiments, L is Gly-Phe-Leu-Gly. In some embodiments, L is Ala-Leu-Ala-Leu.

[0228] In some embodiments, -L-S1- is -Asn-Asn-S1-, -Ala-Ala-Asn-S1-, -Leu-Ser-Gly-Lys-S1-, -Gly-Pro-S1-, -Val-Cit-S1-, -Gly-Phe-Leu-Gly-S1-, Glu-Val-Cit-S1-, -Ala-Leu-Ala-Leu-S1-, -Phe-Lys-S1-, -Val-Cit-S1-, -Ser-Val-Cit-S1-, -cBu-Cit-S1-, -cBu-Val-Cit-S1-, Val-Ala-S1-, -Phe-Lys-S1-, -Gly-Phe-Leu-Gly- S1-, -Ala-Leu-Ala-Leu-S1-, -Asn-Ala-S1-, Gln-Asn-S1-, -Gln-Val-S1-, TyrTrp, -Asn-Aib-S1-, -ValCit-S1-, AsnAsn-S1-, -Asn-Ala-S1-, -Gln-Asn-S1-, -Gln-Val-S1-, -Tyr-Trp-S1-, or -Asn-Aib-S1-. In some embodiments of a conjugate of Formula (I), L comprises Ala-Ala-PABC, Ala-Ala-Ala-PABC, Ala-Ala-Asn-PABC, Ala-Asn-Asn-PABC, Ala-Leu-Ala-Leu-PABC, Asn-Asn-PABC, cBu-Cit-PABC, cBu-Val-Cit-PABC, Glu-Val-Cit-PABC, Gly-Asn-Asn-PABC, Gly-Gly-Pro-PABC, Gly-Phe-Leu-Gly-PABC, Gly-Pro-PABC, Leu-Ser-Gly-Lys-PABC, Phe-Lys-PABC, Ser-Val-Cit-PABC, Val-Ala-PABC, or Val-Cit-PABC. In some embodiments, L written from left to right is also intended to encompass the regioisomer that would result from writing the structure from right to left.

[0229] In some embodiments of a conjugate of Formula (I), L comprises Ala-Ala-PABC.

[0230] In some embodiments of a conjugate of Formula (I), L comprises Ala-Ala-Ala-PABC.

[0231] In some embodiments of a conjugate of Formula (I), L comprises Ala-Ala-Asn-PABC.

[0232] In some embodiments of a conjugate of Formula (I), L comprises Ala-Asn-Asn-PABC.

[0233] In some embodiments of a conjugate of Formula (I), L comprises Ala-Leu- Al a-Leu-PABC.

[0234] In some embodiments of a conjugate of Formula (I), L comprises Asn-Asn-PABC.

[0235] In some embodiments of a conjugate of Formula (I), L comprises cBu-Cit-PABC.

[0236] In some embodiments of a conjugate of Formula (I), L comprises cBu-Val-Cit-PABC.

[0237] In some embodiments of a conjugate of Formula (I), L comprises Glu-Val-Cit-PABC.

[0238] In some embodiments of a conjugate of Formula (I), L comprises Gly-Asn-Asn-PABC.

[0239] In some embodiments of a conjugate of Formula (I), L comprises Gly-Gly-Pro-PABC.

[0240] In some embodiments of a conjugate of Formula (I), L comprises Gly-Phe-Leu-Gly-PABC.

[0241] In some embodiments of a conjugate of Formula (I), L comprises Gly-Pro-PABC.

[0242] In some embodiments of a conjugate of Formula (I), L comprises Leu-Ser-Gly-Lys-PABC.

[0243] In some embodiments of a conjugate of Formula (I), L comprises Phe-Lys-PABC.WSGR Docket No. 68195-704.601

[0244] In some embodiments of a conjugate of Formula (I), L comprises Ser-Val-Cit-PABC.

[0245] In some embodiments of a conjugate of Formula (I), L comprises Val-Ala-PABC.

[0246] In some embodiments of a conjugate of Formula (I), L comprises Val-Cit-PABC.

[0247] In some embodiments of a conjugate of Formula (I), PABC is substituted. In some embodiments of a conjugate of Formula (I), substituted PABC has the following formula:R2wherein R2hydrogen, Ci-Cealkyl, or Ci-C6alkyleneN(Ci-C6alkyl)2.

[0248] In some embodiments of a conjugate of Formula (I), L comprises Glu-Val-Cit-Gly-NH-CH2-.

[0249] In some embodiments of a conjugate of Formula (I), L comprises Gly-Gly-Phe-Gly-NH-CH2-.

[0250] In some embodiments of a conjugate of Formula (I), L comprises Leu-Ser-Gly-Lys-NH-CH2-.

[0251] In some embodiments of a conjugate of Formula (I), L comprises Val-Cit-Gly-NH-CH2-

[0252] In some embodiments of a conjugate of Formula (I), L comprises Val-(A, A- Dipropyl)Lys-Gly-NH-CH2-.

[0253] In some embodiments of a conjugate of Formula (I), L comprisesWSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601from left to right is also intended to encompass the regioisomer that would result from writing the structure from right to left.

[0254] In some embodiments, PABC (para-aminobenzyl carbamate) is a self-immolative spacer which spontaneously undergoes a 1,6-elimination upon proteolysis to release CO2 and azaquinone methide. In some embodiments, PABC links to the degrader. In some embodiments, cBu is cyclobutane- 1,1 -di carb oxami de.

[0255] In some embodiments, D-S^L comprisesWSGR Docket No. 68195-704.601

[0256] In some embodiments, D-S^L comprisesWSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0257] In some embodiments of a conjugate of Formula (I), S2is a compound of Formula (II):Formula (II);wherein:each M is independently -O-, -NRM-, -N(RM)2+-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, - OC(=O)-, -OC(=O)O-, -C(=O)NRM-, -NRMC(=O)-, -OC(=O)NRM-, -NRMC(=O)O-, - NRMC(=O)NRM-, -NRMC(=S)NRM-, -CRM=N-, -N=CRM, -NRMS(=O)2-, -S(=O)2NRM-, - C(=O)NRMS(=O)2-, -S(=O)2NRMC(=O)-, Ci-C30alkylene, C2-C30alkenylene, C2- C3oalkynylene, Ci-C3oheteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is optionally and independently substituted with one or more R;each RMis independently hydrogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4heteroalkyl, C2- Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;n is 1-20; andeach R is independently halogen, -CN, -OH, -SFs, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -S(=O)2H, -NH2, -NHCi- C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci- C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl;or two R on the same atom form an oxo.WSGR Docket No. 68195-704.601

[0258] In some embodiments of a spacer of Formula (II), each M is independently -O-, -NRM-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRM-, -NRMC(=O)-, Ci-C30alkylene, Ci-C3oheteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is optionally and independently substituted with one or more R.

[0259] In some embodiments of a spacer of Formula (II), each M is independently -O-, -NRM-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C3oalkylene, Ci-C3oheteroalkylene, or heteroarylene; wherein each alkylene, heteroalkylene, and heteroarylene is optionally and independently substituted with one or more R.

[0260] In some embodiments of a spacer of Formula (II), each M is independently -O-, -NRM-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C30alkylene, or Ci-C3oheteroalkylene; wherein each alkylene and heteroalkylene is optionally and independently substituted with one or more R.

[0261] In some embodiments of a spacer of Formula (II), each M is independently -O-, -NRM-, -C(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C3oalkylene, Ci-C3oheteroalkylene, or heteroarylene; wherein each alkylene, heteroalkylene, and heteroarylene is optionally and independently substituted with one or more R.

[0262] In some embodiments of a spacer of Formula (II), each M is independently -NRM-, -C(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C3oalkylene, Ci-C3oheteroalkylene, or heteroarylene; wherein each alkylene, heteroalkylene, and heteroarylene is optionally and independently substituted with one or more R.

[0263] In some embodiments of a spacer of Formula (II), each M is independently -NRM-, -C(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C3oalkylene, or Ci-C3oheteroalkylene; wherein each alkylene and heteroalkylene is optionally and independently substituted with one or more R.

[0264] In some embodiments of a spacer of Formula (II), each M is independently -NRM-, -C(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C30alkylene, or Ci-C30heteroalkylene.

[0265] In some embodiments of a spacer of Formula (II), each M is independently -C(=O)NRM-, -NRMC(=O)-, or Ci-C30heteroalkylene.

[0266] In some embodiments of a spacer of Formula (II), each M is independently -C(=O)- or Ci-C3oalkylene.

[0267] In some embodiments of a spacer of Formula (II), each M is independently Ci-C3oalkylene or Ci-C3oheteroalkylene; wherein each alkylene and heteroalkylene is optionally and independently substituted with one or more R.WSGR Docket No. 68195-704.601

[0268] In some embodiments of a spacer of Formula (II), each M is independently Ci-C2oalkylene or Ci-C2oheteroalkylene; wherein each alkylene and heteroalkylene is optionally and independently substituted with one or more R.

[0269] In some embodiments of a spacer of Formula (II), each M is independently Ci-C2oalkylene optionally and independently substituted with one or more R.

[0270] In some embodiments of a spacer of Formula (II), each M is independently Ci-C2oheteroalkylene optionally and independently substituted with one or more R.

[0271] In some embodiments of a spacer of Formula (II), each RMis independently hydrogen or Ci-C4alkyl. In some embodiments of a spacer of Formula (II), each RMis hydrogen.

[0272] In some embodiments of a spacer of Formula (II), n is 1-10. In some embodiments of a spacer of Formula (II), n is 1-9. In some embodiments of a spacer of Formula (II), n is 1-8. In some embodiments of a spacer of Formula (II), n is 1-7. In some embodiments of a spacer of Formula (II), n is 1-6. In some embodiments of a spacer of Formula (II), n is 1-5. In some embodiments of a spacer of Formula (II), n is 1-4. In some embodiments of a spacer of Formula (II), n is 1-3. In some embodiments of a spacer of Formula (II), n is 1-2. In some embodiments of a spacer of Formula (II), n is 2-10. In some embodiments of a spacer of Formula (II), n is 2-9. In some embodiments of a spacer of Formula (II), n is 2-8. In some embodiments of a spacer of Formula (II), n is 2-7. In some embodiments of a spacer of Formula (II), n is 2-6. In some embodiments of a spacer of Formula (II), n is 2-5. In some embodiments of a spacer of Formula (II), n is 2-4. In some embodiments of a spacer of Formula (II), n is 2-3. In some embodiments of a spacer of Formula (II), n is 3-10. In some embodiments of a spacer of Formula (II), n is 3-9. In some embodiments of a spacer of Formula (II), n is 3-8. In some embodiments of a spacer of Formula (II), n is 3-7. In some embodiments of a spacer of Formula (II), n is 3-6. In some embodiments of a spacer of Formula (II), n is 3-5. In some embodiments of a spacer of Formula (II), n is 3-4. In some embodiments of a spacer of Formula (II), n is 4-10. In some embodiments of a spacer of Formula (II), n is 4-9. In some embodiments of a spacer of Formula (II), n is 4-8. In some embodiments of a spacer of Formula (II), n is 4-7. In some embodiments of a spacer of Formula (II), n is 4-6. In some embodiments of a spacer of Formula (II), n is 4-5. In some embodiments of a spacer of Formula (II), n is 5-10. In some embodiments of a spacer of Formula (II), n is 5-9. In some embodiments of a spacer of Formula (II), n is 5-8. In some embodiments of a spacer of Formula (II), n is 5-7. In some embodiments of a spacer of Formula (II), n is 5-6. In some embodiments of a spacer of Formula (II), n is 6-10. In some embodiments of a spacer of Formula (II), n is 6-9. In some embodiments of a spacer of Formula (II), n is 6-8. In some embodiments of a spacer of Formula (II), n is 6-7. In some embodiments of a spacer of Formula (II), n is 7-10. In some embodiments of a spacer of Formula (II), n is 7-9. In someWSGR Docket No. 68195-704.601embodiments of a spacer of Formula (II), n is 7-8. In some embodiments of a spacer of Formula (II), n is 8-10. In some embodiments of a spacer of Formula (II), n is 8-9. In some embodiments of a spacer of Formula (II), n is 9-10. In some embodiments of a spacer of Formula (II), n is 1. In some embodiments of a spacer of Formula (II), n is 2. In some embodiments of a spacer of Formula (II), n is 3. In some embodiments of a spacer of Formula (II), n is 4. In some embodiments of a spacer of Formula (II), n is 5. In some embodiments of a spacer of Formula (II), n is 6. In some embodiments of a spacer of Formula (II), n is 7. In some embodiments of a spacer of Formula (II), n is 8. In some embodiments of a spacer of Formula (II), n is 9. In some embodiments of a spacer of Formula (II), n is 10.

[0273] In some embodiments of a spacer of Formula (II), S2is Ci-C2oalkylene optionally and independently substituted with one or more R.

[0274] In some embodiments of a spacer of Formula (II), S2is Ci-Cioalkylene optionally and independently substituted with one or more R.

[0275] In some embodiments of a spacer of Formula (II), S2is Ci-Csalkylene optionally and independently substituted with one or more R.

[0276] In some embodiments of a spacer of Formula (II), S2is Cs-Csalkylene optionally and independently substituted with one or more R.

[0277] In some embodiments of a spacer of Formula (II), S2is Cs-Cealkylene optionally and independently substituted with one or more R.

[0278] In some embodiments of a spacer of Formula (II), S2is -CH2CH2CH2CH2CH2-. In some embodiments of a spacer of Formula (II), S2is -CH2CH2CH2CH2-. In some embodiments of a spacer of Formula (II), S2is -CH2CH2CH2-. In some embodiments of a spacer of Formula (II), S2is -CH2CH2-. In some embodiments of a spacer of Formula (II), S2is -CH2CH2-.

[0279] In some embodiments of a spacer of Formula (II), S2is Ci-Csoheteroalkylene optionally and independently substituted with one or more R. In some embodiments of a spacer of Formula (II), S2is Ci-Csoheteroalkylene.

[0280] In some embodiments of a spacer of Formula (II), S2is Ci-C2oheteroalkylene optionally and independently substituted with one or more R. In some embodiments of a spacer of Formula (II), S2is Ci-C2oheteroalkylene.

[0281] In some embodiments of a spacer of Formula (II), S2is Ci-Cioheteroalkylene optionally and independently substituted with one or more R. In some embodiments of a spacer of Formula (II), S2is Ci-Cioheteroalkylene.

[0282] In some embodiments of a spacer of Formula (II), S2is Ce-Cuheteroalkylene optionally and independently substituted with one or more R. In some embodiments of a spacer of Formula (II), S2is Ce-Cuheteroalkylene.WSGR Docket No. 68195-704.601

[0283] In some embodiments of a spacer of Formula (II), S2is Cs-Cnheteroalkylene optionally and independently substituted with one or more R. In some embodiments of a spacer of Formula (II), S2is Cs-Cnheteroalkylene.

[0284] In some embodiments of a spacer of Formula (II), S2is Cioheteroalkylene optionally and independently substituted with one or more R. In some embodiments of a spacer of Formula (II), S2is Cioheteroalkylene.

[0285] In some embodiments of a spacer of Formula (II), S2is orand m is 1-15. In some embodiments of a spacer of Formula (II), S2isorm. In some embodiments of a spacer of Formula (II), S2is. In some embodiments of a spacer of Formula (II), S2iso Am H '

[0286] In some embodiments of a spacer of Formula (II), S2is orand m is 1-15. In some embodiments of a spacer of Formula (II), S2is. In some embodiments of a spacer of Formula (II), S2is. In some embodiments of a spacer of Formula (II), S2is

[0287] In some embodiments of a spacer of Formula (II), S2isand m is 1-15. In some embodiments of a spacer of Formula (II), S2is Hor. In some embodiments of a spacer of Formula (II),. In some embodiments of a spacer of Formula (II), S2isWSGR Docket No. 68195-704.601

[0288] In some embodiments of a spacer of Formula (II), S2isand m is 1-15. In some embodiments of a spacer of Formula (II), S2is. In some embodiments of a spacer of Formula (II), S2is. In some embodiments of a spacer of Formula (II), S2is

[0289] In some embodiments of a spacer of Formula (II), S2isand m is 1-15. In some embodiments of a spacer of Formula (II), S2spacer of Formula (II), S2is In some embodiments of a spacer ofFormula (II), S2is

[0290] In some embodiments of a spacer of Formula (II), S2iso o o o o om is 1-15. In some embodiments of a spacer of Formula (II), S2isO O O 0 0 0and each m is independently 1-15. In some embodiments of a spacer of Formula (II), S2is o o o X" N N N ° N H H ' m H 'Zm H. In some embodiments of a spacer of Formula (II), o o o — ■°'V^N„2 • H ' 'm H m H H SisWSGR Docket No. 68195-704.601

[0291] In some embodiments of a spacer of Formula (II), S2iso o o o \ JL Lo 1 X Lo A \ / ' m H ' rn H H 'mHmfor and m is 1-15. In someembodiments of a spacer of Formula (II), S2is, and each m is independently 1-15. In some embodiments ofa spacer of Formula (II), S2iso oNHspacer of Formula (II), S2is

[0292] In some embodiments, each m is independently 1-9. In some embodiments, each m is independently 1-8. In some embodiments, each m is independently 1-7. In some embodiments, each m is independently 1-6. In some embodiments, each m is independently 1-5. In some embodiments, each m is independently 1-4. In some embodiments, each m is independently 1-3. In some embodiments, each m is independently 1-2. In some embodiments, each m is independently 2-9. In some embodiments, each m is independently 2-8. In some embodiments, each m is independently 2-7. In some embodiments, each m is independently 2-6. In some embodiments, each m is independently 2-5. In some embodiments, each m is independently 2-4. In some embodiments, each m is independently 2-3. In some embodiments, each m is independently 3-9. In some embodiments, each m is independently 3-8. In some embodiments, each m is independently 3-7. In some embodiments, each m is independently 3-6. In some embodiments, each m is independently 3-5. In some embodiments, each m is independently 3-4. In some embodiments, each m is independently 4-12. In some embodiments, each m is independently 4-11. In some embodiments, each m is independently 4-10. In some embodiments, each m is independently 4-9. In some embodiments, each m is independently 4-8. In some embodiments, each m is independently 4-7. In some embodiments, each m is independently 4-6. In some embodiments, each m is independently 6-12. In some embodiments, each m is independently 7-12. In some embodiments, each m is independently 8-12. In some embodiments, each m is independently 9-12. In some embodiments, each m is independently 10-

[0293] In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, m is 1, 2,WSGR Docket No. 68195-704.6013, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 15. In some embodiments, m is 14. In some embodiments, m is 13. In some embodiments, m is 12. In some embodiments, m is 11. In some embodiments, m is 10. In some embodiments, m is 9. In some embodiments, m is 8. In some embodiments, m is 7. In some embodiments, m is 6. In some embodiments, m is 5. In some embodiments, m is 4. In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 1.o o

[0294] In some embodiments of a spacer of Formula (II), S2iso O N^ H H \ / qand q is 1-10. In some embodiments of a spacer of Formula (II), S2is. In some embodiments of a spacer of Formula (II), S2o o. In some embodiments of a spacer of Formula (II), S2is

[0295] In some embodiments of a spacer of Formula (II), S2isorand q is 1-10. In some embodiments of a spacer of Formula (II), S2isor. In some embodiments of a spacer of Formula (II), S2is. In some embodiments of a spacer of Formula (II), S2isIn some embodiments of a spacer of Formula (II), S2is and q is 1-10. Insome embodiments of a spacer of Formula (II), S2is. In someWSGR Docket No. 68195-704.601embodiments of a spacer of Formula (II), S2isq. In some embodiments of a spacer oftoFormula (II), S2isq.

[0296] In some embodiments, q is 1-9. In some embodiments, q is 1-8. In some embodiments, q is 1-7. In some embodiments, q is 1-6. In some embodiments, q is 1-5. In some embodiments, q is 1-4. In some embodiments, q is 1-3. In some embodiments, q is 1-2. In some embodiments, q is 2-9. In some embodiments, q is 2-8. In some embodiments, q is 2-7. In some embodiments, q is 2-6. In some embodiments, q is 2-5. In some embodiments, q is 2-4. In some embodiments, q is 2-3. In some embodiments, q is 3-9. In some embodiments, q is 3-8. In some embodiments, q is 3-7. In some embodiments, q is 3-6. In some embodiments, q is 3-5. In some embodiments, q is 3-4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6. In some embodiments, q is 7. In some embodiments, q is 8. In some embodiments, q is 9. In some embodiments, q is 10.

[0297] In some embodiments of a conjugate of Formula (II), S2does not compriseOWSGR Docket No. 68195-704.601

[0299] In some embodiments, S2is O o O NHo oor

[0300] In some embodiments, S2is absent.

[0301] In some embodiments of a conjugate of Formula (I), AB isIn some embodiments of a conjugate of Formula (I), AB isIn some embodiments of a conjugate of Formula (I), AB isconjugate of Formula (I), AB isIn some embodiments of a conjugate of Formula (I), AB is In some embodiments of a conjugate ofWSGR Docket No. 68195-704.601Formula (I), AB isembodiments of a conjugate of Formula (I), AB isembodiments of a conjugate of Formula (I), AB isembodiments of a conjugate of Formula (I), AB is

[0302] In some embodiments of a conjugate of Formula (I), AB comprises an acylated heptapeptide. In some embodiments of a conjugate of Formula (I), AB comprises the heptapeptide Glu-Tyr-Glu-Lys-Glu-Tyr-Glu with the side chain of lysine acylated with a fatty acid. In some embodiments, the fatty acid used to acylate the side chain of lysine is lauric acid. In some embodiments, the fatty acid used to acylate the side chain of lysine is myristic acid. In some embodiments, the fatty acid used to acylate the side chain of lysine is palmitic acid. In some embodiments, the fatty acid used to acylate the side chain of lysine is stearic acid. In some embodiments, the fatty acid used to acylate the side chain of lysine is capric acid. In some embodiments, the fatty acid used to acylate the side chain of lysine is caprylic acid. In some embodiments, the fatty acid used to acylate the side chain of lysine is caproic acid.WSGR Docket No. 68195-704.601

[0303] In some embodiments of a conjugate of Formula (I), AB isOHorIn some embodiments of a conjugate of FormulaOH(I), AB is. In some embodiments of a conjugate OHof Formula (I), AB is. In some embodiments of aOHconjugate of Formula (I), AB is orWSGR Docket No. 68195-704.601embodiments of a conjugate of Formula (I), AB isWSGR Docket No. 68195-704.601conjugate of Formula (I), AB isWSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0307] In some embodiments of a conjugate of Formula (I), AB comprises a maleimide derivative.

[0308] In some embodiments of a conjugate of Formula (I), AB comprises maleimide.

[0309] In some embodiments of a conjugate of Formula (I), AB ishydrogen or halogen.

[0310] In some embodiments of a conjugate of Formula (I), AB isI— S2-AB.In some embodiments of a conjugate of Formula (I), I isoWSGR Docket No. 68195-704.601H O

[0312] In some embodiments of a conjugate disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo. In some embodiments of a conjugate disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo. In some embodiments of a conjugate disclosed herein, each R is independently halogen, -CN, -OH, -NH2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, or Ci-C3haloalkoxy; or two R on the same atom form an oxo. In some embodiments of a conjugate disclosed herein, each R is independently halogen, -CN, -OH, -NH2, Ci-C3alkyl, or Ci-C3haloalkyl; or two R on the same atom form an oxo. In some embodiments of a conjugate disclosed herein, each R is independently halogen, Ci-C3alkyl, or Ci-C3haloalkyl; or two R on the same atom form an oxo.WSGR Docket No. 68195-704.601

[0313] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:Example 1:Example 2:Example 3:WSGR Docket No. 68195-704.601Example 4:Example 5:Example 6:Example 7:Example 8:WSGR Docket No. 68195-704.601Example 9:RExample 10:or a pharmaceutically acceptable salt thereof,wherein Ris

[0314] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:Example 13:H2NXX>° HNWSGR Docket No. 68195-704.601Example 14: wherein R is Example 15:Example 20:WSGR Docket No. 68195-704.601wherein R is / ; or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:Example 11:RExample 12:RExample 16:WSGR Docket No. 68195-704.601Example 17:Example 18:Example 19:Ror a pharmaceutically acceptable salt thereof,wherein Ris

[0316] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:WSGR Docket No. 68195-704.601Example 21:Example 22:Example 23:RExample 24: RH2NWSGR Docket No. 68195-704.601Example 25:Example 26:Example 28:or a pharmaceutically acceptable salt thereof,

[0317] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:WSGR Docket No. 68195-704.601Example 36:Example 37:or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:Example 38:H2N^OWSGR Docket No. 68195-704.601Example 39:or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is: Example 40:H2NyP HNor a pharmaceutically acceptable salt thereof.WSGR Docket No. 68195-704.601

[0320] In some embodiments, the albumin binder conjugated MYC PROTAC degrader is selected from:Example 29:H2N, OExample 31:WSGR Docket No. 68195-704.601Example 32:orExample 33:or a pharmaceutically acceptable salt thereof,wherein Ris

[0321] In some embodiments, the albumin binder conjugated FGFR2 PROTAC degrader is selected from:Example 34:H2N OWSGR Docket No. 68195-704.601Example 35:or a pharmaceutically acceptable salt thereof,

[0322] In some embodiments, the albumin binder conjugated RIPK2 PROTAC degrader is selected from:Example 41:wherein R is or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments of a conjugate disclosed herein, the albumin binder conjugated BRD4 PROTAC degrader is selected from a conjugate of Table 1, or a pharmaceutically acceptable salt thereof:WSGR Docket No. 68195-704.601TABLE 1WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0324] In some embodiments of a conjugate disclosed herein, R of Table 1 is any PROTAC contemplated herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0325] In some embodiments of a conjugate disclosed herein, the albumin binder conjugated ER PROTAC degrader is selected from a conjugate of Table 2, or a pharmaceutically acceptable salt thereof:WSGR Docket No. 68195-704.601TABLE 2WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0326] In some embodiments of a conjugate disclosed herein, R of Table 2 is any PROTAC contemplated herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0327] In some embodiments of a conjugate disclosed herein, the albumin binder conjugated MYC PROTAC degrader is selected from a conjugate of Table 3, or a pharmaceutically acceptable salt thereof:WSGR Docket No. 68195-704.601TABLE 3WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0328] In some embodiments of a conjugate disclosed herein, R of Table 3 is any PROTAC contemplated herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0329] In some embodiments of a conjugate disclosed herein, the albumin binder conjugated FGFR2 PROTAC degrader is selected from a conjugate of Table 4, or a pharmaceutically acceptable salt thereof:TABLE 4WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0330] In some embodiments of a conjugate disclosed herein, R of Table 4 is any PROTAC contemplated herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0331] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:H2N -OHNExample 42:WSGR Docket No. 68195-704.601Example 43:WSGR Docket No. 68195-704.601Example 48:Example 49:Example 50:Example 51:Example 54:WSGR Docket No. 68195-704.601Example 55:or a pharmaceutically acceptable salt thereof,WSGR Docket No. 68195-704.601

[0332] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:or a pharmaceutically acceptable salt thereof,

[0333] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:Example 61:WSGR Docket No. 68195-704.601or a pharmaceutically acceptable salt thereof,

[0334] In some embodiments, the albumin binder conjugated BRD4 PROTAC degrader is selected from:or a pharmaceutically acceptable salt thereof;WSGR Docket No. 68195-704.601N-Nwherein Ris

[0335] In some embodiments, the albumin binder conjugated MYC PROTAC degrader is selected from:or a pharmaceutically acceptable salt thereof,wherein Ris

[0336] In some embodiments, the albumin binder conjugated FGFR2 PROTAC degrader is selected from:WSGR Docket No. 68195-704.601Example 65:or a pharmaceutically acceptable salt thereof,

[0337] In some embodiments of a conjugate disclosed herein, the albumin binder conjugated BRD4 PROTAC degrader is selected from a conjugate of Table 5, or a pharmaceutically acceptable salt thereof:WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0338] In some embodiments of a conjugate disclosed herein, R of Table 5 is any PROTAC contemplated herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.WSGR Docket No. 68195-704.601

[0339] In some embodiments of a conjugate disclosed herein, the albumin binder conjugated ER PROTAC degrader is selected from a conjugate of Table 6, or a pharmaceutically acceptable salt thereof:WSGR Docket No. 68195-704.601

[0340] In some embodiments of a conjugate disclosed herein, R of Table 6 is any PROTAC contemplated herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0341] In some embodiments of a conjugate disclosed herein, the albumin binder conjugated MYC PROTAC degrader is selected from a conjugate of Table 7, or a pharmaceutically acceptable salt thereof:TABLE 7WSGR Docket No. 68195-704.601WSGR Docket No. 68195-704.601

[0342] In some embodiments of a conjugate disclosed herein, R of Table 7 is any PROTAC contemplated herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0343] In some embodiments of a conjugate disclosed herein, the albumin binder conjugated FGFR2 PROTAC degrader is selected from a conjugate of Table 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:TABLE 8WSGR Docket No. 68195-704.601

[0344] In some embodiments of a conjugate disclosed herein, R of Table 8 is any PROTAC contemplated herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.Further Forms of Conjugates Disclosed HereinIsomer s / Stereoisomers

[0345] In some embodiments, the conjugates described herein exist as geometric isomers. In some embodiments, the conjugates described herein possess one or more double bonds. The conjugates presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the conjugates described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The conjugates described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the conjugates and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the conjugates described herein are prepared as their individual stereoisomers by reacting a racemic mixture of theWSGR Docket No. 68195-704.601conjugates with an optically active resolving agent to form a pair of diastereoisomeric conjugates, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled Conjugates

[0346] In some embodiments, the conjugates described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled conjugates. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled conjugates as pharmaceutical compositions. Thus, in some embodiments, the conjugates disclosed herein include isotopically-labeled conjugates, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into conjugates disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively. Conjugates described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled conjugates, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a conjugate disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a conjugate disclosed herein has been replaced by a deuteroalkyl substituents.

[0347] In some embodiments, the conjugates described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.WSGR Docket No. 68195-704.601Pharmaceutically acceptable salts

[0348] In some embodiments, the conjugates described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0349] In some embodiments, the conjugates described herein possess acidic or basic groups and therefore react with any number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the conjugates disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified conjugate in its free form with a suitable acid or base, and isolating the salt thus formed.

[0350] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the conjugates described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0351] Further, the conjugates described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the conjugate with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid,WSGR Docket No. 68195-704.6013-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the conjugates disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0352] In some embodiments, those conjugates described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Ci-C4 alkyl)4 hydroxide, and the like.

[0353] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the conjugates described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.Solvates

[0354] In some embodiments, the conjugates described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0355] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the conjugates described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the conjugates described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the conjugates provided herein can exist in unsolvated as well as solvatedWSGR Docket No. 68195-704.601forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the conjugates and methods provided herein.Preparation of the Conjugates

[0356] The conjugates used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from conjugates described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U. K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U. K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co.(Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U. K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U. K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0357] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of conjugates described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modem Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of conjugates described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5;Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley &WSGR Docket No. 68195-704.601Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley -VCH, ISBN: 3-527-29871-1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0358] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the conjugates described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.Methods of Treatment

[0359] Disclosed herein are methods for treating cancer in a subject in need thereof, including administering to the subject a therapeutically effective amount of an albumin conjugated PROTAC degraders disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0360] In some embodiments, described herein is a method enhancing transport of a protein degrader to a tumor in a mammal; increasing the accumulation of a heterobifunctional protein degrader in a tumor of a mammal; or improving the pharmacokinetic profile of a heterobifunctional protein degrader in a mammal; or a combination thereof, wherein the method comprises administering to the mammal a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition described herein.

[0361] In some embodiments, the protein is bromodomain-containing protein 4 (BRD4), estrogen receptor (ER), Myc, fibroblast growth factor receptor 2 (FGFR2), or receptorinteracting protein kinase 2 (RIPK2). In some embodiments, protein is estrogen receptor (ER), Myc, fibroblast growth factor receptor 2 (FGFR2), or receptor-interacting protein kinase 2 (RIPK2)WSGR Docket No. 68195-704.601

[0362] In some embodiments, the method comprises administering to the mammal a compound described herein comprising a non-covalent albumin binder.

[0363] In some embodiments, the method comprises administering to the mammal a compound described herein comprising a covalent albumin binder.Dosing

[0364] In certain embodiments, the compositions containing the conjugate(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0365] When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a conjugate described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0366] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the conjugates are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0367] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.

[0368] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular conjugate, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined accordingWSGR Docket No. 68195-704.601to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.Routes of Administration

[0369] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. In some embodiments, the route of administration is intravenous.

[0370] In certain embodiments, a conjugate as described herein is administered in a local rather than systemic manner, for example, via injection of the conjugate directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the conjugate as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediaterelease formulation.Pharmaceutical Compositions / Formulations

[0371] The conjugates described herein are administered to a subject, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the conjugates disclosed herein may be administered to animals. The conjugates can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0372] In another aspect, provided herein are pharmaceutical compositions comprising a conjugate described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active conjugates into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. AWSGR Docket No. 68195-704.601summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.Combination

[0373] In certain instances, the conjugate described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent or a cancer-targeted agent.EXAMPLESGeneral Methods

[0374] All temperatures are in degrees Celsius (°C) and are uncorrected. Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and unless otherwise mentioned, were used without further purification. Silica gel chromatography was performed on automated instruments using pre-packaged disposable SiO₂ stationary phase columns with eluent flow-rate ranges of 15 to 200 mL / min, UV detection (254 and 280 nm). Reverse phase purification was carried out using C18 columns, UV detection (214 and 254 nm). The chemical shifts are reported in parts-per-million and are referenced to solvent peaks, which in 'H NMR appear at 7.26 ppm for CDCl₃, 2.50 for DMSO-d₆, and 3.31 ppm for CD₃OD.Terms and Abbreviationsaq aqueous;DCM dichloromethane;DIPEA N, N-diisopropylethylamine;EtOAc ethyl acetate;h hour(s);HC1 hydrochloride;HPLC high performance liquid chromatography;LCMS liquid chromatography mass spectrometry;min minute(s);NaHCO3 sodium bicarbonate;NMR nuclear magnetic resonance;WSGR Docket No. 68195-704.601sat. saturated;THF tetrahydrofuran;

[0375] Synthesis of Degrader B:

[0376] (2S,4R)-l-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino] ethoxy]propoxy] acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(lS)-l-[2-hydroxy-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide.B-6 B-3B-1 B-2 B-4

[0377] General procedure of Degrader B:

[0378] To a solution of B-1 (10 g, 46.5 mmol, 1 eq) in DCM (200 mL) was added DIEA (18 g, 139 mmol, 24 mL, 3 eq) and M0MC1 (5.3 g, 65 mmol, 5 mL, 1.42 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (1 L), then extracted with DCM (500 mL><3), then the combined organic layers were washed with brine (500 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiC>2, Petroleum ether: EtOAc=l / 0 to 100 / 1) to afford B-2 (8.4 g, 32.4 mmol, 69% yield) as a yellow liquid.XH NMR (400 MHz, CDCl₃-d) 8 = 7.60 (d, J= 8.3 Hz, 1H), 7.37 (d, J= 1.8 Hz, 1H), 7.19 (dd, J = 1.8, 8.4 Hz, 1H), 5.28 (s, 2H), 3.52 (s, 3H), 2.62 - 2.60 (m, 3H).

[0379] To a solution of B-2 (8.2 g, 31 mmol, 1 eq) and B-3 (15.3 g, 126 mmol, 4 eq) in THF (82 mL) was added 4A MS (8.2 g) and Ti(OEt)4 (29 g, 126 mmol, 26 mL, 4 eq) at 0 °C. The mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (1 L), then extracted with EtOAc (500 mL><3), then the combined organic layers wereWSGR Docket No. 68195-704.601washed with brine (500 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiO₂, Petroleum ether: EtOAc=1 / 0 to 100 / 1) to afford B-4 (11.1 g, 30.6 mmol, 97% yield) as a yellow oil. LC-MS (ESI+): m / z = 361.8 / 363.8 (M+H)+. SFC:100.0% ee.

[0380] To a solution of B-4 (4 g, 11 mmol, 1 eq) in THF (40 mL) was added L-selectride (1 M, 16.5 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated NH₄Cl (500 mL), then extracted with EtOAc (100 mL><4), then the combined organic layers were washed with brine (100 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a crude. The crude afforded B-5 (4 g, crude) as a yellow liquid. LC-MS (ESI+): m / z = 364.0 / 366.0 (M+H)+. SFC: dr=94.01:5.99.

[0381] To a solution of B-5 (1.2 g, 3.3 mmol, 1 eq) and B-6 (980 mg, 9.9 mmol, 899 pL, 3 eq) in DMA (12 mL) was added Pd(OAc)2 (74 mg, 329 pmol, 0.1 eq) and KO Ac (646 mg, 6.6 mmol, 2 eq). The mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (500 mL), then extracted with EtOAc (100 mL><3), then the combined organic layers were washed with brine (100 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a crude. The crude was purified by column chromatography (SiO2, Petroleum ether: EtOAc=10 / l to 1 / 1, Rf = 0.30) to afford B-7 (770 mg, 2 mmol, 61% yield) as a yellow liquid. LC-MS (ESI+): m / z = 383.1 (M+H)+. 'H NMR (400 MHz, DMSO-d₆) δ = 8.98 (s, 1H), 7.49 (d, J= 7.8 Hz, 1H), 7.17 - 7.09 (m, 2H), 5.36 - 5.28 (m, 3H), 4.81 (t, J= 6.4 Hz, 1H), 3.42 (s, 3H), 2.46 (s, 3H), 1.45 (d, J= 6.8 Hz, 3H), 1.12 (s, 9H). SFC: 93.72:6.28.

[0382] To a solution of B-7 (750 mg, 1.96 mmol, 1 eq) in DCM (7.5 mL) was added HCl / EtOAc (4 M, 7.5 mL). The mixture was stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a crude. The crude afforded B-8 (440 mg, crude) as a yellow solid. LC-MS (ESI+): m / z = 235.0 (M+H)+.

[0383] To a solution of B-8 (210 mg, 896 pmol, 1 eq) and B-9 (370 mg, 1.1 mmol, 1.2 eq) in DMF (2.1 mL) was added Et3N (272 mg, 2.7 mmol, 374 pL, 3 eq) and T4P (968 mg, 1.34 mmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL), then extracted with EtOAc (50 m[y3), then the combined organic layers were washed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18 150><40x7um; Mobile Phase: [H2O (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; Gradient: 30-60% B over 8.0 min) to afford B-10 (66 mg, 117 pmol, 13% yield) as a white solid. LC-MS (ESI+): m / z = 561.3 (M+H)+. SFC: 100.0% de.WSGR Docket No. 68195-704.601

[0384] To a solution of B-10 (56 mg, 99 pmol, 1 eq) in DCM (0.56 mL) was added HCl / EtOAc (4 M, 0.56 mL). The mixture was stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a crude. The crude B-11 (40 mg, crude) as a white solid. LC-MS (ESI+): m / z = 461.1 (M+H)+.Compound StructureIntermediate I

[0385] To a solution of B-11 (40 mg, 86 pmol, 1 eq) and Intermediate I (58 mg, 104 pmol, 1.2 eq) in DMF (0.4 mL) was added Et₃N (260 mg, 260 pmol, 36 pL, 3 eq) and T4P (94 mg, 130 pmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (50 mL), then extracted with EtOAc (20 mL×3), then >0the combined organic layers were washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a crude. The crude was purified by 0prep-HPLC (Column: Waters Xbridge BEH C18 100><30mmxl0um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 40-70% B over 8.0 min) to afford Degrader B (23 mg, 22pmol, 26% yield) as a white solid. HRMS (ESI+): m / z = 1002.3800 (M+H)⁺. ¹H NMR (400MHz, DMSO-c / r,) 6 = 9.77 (br s, 1H), 8.95 (s, 1H), 8.37 - 8.24 (m, 2H), 7.50 - 7.45 (m, 2H), 7.45 - 7.40 (m, 2H), 7.33 (br d, J= 9.3 Hz, 1H), 7.20 (br d, J= 7.8 Hz, 1H), 6.94 - 6.84 (m, 2H), 5.16 - 5.05 (m, 2H), 4.57 - 4.44 (m, 3H), 4.28 (br s, 1H), 3.95 - 3.84 (m, 2H), 3.61 - 3.53 (m, 4H), 3.50 (br t, J= 6.1 Hz, 2H), 3.42 (br d, J= 5.3 Hz, 2H), 3.27 - 3.20 (m, 4H), 2.59 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H), 2.11 - 2.01 (m, 1H), 1.84 - 1.75 (m, 3H), 1.62 (s, 3H), 1.29 (br d, J= 6.8 Hz, 3H), 0.93 (br s, 9H). SFC: 100.0% de.

[0386] Synthesis of Degrader C:

[0387] (2S,4R)-N-[(lR)-2-Amino-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]-l-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]propoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601C-2C-13Degrader C

[0388] General procedure of Degrader C:

[0389] To a mixture of C-l (25 g, 79.1 mmol, 1 eq) and C-2 (15.7 g, 158 mmol, 14.3 mL, 2 eq) in DMA (500 mL) was added KOAc (15.52 g, 158 mmol, 2 eq) and Pd(OAc)2 (1.78 g, 7.91 mmol, 0.1 eq), and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was poured into water (500 mL), then extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether: EtOAc = 50 / 1 to 1 / 1) to afford C-3 (25 g, 74.7 mmol, 94% yield) as a yellow oil. LCMS (ESI+): m / z = 335.0 (M+H)+. 'H NMR (400 MHz, DMSO-d₆) δ = 8.98 (s, 1H), 7.46 - 7.41 (m, 2H), 7.40 - 7.36 (m, 2H), 7.29 (br d, J =WSGR Docket No. 68195-704.6018.3 Hz, 1H), 4.84 (t, J = 5.8 Hz, 1H), 4.56 (br d, J = 7.4 Hz, 1H), 3.52 (t, J = 6.2 Hz, 2H), 2.45 (s, 3H), 1.37 (s, 9H).

[0390] To a mixture of C-3 (5 g, 14.9 mmol, 1 eq) in DCM (50 mL) was added EtsN (3.03 g, 29.9 mmol, 4.16 mL, 2 eq) and MsCl (2.66 g, 23.2 mmol, 1.80 mL, 1.55 eq) at 0 °C, and then the mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCO₃ (300 mL), then extracted with DCM (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The reaction was without further purification to afford C-4 (6 g, crude) as a yellow oil. LCMS (ESI+): m / z = 413.1 (M+H)+.

[0391] To a mixture C-4 (6 g, 14.5 mmol, 1 eq) in DMF (60 mL) was added and NaNs (0.91 g, 14 mmol, 0.9 eq), and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was poured into saturated Na₂CO₃ (300 mL), then extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The reaction was without further purification to afford C-5 (5 g, crude) as a yellow oil. LCMS (ESI+): m / z = 360.0 (M+H)+.

[0392] To a mixture of C-5 (5 g, 13.9 mmol, 1 eq) in THF (30 mL) and H2O (15 mL) was added and PPh₃ (7.30 g, 27.8 mmol, 2 eq), and then the mixture was stirred at 50 °C for 16 h under N2 atmosphere. The reaction mixture was poured into saturated EDTA (150 mL) and stirred for 2 h, then extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: EtOAc = 1 / 0 to 0 / 1 and DCM: MeOH = 50:1 to 20:1) to afford C-6 (3.6 g, 10.8 mmol, 77% yield) as a yellow oil. LCMS (ESI+): m / z = 334.1 (M+H)+.1H NMR (400 MHz, DMSO-d₆) δ = 8.98 (s, 1H), 7.44 (br d, J = 8.1 Hz, 2H), 7.39 - 7.32 (m, 3H), 4.46 (br d, J = 5.3 Hz, 1H), 2.70 (br d, J = 7.6 Hz, 2H), 2.46 (s, 3H), 1.85 - 1.51 (m, 2H), 1.38 (br s, 9H). SFC: 98.82% ee.

[0393] To a mixture C-6 (3.4 g, 10.2 mmol, 1 eq) in toluene (34 mL) was added DIEA (3.95 g, 30.6 mmol, 5.33 mL, 3 eq) and C-7 (3.02 g, 20.4 mmol, 2 eq), and then the mixture was stirred at 110 °C for 16 h under N2 atmosphere. The reaction mixture was poured into water (200 mL), then extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 1:0 to 5 / 1, DCM: MeOH = 10:1) to afford C-8 (4.8 g, 9.3 mmol, 91% yield) as a yellow solid. LCMS (ESI+): m / z = 464.1 (M+H)+. SFC: 98.96% ee.WSGR Docket No. 68195-704.601

[0394] To a mixture of C-8 (2 g, 4.15 mmol, 1 eq) in THF (20 mL) was added HCl / EtOAc (4 M, 20 mL), and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction was without further purification to afford C-9 (1.8 g, crude) as a yellow solid. LCMS (ESI+): m / z = 364.1 (M+H)+.

[0395] To a mixture of C-9 (400 mg, 1.05 mmol, 1 eq) and C-10 (397 mg, 1.15 mmol, 1.1 eq) in DMF (4 mL) was added Et₃N (530 mg, 5.24 mmol, 730 pL, 5 eq) and T4P (2.27 g, 3.15 mmol, 50% purity, 3 eq), and then the mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. The reaction mixture was poured into water (100 mL), then extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether: EtOAc = 50 / 1 to 0 / 1) to afford C-11 (600 mg, 847 pmol, 80% yield) as a white solid. LCMS (ESI+): m / z = 690.3 (M+H)+. SFC: 100.0% de.

[0396] To a mixture of C-11 (500 mg, 706 pmol, 1 eq) in THF (5 mL) was added HCl / EtOAc (4 M, 10 mL), and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction was without further purification to afford C-12 (500 mg, crude) as a yellow solid. LCMS (ESI+): m / z = 590.3 (M+H)+.

[0397] To a mixture of C-12 (300 mg, 493 pmol, 1 eq) and Intermediate I (276 mg, 493 pmol, 1 eq) in DMF (3 mL) was added Et₃N (250 mg, 2.47 mmol, 343 pL, 5 eq) and T4P (1.07 g, 1.48 mmol, 50% purity, 3 eq) at 0 °C and purged with N2 for 3 times, then the mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. The reaction mixture was poured into water (50 mL), then extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to afford C-13 (350 mg, 304 pmol, 61.67% yield) as a white solid. LCMS (ESI+): m / z = 1131.4 (M+H)+. SFC: 100.0% de.

[0398] To a mixture of C-13 (150 mg, 130 pmol, 1 eq) in EtOH (2 mL) was added N₂H₄·H₂O (0.18 g, 3.52 mmol, 174 pL, 27 eq), and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. The reaction mixture was poured into water (50 mL), then extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Waters Xbridge BEH C18 100x30mmxl0um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 35-70% B over 8.0 min) to affordWSGR Docket No. 68195-704.601Degrader C (21 mg, 21.6 pmol, 16% yield) as a white solid. LCMS: 99.84% purity. HRMS (ESI+): m / z=1001.3917 (M+H)+. 'HNMR (400 MHz, DMSO-c / ) 6 = 8.98 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.35 - 8.24 (m, 1H), 7.51 - 7.29 (m, 9H), 5.15 (d, J = 3.3 Hz, 1H), 4.90 - 4.67 (m, 1H), 4.58 - 4.21 (m, 4H), 3.98 - 3.86 (m, 2H), 3.65 - 3.42 (m, 8H), 3.29 - 3.19 (m, 5H), 2.82 -2.70 (m, 1H), 2.59 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H), 2.03 (br dd, J = 7.6, 12.3 Hz, 1H), 1.85 -1.76 (m, 3H), 1.62 (s, 3H), 0.93 (s, 9H). SFC: 100.0% de.

[0399] Synthesis of Degrader D:

[0400] (2S,4R)-l-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]propoxy] acetyl]amino]-3,3-dimethyl-butanoyl]-N-[(lS)-l-[2-[2-(2,2-difluoroethylamino)ethoxy]-4-(4-methylthiazol-5-yl)phenyl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601

[0401] General procedure of Degrader D:

[0402] To a solution of D-l (1 g, 3 mmol, 1 eq) andl D-2 (5.62 g, 29.9 mmol, 2.26 mL, 10 eq) in DMF (1 mL) was added K2CO3 (826 mg, 5.98 mmol, 2 eq). The mixture was stirred at 70 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (80 mL), then extracted with EtOAc (50 mL><3). The combined organic layers were washed by saturated brine (80 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 1 / 0 to 3 / 1) to afford D-3 (920 mg, 2.08 mmol, 69% yield) as a yellow solid. LC-MS (ESI+): m / z = 443.0 (M+H)+. 'H NMR (400 MHz, DMSO-cL) 6 = 8.98 (s, 1H), 7.36 (t, J = 9.4 Hz, 2H), 7.06 (d, J = 7.9 Hz, 1H), 7.02 (s, 1H), 5.05 - 4.94 (m, 1H), 4.47 - 4.33 (m, 2H), 3.90 - 3.81 (m, 2H), 2.48 - 2.46 (m, 3H), 1.37 (s, 9H), 1.30 (br d, J = 7.0 Hz, 3H). SFC: 100.0% ee.

[0403] Compounds E-l & F-l was prepared according to the procedures described in D-3 using the appropriate intermediates.Compound Structure LCMSBocHNE-l (ESI+): m / z = 457.0 (M+H)+Br7^WSGR Docket No. 68195-704.601Compound Structure LCMSBocHNSF-l (ESI+): m / z = 442.8 (M+H)+Br7^

[0404] To a solution of D-3 (870 mg, 1.97 mmol, 1 eq) and D-4 (1.60 g, 19.7 mmol, 10 eq) in MeCN (8.7 mL) was added K2CO3 (544 mg, 3.94 mmol, 2 eq). The mixture was stirred at 70 °C for 48 h under N2 atmosphere. The reaction mixture was poured into H2O (80 mL), then extracted with EtOAc (50 mL><3). The combined organic layers were washed by saturated brine (80 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 1 / 0 to 1 / 2) to afford D-5 (550 mg, 1.25 mmol, 63% yield) as a yellow oil. LC-MS (ESI+): m / z = 442.1 (M+H)+. 'H NMR (400 MHz, DMSO-cL) 6 = 8.99 (s, 1H), 7.46 - 7.40 (m, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.05 - 7.01 (m, 2H), 6.27 - 5.84 (m, 1H), 5.02 - 4.92 (m, 1H), 4.13 - 4.07 (m, 2H), 3.05 - 2.92 (m, 5H), 2.47 (s, 3H), 1.37 (s, 9H), 1.26 (br d, J = 6.9 Hz, 3H).

[0405] Compounds E-2 & F-2 was prepared according to the procedures described in D-5 using the appropriate intermediates.Compound Structure LCMSBocHNE-2 (ESI+): m / z = 456.3 (M+H)+HN^F"^BocHNF-2 (ESI+): m / z = 442.1 (M+H)+HN^

[0406] To a solution of D-5 (400 mg, 905 pmol, 1 eq) anc D-6 (677 mg, 2.72 mmol, 3 eq) in DMF (4 mL) was added DIEA (585 mg, 4.53 mmol, 789 pL, 5 eq). The mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column:WSGR Docket No. 68195-704.601Phenomenex Gemini C1875x40mmx5um; Mobile Phase: [H2O (10 mM NELElCOs^ACN]; Gradient: 55-85% B over 8.0 min) to afford D-7 (180 mg, 312 pmol, 34% yield) as a white solid. LC-MS (ESI+): m / z = 576.2 (M+H)+.

[0407] Compounds E-3 & F-3 was prepared according to the procedures described in D-7 using the appropriate intermediates.Compound Structure LCMSBocHNcAZ''OE-3 (ESI+): m / z = 590.2 (M+H)+Cbz„N-^BocHNF-3 (ESI+): m / z = 576.3 (M+H)+Cbz^N^

[0408] A solution of D-7 (150 mg, 260 pmol, 1 eq) was added HCl / EtOAc (4 M, 3 mL) was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford D-8 (120 mg, 252 pmol, 96% yield) as a white solid. LC-MS (ESI+): m / z = 476.2 (M+H)+.

[0409] Compounds E-4 & F-4 was prepared according to the procedures described in D-8 using the appropriate intermediates.Compound Structure LCMSCIH3NE-4 (ESI+): m / z = 490.1 (M+H)+Cbz^N<^WSGR Docket No. 68195-704.601Compound Structure LCMSCIH3NF-4 (ESI+): m / z = 476.2 (M+H)+Cbz^.N^F'^

[0410] To a solution of D-8 (120 mg, 252 pmol, 1 eq) and D-9 (130 mg, 378 pmol, 1.5 eq) in DMF (2.4 mL) was added Et3N (127 mg, 1.26 mmol, 175 pL, 5 eq) and T4P (272 mg, 378 pmol, 50% purity, 1.5 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18 150 40 lOum; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 50-80% B over 8.0 min) to afford D-10 (150 mg, 187 pmol, 74% yield) as a white solid. LC-MS (ESI+): m / z = 802.4 (M+H)+.

[0411] Compounds E-5 & F-5 was prepared according to the procedures described in D-10 using the appropriate intermediates.Compound Structure LCMSOHBocHN ±^Y0 'YO ^NHE-5 (ESI+): m / z = 816.3 (M+H)+Cbz^N-^I PHBOCHNXY<^N'Y>° QA'NHF-5 (ESI+): m / z = 802.4 (M+H)+Cbz-N^F~^WSGR Docket No. 68195-704.601

[0412] A solution of D-10 (100 mg, 124 pmol, 1 eq) was added HCl / EtOAc (4 M, 2 mL) stirred at 25 °C for 3 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford D-ll (80 mg, 114 pmol, 91% yield) as a white solid. LC-MS (ESI+): m / z = 702.3 (M+H)+.

[0413] Compounds E-6 & F-6 was prepared according to the procedures described in D-ll using the appropriate intermediates.Compound Structure LCMS1 PHCIH3N^yNV° QA'NHE-6 (ESI+): m / z = 716.3 (M+H)+F~^1?HCIH3N^YNY° QA'NHF-6 (ESI+): m / z = 702.3 (M+H)+Cbz^N^

[0414] To a solution of D-ll (80 mg, 114 pmol, 1 eq) and Intermediate I (70 mg, 125 pmol, 1.1 eq) in DMF (0.8 mL) was added Et3N (34 mg, 341 pmol, 47 pL, 3 eq) and T4P (123 mg, 171 pmol, 50% purity, 1.5 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18 100><30x7um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 60-90% B over 8.0 min) to afford D-12 (90 mg, 72.3 pmol, 63% yield) as a white solid. LC-MS (ESI+): m / z = 1243.4 (M+H)+.

[0415] Compounds E-7 & F-7 was prepared according to the procedures described in D-12 using the appropriate intermediates.WSGR Docket No. 68195-704.601

[0416] To a solution of D-12 (90 mg, 72.3 pmol, 1 eq) in DCM (1.8 mL) was added HBr (29 mg, 361 pmol, 90 pL, 5 eq). The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18 100><30x7um; Mobile Phase: [H2O (10 mM NH4HCC>3)-ACN]; Gradient: 25-75% B over 8.0 min) to afford Degrader D (38 mg, 34.4 pmol, 47% yield) as a white solid. LCMS: 100.0% purity. HRMS (ESI+): m / z = 1109.4302 (M+H)+. 'H NMR (400 MHz, DMSO-cC) 8 = 8.98 (s, 1H), 8.35 (d, J = 7.9 Hz, 1H), 8.27 (t, J = 5.4 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.45 - 7.39 (m, 2H), 7.33 (d, J = 9.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.12 - 7.00 (m, 2H), 6.16 - 5.84 (m, 1H), 5.22 - 4.95 (m, 2H), 4.68 - 4.38 (m, 3H), 4.31 - 4.21 (m, 1H), 4.09 (br t, J = 5.3 Hz, 2H), 3.97 - 3.83 (m, 2H), 3.64 - 3.47 (m, 6H), 3.46 - 3.41 (m, 2H), 3.31 - 3.17 (m, 4H), 3.03 - 2.91 (m, 4H), 2.62 - 2.57 (m, 3H), 2.49 - 2.37 (m, 6H), 2.25 - 2.00 (m, 2H), 1.82 - 1.60 (m, 5H), 1.31 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H). SFC: 100.0% de.

[0417] Compound Degrader E & F was prepared according to the procedures described in Degrader D using the appropriate intermediates.WSGR Docket No. 68195-704.601Compound HRMS 'll NMR(400 MHz, DMSO-c / r,) 8 = 8.98 (s, 1H), 8.37 (br d, J = 8.0 Hz, 1H), 8.27 (brt, J = 5.4 Hz, 1H), 8.13 (s, 1H), 7.50 - 7.40 (m, 4H), 7.35 - 7.25 (m, 2H), 7.05 - 6.98 (m, 2H), 6.04 (br t, J = 55.9 Hz, 1H), 5.23 - 5.10 (m, 2H), 4.57 - 4.42 (m, 3H), 4.31 - 4.21 (m, 1H), 4.10 (brt, J = 5.9 Hz, 2H), 3.94 - (ESI+): m / z =Degrader E 3.82 (m, 2H), 3.61 - 3.52 (m, 4H), 3.50 (brt, J =1123.4441 (M+H)+.6.4 Hz, 2H), 3.45 - 3.41 (m, 2H), 3.30 - 3.19 (m, 5H), 3.06 - 2.93 (m, 2H), 2.83 (br d, J = 5.5 Hz, 2H), 2.59 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H), 2.12 - 2.03 (m, 1H), 1.97 - 1.89 (m, 2H), 1.84 - 1.75 (m, 3H), 1.62 (s, 3H), 1.40 - 1.28 (m, 3H), 0.93 (s, 9H).(400 MHz, DMSO-c / r,) 6 = 9.02 - 8.97 (m, 1H), 8.75 - 8.41 (m, 1H), 8.31 - 8.24 (m, 1H), 7.50 - 7.40 (m, 4H), 7.36 - 7.24 (m, 2H), 7.11 - 7.01 (m, 1H), 6.96 - 6.90 (m, 1H), 6.10 - 5.77 (m, 1H), 5.17 - 4.98 (m, 1H), 4.95 - 4.86 (m, 1H), 4.70 - 4.42 (m, (ESI+): m / z = 3H), 4.32 - 4.22 (m, 1H), 4.08 - 3.99 (m, 2H), 3.96 Degrader F1109.4338 (M+H)+- 3.86 (m, 2H), 3.63 - 3.53 (m, 4H), 3.50 (t, J = 6.4Hz, 2H), 3.45 - 3.41 (m, 2H), 3.30 - 3.19 (m, 4H), 2.92 - 2.82 (m, 4H), 2.59 (s, 3H), 2.43 - 2.39 (m, 3H), 2.32 - 2.30 (m, 3H), 2.10 - 2.04 (m, 1H), 1.84 - 1.75 (m, 3H), 1.64 - 1.60 (m, 3H), 1.49 - 1.35 (m, 3H), 0.96 - 0.91 (m, 9H).

[0418] Synthesis of Degrader G:

[0419] (2S,4R)-l-[(2S)-2-[[2-[2-[2-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia- l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy] ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-N-[[2-[2-(2,2-difluoroethylamino) ethoxy]-4-(4-methylthiazol-5-yl)phenyl]methyl]-4-hydroxy-pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601G-2

[0420] General procedure of Degrader G:

[0421] To a solution of G-l (800 mg, 2 mmol, 1 eq) and G-2 (525 mg, 2 mmol, 1 eq) in DMF (8 mL) was added EtsN (605 mg, 6 mmol, 833 pL, 3 eq) and T4P (2.16 g, 3 mmol, 50% purity, 1.5 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL), then extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 1 / 0 to 0 / 1 to DCM: MeOH = 10:1) to afford G-3 (650 mg, 1 mmol, 50% yield) as a yellow solid. LCMS (ESI+): m / z = 646.1 (M+H)+.

[0422] To a solution of G-3 (600 mg, 928 pmol, 1 eq) in DCM (7.2 mL) was added TFA (2.4 mL). The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction was concentrated and purified by prep-HPLC (Column: Phenomenex Luna C18 (250x70mm><15WSGR Docket No. 68195-704.601um); Mobile Phase: [H2O (0.04% HC1)-ACN]; Gradient: 20-50% B over 20.0 min) to afford G-4 (280 mg, 474 pmol, 51% yield) as a yellow solid. LCMS (ESI+): m / z = 590.1 (M+H)+.

[0423] To a solution of G-4 (100 mg, 169 pmol, 1 eq) and G-5 (93 mg, 135 pmol, 0.8 eq) in DMF (2 mL) was added Et3N (85 mg, 847 pmol, 118 pL, 5 eq) and T4P (91 mg, 254 pmol, 1.5 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL), then extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, DCM: MeOH = 10:1) to afford G-6 (100 mg, 79.4 pmol, 46% yield) as a yellow oil. LCMS (ESI+): m / z = 1259.3 (M+H)+.

[0424] To a solution of G-6 (100 mg, 79.4 pmol, 1 eq) in DCM (2 mL) was added HBr (97 mg, 396 pmol, 65 pL, 33% purity, 5 eq). The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction was concentrated and purified by prep-HPLC (Column: WePure Biotech XP tC18 100x30x7um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 35-65% B over 8.0 min) to afford Degrader G (52 mg, 46 pmol, 58% yield) as a white solid.LCMS: 99.4% purity. HRMS (ESI+): m / z = 1125.4281 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 5 = 8.97 (s, 1H), 8.46 (t, J = 5.9 Hz, 1H), 8.26 (t, J = 5.5 Hz, 1H), 7.51 - 7.26 (m, 6H), 7.01 (d, J = 1.3 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.20 - 5.81 (m, 1H), 5.15 (d, J = 3.6 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.53 - 4.42 (m, 2H), 4.35 (br s, 1H), 4.32 - 4.19 (m, 2H), 4.08 (t, J = 5.3 Hz, 2H), 3.98 (s, 2H), 3.69 - 3.52 (m, 10H), 3.43 (t, J = 5.9 Hz, 2H), 3.30 - 3.17 (m, 4H), 3.03 - 2.92 (m, 4H), 2.59 (s, 3H), 2.47 - 2.44 (m, 3H), 2.40 (s, 3H), 2.28 (br d, J = 8.3 Hz, 1H), 2.10 - 2.01 (m, 1H), 1.95 - 1.86 (m, 1H), 1.62 (s, 3H), 0.93 (s, 9H). SFC: 100.0% de.

[0425] Synthesis of Degrader H:

[0426] (2S,4R)-l-[(2S)-2-[[2-[2-[2-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy] ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[2-[2-(methylamino) ethoxy]-4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601H-11 H-12

[0427] General procedure of Degrader H:

[0428] To a solution of H-l(2.2 g, 6.87 mmol, 1 eq) and H-2 (25.8 g, 137 mmol, 10.3 mL, 20 eq) in DMF (22 mL) was added CS2CO3 (22.3 g, 68.6 mmol, 10 eq). The mixture was stirred at 50 °C for 2 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtO Ac =WSGR Docket No. 68195-704.6011 / 0 to 3 / 1) to afford H-3 (2.1 g, 4.91 mmol, 71% yield) as a yellow oil. LCMS (ESI+): m / z = 426.9 / 429.0 (M+H)+.

[0429] To a solution of H-3 (900 mg, 2.11 mmol, 1 eq) and H-4 (749 mg, 10.5 mmol, 1 mL, 5 eq) in ACN (10 mL) was added K2CO3 (873 mg, 6.32 mmol, 3 eq). The mixture was stirred at 70 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (80 mL) and extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue.

[0430] The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 1 / 0 to 0 / 1) to afford H-5 (820 mg, 1.96 mmol, 93% yield) as ayellow oil. LCMS (ESI+): m / z = 418.1 (M+H)+.

[0431] To a solution of H-5 (800 mg, 1.92 mmol, 1 eq) in DCM (8 mL) was added Pd(PPh3)4 (442 mg, 383 pmol, 0.2 eq) and 1,3 -dimethylbarbituric acid (598 mg, 3.83 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 1 / 0 to 10 / 1) to afford H-6 (270 mg, 715 pmol, 37% yield) as a yellow oil. LCMS (ESI+): m / z = 378.1 (M+H)+.

[0432] To a solution of H-6 (250 mg, 662 pmol, 1 eq) and H-7 (495 mg, 2 mmol, 3 eq) in DMF (2.5 mL) was added DIEA (427 mg, 3.31 mmol, 577 pL, 5 eq). The mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 20: 1) to afford H-8 (110 mg, 215 pmol, 32% yield) as a yellow oil. LCMS (ESI+): m / z = 512.2 (M+H)+.

[0433] A solution of H-8 (110 mg, 215 pmol, 1 eq) was added HCl / EtO Ac (4 M, 1.10 mL) was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction was without purification to afford H-9 (80 mg, crude) as ayellow solid. LCMS (ESI+): m / z = 412.1 (M+H)+.

[0434] To a solution of H-10 (87 mg, 252 pmol, 1.3 eq) and H-9 (80 mg, 194 pmol, 1 eq) in DMF (1 mL) was added EtsN (98 mg, 972 pmol, 135 pL, 5 eq) and T4P (140 mg, 194 pmol, 50% purity, 1 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL><3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filteredWSGR Docket No. 68195-704.601and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, DCM: MeOH = 10:1) to afford H-ll (70 mg, 94.8 pmol, 48% yield) as a yellow solid. LCMS (ESI+): m / z = 738.2 (M+H)+.

[0435] A solution of H-ll (70 mg, 94.8 pmol, 1 eq) was added HCl / EtOAc (4 M, 1.40 mL) was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction was without purification to afford H-12 (55 mg, crude) as a yellow oil. LCMS (ESI+): m / z = 638.2 (M+H)+.

[0436] To a solution of H-12 (50 mg, 78.4 pmol, 1 eq) and H-13 (60 mg, 101 pmol, 1.3 eq) in DMF (1 mL) was added EtiN (39 mg, 392 pmol, 54 pL, 5 eq) and T4P (56 mg, 78.4 pmol, 50% purity, 1 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL><3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, DCM: MeOH = 10:1) to afford H-14 (40 mg, 33 pmol, 42% yield) as a white solid.LCMS (ESI+): m / z = 1209.5 (M+H)+.

[0437] To a solution of H-14 (35 mg, 28.9 pmol, 1 eq) in DCM (0.7 mL) was added HBr (35 mg, 144 pmol, 23 pL, 33% purity, 5 eq). The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 100x40mm><5 um; Mobile Phase: [H2O (0.2% FA)-ACN]; Gradient: 10-50% B over 8.0 min) to afford Degrader H (8 mg, 7.31 pmol, 25% yield) as a white solid. LCMS: 98.3% purity. HRMS (ESI+): m / z = 1075.4269 (M+H)+. 'H NMR (400 MHz, DMSO-c / ) 8 = 8.97 (s, 1H), 8.48 (br t, J = 5.9 Hz, 1H), 8.30 (s, 1H), 8.27 (br t, J = 5.5 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.45 - 7.39 (m, 4H), 7.04 - 7.00 (m, 1H), 6.94 (d, J = 7.9 Hz, 1H), 5.16 (br d, J = 4.4 Hz, 1H), 4.56 (d, J = 9.5 Hz, 1H), 4.52 - 4.44 (m, 2H), 4.35 (br s, 1H), 4.27 (br d, J = 5.8 Hz, 2H), 4.12 (br t, J = 5.1 Hz, 2H), 3.97 (s, 2H), 3.69 - 3.64 (m, 1H), 3.62 - 3.54 (m, 9H), 3.45 - 3.42 (m, 2H), 3.27 - 3.21 (m, 5H), 2.92 (brt, J = 5.1 Hz, 2H), 2.59 (s, 3H), 2.45 (s, 3H), 2.40 (d, J = 6.1 Hz, 6H), 2.08 - 2.01 (m, 1H), 1.90 (ddd, J = 4.4, 8.5, 12.9 Hz, 1H), 1.62 (s, 3H), 0.92 (s, 9H). SFC: 100.0% de.

[0438] Synthesis of Degrader I:

[0439] (2S,4R)-l-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]propoxy] acetyl]amino]-3,3-dimethyl-butanoyl]-N-[(lS)-l-[2-[(2,2-difluoroethylamino)methyl]-4-(4-methylthiazol-5-yl)phenyl]ethyl]-4-hydroxy -pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601

[0440] General procedure of Degrader I-K:

[0441] To a solution of 1-1 (25 g, 79.9 mmol, 1 eq) in THF (250 mL) was added imidazole (10.8 g, 159 mmol, 2 eq) at 0 °C. Then TBSC1 (14.5 g, 95.8 mmol, 11.8 mL, 1.2 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, hexanes: EtOAc = 10:1) to afford 1-2 (34 g, 79.6 mmol, 99% yield) as a colorless oil. 'H NMR (400 MHz, DMSO-c / ) 6 = 7.75 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 2.4, 8.3 Hz, 1H), 4.56 (s, 2H), 0.91 (s, 9H), 0.11 (s, 6H).

[0442] Compound K-l was prepared according to the procedures described in 1-2 using the appropriate intermediates.WSGR Docket No. 68195-704.601Compound Structure 'll NMR(400 MHz, DMSO-c / r,) 5 = 7.81 - 7.77 (m, 1H), 7.59 - 7.53 (m, 1H), K-l 'XK 7.38 (d, J = 8.3 Hz, 1H), 4.65 (s, TBSCT 2H), 0.93 - 0.90 (m, 9H), 0.11 (s,6H)

[0443] To a solution of 1-2 (34 g, 79.6 mmol, 1 eq) in THF (340 mL) was added dropwise iPrMgCl (2 M, 43.7 mL, 1.1 eq) at -70 °C. After addition, the mixture was stirred at -70 °C for 0.5 h, and then AC2O (10.6 g, 103 mmol, 9.72 mL, 1.3 eq) was added dropwise at -70 °C. The resulting mixture was stirred at 25 °C for 1.5 h under N2 atmosphere. The reaction mixture was quenched by addition into saturated NH₄Cl (600 mL) at 0 °C and then diluted with H2O (600 mL) then extracted with EtOAc (400 mL><3). The combined organic layers were washed with saturated brine (500 mL><3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 10:1) to afford 1-3 (24 g, 69.9 mmol, 87% yield) as a colorless oil.

[0444] Compound K-2 was prepared according to the procedures described in 1-3 using the appropriate intermediates.Compound Structure Hl NMR0 (400 MHz, DMSO-c / r,) 6 = 8.06 (s,1H), 7.77 (q, J = 8.2 Hz, 2H), 4.74 K-2(s, 2H), 2.57 (s, 3H), 0.94 (s, 9H), TBSO'0.12 (s, 6H)

[0445] To a solution of 1-3 (18 g, 52.4 mmol, 1 eq) in THF (360 mL) was added 1-4 (25.4 g, 209 mmol, 4 eq), 4A MS (16 g) and Ti(OEt)4 (29.9 g, 131 mmol, 27.1 mL, 2.5 eq). The resulting mixture was stirred at 80 °C for 20 h under N2 atmosphere. The reaction mixture was diluted with H2O (450 mL). The mixture was adjusted to pH = 9 at 25 °C, then extracted with EtOAc (200 mL><3). The organic phase washed with brine (200 mL><3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 1:0 to 50:1) to afford 1-5 (19.5 g, 43.6 mmol, 83% yield) as a yellow oil. 'HNMR (400 MHz, DMSO-c / ) 8 = 7.80 - 7.73 (m, 1H), 7.61 - 7.57 (m, 1H), 7.56 - 7.52 (m, 1H), 4.86 (s, 2H), 2.66 (s, 3H), 1.19 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H).

[0446] Compound K-3 was prepared according to the procedures described in 1-5 using the appropriate intermediates.WSGR Docket No. 68195-704.601Compound Structure LCMSt-BuAtK-3 AQ-B. (ESI+): m / z = 448.2 (M+H)+TBSC)

[0447] To a solution of 1-5 (19.5 g, 43.6 mmol, 1 eq) in THF (195 mL) was added L-Selectride (1 M, 87.3 mL, 2 eq) at 0 °C. The mixture was then stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated NH₄Cl (300 mL) and extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated NH₄Cl (300 mL><5) and saturated brine (300 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Welch Xtimate C18 180x70mmxl0um; Mobile Phase: [H2O (10 mM NH4HCO3) - ACN]; Gradient: 60-95% B over 17.0 min) to afford 1-6 (15 g, 33.4 mmol, 76% yield) as a yellow oil. LCMS (ESI+): m / z = 450.2 (M+H)+.

[0448] Compound K-4 was prepared according to the procedures described in 1-6 using the appropriate intermediates.Compound Structure LCMSt-Bug-S-N"K-4 •■'YL (ESI+): m / z = 450.1(M+H)+TBSCT

[0449] To a solution of 1-6 (15 g, 33.4 mmol, 1 eq) in DMA (300 mL) was added 1-7 (13.2 g, 133 mmol, 12.17 mL, 4 eq), KOAc (6.56 g, 66.8 mmol, 2 eq) and Pd(OAc)2 (750 mg, 3.34 mmol, 0.1 eq). The mixture was stirred at 110 °C for 24 h under N2 atmosphere. The reaction mixture was poured into saturated EDTA (100 mL) and stirred at 25 °C for 2 h, then extracted with EtOAc (100 mLx3). The combined organic layers were washed with saturated brine (100 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 5:1 to 1:2) and purified by prep-HPLC (Column: Phenomenex Luna C18250xl50mmxl5um; Mobile Phase: [H2O (0.1% TFA)-ACN]; Gradient: 15-45% B over 20.0 min) to afford 1-8 (6 g, 12.8 mmol, 38% yield) as a yellow oil and 1-9 (5 g, 14.1 mmol, 42% yield) as a yellow oil. 1-8: LCMS (ESI+): m / z = 467.3 (M+H)+. 1-9: LCMS (ESI+): m / z = 353.3 (M+H)+.

[0450] Compound K-5 was prepared according to the procedures described in 1-8 using the appropriate intermediates.WSGR Docket No. 68195-704.601Compound Structure LCMSt-BucANHK-5 (ESI+): m / z = 353.2 (M+H)+V wHO' '

[0451] To a solution of 1-8 (6 g, 12.8 mmol, 1 eq) in THF (60 mL) was added TBAF (1 M, 14.1 mL, 1.1 eq). The mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, hexanes: EtOAc = 2:1 to 1:2) to afford 1-9 (3.5 g, 9.93 mmol, 77% yield) as a yellow oil. LCMS (ESI+): m / z = 353.2 (M+H)+.

[0452] To a solution of 1-9 (7.5 g, 21.2 mmol, 1 eq) in EtOAc (75 mL) was added HClZEtOAc (4 M, 150 mL). The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford 1-10 (6 g, crude, HC1) as a lightyellow solid. LCMS (ESI+): m / z = 249.2 (M+H)+.

[0453] Compound K-6 was prepared according to the procedures described in 1-10 using the appropriate intermediates.Compound Structure LCMSCIH3NK-6 (ESI+): m / z = 249.2 (M+H)+HO< '

[0454] To a solution of 1-10 (6 g, 21.1 mmol, 1 eq, HC1) in THF (120 mL) was added DIEA (10.9 g, 84.2 mmol, 14.6 mL, 4 eq) and BOC2O (13.8 g, 63.2 mmol, 14.5 mL, 3 eq). The mixture was stirred at 25 °C for 5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (100 mL) and extracted with EtOAc (300 mL><3). The combined organic layers were washed with saturated brine (100 mL><3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 5:1 to 2:1) to afford 1-11 (5.5 g, 15.8 mmol, 74% yield) as a yellow oil. LCMS (ESI+): m / z = 349.2 (M+H)+.

[0455] Compound K-7 was prepared according to the procedures described in 1-11 using the appropriate intermediates.WSGR Docket No. 68195-704.601Compound Structure LCMSBocHNK-7 (ESI+): m / z = 349.2 (M+H)+HO^ '

[0456] To a solution 1-11 (1 g, 2.87 mmol, 1 eq) in DCM (20 mL) was added DIEA (1.11 g, 8.61 mmol, 1.50 mL, 3 eq) and MS2O (750 mg, 4.30 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated with N2 to afford 1-12 (1.2 g, crude) as a light yellow solid. LCMS (ESI+): m / z = 427.2 (M+H)+.

[0457] Compound K-8 was prepared according to the procedures described in 1-12 using the appropriate intermediates.Compound Structure LCMSBocHNK-8 (ESI+): m / z = 427.2 (M+H)+Mscr 'WSGR Docket No. 68195-704.601

[0458] To a solution of 1-12 (1.2 g, 2.81 mmol, 1 eq) in MeCN (36 mL) was added DIEA (1.09 g, 8.44 mmol, 1.47 mL, 3 eq) and 1-13 (2.28 g, 28.1 mmol, 10 eq). The mixture was stirred at 70 °C for 1.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, hexanes: EtOAc = 5:1 to 2: 1) to afford 1-14 (1 g, 2.43 mmol, 86% yield,) as a yellow solid. LCMS (ESI+): m / z = 412.3 (M+H)+.

[0459] Compounds J-l & K-9 was prepared according to the procedures described in 1-14 using the appropriate intermediates.Compound Structure LCMSBocHNJ-l (ESI+): m / z = 394.2 (M+H) NH / +JWSGR Docket No. 68195-704.601Compound Structure LCMSBocHNK-9 (ESI+): m / z = 412.3 (M+H) HN' '+

[0460] To a solution of 1-14 (900 mg, 2.19 mmol, 1 eq) and 1-15 (1.64 g, 6.56 mmol, 3 eq) in DMF (18 mL) was added DIEA (1.41 g, 10.9 mmol, 1.90 mL, 5 eq). The mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (80 mL) and extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtO Ac = 1 / 0 to 0 / 1) to afford 1-16 (1 g, 1.83 mmol, 83.80% yield) as a yellow oil. LCMS (ESI+): m / z = 546.2 (M+H)+.

[0461] Compound J-2 & K-10 was prepared according to the procedures described in 1-16 using the appropriate intermediates.Compound Structure LCMSBocHNJ-2 (ESI+): m / z = 528.2 (M+H)+y^'CbZrBocHNK-10 Cbz^N' / (ESI+): m / z = 546.2 (M+H)+

[0462] A solution of 1-16 (1 g, 1.83 mmol, 1 eq) was added HCl / EtOAc (4 M, 10 mL, 21 eq) stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction was without purification to afford 1-17 (800 mg, crude) as a white solid. LCMS (ESI+): m / z = 446.3 (M+H)+.

[0463] Compound J-3 & K-ll was prepared according to the procedures described in 1-17 using the appropriate intermediates.WSGR Docket No. 68195-704.601Compound Structure LCMSCIH3NJ-3 (ESI+): m / z = 428.1 (M+H)+^" CbzF CIH3NK-ll Cbz^N / / (ESI+): m / z = 446.2 (M+H)+

[0464] To a solution of 1-17 (750 mg, 1.68 mmol, 1 eq) and 1-18 (695 mg, 2.02 mmol, 1.2 eq) in DMF (7.5 mL) was added EtsN (851 mg, 8.42 mmol, 1.17 mL, 5 eq) and T4P (1.21 g, 1.68 mmol, 50% purity, 1 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (80 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, DCM: MeOH = 1 / 0 to 10 / 1) to afford 1-19 (1 g, 1.30 mmol, 77% yield) as a yellow solid. LCMS (ESI+): m / z = 772.2 (M+H)+.

[0465] Compound J-4 & K-12 was prepared according to the procedures described in 1-19 using the appropriate intermediates.Compound Structure LCMS1 9HBOCHN-^YN^ / ° Q^ 'NHJ-4 (ESI+): m / z = 754.2 (M+H)+,^~CbzWSGR Docket No. 68195-704.601

[0466] A solution of 1-19 (1 g, 1.30 mmol, 1 eq) was added HCl / EtOAc (4 M, 10 mL, 30.8 eq) stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction was without purification to afford 1-20 (850 mg, crude) as a white solid. LCMS (ESI+): m / z = 672.2 (M+H)+.

[0467] Compound J-5 & K-13 was prepared according to the procedures described in 1-20 using the appropriate intermediates.Compound Structure LCMS1 PHCIH3N-^yNV>° (jA-NHJ-5 (ESI+): m / z = 654.2 (M+H)+r1 PHCIH3N-^YN^ / ° (j^NHK-13 (ESI+): m / z = 672.5 (M+H)+Cbz^N / /

[0468] To a solution of 1-20 (547 mg, 814 pmol, 1.2 eq) and Intermediate I (380 mg, 678 pmol, 1 eq) in DMF (3.8 mL) was added EtiN (343 mg, 3.39 mmol, 472 pL, 5 eq) and T4P (489 mg, 678 pmol, 50% purity, 1 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (80 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrousWSGR Docket No. 68195-704.601Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, DCM: MeOH = 1 / 0 to 10 / 1) to afford 1-21 (600 mg, 494 pmol, 72% yield) as a yellow solid. LCMS (ESI+): m / z = 1213.3 (M+H)+.

[0469] Compound J-6 & K-14 was prepared according to the procedures described in 1-21 using the appropriate intermediates.

[0470] To a solution of 1-21 (400 mg, 329 pmol, 1 eq) in DCM (4 mL) was added HBr (404 mg, 1.65 mmol, 271 pL, 33% purity, 5 eq). The mixture was stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 100x40mmx5um; Mobile Phase: [H2O (0.2% FA)-ACN]; gradient: 20%-55% B over 8.0 min) to afford Degrader I (174 mg, 159 pmol, 48% yield) as a white solid. LCMS: 99.2% purity. HRMS (ESI+): m / z = 1079.4232 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 8 = 8.98 (s, 1H), 8.51 (br d, J = 7.4 Hz, 1H), 8.27 (br t, J = 5.5 Hz, 1H), 8.13 (s, 1H), 7.50 - 7.46 (m, 2H), 7.44 - 7.39 (m, 4H), 7.39 -7.35 (m, 1H), 7.33 (d, J = 9.5 Hz, 1H), 6.17 - 5.82 (m, 1H), 5.13 - 4.95 (m, 2H), 4.65 - 4.48 (m, 2H), 4.41 (t, J = 8.2 Hz, 1H), 4.24 (br s, 1H), 3.96 - 3.87 (m, 2H), 3.85 - 3.81 (m, 2H), 3.58 -3.47 (m, 6H), 3.45 - 3.41 (m, 2H), 3.30 - 3.19 (m, 4H), 2.90 (ddd, J = 3.2, 12.5, 16.0 Hz, 2H), 2.59 (s, 3H), 2.46 (s, 3H), 2.41 (s, 3H), 1.99 (br s, 1H), 1.83 - 1.77 (m, 2H), 1.66 (s, 1H), 1.62 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H), 0.92 (s, 9H). SFC: 100.0% de.WSGR Docket No. 68195-704.601

[0471] Compound Degrader J & K was prepared according to the procedures described in Degrader I using the appropriate intermediates.Compound HRMS m NMR(400 MHz, DMSO-cC) 8 = 8.98 (s, 1H), 8.56 (br d, J = 7.1 Hz, 1H), 8.27 (br t, J = 5.5 Hz, 1H), 8.14 (s, 1H), 7.50 - 7.46 (m, 2H), 7.43 (s, 2H), 7.41 (d, J = 2.4 Hz, 1H), 7.40 - 7.07 (m, 3H), 5.13 - 4.95 (m, 2H), 4.65 - 4.49 (m, 3H), 4.43 - 4.39 (m, 2H), (ESI+): m / z = 4.24 (br s, 1H), 3.95 - 3.89 (m, 2H), 3.86 - 3.82 Degrader J1061.4348 (M+H)+(m, 2H), 3.58 - 3.52 (m, 4H), 3.51 - 3.47 (m, 2H),3.45 - 3.41 (m, 2H), 3.28 - 3.22 (m, 4H), 2.88 (br s, 1H), 2.81 (br s, 1H), 2.59 (s, 3H), 2.46 (s, 3H), 2.41 (s, 3H), 2.02 - 1.97 (m, 1H), 1.80 (t, J = 6.4 Hz, 2H), 1.70 - 1.64 (m, 1H), 1.62 (s, 3H), 1.36 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H).(400 MHz, DMSO-tfc) 6 = 9.04 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 8.33 - 8.23 (m, 1H), 7.64 - 7.46 (m, 3H), 7.45 - 7.40 (m, 2H), 7.37 - 7.27 (m, 1H), 7.21 (q, J = 8.0 Hz, 2H), 6.07 - 5.74 (m, 1H), 5.15 - 4.96 (m, 1H), 4.91 (quin, J = 7.2 Hz, 1H), 4.70 - (ESI+): m / z =Degrader K 4.41 (m, 3H), 4.32 - 4.23 (m, 1H), 3.93 - 3.82 (m,1079.4227 (M+H)+2H), 3.60 - 3.40 (m, 11H), 3.27 - 3.21 (m, 3H), 2.77 (dt, J = 4.2, 15.9 Hz, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 2.17 (s, 3H), 2.11 - 2.02 (m, 1H), 1.84 - 1.76 (m, 3H), 1.62 (s, 3H), 1.35 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H).

[0472] Synthesis of Degrader L:

[0473] (2S,4R)-l-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia- l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy] propoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-N-[(lS)-l-[4-[4-[(2,2-difluoroethyl amino)methyl]thiazol-5-yl]phenyl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601L-3

[0474] General procedure of Degrader L:

[0475] To a solution of L-l (25 g, 83.2 mmol, 1 eq) and bis(pinacolato)diboron (31.7 g, 125 mmol, 1.5 eq) in dioxane (250 mL) was added KO Ac (24.5 g, 250 mmol, 3 eq) and Pd(dppf)C12 (1.83 g, 2.50 mmol, 0.03 eq). The mixture was stirred at 90 °C for 16 h under N2 atmosphere.WSGR Docket No. 68195-704.601The reaction mixture was poured into EDTA (500 mL) and stirred for 2 h, then extracted with EtOAc (350 mL><3). The combined organic layers were washed with saturated brine (200 mL><2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford L-2 (28.8 g, crude) as a brown oil. LCMS (ESI+): m / z = 292.3 (M+H-tBu)+.

[0476] To a solution of L-2 (14.4 g, 41.4 mmol, 1 eq) and L-3 (9.79 g, 41.4 mmol, 1 eq) in dioxane (325 mL) and H2O (55 mL) was added K2CO3 (11.4 g, 82.9 mmol, 2 eq) and Pd(dppf)C12 (303 mg, 414 pmol, 0.01 eq). The mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was poured into EDTA (500 mL) and stirred for 2 h, then extracted with EtOAc (600 mLx3). The combined organic layers were washed with saturated brine (400 mLx2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 20 / 1 to 1 / 1) to afford L-4 (8.55 g, 22.3 mmol, 53% yield) as a yellow solid. LCMS (ESI+): m / z = 377.3 (M+H)+.

[0477] To a solution of L-4 (4 g, 10.6 mmol, 1 eq) in THF (80 mL) and H2O (40 mL) was added CaCh (3.54 g, 31.8 mmol, 3 eq) followed by NaBEL (790 mg, 20.8 mmol, 1.97 eq) at 0 °C. The mixture was stirred at 0 °C, then allowed to warm to 20 °C for 5 h under N2 atmosphere. The reaction mixture was poured into saturated NH₄Cl (300 mL) then extracted with EtOAc (200 mLx3). The combined organic layers were washed with saturated brine (150 mLx3), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (50 mL) at 20 °C for 5 min, filtered and concentrated under reduced pressure to afford L-5 (2.7 g, 7.81 mmol, 73% yield) as a white solid. LCMS (ESI+): m / z = 335.1 (M+H)+. SFC: 100.0% de.

[0478] To a solution of L-5 (2 g, 5.98 mmol, 1 eq) in DCM (40 mL) was added DIPEA (2.32 g, 17.9 mmol, 3.12 mL, 3 eq) followed by MS2O (1.56 g, 8.97 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25°C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford L-6 (2.4 g, crude) as a yellow oil.

[0479] To a solution of L-6 (2.4 g, 5.82 mmol, 1 eq) and L-7 (4.72 g, 58.1 mmol, 10 eq) in ACN (72 mL) was added DIPEA (2.26 g, 17.4 mmol, 3.04 mL, 3 eq). The mixture was stirred at 70 °C for 1.5 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL) then extracted with EtOAc (100 mLx3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtO Ac = 50 / 1 to 0 / 1) to afford L-8 (2.2 g, 4.69 mmol, 80% yield) as a yellow solid. LCMS (ESI+): m / z = 398.1 (M+H)+.WSGR Docket No. 68195-704.601

[0480] To a solution of L-8 (2 g, 5.03 mmol, 1 eq) in DMF (40 mL) was added DIPEA (3.25 g, 25.1 mmol, 4.38 mL, 5 eq) and L-9 (3.76 g, 15.1 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL), then extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtO Ac = 100 / 1 to 1 / 1) to afford L-10 (2.4 g, 4.05 mmol, 80% yield) as a yellow oil. LCMS (ESI+): m / z = 532.1 (M+H)+. SFC: 100.0% de.

[0481] A mixture of L-10 (1 g, 1.88 mmol, 1 eq) in HCl / EtOAc (4 M, 10 mL) was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford L-ll (750 mg, crude, HC1) as a yellow solid. LCMS (ESI+): m / z = 432.3 (M+H)+.

[0482] To a solution of L-ll (700 mg, 1.50 mmol, 1 eq) and L-12 (618 mg, 1.80 mmol, 1.2 eq) in DMF (7 mL) was added EtsN (756 mg, 7.48 mmol, 1.04 mL, 5 eq) and T4P (1.08 g, 1.50 mmol, 50% purity, 1 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (20 mL) then extracted with EtOAc (30 mL*3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 10 / 1 to 1 / 3) to afford L-13 (840 mg, 980 pmol, 65% yield) as a yellow oil. LCMS (ESI+): m / z = 758.5 (M+H)+. SFC: 100.0% de.

[0483] A mixture of L-13 (840 mg, 1.11 mmol, 1 eq) in HCl / EtO Ac (4 M, 10 mL) was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford L-14 (740 mg, crude) as a white solid. LCMS (ESI+): m / z = 658.5 (M+H)+.

[0484] To a solution of L-14 (413 mg, 595 pmol, 1 eq) and Intermediate I (400 mg, 714 pmol, 1.2 eq) in DMF (7 mL) was added EtsN (361 mg, 3.57 mmol, 497 pL, 6 eq) and T4P (514 mg, 714 pmol, 50% purity, 1.2 eq). The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (20 mL) then extracted with EtOAc (30 mL*3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 100 / 1 to 10 / 1) to afford L-15 (660 mg, 537 pmol, 90% yield) as a yellow oil. LCMS (ESI+): m / z = 1199.5 (M+H)+.

[0485] To a solution of L-15 (350 mg, 291 pmol, 1 eq) in DCM (3.5 mL) was added HBr (357 mg, 1.46 mmol, 240 pL, 33% purity, 5 eq). The mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18WSGR Docket No. 68195-704.601150x40x7um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 40-70% B over 10.0 min) to afford Degrader L (81 mg, 76.1 pmol, 26% yield) as a white solid. LCMS: 99.3% purity. HRMS (ESI+): m / z = 1065.4066 (M+H)+. 'HNMR (400 MHz, DMSO-c / ) 6 = 9.07 -9.03 (m, 1H), 8.75 - 8.42 (m, 1H), 8.30 - 8.24 (m, 1H), 7.52 - 7.46 (m, 4H), 7.44 - 7.40 (m, 2H), 7.38 - 7.09 (m, 3H), 6.16 - 5.83 (m, 1H), 5.15 - 4.97 (m, 1H), 4.94 - 4.65 (m, 1H), 4.56 - 4.41 (m, 3H), 4.31 - 4.22 (m, 1H), 3.97 - 3.88 (m, 2H), 3.84 (d, J = 6.4 Hz, 2H), 3.62 - 3.53 (m, 4H), 3.50 (t, J = 6.4 Hz, 2H), 3.45 - 3.41 (m, 2H), 3.30 (br s, 4H), 3.00 - 2.89 (m, 2H), 2.60 - 2.58 (m, 3H), 2.48 - 2.44 (m, 1H), 2.42 - 2.39 (m, 3H), 2.11 - 1.98 (m, 1H), 1.83 - 1.72 (m, 3H), 1.64 -1.60 (m, 3H), 1.48 - 1.35 (m, 3H), 0.95 - 0.91 (m, 9H). SFC: 100.0% de.

[0486] Synthesis of Degrader M:

[0487] (2S,4R)-l-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]propoxy] acetyl]amino]-3,3-dimethyl-butanoyl]-N-[(lR)-2-(2,2-difluoroethylamino)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]-4-hydroxy-pyrrolidine-2-carb oxami de.WSGR Docket No. 68195-704.601

[0488] General procedure of Degrader M:

[0489] To a mixture of M-l (2.1 g, 4.36 mmol, 1 eq) in EtOH (21 mL) was added NH2NH2-H2O (0.530 g, 10.38 mmol, 513 pL, 98% purity, 2.38 eq), then stirred at 70 °C for 1 h under N2atmosphere. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (50 mLx 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue yielded M-2 (1.7 g, crude) as a yellow oil. LCMS (ESI+): m / z = 334.1 (M+H)+.

[0490] To a mixture of M-2 (1.7 g, 5.10 mmol, 1 eq) and 2,2-difluoroethyl trifluoromethanesulfonate (3.27 g, 15.29 mmol, 3 eq) in THF (34 mL) was added EtsN (2.58 g,WSGR Docket No. 68195-704.60125.5 mmol, 3.55 mL, 5 eq), then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 50 / 1 to 1 / 1) to afford M-3 (1.5 g, 3.77 mmol, 74% yield) as a yellow solid. LCMS (ESI+): m / z = 398.1 (M+H)+. SFC: 100.0% ee.

[0491] To a mixture of M-3 (1.5 g, 3.77 mmol, 1 eq) and benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (1.88 g, 7.55 mmol, 2 eq) in DMF (15 mL) was added DIEA (2.44 g, 18.8 mmol, 3.29 mL, 5 eq), then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 (250x70mm><15 um); Mobile Phase: [H2O (0.1% TFA)-ACN];Gradient: 40-70% B over 25.0 min) to afford M-4 (1.2 g, 2.26 mmol, 60% yield) as a yellow solid. LCMS (ESI+): m / z = 532.2 (M+H)+. SFC: 100.0% ee.

[0492] A mixture of M-4 (1.2 g, 2.26 mmol, 1 eq) in HCl / EtOAc (4 M, 12 mL) was stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue yielded M-5 (840 mg, crude) as a yellow solid. LCMS (ESI+): m / z = 432.0 (M+H)+.

[0493] To a mixture of M-5 (840 mg, 1.80 mmol, 1 eq) and M-6 (680 mg, 1.97 mmol, 1.1 eq) in DMF (1 mL) was added EtsN (545 mg, 5.39 mmol, 750 pL, 3 eq) and T4P (1.94 g, 2.69 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred for 1 h under N2 atmosphere. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 50 / 1 to 0 / 1) to afford M-7 (1.1 g, 1.45 mmol, 81% yield) as a yellow solid. LCMS (ESI+): m / z = 758.3 (M+H)+.

[0494] To a mixture of M-7 (1.1 g, 1.45 mmol, 1 eq) in THF (11 mL) was added HCl / EtOAc (4 M, 11 mL) and stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue yielded M-8 (1 g, crude) as a yellow solid. LCMS (ESI+): m / z = 658.2 (M+H)+.

[0495] To a mixture of M-8 (500 mg, 720 pmol, 1 eq) and Intermediate I (403 mg, 720 pmol, 1 eq) in DMF (5 mL) was added EtsN (364 mg, 3.60 mmol, 501 pL, 5 eq) and T4P (778 mg, 1.08 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred for 0.5 h under N2 atmosphere. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mLx3). The combinedWSGR Docket No. 68195-704.601organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, DCM: MeOH = 80:1 to 10 / 1) to afford M-9 (670 mg, 558 pmol, 77% yield) as a yellow solid. LCMS (ESI+): m / z = 1199.4 (M+H)+.

[0496] To a mixture of M-9 (600 mg, 500 pmol, 1 eq) in DCM (6 mL) was added HBr (613 mg, 2.50 mmol, 411 pL, 33% purity, 5 eq), then stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 100x40mm><5 um; Mobile Phase:[H2O (0.2% FA)-ACN]; Gradient: 15-50% B over 8.0 min) to afford Degrader M (118 mg, 107 pmol, 21% yield) as a white solid. LCMS: 96.7% purity. HRMS (ESI+): m / z = 1065.4080 (M+H)+. 'H NMR (400 MHz, DMSO-c / ) 6 = 8.99 (s, 1H), 8.52 (d, J = 8.6 Hz, 1H), 8.26 (t, J = 5.6 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.46 - 7.39 (m, 6H), 7.37 - 7.20 (m, 1H), 6.15 - 5.77 (m, 1H), 5.18 - 4.98 (m, 2H), 4.90 - 4.48 (m, 2H), 4.48 - 4.38 (m, 1H), 4.32 (br s, 1H), 3.98 - 3.89 (m, 2H), 3.67 - 3.53 (m, 4H), 3.49 (t, J = 6.4 Hz, 2H), 3.45 - 3.40 (m, 2H), 3.29 - 3.19 (m, 4H), 2.98 - 2.80 (m, 4H), 2.59 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H), 2.24 (br s, 1H), 2.02 (br dd, J = 7.3, 12.8 Hz, 1H), 1.84 - 1.76 (m, 3H), 1.62 (s, 3H), 0.94 (s, 9H). SFC: 100.0% de.

[0497] Synthesis of Degrader N:

[0498] (2S,4R)-l-[(2S)-2-[[2-[3-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]propoxy] acetyl]amino]-3,3-dimethyl-butanoyl]-N-[(lS)-l-[2-[3-(2,2-difluoroethylamino)propyl]-4-(4-methylthiazol-5-yl)phenyl]ethyl]-4-hydroxy -pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601

[0499] General procedure of Degrader N:

[0500] To a solution of N-l (35 g, 111.8 mmol, 1 eq) in DCM (700 mL) was added DIEA (43.3 g, 335 mmol, 58.4 mL, 3 eq), methanesulfonic anhydride (29.22 g, 167 mmol, 1.5 eq) at 0 °C, then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated with N2 to give N-2 (43.7 g, crude) as a yellow oil.

[0501] To a solution of diethyl propanedioate (35.80 g, 223 mmol, 33.9 mL, 2 eq) in DMF (437 mL) was added CS2CO3 (91.03 g, 279 mmol, 2.5 eq) at 0 °C, then stirred for 0.5 h. A solution of N-2 (43.7 g, 111.76 mmol, 1 eq) in DMF (210 mL) was added dropwise at 0 °C, then stirred at 25 °C for 15.5 h under N2 atmosphere. The reaction mixture was poured into H2O (3.5 L) and extracted with EtOAc (1 L><3). The combined organic layers were washed with saturated brine (1 L), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 5 / 1) to give N-3 (28 g, 61.5 mmol, 55% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-c / ) 6 = 7.77 (dd, J = 0.9, 8.5 Hz, 1H), 7.48 (d, J = 1.0 Hz, 1H), 7.20 (dd, J = 1.1, 8.4 Hz, 1H), 4.10 (d, J = 7.2 Hz, 4H), 3.88 - 3.79 (m, 1H), 3.18 (d, J = 7.9 Hz, 2H), 1.13 (dt, J = 0.9, 7.1 Hz, 6H).WSGR Docket No. 68195-704.601

[0502] To a solution of N-3 (28 g, 61.53 mmol, 1 eq) in MeOH (420 mL) was added NaOH (1 M, 420 mL) and stirred at 70 °C for 2 h under N2 atmosphere. The reaction mixture was adjusted to pH 3 with HC1 (2 M), then concentrated under reduced pressure to remove MeOH, and extracted with EtOAc (400 mL><3). The combined organic layers were washed with saturated brine (400 mL><2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with EtOAc: hexanes (1:50, 500 mL), filtered and the filter cake was concentrated under reduced pressure to give N-4 (24 g, 60.1 mmol, 98% yield) as a white solid. LCMS (ESI-): m / z = 396.8 (M-H)’.

[0503] A solution of N-4 (24 g, 60.15 mmol, 1 eq) in NMP (240 mL) was pumped by Pump 1 {SI, Pl, 5.5 mL / min} to flow reactor 1 {FLR1, SS, Coils reactor, 3.175(1 / 8") mm, 55.0 mL, 150 °C}. The reaction had a residence time in flow reactor 1 {FLR1, 10.0 min} and pressurized at 4 Mpa. The reaction mixture was poured into H2O (1.5 L) and extracted with EtOAc (500 mL><3). The combined organic layers were washed with saturated brine (500 mL><2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 100 / 1 to 5 / 1) to give the N-5 (19 g, 53.5 mmol, 89% yield) as a white solid. LCMS (ESI-): m / z = 352.8 (M-H); 'H NMR (400 MHz, DMSO-c / r,) 6 = 12.26 (br s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.20 - 7.12 (m, 1H), 2.86 (t, J = 7.8 Hz, 2H), 2.50 - 2.47 (m, 2H).

[0504] To a solution of N-5 (19 g, 53.5 mmol, 1 eq) in THF (190 mL) was added BHi’THF (1 M, 107 mL, 2 eq) at 0 °C, then stirred at 25 °C for 2 h under N2 atmosphere. To this was then added MeOH (190 mL) dropwise, then stirred for 1 h at 70 °C under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 50 / 1 to 10 / 1) to give N-6 (17 g, 49.9 mmol, 93% yield) as colorless oil.1H NMR (400 MHz, DMSO-c / ) 6 = 7.79 - 7.72 (m, 1H), 7.53 - 7.46 (m, 1H), 7.18 - 7.12 (m, 1H), 4.59 - 4.50 (m, 1H), 3.47 - 3.39 (m, 2H), 2.73 - 2.63 (m, 2H), 1.73 - 1.58 (m, 2H).

[0505] To a solution N-6 (17 g, 49.9 mmol, 1 eq) in THF (170 mL) was added imidazole (6.79 g, 99.7 mmol, 2 eq) and TBSC1 (9.02 g, 59.8 mmol, 7.36 mL, 1.2 eq), then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 1 / 0) to give N-7 (22 g, 48.3 mmol, 97% yield) as a colorless oil.1H NMR (400 MHz, DMSO-c / r,) 8 = 7.79 - 7.69 (m, 1H), 7.51 - 7.43 (m, 1H), 7.15 (dd, J = 2.3, 8.4 Hz, 1H), 3.68 - 3.56 (m, 2H), 2.74 - 2.63 (m, 2H), 1.79 - 1.66 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H).

[0506] To a solution of N-7 (22 g, 48.3 mmol, 1 eq) in THF (220 mL) was added dropwise chloro(isopropyl)magnesium (2 M, 26.58 mL, 1.1 eq) at -70 °C and stirred for 0.5 h. To this wasWSGR Docket No. 68195-704.601then added acetic anhydride (14.80 g, 145 mmol, 13.62 mL, 3 eq) dropwise, maintaining the temperature at -70 °C. The mixture was then stirred at 25 °C for 2 h under N2 atmosphere. This was poured into saturated NH₄Cl (500 mL) and extracted with EtOAc (200 mL / 3). The combined organic layers were washed with brine (200 mL><3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes) to give N-8 (10.5 g, 28.2 mmol, 58% yield) as a yellow solid. 'HNMR (400 MHz, DMSO-c / ) 6 = 7.71 (d, J = 8.3 Hz, 1H), 7.50 (br d, J = 1.9 Hz, 2H), 3.56 (t, J = 6.3 Hz, 2H), 2.81 - 2.76 (m, 2H), 2.53 (s, 3H), 1.71 - 1.65 (m, 2H), 0.87 (s, 9H), 0.02 (s, 6H).

[0507] To a solution of N-8 (10.5 g, 28.2 mmol, 1 eq) in THF (210 mL) was added (R)-2-methylpropane-2-sulfmamide (13.7 g, 113 mmol, 4 eq), 4AMS (10.5 g, 1.00 eq) and tetraethoxytitanium (16.12 g, 70.68 mmol, 14.66 mL, 2.5 eq), then stirred at 80 °C for 10 h under N2 atmosphere. The reaction mixture was poured into saturated Na2CO3(450 mL) and extracted with EtOAc (400 mL><3). The combined organic layers were washed with saturated brine (400 mL><3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 1 / 0 to 50 / 1) to give N-9 (11 g, 23.18 mmol, 82% yield) as a yellow oil. LCMS (ESI+): m / z = 476.2 (M+H)+.

[0508] To a solution of N-9 (11 g, 23.18 mmol, 1 eq) in THF (110 mL) was added lithium trisec-butylboranuide (1 M, 46.36 mL, 2 eq) at 0 °C, then stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated NH₄Cl (300 mL) and extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated NH₄Cl (300 mL><5) and saturated brine (300 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Welch Xtimate C18250xl00mmxl0um; Mobile Phase: [H2O (10 mMNH4HCO3) - ACN]; Gradient: 55-90% B over 20.0 min) to give N-10 (9.5 g, 19.9 mmol, 86% yield) as a yellow oil. LCMS (ESI+): m / z = 478.1 (M+H)+. SFC: 92.5% de.

[0509] To a solution of N-10 (9.5 g, 19.93 mmol, 1 eq) and 4-methylthiazole (7.91 g, 79.7 mmol, 7.25 mL, 4 eq) in DMA (190 mL) was added KOAc (3.91 g, 39.8 mmol, 2 eq) and Pd(OAc)2 (447 mg, 1.99 mmol, 0.1 eq), then stirred at 120 °C for 48 h under N2 atmosphere. The reaction mixture was poured into saturated EDTA (400 mL) and stirred at 25 °C for 2 h, then extracted with EtOAc (200 mLx5). The combined organic layers were washed with saturated brine (200 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18250xl50mmxl5um; Mobile Phase: [H2O (0.1% TFA)-ACN]; Gradient: 25-55% B overWSGR Docket No. 68195-704.60120.0 min) to give N-ll (4 g, 10.51 mmol, 52% yield) as a yellow solid. LCMS (ESI+): m / z = 381.1 (M+H)+.

[0510] To a solution of N-ll (3 g, 7.88 mmol, 1 eq) in EtOAc (30 mL) was added HClZEtOAc (4 M, 60 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give N-12 (2.1 g, crude, HC1) as a yellow solid. LCMS (ESI+): m / z = 277.1 (M+H)+.

[0511] To a solution of N-12 (2.1 g, 6.71 mmol, 1 eq, HC1) in THF (42 mL) was added BOC2O (4.39 g, 20.1 mmol, 4.63 mL, 3 eq) and DIEA (3.47 g, 26.8 mmol, 4.68 mL, 4 eq), then stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (90 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 5 / 1 to 1 / 1) to give N-13 (1.5 g, 3.98 mmol, 59% yield) as a yellow oil. LCMS (ESI+): m / z = 377.2 (M+H)+.

[0512] To a solution of N-13 (1.5 g, 3.98 mmol, 1 eq) in DCM (75 mL) was added DMP (2.03 g, 4.78 mmol, 1.48 mL, 1.2 eq) at 0 °C, then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with H2O (60 mL) and saturated Na₂CO₃ (60 mL), then extracted with DCM (90 mL><3). The combined organic layers were washed with saturate brine (90 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 10 / 1 to 3 / 1) to give N-14 (700 mg, 1.87 mmol, 47% yield) as a yellow oil. LCMS (ESI+): m / z = 375.1 (M+H)+.

[0513] To a solution of N-14 (700 mg, 1.87 mmol, 1 eq) and 2,2-difluoroethanamine (454 mg, 5.61 mmol, 3 eq) in AcOH (4.2 mL) and DCE (12.60 mL) was added NaBH(OAc)3 (1.19 g, 5.61 mmol, 3 eq), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) then adjusted to pH 8 with saturated Na₂CO₃, and extracted with DCM (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, DCM: MeOH = 15 / 1, Rf = 0.3) to give N-15 (700 mg, 1.59 mmol, 85% yield) as a yellow solid. LCMS (ESI+): m / z = 440.3 (M+H)+.

[0514] To a solution of N-15 (650 mg, 1.48 mmol, 1 eq) in DMF (6.5 mL) was added DIEA (764 mg, 5.91 mmol, 1.03 mL, 4 eq) and benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (1.11 g, 4.44 mmol, 3 eq), then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (40 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2,WSGR Docket No. 68195-704.601hexanes: EtOAc = 10 / 1 to 5 / 1) to give N-16 (800 mg, 1.39 mmol, 94% yield) as a yellow oil. LCMS (ESI+): m / z = 574.3 (M+H)+.

[0515] To a solution of N-16 (300 mg, 523 pmol, 1 eq) in EtOAc (3 mL) was added HCl / EtOAc (4 M, 6 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give N-17 (240 mg, crude, HC1) as a yellow solid. LCMS (ESI+): m / z = 474.2 (M+H)+.

[0516] To a solution of N-17 (240 mg, 470 pmol, 1 eq, HC1) and N-18 (162 mg, 470 pmol, 1 eq) in DMF (2.4 mL) was added EtsN (238 mg, 2.35 mmol, 327 pL, 5 eq) and T4P (508 mg, 705WSGR Docket No. 68195-704.601pmol, 50% purity, 1.5 eq) at 0 °C, then stirred for 0.5 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL><3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, hexanes: EtOAc = 1 / 1) to give N-19 (240 mg, 300 pmol, 63% yield) as a yellow solid. LCMS (ESI+): m / z = 800.5 (M+H)+.

[0517] To a solution of N-19 (200 mg, 250 pmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 4 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give N-20 (160 mg, crude, HC1) as a yellow solid. LCMS (ESI+): m / z = 700.3 (M+H)+.

[0518] To a solution of N-20 (160 mg, 217.30 pmol, 1 eq, HC1) and Intermediate I (121 mg, 217 pmol, 1 eq) in DMF (1.6 mL) was added EtsN (110 mg, 1.09 mmol, 151 pL, 5 eq) and T4P (234 mg, 326 pmol, 50% purity, 1.5 eq) at 0 °C, then stirred for 0.5 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL / 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 15 / 1, Rf = 0.2) to give N-21 (160 mg, 128 pmol, 59% yield) as a yellow solid. LCMS (ESI+): m / z = 621.8 (M / 2+H)+.

[0519] To a solution of N-21 (160 mg, 128 pmol, 1 eq) in DCM (1.6 mL) was added HBr (158 mg, 644 pmol, 106 pL, 33% purity, 5 eq), then stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18 150><40x7um; Mobile Phase:[H2O (10 mM NH4HCO3) - ACN]; Gradient: 50-80% B over 8.0 min) to give Degrader N (55 mg, 50 pmol, 38% yield) as a white solid. LCMS: 100.0% purity, HRMS (ESI+): m / z =1107.4534 (M+H)+, 'H NMR (400 MHz, DMSO-c / ) 6 =8.99 - 8.95 (m, 1H), 8.76 - 8.38 (m, 1H), 8.29 - 8.24 (m, 1H), 7.50 - 7.46 (m, 2H), 7.44 - 7.37 (m, 3H), 7.35 - 7.28 (m, 2H), 7.24 -7.07 (m, 1H), 6.11 - 5.80 (m, 1H), 4.96 (br d, J = 3.0 Hz, 2H), 4.67 - 4.49 (m, 2H), 4.44 - 4.38 (m, 1H), 4.28 - 4.18 (m, 1H), 3.96 - 3.81 (m, 2H), 3.61 - 3.48 (m, 6H), 3.45 - 3.41 (m, 2H), 3.28 - 3.19 (m, 4H), 2.90 - 2.81 (m, 2H), 2.71 - 2.58 (m, 7H), 2.46 - 2.44 (m, 3H), 2.40 (s, 3H), 2.04 -1.92 (m, 2H), 1.83 - 1.66 (m, 5H), 1.62 (s, 3H), 1.42 - 1.32 (m, 3H), 0.93 (s, 9H), SFC: 100.0% de.

[0520] Synthesis of Degrader O:WSGR Docket No. 68195-704.601

[0521] 4-[3-[4-[2-(5-Benzyl-13-methyl-8-oxa-3-thia-l,l l,12-triazatricyclo[8.3.0.02,6]trideca-2(6), 4, 10,12-tetraen-4-yl)ethynyl]pyrazol- 1 -y 1 ] -3 -(2-hydroxyethyl)azetidin- 1 -yl]-2-(2,6-dioxo-3 -piperidyl)isoindoline- 1,3 -di one.0-2MeO0-1 0-3 0-4

[0522] General procedure of Degrader O:

[0523] To a solution of 0-1 (19 g, 206 mmol, 1 eq) and 0-2 (46.88 g, 206 mmol, 1 eq) in ACN (190 mL) was added DBU (31.41 g, 206 mmol, 31.10 mL, 1 eq). The mixture was stirred at 70 °C for 2 h under N2 atmosphere. The reaction mixture was poured into H2O (1 L) and extracted with EtOAc (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 30 / 1 to 20 / 1) to afford O-3 (26 g, 81.41 mmol, 39% yield) as a white solid. LC-MS (ESI+): m / z = 264.0 (M-tBu+H)+. 'H NMR (400 MHz, CDC13) 8 = 7.81 (s, 1H), 7.63 (s, 1H), 4.39 (d, J= 9.6 Hz, 2H), 4.26 (d, J= 9.6 Hz, 2H), 3.63 (s, 3H), 3.21 (s, 2H), 3.01 (s, 1H), 1.45 (s, 9H).

[0524] To a solution of O-3 (26 g, 81.4 mmol, 1 eq) in MeOH (52 mL) was added THF (260 mL) and LiBH4 (2 M, 101 mL, 2.5 eq) at 0 °C, then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into saturated NH₄Cl (1 L) and extracted with EtOAc (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 30 / 1 to 2 / 1) to afford O-4 (22 g, 75.5 mmol, 96% yield) as a white solid. LCMS (ESI+): m / z = 236.1 (M-tBu+H)+. 'H NMR (400 MHz, CDC13) 6 = 7.73 (s, 1H), 7.68 (s, 1H), 4.41 (d, J= 9.4 Hz, 2H), 4.25 (d, J= 9.4 Hz, 2H), 3.45 (t, J= 5.7 Hz, 2H), 3.04 (s, 1H), 2.33 (br t, J= 5.6 Hz, 2H), 1.45 (s, 9H).WSGR Docket No. 68195-704.6010-19 Degrader O

[0525] To a solution of O-5 (50 g, 657 mmol, 40 mL, 1 eq) in DCM (600 mL) was added imidazole (89.5 g, 1.31 mol, 2 eq) and TBDPSC1 (198.8 g, 723 mmol, 185 mL, 1.1 eq), then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was quenched with H2O (1 L) and extracted with DCM (600 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 40 / 1 to 10 / 1) to afford O-6 (42 g, 133 mmol, 20% yield) as lightyellow oil. LCMS (ESI-): m / z = 313.0 (M-H)'. 'H NMR (400 MHz, DMSO-c / ) 6 = 12.56 (br s, 1H), 7.64 (dd, J= 1.6, 7.8 Hz, 4H), 7.50 - 7.39 (m, 6H), 4.19 (s, 2H), 1.01 (s, 9H).

[0526] To a solution of O-6 (40 g, 127 mmol, 1 eq) in DCM (400 mL) was added (COC1)2 (32.3 g, 254 mmol, 22.2 mL, 2 eq) at 0 °C, then added DMF (929 mg, 12.7 mmol, 978 pL, 0.1 eq). The resulting mixture was stirred at 0 °C for 1 h under N2 atmosphere, then concentrated under reduced pressure. The residue was then dissolved in DCM (50 mL) and added to aWSGR Docket No. 68195-704.601solution of 0-7 (27.85 g, 114 mmol, 0.9 eq) in DCM (400 mL) and DIPEA (24.6 g, 190 mmol, 33.24 mL, 1.5 eq) at 0 °C, then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was quenched with H2O (I L) and extracted with DCM (300 mL><3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 40 / 1 to 30 / 1) to afford O-8 (46.3 g, 85.8 mmol, 67% yield) as yellow oil. LC-MS (ESI+): m / z = 540.1 (M+H)+. 'H NMR (400 MHz, CDCl₃-d) 6 = 11.97 (s, 1H), 7.73 - 7.68 (m, 4H), 7.50 - 7.39 (m, 6H), 7.17 (d, J= 0.6 Hz, 1H), 4.34 (q, J= 7.2 Hz, 4H), 4.30 (s, 2H), 1.36 (td, J= 7.1, 14.2 Hz, 6H), 1.19 (s, 9H).

[0527] To a solution of O-8 (46 g, 85.2 mmol, 1 eq) in dioxane (400 mL) was added Lawesson’s reagent (20.7 g, 51.1 mmol, 0.6 eq) then stirred at 100 °C for 4 h under N2 atmosphere. The reaction mixture was quenched with H2O (1 L) and extracted with DCM (600 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 40 / 1 to 30 / 1) to afford O-9 (46 g, 82.7 mmol, 97% yield) as yellow oil. LC-MS (ESI+): m / z = 556.1 (M+H)+.

[0528] To a solution of O-9 (43 g, 71.9 mmol, 1 eq) in THF (200 mL) was added N₂H₄·H₂O (8.02 g, 160 mmol, 7.78 mL, 2.23 eq) at 0 °C, then stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was quenched with H2O (300 mL) and extracted with EtOAc (100 mL / 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford 0-10 (43 g, crude) as yellow oil. LC-MS (ESI+): m / z = 554.2 (M+H)+.

[0529] To a solution of 0-10 (43 g, 72.2 mmol, 1 eq) in EtOH (100 mL) and THF (20 mL) was added 1,1,1 -tri ethoxy ethane (35.16 g, 216 mmol, 39.7 mL, 3 eq) then stirred at 80 °C for 2 h under N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was dissolved in AcOH (80 mL), then stirred at 120 °C for 2 h under N2 atmosphere. The reaction mixture was quenched with saturated Na₂CO₃ (200 mL) and extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 40 / 1 to 1 / 1) to afford O-ll (36.5 g, 63.1 mmol, 84% yield) as yellow oil. LC-MS (ESI+): m / z = 578.2 (M+H)+.

[0530] To a solution of O-ll (36.5 g, 63.1 mmol, 1 eq) in THF (100 mL) was added LiBHi (2 M, 126 mL, 4 eq) at 0 °C under N2 atmosphere. To this was then added MeOH (30 mL) and stirred at 25 °C for 6 h under N2 atmosphere. The reaction mixture was quenched with saturatedWSGR Docket No. 68195-704.601NH₄Cl (400 mL) and extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / EtOAc = 10 / 1 to 0 / 1) then (SiCh, DCM / MeOH = 30 / 1 to 20 / 1) to afford 0-12 (18 g, 10.13 mmol, 58% yield) as yellow oil. LC-MS (ESI+): m / z = 494.1 (M+H)+.

[0531] To a solution of 0-12 (18 g, 36.4 mmol, 1 eq) in DCM (200 mL) was added SOCI2 (21.7 g, 182 mmol, 13.24 mL, 5 eq) at 0 °C, then stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was then dissolved in EtOAc (100 mL) and washed with 2 M Na₂CO₃ (150mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 40 / 1 to 0 / 1) to afford 0-13 (18 g, 33.9 mmol, 93% yield) as yellow oil. LC-MS (ESI+): m / z = 530.1 / 532.0 (M+H)+.

[0532] To a solution of 0-13 (18 g, 33.9 mmol, 1 eq) in THF (150 mL) was added TBAF (1 M, 37.3 mL, 1.1 eq) at 0 °C, then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was quenched with H2O (1 L) and extracted with EtOAc (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 40 / 1 to 10 / 1) to afford 0-14 (4.8 g, 16.43 mmol, 48% yield) as yellow solid. LC-MS (ESI+): m / z = 292.0 (M+H)+.

[0533] To a solution of 0-14 (4.8 g, 16.4 mmol, 1 eq) in t-BuOH (50 mL) was added t-BuOK (1 M, 18.07 mL, 1.1 eq) then stirred at 80 °C for 10 min under N2 atmosphere. The reaction mixture was quenched with H2O (150 mL) and extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 40 / 1 to 0 / 1) to afford 0-15 (2.1 g, 8.21 mmol, 50% yield) as yellow solid. LC-MS (ESI+): m / z = 255.9 (M+H)+.

[0534] To a solution of 0-15 (2.1 g, 8.21 mmol, 1 eq) and phenylboronic acid (1.2 g, 9.85 mmol, 1.2 eq) in THF (5 mL) and H2O (5 mL) was added PdCL (73 mg, 410 pmol, 0.05 eq), PPhs (237 mg, 903 pmol, 0.11 eq) and Na₂CO₃ (1.31 g, 12.3 mmol, 1.5 eq), then stirred at 60 °C for 6 h under N2 atmosphere. The reaction mixture was quenched with H2O (150 mL), then added saturated EDTA (20 mL) and stirred at 25 °C for 2 h. The reaction mixture was then extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleumWSGR Docket No. 68195-704.601ether / EtOAc = 40 / 1 to 0 / 1) then (SiO2, DCM / MeOH = 40 / 1 to 20 / 1) to afford 0-16 (1.8 g, 6.05 mmol, 73% yield) as yellow solid. LC-MS (ESI+): m / z = 298.0 (M+H)+.

[0535] To a solution of 0-16 (1.8 g, 6.05 mmol, 1 eq) in AcOH (20 mL) was added NBS (1.13 g, 6.36 mmol, 1.05 eq), then stirred at 25 °C for 1 h under N2atmosphere. The reaction mixture was quenched by saturated Na2CO3(150 mL) and extracted with EtOAc (80 mL><3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 40 / 1 to 0 / 1) then (SiO2, DCM / MeOH = 40 / 1 to 20 / 1) to afford 0-17 (1.8 g, 4.78 mmol, 79% yield) as yellow solid. LC-MS (ESI+): m / z = 376.0 / 378.0 (M+H)+.

[0536] To a solution of 0-17 (1.8 g, 4.78 mmol, 1 eq) in DMF (10 mL) was added Pd(PPh3)2Cl2(335 mg, 478 pmol, 0.1 eq), Cui (182 mg, 956 pmol, 0.2 eq) and O-4 (1.67 g, 5.74 mmol, 1.2 eq) then added DMF (5 mL) and Et3N (6.93 g, 68.5 mmol, 9.54 mL, 14.32 eq), then stirred at 80 °C for 5 h under N2atmosphere. The reaction mixture was quenched with H2O (150 mL), then added saturated EDTA (20 mL) and stirred at 25 °C for 2 h. The reaction mixture was then extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 20 / 1 to 0 / 1) then (SiO2, DCM: MeOH = 40 / 1 to 30 / 1) to afford 0-18 (1.7 g, 2.90 mmol, 60% yield) as yellow solid. LC-MS (ESI+): m / z = 587.2 (M+H)+.

[0537] To a solution of 0-18 (250 mg, 426 pmol, 1 eq) in DCM (4 mL) was added TFA (1.37 g, 12.02 mmol, 892 pL, 28.21 eq), then stirred at 25 °C for 2 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was then dissolved in ACN (1 mL) and H2O (2 mL), and added Na2CO3(135 mg, 1.28 mmol, 3 eq) then stirred at 60 °C for 2 h under N2atmosphere. The reaction mixture was then quenched with H2O (80 mL) and extracted with CHCl3 / i-PrOH (3:1, 100 mL><5). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 0-19 (170 mg, crude) as yellow solid. LC-MS (ESI+): m / z = 487.0 (M+H)+.

[0538] To a solution of 0-19 (150 mg, 308 pmol, 1 eq) and 0-20 (93 mg, 339 pmol, 1.1 eq) in DMF (4 mL) was added DIPEA (119 mg, 924 pmol, 161 pL, 3 eq) then stirred at 90 °C for 16 h under N2atmosphere. The reaction mixture was quenched with H2O (80 mL) and extracted with DCM (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XPt C18150x40x7um; MobileWSGR Docket No. 68195-704.601Phase: [H2O (10 mM NH4HCC>3)-ACN]; Gradient: 30-60% B over 8.0 min) to afford Degrader O (51 mg, 65 pmol, 21% yield) as yellow solid. LCMS: 95.35% purity. HRMS (ESI+): m / z = 743.2411 (M+H)+. 'H NMR (400 MHz, DMSO-tZ6) 5 = 11.11 - 11.01 (m, 1H), 8.49 (s, 1H), 7.87 (s, 1H), 7.61 (dd, J = 7.2, 8.5 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.26 - 7.17 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 5.05 (dd, J = 5.4, 12.7 Hz, 1H), 4.69 (d, J = 11.5 Hz, 6H), 4.59 (t, J = 4.8 Hz, 1H), 4.52 (br d, J = 9.5 Hz, 2H), 4.05 (s, 2H), 3.25 - 3.19 (m, 2H), 2.93 - 2.81 (m, 1H), 2.65 (s, 3H), 2.62 - 2.55 (m, 1H), 2.52 (br s, 1H), 2.34 - 2.27 (m, 2H), 2.04 - 1.96 (m, 1H). dr = 50.26:49.74.

[0539] Synthesis of Degrader P:

[0540] 4-[3-[4-[2-(5-Benzyl-13-methyl-8-oxa-3-thia-l,ll,12-triazatricyclo[8.3.0.02,6]trideca- 2(6), 4, 10,12-tetraen-4-yl)ethynyl]pyrazol- 1 -y 1 ] -3 -(2-piperazin- 1 -ylethyl)azetidin- 1 -y 1 ] -2-(2, 6-P-1 P-2P-3 Degrader P

[0541] General procedure of Degrader P:

[0542] To a solution of P-1 (1.2 g, 1.62 mmol, 1 eq) in DCM (15 mL) was added DMP (1.37 g, 3.23 mmol, 1 mL, 2 eq) then stirred at 25 °C for 6 h under N2 atmosphere. The reaction mixture was quenched by saturated NaHCO₃ (100 mL) and extracted with DCM (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue wasWSGR Docket No. 68195-704.601purified by column chromatography (SiCh, petroleum ether / EtOAc = 40 / 1 to 0 / 1) then (SiCh, DCM / MeOH = 40 / 1 to 30 / 1) to afford P-2 (850 mg, 1.15 mmol, 71% yield) as yellow solid. LC-MS (ESI+): m / z = 741.0 (M+H)+.

[0543] To a mixture of P-2 (280 mg, 377 pmol, 1 eq) and tert-butyl piperazine- 1 -carboxylate (140 mg, 755 pmol, 2 eq) in DCE (3 mL) was added NaBH(OAc)3 (120 mg, 567 pmol, 1.5 eq), then stirred at 25 °C for 6 h under N2 atmosphere. The reaction mixture was poured into water (50 mL), then extracted with DCM (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, DCM: MeOH = 10:1, Rf = 0.50) to afford P-3 (230 mg, 252 pmol, 66% yield) as a yellow solid. LCMS (ESI+): m / z = 911.3 (M+H)+.

[0544] To a mixture of P-3 (200 mg, 219 pmol, 1 eq) in DCM (1.8 mL) was added TFA (0.6 mL) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was poured into saturated Na2CO3 (50 mL) and extracted with DCM (30 mL><3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 100x40mm><5 um; Mobile Phase: [H2O (0.2% FA)-ACN]; Gradient: 10-50% B over 8.0 min) to afford Degrader P (54 mg, 64.4 pmol, 29% yield) as a yellow solid. LCMS: 96.40% purity. HRMS (ESI+): m / z = 811.3156 (M+H)+. 'H NMR (400 MHz, DMSO-c / r,) 6 = 11.08 (br s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.62 (dd, J = 7.2, 8.3 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.27 - 7.17 (m, 4H), 6.88 (d, J = 8.5 Hz, 1H), 5.06 (dd, J = 5.4, 12.7 Hz, 1H), 4.70 (d, J = 9.9 Hz, 6H), 4.45 (br d, J = 7.8 Hz, 2H), 4.05 (s, 2H), 2.91 - 2.84 (m, 1H), 2.77 (br d, J = 4.5 Hz, 4H), 2.65 (s, 3H), 2.62 - 2.53 (m, 2H), 2.34 - 2.26 (m, 6H), 2.04 -1.98 (m, 3H). dr = 51.23:48.77.

[0545] Synthesis of Degrader Q:

[0546] 4-[3-(2-Aminoethyl)-3-[4-[2-(5-benzyl-13-methyl-8-oxa-3-thia-l,l 1,12-triazatricyclo[8.3.0.02,6]trideca-2(6),4,10,12-tetraen-4-yl)ethynyl]pyrazol-l-yl]azetidin-l-yl]-2-(2,6-dioxo-3 -piperidyl)isoindoline- 1,3 -di one.WSGR Docket No. 68195-704.601Q-1 Degrader Q

[0547] General procedure of Degrader Q:

[0548] To a solution of Q-l (100 mg, 135 pmol, 1 eq) in MeOH (1 mL) was added NT OAc (104 mg, 1.35 mmol, 10 eq) and NaBHsCN (34 mg, 540 pmol, 4 eq) then stirred at 70 °C for 1.5 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 100x40mm><5 um; Mobile Phase: [H2O (0.2% FA)-ACN]; Gradient: 15-50% B over 8.0 min) to afford Degrader Q (9 mg, 12.56 pmol, 9% yield) as yellow solid. LCMS: 97.87% purity.HRMS (ESI+): m / z = 742.2527 (M+H)+. 'H NMR (400 MHz, DMSO-c / ) 6 = 11.67 - 10.45 (m, 1H), 8.55 (s, 1H), 7.89 (s, 1H), 7.67 - 7.60 (m, 1H), 7.35 - 7.29 (m, 2H), 7.26 - 7.19 (m, 4H), 6.89 (d, J= 8.6 Hz, 1H), 5.06 (dd, J= 5.4, 12.7 Hz, 1H), 4.73 - 4.59 (m, 6H), 4.55 - 4.45 (m, 2H), 4.05 (s, 2H), 2.87 (ddd, J= 5.6, 13.9, 17.2 Hz, 1H), 2.65 (s, 3H), 2.60 (br d, J= 2.9 Hz, 1H), 2.57 (br d, J= 6.3 Hz, 1H), 2.45 (br d, J= 3.8 Hz, 2H), 2.38 (br d, J= 8.1 Hz, 2H), 2.04 -1.96 (m, 1H). dr = 52.78:47.22.

[0549] Degrader R-W were prepared according to the procedures described in Degrader Q using the corresponding amines.Compound HRMS Hl NMR(400 MHz, DMSO-tfc) 6 = 11.52 - 10.52 (m, 1H), 8.52 (s, 1H), 8.32 (s, 0.532H), 7.88 (s, 1H), 7.63 (dd, J= 7.1, 8.4 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.28 (ESI+): m / z = - 7.18 (m, 4H), 6.89 (d, J= 8.5 Hz, 1H), 5.07 (dd, Degrader R756.2709 (M+H)+J = 5.6, 12.7 Hz, 1H), 4.70 (d, J= 11.4 Hz, 6H),4.49 (br d, J= 9.8 Hz, 2H), 4.06 (s, 2H), 2.94 - 2.82 (m, 1H), 2.66 (s, 3H), 2.61 - 2.55 (m, 2H), 2.32 (br s, 4H), 2.26 (s, 3H), 2.05 - 1.97 (m, 1H).WSGR Docket No. 68195-704.601Compound HRMS 'll NMR(400 MHz, DMSO-tfc) 6 = 11.09 (br s, 1H), 8.51 (s, 1H), 8.23 (s, 0.431H), 7.87 (s, 1H), 7.62 (dd, J = 7.2, 8.3 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.27 - 7.17 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 5.06 (dd, J = 5.6, (ESI+): m / z = 12.7 Hz, 1H), 4.73 - 4.63 (m, 6H), 4.51 - 4.42 (m, Degrader S796.3004 (M+H)+2H), 4.05 (s, 2H), 3.06 (br t, J = 7.2 Hz, 1H), 2.93- 2.82 (m, 1H), 2.65 (s, 3H), 2.60 - 2.56 (s, 1H), 2.47 - 2.41 (m, 1H), 2.29 - 2.22 (m, 2H), 2.21 - 2.15 (m, 2H), 2.05 - 1.96 (m, 3H), 1.63 - 1.46 (m, 4H).(400 MHz, DMSO-t / e) 6 = 11.00 (br s, 1H), 8.50 (s, 1H), 7.86 (s, 1H), 7.61 (dd, J= 7.2, 8.4 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.26 - 7.17 (m, 4H), 6.88 (ESI+): m / z = (d, J= 8.6 Hz, 1H), 5.05 (dd, J= 5.4, 12.7 Hz, Degrader T800.3001 (M+H)+1H), 4.74 - 4.61 (m, 6H), 4.53 - 4.39 (m, 2H), 4.05(s, 2H), 3.30 (s, 2H), 3.19 (s, 3H), 2.87 (br d, J = 1.8 Hz, 1H), 2.65 (s, 3H), 2.62 - 2.52 (m, 4H), 2.26 (s, 4H), 2.00 (br d, J = 5.4 Hz, 1H).(400 MHz, DMSO-tfc) 6 = 11.08 (br s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.65 - 7.58 (m, 1H), 7.34 - 7.29 (m, 2H), 7.22 - 7.18 (m, 4H), 6.88 (ESI+): m / z = (d, J= 8.4 Hz, 1H), 5.09 - 5.02 (m, 1H), 4.76 - Degrader U786.2814 (M+H)+4.60 (m, 6H), 4.48 (br d, J= 9.6 Hz, 2H), 4.05 (s,2H), 3.41 (br s, 2H), 2.92 - 2.83 (m, 1H), 2.65 (s, 3H), 2.60 (br d, J= 2.8 Hz, 1H), 2.55 (br t, J= 5.6 Hz, 4H), 2.34 (br s, 4H), 2.04 - 1.96 (m, 1H).WSGR Docket No. 68195-704.601Compound HRMS 'll NMR(400 MHz, DMSO-t / e) 6 = 1 E07 (br s, 1H), 8.57 - 8.54 (m, 1H), 8.51 (s, 1H), 7.87 (s, 1H), 7.66 - 7.45 (m, 1H), 7.35 - 7.28 (m, 2H), 7.27 - 7.17 (m, 4H), 6.88 (d, J = 8.5 Hz, 1H), 5.06 (dd, J = 5.6, (ESI+): m / z =Degrader V 12.7 Hz, 1H), 4.70 (d, J = 11.0 Hz, 6H), 4.54 - 788.2785 (M+H)+4.42 (m, 3H), 4.33 (t, J = 4.8 Hz, 1H), 4.05 (s, 2H), 2.88 (br s, 1H), 2.78 - 2.71 (m, 1H), 2.65 (s, 4H), 2.56 (br s, 2H), 2.45 (br s, 1H), 2.30 (br s, 3H), 2.05 - 1.95 (m, 1H).(400 MHz, DMSO-tfc) 8 = 11.07 (s, 1H), 8.51 (s, 1H), 7.87 (s, 1H), 7.62 (dd, J = 7.3, 8.4 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.27 - 7.16 (m, 4H), 6.88 (d, J (ESI+): m / z=806.2676 = 8.4 Hz, 1H), 6.10 - 5.75 (m, 1H), 5.06 (dd, J = Degrader W(M+H)+5.5, 12.6 Hz, 1H), 4.73 - 4.62 (m, 6H), 4.47 (br d,J = 9.1 Hz, 2H), 4.05 (s, 2H), 2.93 - 2.74 (m, 3H), 2.67 - 2.54 (m, 5H), 2.33 - 2.23 (m, 4H), 2.01 (br dd, J = 5.2, 10.9 Hz, 1H).

[0550] Synthesis of Degrader X:

[0551] 3-[4-[3-[4-[2-(5-Benzyl-13-methyl-8-oxa-3-thia-l,ll,12-triazatricyclo[8.3.0.02,6]trideca-2(6),4,10,12-tetraen-4-yl)ethynyl]pyrazol-l-yl]-3-[2-(2,2-difluoroethylamino)ethyl]azetidin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione.WSGR Docket No. 68195-704.601Degrader X

[0552] General procedure of Degrader X:

[0553] To a mixture of X-l (3 g, 5.11 mmol, 1 eq) in DCM (30 mL) was added DMP (4.34 g, 10.2 mmol, 3.17 mL, 2 eq) and purged with N2 for 3 times. The reaction mixture was then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCO₃ (200 mL) and extracted with DCM (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 50 / 1 to 0 / 1 then DCM: MeOH = 50: 1 to 20: 1) to afford X-2 (2.4 g, 4.10 mmol, 80% yield) as a yellow solid. LCMS (ESI+): m / z = 585.3 (M+H)+.

[0554] To a mixture of X-2 (2.4 g, 4.10 mmol, 1 eq) and 2,2-difhioroethanamine (665 mg, 8.21 mmol, 2 eq) in DCE (18 mL) and AcOH (6 mL) was added NaBH(OAc)3 (2.61 g, 12.3 mmol, 3WSGR Docket No. 68195-704.601eq), then purged with N2 for 3 times. The reaction mixture was then stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated Na₂CO₃ (200 mL) and extracted with DCM (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 1 / 0 to 0 / 1, then DCM: MeOH = 50:1 to 20:1, DCM: MeOH = 10:1) to afford X-3 (2.2 g, 3.39 mmol, 82% yield) as a yellow solid. LCMS (ESI+): m / z = 650.2 (M+H)+.

[0555] To a mixture of X-3 (2.1 g, 3.23 mmol, 1 eq) and benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (966 mg, 3.88 mmol, 1.2 eq) in DMF (21 mL) was added DIEA (1.25 g, 9.70 mmol, 1.69 mL, 3 eq), then purged with N2 for 3 times. The reaction mixture was then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 1 / 0 to 0 / 1, then DCM: MeOH = 50:1 to 20:1, DCM: MeOH = 10:1) to afford X-4 (1.9 g, 2.42 mmol, 75% yield) as a yellow solid. LCMS (ESI+): m / z = 784.3 (M+H)+.

[0556] To a solution of X-4 (1.8 g, 2.30 mmol, 1 eq) in DCM (15 mL) was added TFA (5 mL) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was poured into saturated Na₂CO₃ (200 mL) and extracted with DCM (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18 150><40x7um; Mobile Phase: [H2O (10 mM NH4HCO3) -ACN]; Gradient: 30-70% B over 8.0 min) to afford X-5 (1.3 g, 1.90 mmol, 82% yield) as a white solid. LCMS (ESI+): m / z = 684.1 (M+H)+.

[0557] To a mixture of X-5 (152 mg, 37.1 pmol, 1.2 eq) and X-6 (60 mg, 30.9 pmol, 1 eq) in 2-methylbutan-2-ol (3.6 mL) was added NaOtBu (2 M, 185 pL, 2 eq) and SPhos Pd G3 (14 mg, 3.09 pmol, 0.1 eq), then stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was poured into saturated EDTA (50 mL) and stirred for 2 h. The reaction mixture was then extracted with EtOAc (30 mLx3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1, Rf = 0.50) to afford X-7 (30 mg, 32.4 pmol, 17% yield) as a yellow solid. LCMS (ESI+): m / z = 926.4 (M+H)+.

[0558] To a mixture of X-7 (30 mg, 32.4 pmol, 1 eq) in DCM (15 mL) was added TFA (1.5 mL) and TsOH»H2O (61 mg, 324 pmol, 10 eq), then stirred at 25 °C for 16 h under N2WSGR Docket No. 68195-704.601atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 100x40mm><5 um; Mobile Phase: [H2O (0.2% FA)-ACN]; Gradient: 10-50% B over 8.0 min) to afford Degrader X (10 mg, 13.2 pmol, 40% yield) as a white solid. LCMS: 98.9% purity. HRMS (ESI+): m / z = 792.2881 (M+H)+. 'HNMR (400 MHz, DMSO-c / 6) 8 = 10.99 (s, 1H), 8.51 (s, 1H), 7.87 (s, 1H), 7.37 - 7.29 (m, 3H), 7.26 - 7.19 (m, 3H), 7.11 (br d, J = 7.5 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 6.16 - 5.75 (m, 1H), 5.12 (br dd, J = 5.2, 13.1 Hz, 1H), 4.69 (br d, J = 13.6 Hz, 4H), 4.51 - 4.43 (m, 3H), 4.34 - 4.26 (m, 3H), 4.05 (s, 2H), 2.93 (br s, 1H), 2.85 - 2.75 (m, 2H), 2.65 (s, 3H), 2.62 (br d, J= 1.6 Hz, 2H), 2.43 - 2.32 (m, 4H), 2.02 - 1.95 (m, 1H). SFC: dr = 52.49:47.51.

[0559] Synthesis of Degrader Y:

[0560] 3-[5-[[[l-[5-(3-Chlorophenyl)-3-(trifluoromethyl)-2-pyridyl]-4-piperidyl]methylamino] methyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione 3-[5-[[[l-[5-(3-chlorophenyl)-3-(trifluoro methyl)-2-pyridyl]-4-piperidyl]methylamino]methyl]-l-oxo-isoindolin-2-yl]piperidine-2,6-di one.

[0561] General procedure of Degrader Y:

[0562] To a solution of Y-l (9 g, 34.5 mmol, 1 eq) and 4-piperidylmethanol (4.78 g, 41.4 mmol, 1.2 eq) in DMF (90 mL) was added K2CO3 (9.55 g, 69.1 mmol, 2 eq), then stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (100 mL><3). The combined organic layers were washed by saturated brine (100 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / EtOAc = 1 / 0 to 10 / 1) to afford Y-2 (9.5 g, 28 mmol, 81% yield) as a yellow solid. LC-MSWSGR Docket No. 68195-704.601(ESI+) m / z = 338.9 (M+H)+. 'HNMR (400 MHz, DMSO-c / ) 6 = 8.54 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 4.49 (t, J = 5.3 Hz, 1H), 3.55 (br d, J = 12.5 Hz, 2H), 3.28 (t, J = 5.7 Hz, 2H), 2.84 (br t, J= 12.1 Hz, 2H), 1.72 (br d, J = 12.4 Hz, 2H), 1.59 - 1.50 (m, 1H), 1.22 (br dd, J = 3.2, 12.2 Hz, 2H).

[0563] To a solution of Y-2 (2.5 g, 7.37 mmol, 1 eq) and (3 -chlorophenyl) boronic acid (2.31 g, 14.7 mmol, 2 eq) in dioxane (15 mL) and H2O (5 mL) was added K2CO3 (3.06 g, 22.1 mmol, 3 eq) and Pd(PPh3)4 (425 mg, 368 pmol, 0.05 eq), then stirred at 100 °C for 6 h under N2 atmosphere. The reaction mixture was poured into saturated EDTA (80 mL) and stirred at 25 °C for 2 h. This was then extracted with EtOAc (50 mL><3). The combined organic layers were washed by saturated brine (50 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / EtOAc = 1 / 0 to 5 / 1) to afford Y-3 (2.5 g, 6.74 mmol, 91% yield) as a black oil. LC-MS (ESI+) m / z = 371.0 (M+H)+. 'H NMR (400 MHz, DMSO-c / ) 8 = 8.82 (d, J = 2.2 Hz, 1H), 8.32 - 8.27 (m, 1H), 7.85 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.40 (s, 1H), 4.50 (t, J = 5.3 Hz, 1H), 3.69 - 3.61 (m, 2H), 3.32 - 3.29 (m, 2H), 2.91 (br t, J = 11.6 Hz, 2H), 1.81 - 1.71 (m, 2H), 1.63 - 1.53 (m, 1H), 1.35 - 1.20 (m, 2H).

[0564] To a solution of Y-3 (900 mg, 2.43 mmol, 1 eq) in DCM (9 mL) was added DMP (1.54 g, 3.64 mmol, 1.13 mL, 1.5 eq) at 0 °C, then stirred at 25 °C for 3 h under N2 atmosphere. The reaction mixture was poured into H2O (80 mL) and extracted with EtOAc (50 mL / 3). The combined organic layers were washed by saturated brine (50 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 1 / 0 to 10 / 1) to afford Y-4 (550 mg, 1.49 mmol, 61% yield) as a yellow oil. LC-MS (ESI+) m / z = 369.0 (M+H)+. 'H NMR (400 MHz, DMSO-c / r,) 6 = 9.65 (s, 1H), 8.85 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.87 (t, J = 1.7 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.53 - 7.42 (m, 2H), 3.55 (td, J = 3.5, 12.7 Hz, 2H), 2.61 - 2.53 (m, 1H), 1.97 (br dd, J = 3.4, 13.3 Hz, 2H), 1.68 - 1.58 (m, 2H).

[0565] To a solution of Y-4 (450 mg, 1.22 mmol, 1 eq) and Y-5 (333 mg, 1.22 mmol, 1 eq) in MeOH (5 mL) was added NaBH3CN (153 mg, 2.44 mmol, 2 eq) then stirred at 25 °C for 10 min. To this was then added AcOH (73 mg, 1.22 mmol, 69 pL, 1 eq) and stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCO₃ (80 mL) and extracted with chloroform (50 mL><3). The combined organic layers were washed by saturated brine (50 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by perp-HPLC (Column: WePure Biotech XP tC18 150x40x 10um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 50-80% B over 8.0 min) to afford Degrader Y (130 mg, 199 pmol, 16% yield) as a white solid. LC-MS: 95.84%WSGR Docket No. 68195-704.601purity. HRMS (ESI+) m / z = 626.2175 (M+H)+. 'H NMR (400 MHz, DMSO-c / ) 6 = 10.98 (br s, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.86 (t, J = 1.7 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.53 - 7.43 (m, 3H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.36 - 4.26 (m, 1H), 3.82 (s, 2H), 3.64 (br d, J = 12.6 Hz, 2H), 2.96 - 2.86 (m, 3H), 2.60 (td, J = 2.0, 15.3 Hz, 1H), 2.44 - 2.35 (m, 3H), 2.05 - 1.97 (m, 1H), 1.84 (br d, J = 11.6 Hz, 2H), 1.72 - 1.60 (m, 1H), 1.32 - 1.21 (m, 2H). SFC: dr = 49.74:50.26.

[0566] Synthesis of Degrader Z:

[0567] N-[2-[[2-(2,6-Dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]ethyl]-7-[4-[7-[N-[2- (isopropylamino)ethyl]-3,5-dimethoxy-anilino]quinoxalin-2-yl]pyrazol-l-yl]heptanamide.

[0568] General procedure of Degrader Z:

[0569] To a solution of Z-l (5 g, 18.1 mmol, 1 eq) and tert-butyl N-(2-aminoethyl)carbamate (3.48 g, 21.7 mmol, 3.43 mL, 1.2 eq) in DMSO (50 mL) was added DIEA (7.02 g, 54.3 mmol, 9.46 mL, 3 eq), then stirred at 130 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (500 mL) and extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated brine (200 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18250x70xl0um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 25-60% B over 20.0 min) to afford Z-2 (3.6 g, 8.64 mmol, 47% yield) as a green solid. LC-MS (ESI+): m / z = 417.1 (M+H)+.

[0570] To a solution of Z-2 (3 g, 7.20 mmol, 1 eq) in DCM (30 mL) was added TFA (10 mL) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue yielded Z-3 (2.1 g, crude) as a black brown oil. LC-MS (ESI+): m / z = 317.0 (M+H)+.WSGR Docket No. 68195-704.601

[0571] To a solution of Z-4 (24 g, 98.5 mmol, 1 eq) and l-tetrahydropyran-2-yl-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (27.4 g, 98.5 mmol, 1 eq) in dioxane (200 mL) and H2O (50 mL), was added K2CO3 (27.2 g, 197 mmol, 2 eq) and Pd(dppf)C12 (3.61 g, 4.93 mmol, 0.05 eq), then stirred at 100 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (1 L) and extracted with DCM (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Welch Xtimate C18250xl00mmxl0um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN];WSGR Docket No. 68195-704.601Gradient: 36-66% B over 18.0 min) to afford Z-5 (26.6 g, 74.1 mmol, 75% yield) as a yellow solid. LC-MS (ESI+): m / z = 359.0 (M+H)+.

[0572] To a solution of Z-5 (25.6 g, 71.2 mmol, 1 eq) and 3, 5 -dimethoxy aniline (16.3 g, 106 mmol, 1.5 eq) in toluene (256 mL) was added CS2CO3 (32.5 g, 99.7 mmol, 1.4 eq), BINAP (2.22 g, 3.56 mmol, 0.05 eq) and Pd2(dba)s (3.26 g, 3.56 mmol, 0.05 eq), then stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (I L) and extracted with EtOAc (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Welch Xtimate C18 250xl00mmxl0um; Mobile Phase: [H2O (10 mM NBLJTCC^-ACN]; Gradient: 36-66% B over 18.0 min) to afford Z-6 (16.7 g, 38.7 mmol, 54% yield) as a yellow oil. LC-MS (ESI+): m / z = 432.2 (M+H)+.

[0573] To a solution of Z-6 (16.2 g, 37.5 mmol, 1 eq) in DMF (162 mL) was added NaH (3 g, 75.1 mmol, 60% purity, 2 eq) then stirred at 0 °C for 0.5 h under N2 atmosphere. To this was then added 2-bromoethoxy-tert-butyl-dimethyl-silane (17.9 g, 75.1 mmol, 2 eq) and stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into saturated NH₄Cl (500 mL) and extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated brine (200 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 30 / 1 to 1 / 1) to afford Z-7 (20.3 g, 34.4 mmol, 91% yield) as a yellow oil. LC-MS (ESI+): m / z = 590.3 (M+H)+.

[0574] To a solution of Z-7 (20.3 g, 34.4 mmol, 1 eq) in THF (203 mL) was added TBAF (1 M, 41.3 mL, 1.2 eq) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (1 L) and extracted with EtOAc (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 30 / 1 to 0 / 1) to afford Z-8 (15.6 g, 32.8 mmol, 95% yield) as a yellow solid. LC-MS (ESI+): m / z = 476.2 (M+H)+.

[0575] To a solution of Z-8 (15.1 g, 31.7 mmol, 1 eq) in DCM (151 mL) was added EtsN (8.03 g, 79.3 mmol, 11.05 mL, 2.5 eq) and MsCl (12.4 g, 108 mmol, 8.39 mL, 3.41 eq) at 0 °C, then stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCO₃ (1 L), and extracted with DCM (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatographyWSGR Docket No. 68195-704.601(SiC>2, petroleum ether / EtOAc = 30 / 1 to 0 / 1) to afford Z-9 (15.2 g, 27.4 mmol, 86% yield) as a yellow oil. LC-MS (ESI+): m / z = 554.2 (M+H)+.

[0576] To a solution of Z-9 (14.7 g, 26.55 mmol, 1 eq) in MeCN (147 mL) was added propan-2-amine (7.85 g, 132 mmol, 11.41 mL, 5 eq) then stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (1 L) and extracted with EtOAc (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / EtOAc = 30 / 1 to 0 / 1 then DCM: MeOH = 10 / 1) to afford Z-10 (10.7 g, 20.7 mmol, 78% yield) as a yellow oil. LC-MS (ESI+): m / z = 517.3 (M+H)+.

[0577] To a solution of Z-10 (10.2 g, 19.7 mmol, 1 eq) in DCM (102 mL) was added EtsN (6 g, 59.2 mmol, 8.24 mL, 3 eq) and CbzCl (6.74 g, 39.5 mmol, 5.64 mL, 2 eq) at 0 °C, then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (1 L) and extracted with DCM (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / EtOAc = 30 / 1 to 1 / 1) to afford Z-ll (12.1 g, 18.6 mmol, 94% yield) as a yellow oil. LC-MS (ESI+): m / z = 651.3 (M+H)+.

[0578] To a solution of Z-ll (11.8 g, 18.1 mmol, 1 eq) in DCM (118 mL) was added HCl / MeOH (4 M, 118 mL, 26 eq) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCOs (1 L) and extracted with DCM (500 mL / 3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue yielded Z-12 (9.6 g, crude) as a yellow solid. LC-MS (ESI+): m / z = 567.2 (M+H)+.

[0579] To a solution of Z-12 (7 g, 12.3 mmol, 1 eq) in DMF (70 mL) was added CS2CO3 (8.05 g, 24.7 mmol, 2 eq) and tert-butyl 7-bromoheptanoate (4.91 g, 18.5 mmol, 1.5 eq) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (I L) and extracted with (500 mL><3). The combined organic layers were washed with saturated brine (500 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / EtOAc = 30 / 1 to 1 / 3) to afford Z-13 (9 g, 12 mmol, 97% yield) as a yellow oil. LC-MS (ESI+): m / z = 751.2 (M+H)+.

[0580] To a solution of Z-13 (8.8 g, 11.7 mmol, 1 eq) in DCM (60 mL) was added TF A (20 mL) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCOs (1 L) and extracted with DCM (500 mL><3). The combined organic layersWSGR Docket No. 68195-704.601were washed with saturated brine (500 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue yielded Z-14 (8 g, crude) as a yellow solid. LC-MS (ESI+): m / z = 695.2 (M+H)+.

[0581] To a solution of Z-14 (4 g, 5.76 mmol, 1 eq) in DMF (40 mL) was added DIEA (7.44 g, 57.5 mmol, 10 mL, 10 eq), HATU (2.63 g, 6.91 mmol, 1.2 eq) andZ-3 (2 g, 6.33 mmol, 1.1 eq) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / EtOAc = 30 / 1 to 0 / 1 then DCM: MeOH = 10:1) to afford Z-15 (5.1 g, 5.14 mmol, 89% yield,) as a yellow solid. LC-MS (ESI+): m / z = 993.4 (M+H)+.

[0582] To a solution of Z-15 (150 mg, 151 pmol, 1 eq) in DCM (1.5 mL) was added HBr (185 mg, 755 pmol, 124 pL, 33% purity, 5 eq) then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XPtC18 150*40* lOum; Mobile Phase: [H2O (10 mM NELEtCC^-ACN]; Gradient: 30-60% B over 8.0 min) to afford Degrader Z (97 mg, 111 pmol, 74% yield) as a yellow solid. LCMS: 99.16% purity. HRMS (ESI+): m / z = 859.4263 (M+H)+. 'H NMR (400 MHz, DMSO-c / ) 6 = 11.61 - 10.60 (m, 1H), 8.95 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.00 (t, J= 5.4 Hz, 1H), 7.76 (d, J= 9.3 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.27 (dd, J = 2.6, 9.3 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 2.6 Hz, 1H), 7.01 (d, = 7.0 Hz, 1H), 6.70 (t, J = 6.1 Hz, 1H), 6.46 (d, J = 2.1 Hz, 2H), 6.42 - 6.38 (m, 1H), 5.04 (dd, J = 5.4, 12.8 Hz, 1H), 4.15 (t, J = 6.9 Hz, 2H), 3.87 (br t, J = 7.1 Hz, 2H), 3.74 (s, 6H), 3.39 - 3.33 (m, 2H), 3.22 (q, J = 6.1 Hz, 2H), 2.92 - 2.82 (m, 1H), 2.79 (br t, J = 6.9 Hz, 2H), 2.73 - 2.67 (m, 1H), 2.62 - 2.52 (m, 2H), 2.06 - 1.99 (m, 3H), 1.80 (br t, J = 6.4 Hz, 2H), 1.51 - 1.44 (m, 2H), 1.28 - 1.20 (m, 4H), 0.95 (s, 3H), 0.94 (s, 3H). SFC: dr = 54.59:45.41.

[0583] Synthesis of Degrader AA:

[0584] (2S,4S)-4-(2-(3-(2-(2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo [4,3-a][l,4]diazepin-6-yl)acetamido)ethoxy)propoxy)acetamido)-N-(2,6-difluorophenyl)-l-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido)butanoyl)pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601AA-5AA-1 AA-3 AA-4 AA-6AA-7 AA-9 AA-10AA-11 AA-12 AA-13Degrader AA

[0585] General procedure of Degrader AA:

[0586] To a solution of AA-1 (15 g, 64.9 mmol, 1 eq) and 2 AA-2 (9.21 g, 71.4 mmol, 7.21 mL, 1.1 eq) in DCM (150 mL) was added DCC (14.7 g, 71.4 mmol, 14.4 mL, 1.1 eq), then stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, hexanes: EtOAc = 1 / 0 to 0 / 1) to afford AA-3 (16.6 g, 48.5 mmol, 75% yield) as a white solid. LCMS (ESI-): m / z = 341.2 (M-H)'.

[0587] To a solution of AA-3 (15.6 g, 45.6 mmol, 1 eq) in THF (156 mL) was added HCl / EtOAc (4 M, 312 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give AA-4 (11 g, crude) as a white solid. LCMS (ESI+): m / z = 243.0 (M+H)+.

[0588] To a solution of AA-4 (11 g, 45.4 mmol, 1 eq) and AA-5 (10.5 g, 45.4 mmol, 1 eq) in DMF (110 mL) was added EtsN (23 g, 227 mmol, 31.6 mL, 5 eq) and T4P (49.1 g, 68.1 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 0.5 h under N2 atmosphere. The reaction mixture was poured into H2O (500 mL), then extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated brine (200 mL), dried with anhydrous Na2SO4,WSGR Docket No. 68195-704.601filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, hexanes: EtOAc = 1 / 0 to 1 / 3) to afford AA-6 (16 g, 35.1 mmol, 77% yield) as a white oil. LCMS (ESI+): m / z = 456.2 (M+H)+.

[0589] To a solution of AA-6 (15 g, 32.9 mmol, 1 eq) in THF (150 mL) was added HCl / EtOAc (4 M, 300 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give AA-7 (11 g, crude) as a white solid. LCMS (ESI+): m / z = 356.1 (M+H)+.

[0590] To a solution of AA-7 (11 g, 31 mmol, 1 eq) and AA-8 (6.3 g, 31 mmol, 1 eq) in DMF (110 mL) was added Et3N (15.7 g, 155 mmol, 21.5 mL, 5 eq) and T4P (33.5 g, 46.4 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 0.5 h under N2 atmosphere. The reaction mixture was poured into H2O (500 mL), then extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated brine (200 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 1 / 0 to 1 / 3) then purified by prep-HPLC (Column: WePure Biotech XP tC18 150x40x7um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN];Gradient: 45-75% B over 8.0 min) to afford AA-9 (15 g, 27.8 mmol, 90% yield) as a white oil. LCMS (ESI+): m / z = 541.3 (M+H)+.

[0591] To a solution of AA-9 (9 g, 16.7 mmol, 1 eq) in DCM (90 mL) was added Et3N (3.37 g, 33.3 mmol, 4.63 mL, 2 eq) and MsCl (3.4 g, 29.7 mmol, 2.30 mL, 1.78 eq) at 0 °C, then stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated Na2CO3(500 mL), then extracted with EtOAc (200 mLx3). The combined organic layers were washed with saturated brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give AA-10 (10 g, crude) as a yellow oil. LCMS (ESI+): m / z = 619.3 (M+H)+.

[0592] To a solution of AA-10 (10 g, 16.16 mmol, 1 eq) in DMF (100 mL) was added NaN3(1.53 g, 23.5 mmol, 1.46 eq), then stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was poured into saturated Na2CO3(500 mL), then extracted with EtOAc (200 mLx3). The combined organic layers were washed with saturated brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give AA-11 (9 g, crude) as a white oil. LCMS (ESI+): m / z = 566.3 (M+H)+.

[0593] To a solution of AA-11 (9 g, 15.9 mmol, 1 eq) in THF (60 mL) was added H2O (30 mL) and PPh3(8.35 g, 31.8 mmol, 2 eq), then stirred at 50 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (500 mL), then extracted with EtOAc (200 mLx3). The combined organic layers were washed with saturated brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue wasWSGR Docket No. 68195-704.601purified by column chromatography (SiCh, hexanes: EtOAc = 1 / 0 to 0 / 1 to DCM: MeOH = 10 / 1) to afford AA-12 (4.9 g, 9.08 mmol, 57% yield) as a white solid. LCMS (ESI+): m / z = 540.3 (M+H)+.

[0594] To a solution of Intermediate I (300 mg, 535 pmol, 1 eq) and AA-12 (318 mg, 589 pmol, 1.1 eq) in DMF (3 mL) was added EtiN (271 mg, 2.68 mmol, 373 pL, 5 eq) and T4P (579 mg, 803 pmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 0.5 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL), then extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 1 / 0 to 0 / 1 to DCM: MeOH = 10 / 1) to afford AA-13 (400 mg, 369 pmol, 69% yield) as a white solid. LCMS (ESI+): m / z = 1081.4 (M+H)+.

[0595] To a solution of AA-13 (400 mg, 369 pmol, 1 eq) in DCM (3 mL) was added TFA (1 mL), then stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 100><30mmx3um; Mobile Phase: [H2O (0.2% FA)-ACN]; Gradient: 15-65% B over 8.0 min) to afford Degrader AA (333 mg, 336 pmol, 91% yield) as a white solid. LCMS: 99.1% purity. HRMS (ESI+): m / z = 981.3990 (M+H)+. 'H NMR (400 MHz, DMSO-c / r,) 8 = 9.93 (s, 1H), 8.40 (br d, J= 6.9 Hz, 1H), 8.24 (br t, J= 5.6 Hz, 1H), 8.14 (br d, J = 8.4 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.44 - 7.40 (m, 2H), 7.36 - 7.30 (m, 1H), 7.14 (t, J= 8.1 Hz, 2H), 4.59 - 4.44 (m, 4H), 4.03 (br dd, J= 6.7, 9.7 Hz, 1H), 3.84 - 3.81 (m, 2H), 3.68 (br s, 1H), 3.52 - 3.41 (m, 6H), 3.39 - 3.36 (m, 2H), 3.27 - 3.17 (m, 4H), 2.59 (s, 3H), 2.46 (br d, J= 7.4 Hz, 1H), 2.42 (d, J= 6.8 Hz, 6H), 1.95 (td, J= 7.6, 12.6 Hz, 1H), 1.74 (quin, J= 6.4 Hz, 2H), 1.62 (s, 3H), 1.28 (d, J= 6.9 Hz, 3H), 0.97 (s, 9H). SFC: 100.0% de.

[0596] Synthesis of Degrader AB:

[0597] (2S,4S)-4-[[2-[2-[2-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy] ethoxy]acetyl]amino]-N-(2,6-difluorophenyl)-l-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino) propanoyl]amino]butanoyl]pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601AB-2Degrader AB

[0598] General procedure of Degrader AB:

[0599] To a solution of AB-1 (250 mg, 423 pmol, 1 eq) and AB-2 (251 mg, 466 pmol, 1.1 eq) in DMF (2.5 mL) was added EtsN (214 mg, 2.12 mmol, 295 pL, 5 eq) and T4P (458 mg, 635 pmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 0.5 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL), then extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried with anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 1 / 0 to 0 / 1 to DCM: MeOH = 10 / 1) to afford AB-3 (350 mg, 314 pmol, 74% yield) as a white solid. LCMS (ESI+): m / z = 1111.7 (M+H)+.

[0600] To a solution of AB-3 (300 mg, 269 pmol, 1 eq) in DCM (3 mL) was added TFA (1 mL), then stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex luna C18 100x40mm><5 um; Mobile Phase: [H2O (0.2% FA)-ACN]; Gradient: 10-55% B over 8.0 min) to afford Degrader AB (236 mg, 233 pmol, 86%WSGR Docket No. 68195-704.601yield) as a white solid. LCMS: 99.8% purity. HRMS (ESI+): m / z = 1011.4120 (M+H)+. 'H NMR (400 MHz, DMSO-c / ) 6 = 9.94 (s, 1H), 8.27 (t, J= 5.5 Hz, 1H), 8.18 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.92 (br d, J= 9.1 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.44 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 7.14 (t, J= 8.1 Hz, 2H), 4.57 (t, J= 7.9 Hz, 1H), 4.50 (dd, J= 6.3, 7.9 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.04 (br dd, J= 6.8, 9.8 Hz, 1H), 3.88 (s, 2H), 3.55 - 3.52 (m, 4H), 3.51 (s, 4H), 3.49 -3.42 (m, 4H), 3.26 - 3.18 (m, 4H), 3.07 (br d, J= 6.8 Hz, 1H), 2.59 (s, 3H), 2.47 (br s, 1H), 2.41 (s, 3H), 2.22 (s, 3H), 1.91 (br d, J= 12.5 Hz, 1H), 1.62 (s, 3H), 1.14 (d, J= 6.9 Hz, 3H), 0.93 (s, 9H). SFC: 100.0% de.

[0601] Synthesis of Degrader AC:

[0602] (3S)-7-[2-[2-[2-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy] ethoxy]ethoxy]-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-N- [(lR)-tetralin-l-yl]-3,4-dihydro-lH-isoquinoline-3-carboxamide.AC-2AC-1 AC-3 AC-4 AC-5AC-6AC-9WSGR Docket No. 68195-704.601AC-16 Degrader AC

[0603] General procedure of Degrader AC:

[0604] To a mixture of AC-1(1.9 g, 6.48 mmol, 1 eq) and AC-2 (2.86 g, 19.4 mmol, 3 eq) in DMF (19 mL) was added Et3N (1.97 g, 19.4 mmol, 2.70 mL, 3 eq) and T4P (7 g, 9.72 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Welch Xtimate C18250><70mmxl0um; Mobile Phase: [H2O (10 mM NH4HCC>3)-ACN]; Gradient: 40-65% B over 20.0 min) to afford AC-3 (2 g, 4.73 mmol, 73% yield) as a white solid. LCMS (ESI+): m / z = 423.0 (M+H)+. SFC: 97.5% de.

[0605] A mixture of AC-3 (2 g, 4.73 mmol, 1 eq) in HCl / EtOAc (4 M, 20 mL) was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give AC-4 (1.7 g, crude) as a white solid. LCMS (ESI+): m / z = 323.0 (M+H)+.

[0606] To a mixture of AC-4 (1.6 g, 4.96 mmol, 1 eq) and AC-5 (5.74 g, 24.8 mmol, 5 eq) in DMF (16 mL) was added Et3N (1.51 g, 14.9 mmol, 2.07 mL, 3 eq) and T4P (5.36 g, 7.44 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Welch Xtimate C18250><70mmxl0um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 40-75% B over 19.0 min) to afford AC-6 (1.7 g, 3.17 mmol, 64% yield) as a white solid. LCMS (ESI+): m / z = 536.3 (M+H)+. SFC: 99.1% de.

[0607] A mixture of AC-6 (1.7 g, 3.17 mmol, 1 eq) in HCl / EtOAc (4 M, 17 mL) was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated underWSGR Docket No. 68195-704.601reduced pressure to give AC-7 (1.4 g, 3.10 mmol, 98% yield) as a white solid. LCMS (ESI+): m / z = 436.1 (M+H)+.

[0608] To a mixture AC-7 (1.3 g, 2.98 mmol, 1 eq) and AC-8 (1.21 g, 5.97 mmol, 2 eq) in DMF (13 mL) was added EtsN (906 mg, 8.95 mmol, 1.25 mL, 3 eq) and T4P (3.23 g, 4.48 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Welch Xtimate C18250x70mmxl0um; Mobile Phase:[H2O (10 mM NH4HCO3)-ACN]; Gradient: 45-75% B over 20.0 min) to afford AC-9 (1.5 g, 2.42 mmol, 81% yield) as a white solid. LCMS (ESI+): m / z = 621.2 (M+H)+. SFC: 100.0% de.

[0609] To a mixture of AC-9 (1.4 g, 2.26 mmol, 1 eq) and AC-10 (638 mg, 2.48 mmol, 1.1 eq) in DMF (14 mL) was added CS2CO3 (2.20 g, 6.77 mmol, 3 eq), then stirred at 60 °C for 1 h under N2 atmosphere. The reaction mixture was poured into water (150 mL), then extracted with EtOAc (30 mLx3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 40 / 1 to 1 / 1) to afford AC-11 (1.5 g, 1.88 mmol, 83% yield) as a yellow solid. LCMS (ESI+): m / z = 797.3 (M+H)+.

[0610] To a mixture of AC-11 (1.4 g, 1.76 mmol, 1 eq) in DCM (14 mL) was added EtsN (355 mg, 3.51 mmol, 489 pL, 2 eq) and MsCl (370 mg, 3.23 mmol, 250 pL, 1.84 eq), then stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCO? (200 mL), then extracted with EtOAc (100 mLx3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give AC-12 (1.5 g, crude) as a yellow oil. LCMS (ESI+): m / z = 875.4 (M+H)+.

[0611] To a mixture of AC-12 (1.5 g, 1.71 mmol, 1 eq) in DMF (15 mL) was added NaNs (180 mg, 2.77 mmol, 1.62 eq), then stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was poured into saturated Na2CO3 (100 mL), then extracted with EtOAc (50 mLx3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give AC-13 (1.4 g, crude) as a colorless oil. LCMS (ESI+): m / z = 822.5 (M+H)+.

[0612] To a mixture AC-13 (1.3 g, 1.58 mmol, 1 eq) in H2O (4.3 mL) and THF (8.6 mL) was added PPh₃ (2.07 g, 7.91 mmol, 5 eq), then stirred at 50 °C for 1 h under N2 atmosphere. The reaction mixture was poured into water (150 mL), then extracted with EtOAc (30 mLx3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 50 / 1 to 0 / 1 and DCM: MeOH =WSGR Docket No. 68195-704.60150 / 1 to 5 / 1) to afford AC-14 (700 mg, 879 pmol, 55% yield) as a yellow oil. LCMS (ESI+): m / z = 796.3 (M+H)+.

[0613] To a mixture of AC-14 (600 mg, 753 pmol, 1 eq) and AC-15 (241 mg, 603 pmol, 0.8 eq) in DMF (6 mL) was added EtsN (228 mg, 2.26 mmol, 314 pL, 3 eq) and T4P (814 mg, 1.13 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into water (200 mL), then extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, DCM: MeOH = 100 / 1 to 10 / 1) to afford AC-16 (600 mg, 509 pmol, 67% yield) as a yellow solid. LCMS (ESI-): m / z = 1176.1 (M-H)'. SFC: 100.0% de.

[0614] To a mixture of AC-16 (100 mg, 84.8 pmol, 1 eq) in THF (1 mL) was added HCl / EtOAc (4 M, 1 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Advanchrom C18 100><25mmx5um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 20-90% B over 8.0 min) to afford Degrader AC (51 mg, 47.1 pmol, 56% yield) as a white solid. LCMS: 99.6% purity. HRMS (ESI+): m / z = 1078.4998 (M+H)+.1H NMR (400 MHz, DMSO-c / ) 6 = 8.27 (br t, J = 5.4 Hz, 1H), 8.20 - 8.13 (m, 1H), 7.92 - 7.83 (m, 1H), 7.50 - 7.45 (m, 2H), 7.44 - 7.40 (m, 2H), 7.15 - 6.96 (m, 5H), 6.91 - 6.80 (m, 1H), 6.79 - 6.75 (m, 1H), 5.20 - 4.68 (m, 4H), 4.67 - 4.34 (m, 2H), 4.10 - 4.00 (m, 2H), 3.74 (br d, J = 4.6 Hz, 2H), 3.61 - 3.58 (m, 2H), 3.57 - 3.53 (m, 6H), 3.48 - 3.43 (m, 2H), 3.29 - 3.17 (m, 4H), 3.05 - 2.86 (m, 3H), 2.74 - 2.63 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.17 - 2.00 (m, 4H), 1.90 - 1.73 (m, 2H), 1.72 - 1.64 (m, 1H), 1.62 - 1.52 (m, 4H), 1.10 - 0.93 (m, 12H). SFC:100.0% de.

[0615] Synthesis of Degrader AD:

[0616] (2S)-N-[(lS)-2-[(2S)-2-[4-[3-[2-[2-[2-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino] ethoxy]ethoxy]ethoxy]ethoxy]benzoyl]thiazol-2-yl]pyrrolidin-l-yl]-l-cyclohexyl-2-oxo-ethyl]-2-(methylamino)propenamide.WSGR Docket No. 68195-704.601

[0617] General procedure of Degrader AD:

[0618] To a solution of AD-1 (9.5 g, 41.2 mmol, 1 eq) in EtOH (95 mL) was added AD-2 (11.3 g, 57.7 mmol, 7.22 mL, 1.4 eq), then stirred at 60 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give AD-3 (9.3 g, crude) as a yellow oil. LCMS (ESI+): m / z = 227.0 (M+H)+.

[0619] To a solution of AD-3 (9.3 g, 41.1 mmol, 1 eq) in THF (23 mL) and H2O (23 mL) was added NaHCO₃ (6.90 g, 82.2 mmol, 3.20 mL, 2 eq) and BOC2O (13.5 g, 61.6 mmol, 14.2 mL, 1.5 eq) at 0 °C, then stirred at 25 °C for 14 h under N2 atmosphere. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 20 / 1 to 5 / 1) to give AD-4 (10 g, 30.6 mmol, 75% yield) as a yellowWSGR Docket No. 68195-704.601oil. LCMS (ESI+): m / z = 327.1 (M+H)+. 'HNMR (400 MHz, DMSO-c / ) 6 = 8.55 - 8.30 (m, 1H), 5.20 - 4.98 (m, 1H), 4.35 - 4.23 (m, 2H), 3.52 - 3.35 (m, 2H), 2.40 - 2.23 (m, 1H), 2.04 (br s, 1H), 1.95 - 1.77 (m, 2H), 1.50 - 1.38 (m, 4H), 1.33 - 1.18 (m, 8H).

[0620] To a solution of AD-4 (8 g, 24.5 mmol, 1 eq) in THF (40 mL) and H2O (40 mL) was added LiOH»H2O (3.09 g, 73.5 mmol, 3 eq), then stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was diluted with H2O (200 mL) and adjusted to pH = 4 with HC1 (0.5 M, 200 mL), then extracted with EtOAc (100 mLx3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give AD-5 (7.2 g, crude) as a yellow solid. LCMS (ESI+): m / z = 299.1 (M+H)+.

[0621] To a solution of AD-5 (7.2 g, 24.1 mmol, 1 eq) and HBTU (13.7 g, 36.2 mmol, 1.5 eq) in DMF (72 mL) was added DIEA (15.6 g, 120 mmol, 21 mL, 5 eq) and N-Methoxymethanamine (2.82 g, 28.9 mmol, 1.2 eq, HC1) at 0 °C, then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with H2O (400 mL) and extracted with EtOAc (200 mL><3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 5 / 1 to 2 / 1) to give AD-6 (6.8 g, 19.9 mmol, 83% yield) as a yellow oil. LCMS (ESI+): m / z = 342.1 (M+H)+.

[0622] To a solution of AD-7 (2.82 g, 8.44 mmol, 1.8 eq) in THF (20 mL) was added dropwise i-PrMgCl (2 M, 3.98 mL, 1.7 eq) at 0 °C, then stirred at 0 °C for 0.5 h N2 atmosphere. This solution was then added dropwise to a solution of AD-6 (1.6 g, 4.69 mmol, 1 eq) in THF (4 mL) at 0 °C, then stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated NH₄Cl (100 mL) and extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 20 / 1 to 5 / 1) to give AD-8 (2.2 g, 4.50 mmol, 48% yield, combination of two batches) as a yellow oil. LCMS (ESI+): m / z = 489.2 (M+H)+.

[0623] To a solution of AD-8 (2.2 g, 4.50 mmol, 1 eq) in EtOAc (22 mL) was added HCl / EtOAc (4 M, 44 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give AD-9 (1.9 g, crude, HC1) as a yellow oil. LCMS (ESI+): m / z = 389.1 (M+H)+.

[0624] To a solution of AD-9 (1.7 g, 4 mmol, 1 eq, HC1) and AD-10 (1.54 g, 6 mmol, 1.5 eq) in DMF (17 mL) was added EtsN (1.21 g, 12 mmol, 1.67 mL, 3 eq) and T4P (4.32 g, 6 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 0.5 h under N2 atmosphere. The reaction mixtureWSGR Docket No. 68195-704.601was diluted with H2O (100 mL) and extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (100 mL><2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 20 / 1 to 5 / 1) to give AD-11 (2 g, 3.19 mmol, 79% yield) as a yellow oil. LCMS (ESI+): m / z = 628.3 (M+H)+.

[0625] To a solution of AD-11 (2 g, 3.19 mmol, 1 eq) in HCl / EtOAc (4 M, 60 mL), then stirred at 25 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give AD-12 (1.4 g, crude, HC1) as a white solid. LCMS (ESI+): m / z = 414.2 (M+H)+.

[0626] To a solution of AD-12 (1.2 g, 2.67 mmol, 1 eq, HC1) and AD-13 (813 mg, 4 mmol, 1.5 eq) in DMF (12 mL) was added EtsN (1.35 g, 13.3 mmol, 1.86 mL, 5 eq) and T4P (2.88 g, 4 mmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 0.5 h under N2 atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with saturated brine (100 mL><2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 5 / 1 to 2 / 1) to give AD-14 (1.4 g, 2.34 mmol, 88% yield) as a light yellow solid. LCMS (ESI+): m / z = 599.3 (M+H)+.WSGR Docket No. 68195-704.601Degrader AD

[0627] To a solution of AD-14 (300 mg, 501 mol, 1 eq) in DMF (3 mL) was added CS2CO3 (490 mg, 1.50 mmol, 3 eq) and AD-15 (141 mg, 551 pmol, 1.1 eq), then stirred at 60 °C for 1 hWSGR Docket No. 68195-704.601under N2 atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL><3). The combined organic layers were washed with saturated brine (100 mL><2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, hexanes: EtOAc = 1 / 1, Rf = 0.05) to give AD-16 (310 mg, 400 pmol, 79% yield) as a light yellow solid. LCMS (ESI+): m / z = 775.4 (M+H)+.

[0628] To a solution of AD-16 (310 mg, 400 pmol, 1 eq) in DCM (3.1 mL) was added EtsN (81 mg, 800 pmol, 111 pL, 2 eq) and MsCl (68 mg, 600 pmol, 46 pL, 1.5 eq) at 0 °C, then stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCOs (100 mL), then extracted with DCM (50 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give AD-17 (340 mg, crude) as a light yellow solid. LCMS (ESI+): m / z = 853.3 (M+H)+.

[0629] To a solution of AD-17 (340 mg, 398 pmol, 1 eq) in DMF (8.5 mL) was added NaNs (60 mg, 923 pmol, 2.32 eq), then stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was poured into saturated Na2CCh (100 mL), then extracted with EtOAc (30 mL / 3). The combined organic layers were washed with saturated brine (30 mL><3), dried over anhydrous Na₂SO₄, filtered, filtered and concentrated under reduced pressure to give AD-18 (310 mg, crude) as a yellow oil. LCMS (ESI+): m / z = 800.4 (M+H)+

[0630] To a solution of AD-18 (310 mg, 387 pmol, 1 eq) in EtOH (2 mL) and H2O (1 mL) was added PPh₃ (203 mg, 775 pmol, 2 eq), then stirred at 50 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure give a residue. The residue was purified by prep-TLC (SiC>2, hexanes: EtOAc = 1 / 2, Rf = 0.03) to give AD-19 (200 mg, 258 pmol, 67% yield) as a white solid. LCMS (ESI+): m / z = 774.3 (M+H)+.

[0631] To a solution of AD-19 (150 mg, 193 pmol, 1 eq) and AD-20 (77 mg, 193 pmol, 1 eq) in DMF (1.5 mL) was added EtsN (98 mg, 969 pmol, 134 pL, 5 eq) and T4P (209 mg, 290 pmol, 50% purity, 1.5 eq) at 0 °C, then stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (100 mL), then extracted with EtOAc (30 mL><3). The combined organic layers were washed with saturated brine (30 mL><3), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18 150><40x7um; Mobile Phase: [H2O (10 mM NH4HCO3)-ACN]; Gradient: 50-85% B over 8.0 min) to give AD-21 (100 mg, 86.4 pmol, 44% yield) as a white solid. LCMS (ESI+): m / z = 1156.7 (M+H)+.

[0632] To a solution of AD-21 (100 mg, 86.4 pmol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 2 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reactionWSGR Docket No. 68195-704.601mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: WePure Biotech XP tC18 150><40x7um; Mobile Phase: [H2O (10 mM NH4HCC>3)-ACN]; Gradient: 50-80% B over 8.0 min) and then SFC (Column: Daicel ChiralPak IM (250x25mm i.d. lOum); Mobile Phase: [Heptane-EtOH: ACN= 4:1]; B%: 60%, isocratic elution mode) to give Degrader AD (42 mg, 38.5 pmol, 44% yield) as a white solid. LCMS: 96.1% purity, HRMS (ESI+): m / z = 1056.4243 (M+H)+, 'H NMR (400 MHz, DMSO-c / ) 8 = 8.51 - 8.43 (m, 1H), 8.30 - 8.23 (m, 1H), 8.02 - 7.76 (m, 1H), 7.69 - 7.61 (m, 2H), 7.49 - 7.40 (m, 5H), 7.27 - 7.21 (m, 1H), 5.63 - 5.35 (m, 1H), 4.54 - 4.43 (m, 2H), 4.19 - 4.13 (m, 2H), 3.83 - 3.73 (m, 4H), 3.60 (br d, J = 5.1 Hz, 2H), 3.57 - 3.52 (m, 6H), 3.47 - 3.43 (m, 2H), 3.27 - 3.16 (m, 4H), 3.10 - 2.99 (m, 1H), 2.59 (s, 3H), 2.40 (s, 3H), 2.29 - 2.14 (m, 5H), 2.07 - 1.98 (m, 2H), 1.74 - 1.67 (m, 1H), 1.61 (s, 6H), 1.57 - 1.52 (m, 2H), 0.92 (br s, 9H), SFC: 100.0% de.

[0633] Synthesis of Degrader AE:

[0634] (2S,4S)-4-[3-[2-[2-[2-[2-[[2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy] ethoxy]ethoxy]phenoxy]-l-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino] acetyl]-N-[(lR)-tetralin-l-yl]pyrrolidine-2-carboxamide.WSGR Docket No. 68195-704.601Degrader AE

[0635] General procedure of Degrader AE:

[0636] To a solution of AE-1 (3.8 g, 5.61 mmol, 1 eq) and AE-2 (1.59 g, 6.18 mmol, 1.1 eq) in DMF (38 mL) was added CS2CO3 (5.49 g, 16.8 mmol, 3 eq), then stirred at 60 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (200 mL), then extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, hexanes: EtOAc = 1 / 0 to 0 / 1 to DCM:MeOH = 10 / 1) to afford AE-3 (4 g, 4.69 mmol, 83% yield) as a yellow oil. LCMS (ESI+): m / z = 853.5 (M+H)+.WSGR Docket No. 68195-704.601

[0637] To a solution of AE-3 (4 g, 4.69 mmol, 1 eq) in DCM (40 mL) was added EtsN (949 mg, 9.38 mmol, 1.31 mL, 2 eq) and MsCl (930 mg, 8.12 mmol, 628 pL, 1.73 eq) at 0 °C, then stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into saturated NaHCO₃ (200 mL), then extracted with DCM (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give AE-4 (4.1 g, crude) as a yellow oil. LCMS (ESI+): m / z = 931.5 (M+H)+.

[0638] To a solution of AE-4 (4.1 g, 4.40 mmol, 1 eq) in DMF (41 mL) was added NaNs (500 mg, 7.69 mmol, 1.75 eq), then stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was poured into saturated Na2CCh (200 mL), then extracted with EtOAc (100 mL / 3). The combined organic layers were washed with saturated brine (100 mL><3), dried over anhydrous Na₂SO₄, filtered to give AE-5 (3.6 g, crude) as a yellow liquid. LCMS (ESI+): m / z = 878.4 (M+H)+.

[0639] To a solution of AE-5 (3.5 g, 4 mmol, 1 eq) in THF (70 mL) and H2O (35 mL) was added PPh₃ (5.23 g, 19.9 mmol, 5 eq), then stirred at 50 °C for 16 h under N2 atmosphere. The reaction mixture was poured into H2O (200 mL), then extracted with EtOAc (100 mL / 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 1 / 0 to 0 / 1 to DCM: MeOH = 3 / 1) to afford AE-6 (2.9 g, 3.40 mmol, 85.39% yield) as a yellow solid. LCMS (ESI+): m / z = 852.5 (M+H)+.

[0640] To a solution of AE-6 (2.8 g, 3.29 mmol, 1 eq) and AE-7 (1.05 g, 2.63 mmol, 0.8 eq) in DMF (28 mL) was added EtsN (997 mg, 9.86 mmol, 1.37 mL, 3 eq) and T4P (3.55 g, 4.93 mmol, 50% purity, 1.5 eq), then stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (200 mL), then extracted with EtOAc (100 mL><3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexanes: EtOAc = 1 / 0 to 0 / 1 to DCM: MeOH = 20 / 1) to afford AE-8 (2.9 g, 2.35 mmol, 71% yield) as a yellow solid. LCMS (ESI+): m / z = 1234.4 (M+H)+. SFC: 100.0% de.

[0641] To a solution of AE-8 (200 mg, 162 pmol, 1 eq) in THF (2 mL) was added HCl / EtOAc (4 M, 4 mL), then stirred at 25 °C for 1 h under N2 atmosphere. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 100x40mm><5 um; Mobile Phase: [H2O (0.2% FA)-ACN]; Gradient: 20-50% B over 8.0 min and column: WePure Biotech XP tC18 100><30x7um; Mobile Phase: [H2OWSGR Docket No. 68195-704.601(10 mM NH4HCC>3)-ACN]; Gradient: 25-90% B over 8.0 min) then further separated by SFC (Column: Daicel ChiralPak IM (250x25mm i.d. lOum); Mobile Phase: [CO2-EtOH: ACN = 1:1 (0.1% NH3H2O)]; B%: 65%, isocratic elution mode) to afford Degrader AE (85 mg, 75.1 pmol, 46% yield) as a white solid. LCMS: 99.9% purity. HRMS (ESI+): m / z = 1134.5290 (M+H)+. 'H NMR (400 MHz, DMSO-c / ) 8 = 8.33 (br t, J = 5.5 Hz, 1H), 8.05 - 7.79 (m, 2H), 7.56 - 7.52 (m, 2H), 7.50 - 7.46 (m, 2H), 7.33 - 7.09 (m, 5H), 6.62 - 6.45 (m, 3H), 5.14 - 4.94 (m, 2H), 4.68 -4.32 (m, 4H), 4.12 - 3.97 (m, 2H), 3.81 - 3.75 (m, 2H), 3.70 - 3.59 (m, 9H), 3.51 (t, J = 5.8 Hz, 2H), 3.36 - 3.22 (m, 4H), 3.05 - 2.94 (m, 1H), 2.80 - 2.70 (m, 2H), 2.65 (s, 3H), 2.63 - 2.58 (m, 1H), 2.46 (s, 3H), 2.27 - 2.20 (m, 3H), 2.18 - 1.99 (m, 2H), 1.92 - 1.78 (m, 3H), 1.76 - 1.57 (m, 10H), 1.21 - 1.08 (m, 6H), 1.06 - 0.92 (m, 2H). SFC: 100.0% de.

[0642] Synthesis of Degrader AF:

[0643] 5-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7-yl) oxy)propyl)piperazin-l-yl)-N-((3S,5S)-5-((2,6-difhiorophenyl) carbamoyl)-l-((S)-3,3-dimethyl-2-((S)-2-(methy-lamino)propanamido)butanoyl)pyrrol edin-3 -yl)pyrazine-2-carb oxami de.AF-2AF-1 AF-3 AF-4

[0644] General procedure of Degrader AF:

[0645] To a solution of AF-1 (5.5 g, 27 mmol, 1 eq) and AF-2 (4.5 g, 31 mmol, 1.15 eq) in THF (270 mL) was added EDCI (10.38 g, 54.1 mmol, 2 eq) and HOBt (4.39 g, 32.4 mmol, 1.2 eq), then stirred at 25 °C for 16 h under N2. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (500 mL). The organic phase was washed with IM HC1 (aq.) (300 mLx2), sat. NaHCO3 (200 mL) and brine (200 mL) respectively, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give AF-3 (9 g, crude) as a lightyellow oil. LCMS: [(M-100)+H+] = 231.3. 'H NMR (400 MHz, DMSO-d6) 6 = 7.86-7.66 (m, 1H), 4.62 (s, 1H), 4.17 (d, J=8.8 Hz, 1H), 3.63 (s, 3H), 2.77 (s, 3H), 1.38 (s, 9H), 1.23 (s, 3H), 0.92 (s, 9H).

[0646] To a solution of AF-3 (9 g, 27.2 mmol, 1 eq) in THF (90 mL), MeOH (45 mL) and H2O (90 mL) was added LiOH-H2O (4.57 g, 108.9 mmol, 4 eq), then stirred at 25 °C for 12 h under N2. The reaction mixture was treated with IM HC1 (aq) to pH<7 and extracted with EtOAc (100 mLx2). The combined organic phase was washed with brine (100 mLx2), dried over anhydrousWSGR Docket No. 68195-704.601Na2SC>4, filtered and concentrated under reduced pressure. Compound AF-4 (6.5 g, crude) was obtained as a light-yellow oil. LCMS: [M+H+] = 317.1.AF-7AF-5 AF-6AF-12

[0647] A mixture of AF-5 (45 g, 194 mmol, 1 eq) and 4-methylbenzene-l -sulfonyl chloride (55.6 g, 291 mmol, 1.5 eq) in 10% NaOH (135 mL) was degassed and purged with N2 for 3 times, and then stirred at 20 °C for 12 hr under N2 atmosphere. The reac...

Claims

1. WSGR Docket No. 68195-704.6012.CLAIMS WHAT IS CLAIMED IS:

1. A conjugate of Formula (I):4.D-S1— L— S2-AB5.Formula (I);6.wherein:7.D is a degrader;8.51is absent or a spacer;9.L is a cleavable linker;10.52is absent or a spacer; and11.AB is an albumin binder;12.or a pharmaceutically acceptable salt thereof.

2. The conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein AB is a covalent albumin binder.

3. The conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein AB is a non-covalent albumin binder.

4. The conjugate of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein D is a small molecule degrader.

5. The conjugate of claim 4, or a pharmaceutically acceptable salt thereof, wherein the small molecule degrader comprises a warhead, a protac linker, and an E3 ligase ligand.

6. The conjugate of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein D is a heterobifunctional proteolysis-targeting chimera (PROTAC) compound of Formula (D-l):18.W - LP - E3RL19.Formula (D-l),20.wherein,21.W a warhead that binds to a target protein;22.Lpis a linker;23.E3RL is an E3 ligase ligand.

7. The conjugate of claim 6, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase is the von Hippel-Lindau (VHL) tumor suppressor protein, Cereblon (CRBN), Mouse Double Minute 2 homologue (MDM2), Cellular Inhibitor of Apoptosis (cIAP), X-linked IAP (XIAP), Kelch-like ECH-associated protein 1 (KEAP1), KLHDC2, AhR, RNF2, RNF114, DDB1 and CUL4 Associated Factor 1 (DCAF1), DDB1 and CUL4 Associated Factor 11 (DCAF11), or DDB 1 and CUL4 associated factor 15 (DCAF15).WSGR Docket No. 68195-704.6018. The conjugate of claim 6, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase is VHL and the (E3RL) has the following structure of Formula (E):26.Rb— L127.o R3R128.R5k A A A29.HRI II30.1a^y>^R231.\4R33. 34.1a35.RFormula (E),36.wherein,37.R1is -L2-Ra, -O-L2-Ra, -N(Ra)(R14), -Ci-C6alkyl-CN, Ci-C6heteroalkyl, Ci- Ceheterofluoroalkyl, Ci-Ceheteroalkyl-CN, Ci-Ceheterofluoroalkyl-CN, -OH, -Ci- C6alkyl-OH, -Ci-C6haloalkyl-OH, -Ci-C6alkyl-O-L2-Ra, -Ci-C6haloalkyl-O-L2-Ra, - N(R13)2, -Ci-C6alkyl-N(R13)2, -O-Ci-C6alkyl-N(R13)2, or -O-(CH2CH2O)n-R13;38.L2is absent or -Ci-C6alkyl-N(R14)-;39.or R1is Rla;40.each Rlais independently hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehaloalkoxy, or Ci-Cealkoxy;41.X is N, -CR1-, or -CRla-;42.n is 1, 2, or 3;43.R2is hydrogen, halogen, -CN, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci- C4haloalkoxy, -N(Ci-C4alkyl)2, Cs-Cecycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein Ci-C4alkyl, Ci- C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Cs-Cecycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl is optionally and independently substituted with one or more R;44.o45.

46. r R2is;47.R3is hydrogen, Ci-C6alkyl, Ci-C6alkyl-OH, Ci-C6alkyl-ORa, Ci-C6haloalkyl, -Ci- C6haloalkyl-OH, -Ci-C6alkyl-N(R13)2, -Ci-C6alkyl-N(Ra)(R14), C3-C6cycloalkyl, -Ci- Cealkyl-Cs-Cecycloalkyl, -Ci-C6alkyl-(3-6 membered heterocycloalkyl optionally and independently substituted with one or more R)-Ra, -OP(=O)(OH)2, or -Ci-Cealkyl- OP(=O)(OH)2;48.R4is hydrogen or Ra;49.R5is hydrogen, Ci-Cealkyl, or Ci-C4haloalkyl; WSGR Docket No. 68195-704.60150.L1is -C(=O)(NR12)- or a 5-membered heteroarylene, wherein the 5-membered heteroarylene comprises at least one nitrogen atom and wherein -C(=O)(NR12)- is linked to Rbvia the C atom;51.Rais -S1-L-S2-AB, and Formula (E) comprises only one Rawhen -Lp- and W do not comprise Ra, or Formula (E) does not comprise a Ragroup when -Lp- or W comprise the Ramoiety;52.Rbis -Lp-W;53.R12is hydrogen, Ci-Cealkyl, or Ci-C4haloalkyl;54.each R13is independently hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, C3- Cecycloalkyl or 3-6 membered heterocycloalkyl, wherein Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, Cs-Cecycloalkyl, and 3-6 membered heterocycloalkyl is optionally and independently substituted with one or more R;55.R14is hydrogen, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, Cs-Cecycloalkyl, or 3-6 membered heterocycloalkyl, wherein Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, Cs-Cecycloalkyl, and 3-6 membered heterocycloalkyl is optionally and independently substituted with one or more R;56.each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci- C4alkyl, -S(=O)2NH2, -S(=O)2NHCi-C4alkyl, -S(=O)2N(Ci-C4alkyl)2, -S(=O)2H, -NH2, -NHCi-C4alkyl, -N(Ci-C4alkyl)2, -C(=O)Ci-C4alkyl, -C(=O)OH, -C(=O)OCi-C4alkyl, - C(=O)NH2, -C(=O)NHCi-C4alkyl, -C(=O)N(Ci-C4alkyl)2, Ci-C4alkyl, Ci-C3alkoxy, Ci-C4haloalkyl, Ci-C4haloalkoxy, Ci-Cshydroxyalkyl, Ci-C4aminoalkyl, Ci- C4heteroalkyl, Cs-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl;57.or two R on the same carbon atom form an oxo;58.wherein Formula (E) comprises only one Ra.

9. The conjugate of claim 8, or a pharmaceutically acceptable salt thereof, wherein:60.R4is hydrogen.

10. The conjugate of claim 8, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-l):62.o63.ANH65. 66.RFormula (E-l).

11. The conjugate of any one of claims 8-10, or a pharmaceutically acceptable salt thereof, wherein:WSGR Docket No. 68195-704.60168.R1is -L2-Raor -O-L2-Ra;69.L2is absent or -Ci-C6alkyl-N(R14)-;70.R4is hydrogen; and71.Rais -S^L-S^AB.

12. The conjugate of claim 8, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-2):73.Rb— L174.\.0 _o033 ^ _^L2-S1-LC-S2— AB75.O O RR33OO''276.H I II77.R279.

80. Formula (E-2).

13. The conjugate of claim 8, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-3):82.Rb— L184.

85. Formula (E-3).

14. The conjugate of claim 8, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-4):

88.

89. Formula (E-4).

15. The conjugate of any one of claims 8-14, or a pharmaceutically acceptable salt thereof, wherein:91.R92. 93.2is16. The conjugate of claim 8, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase is VHL and (E3RL) has the following structure of Formula (E-5):WSGR Docket No. 68195-704.60195.Rb— L196., N^.L2_S1_LC_S2_AB98. 99.RFormula (E-5).

17. The conjugate of any one of claims 8-16, or a pharmaceutically acceptable salt thereof, wherein:101.R3is -CH3; and102.R5is -C(CH3)3.

18. The conjugate of any one of claims 8-17, or a pharmaceutically acceptable salt thereof, wherein:104.R14is Ci-Cefhioroalkyl.

19. The conjugate of claim 8-18, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase is VHL and (E3RL) has one of the following structures:

107.

108. WSGR Docket No. 68195-704.60120. The conjugate of any one of claims 8-18, or a pharmaceutically acceptable salt thereof,110.K / O-S1-L-S2-AB111.0<^NH112.wherein the E3 ligase is113.

114. VHL and (E3RL) is / 21. The conjugate of any one of claims 8-20, or a pharmaceutically acceptable salt thereof, wherein L1is -C(=O)(NR12)-.

22. The conjugate of any one of claims 6-21, or a pharmaceutically acceptable salt thereof, wherein W-LP-E3RL is:116.W117.wherein W-Lp-118.E119.

120. 3RL is connected to S1-L-S2-AB at W, E3RL, or 23. The conjugate of claim 6, or a pharmaceutically acceptable salt thereof, wherein E3RL is121.H122.N123.an IAP binder c124.

125. omprising WSGR Docket No. 68195-704.601127.

24. The conjugate of claim 6, or a pharmaceutically acceptable salt thereof, wherein E3RL is an IAP binder comprising130.

131. WSGR Docket No. 68195-704.601133.

25. The conjugate of claim 6, or a pharmaceutically acceptable salt thereof, wherein E3RL is136.a Cereblon binder and comprises137.

140.

26. The conjugate of claim 6, or a pharmaceutically acceptable salt thereof, wherein E3RL is a Cereblon binder and comprises143.

144. or145.

146. WSGR Docket No. 68195-704.60127. The conjugate of any one of claims 5-26, or a pharmaceutically acceptable salt thereof, wherein the warhead comprises a bromodomain-containing protein 4 (BRD4) ligand, an estrogen receptor (ER) ligand, a fibroblast growth factor receptor 2 (FGFR2) ligand, a Myc ligand, or a receptor-interacting protein kinase 2 (RIPK2) ligand.

28. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to BRD4:149.R22150.^23s 5=N152. 153.R154.' 'nFormula (D-2),155.wherein,156.R21is phenyl, Cs-Cecycloalkyl, or 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci- C4alkyl, Ci-C4haloalkyl, C3-C6 cycloalkyl, hydroxyl, Ci-C4alkoxy, or cyano;157.R22and each R23are independently halo, Ci-C4alkyl, Ci-C4haloalkyl, C3-C6 cycloalkyl, hydroxyl, Ci-C4alkoxy, or cyano; and n is 0, 1, 2, 3, or 4.

29. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D is a bromodomain-containing protein 4 (BRD4) degrader.

30. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises ARV-771, ARV-825, BETd-246, BETd-260, dBETl, dBET6, dBET23, QCA276, or QCA570.

31. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to BRD4 comprising:

162.

163. WSGR Docket No. 68195-704.60132. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to BRD4 comprising:

166.

33. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises170.

171. WSGR Docket No. 68195-704.601173.

174. WSGR Docket No. 68195-704.601176.

177. WSGR Docket No. 68195-704.601179.

180. WSGR Docket No. 68195-704.601182.

183. WSGR Docket No. 68195-704.601185.

34. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises189.

190. WSGR Docket No. 68195-704.601192.

193. WSGR Docket No. 68195-704.601195.

35. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises199.

36. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises203.

204. WSGR Docket No. 68195-704.601206.

207. WSGR Docket No. 68195-704.601209.

210. WSGR Docket No. 68195-704.601212.

37. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises216.

38. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises220.

221. WSGR Docket No. 68195-704.601223.

39. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to the estrogen receptor (ER) comprising:

227.

228. WSGR Docket No. 68195-704.601230.

231.

40. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D is an estrogen receptor (ER) degrader comprising:

233.

41. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprisesWSGR Docket No. 68195-704.601237.

42. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to FGFR2 comprising:

241. 243.wherein, each R24is independently hydrogen, Ci-C4alkyl, Ci-C4haloalkyl, or C3-C6 cycloalkyl, cyano; or244.both R24are taken together with the N atom to which they are attached to form a 4 to 6 membered heterocycloalkyl.

43. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D is a fibroblast growth factor receptor 2 (FGFR2) degrader.

44. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises248.

45. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to Myc comprising:WSGR Docket No. 68195-704.601252.

46. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D is a Myc degrader.

47. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises256.O258.

259. WSGR Docket No. 68195-704.601261.

48. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises265.

49. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprises a heterobifunctional PROTAC compound of Formula (D-l), wherein W is a moiety that binds to receptor-interacting protein kinase 2 (RIPK2)269.

50. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D is a RIPK2 degrader.

51. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein D comprisesWSGR Docket No. 68195-704.601274.

52. The conjugate of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein S1is absent.

53. The conjugate of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein S1is a spacer.

54. The conjugate of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein S1comprises a -CH2- spacer.

55. The conjugate of any one of claims 1-51, or a pharmaceutically acceptable salt thereof,281.

282.

56. The conjugate of any one of claims 1-51, or a pharmaceutically acceptable salt thereof,283.wherein S1comprises284.

57. The conjugate of any one of claims 1-51, or a pharmaceutically acceptable salt thereof,288.

58. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises an acid cleavable linker.

59. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises an N-acyl hydrazone linkage, a carbonate linker, or an ester linkage.WSGR Docket No. 68195-704.60160. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises an enzyme cleavable linker.

61. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a protease cleavable linker.

62. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a glycosidase cleavable linker.

63. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a P-glucuronidase-cleavable linker.

64. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a galactosidase cleavable linker.

65. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a P-galactosidase-cleavable linker.

66. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof,299.OH301.

67. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof,304.COOH COOH O305.wherein L comprises OH306.OH OH307.

308. WSGR Docket No. 68195-704.60168. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof,310.COOH O311.wherein L comprises312.

313. wherein R1is hydrogen, Ci- Cealkyl, or Ci-C6alkyleneN(Ci-Cealkyl)2.

69. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof,315.wherein L comprises316.

317. wherein R1is hydrogen, Ci- Cealkyl, or Ci-C6alkyleneN(Ci-C6alkyl)2.

70. The conjugate of claim 68 or 69, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

71. The conjugate of claim 68 or 69, or a pharmaceutically acceptable salt thereof, wherein R1is methyl or ethyl.

72. The conjugate of claim 68 or 69, or a pharmaceutically acceptable salt thereof, wherein R1is -CH2CH2N(CH3)2.

73. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof,323.

324.

74. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a peptide. WSGR Docket No. 68195-704.60175. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a dipeptide.

76. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a tripeptide.

77. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises a tetrapeptide.

78. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein L comprises Ala-Ala-PABC, Ala-Ala-Ala-PABC, Ala-Ala-Asn-PABC, Ala- Asn-Asn-PABC, Ala-Leu-Ala-Leu-PABC, Asn-Asn-PABC, cBu-Cit-PABC, cBu-Val- Cit-PABC, Glu-Val-Cit-PABC, Gly-Asn-Asn-PABC, Gly-Gly-Pro-PABC, Gly-Phe- Leu-Gly-PABC, Gly-Pro-PABC, Leu-Ser-Gly-Lys-PABC, Phe-Lys-PABC, Ser-Val-Cit- PABC, Val-Ala-PABC, or Val-Cit-PABC.

79. The conjugate of any one of claims 1-57, or a pharmaceutically acceptable salt thereof,331.

332. WSGR Docket No. 68195-704.601334.

335. WSGR Docket No. 68195-704.601337.

338. WSGR Docket No. 68195-704.601340.

80. The conjugate of any one of claims 1-79, or a pharmaceutically acceptable salt thereof, wherein D-S^L comprises344.

345. WSGR Docket No. 68195-704.601347.

348.

81. The conjugate of any one of claims 1-79, or a pharmaceutically acceptable salt thereof, wherein D-S^L comprises WSGR Docket No. 68195-704.601350.

351. WSGR Docket No. 68195-704.601352.o353.

354. r82. The conjugate of any one of claims 1-81, or a pharmaceutically acceptable salt thereof, wherein S2is Formula (II):

357. 359.Formula (II);360.wherein:361.each M is independently -O-, -NRM-, -N(RM)2+-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, - C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRM-, -NRMC(=O)-, -OC(=O)NRM-, - NRMC(=O)O-, -NRMC(=O)NRM-, -NRMC(=S)NRM-, -CRM=N-, -N=CRM, - NRMS(=O)2-, -S(=O)2NRM-, -C(=O)NRMS(=O)2-, -S(=O)2NRMC(=O)-, C1- C2oalkylene, C2-C2oalkenylene, C2-C2oalkynylene, Ci-C2oheteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is optionally and independently substituted with one or more R; each RMis independently hydrogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4heteroalkyl, C2- Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;362.n is 1-20; and363.each R is independently halogen, -CN, -OH, -SFs, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci- C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -S(=O)2H, - NH2, -NHC1-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi- C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci- C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl;364.or two R on the same atom form an oxo.

83. The conjugate of claim 82, or a pharmaceutically acceptable salt thereof, wherein each M is independently -O-, -NRM-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NRM-, -NRMC(=O)-, Ci-C2oalkylene, Ci-C2oheteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is optionally and independently substituted with one or more R.

84. The conjugate of claim 82, or a pharmaceutically acceptable salt thereof, wherein each M is independently -O-, -NRM-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRM-, -WSGR Docket No. 68195-704.601367.NRMC(=O)-, Ci-C2oalkylene, Ci-C2oheteroalkylene, or heteroarylene; wherein each alkylene, heteroalkylene, and heteroarylene is optionally and independently substituted with one or more R.

85. The conjugate of claim 82, or a pharmaceutically acceptable salt thereof, wherein each M is independently -O-, -NRM-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRM-, - NRMC(=O)-, Ci-C2oalkylene, or Ci-C2oheteroalkylene; wherein each alkylene and heteroalkylene is optionally and independently substituted with one or more R.

86. The conjugate of claim 82, or a pharmaceutically acceptable salt thereof, wherein each M is independently -O-, -NRM-, -C(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C2oalkylene, Ci-C2oheteroalkylene, or heteroarylene; wherein each alkylene, heteroalkylene, and heteroarylene is optionally and independently substituted with one or more R.

87. The conjugate of claim 82, or a pharmaceutically acceptable salt thereof, wherein each M is independently -C(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C2oalkylene, Ci- C2oheteroalkylene, or heteroarylene; wherein each alkylene, heteroalkylene, and heteroarylene is optionally and independently substituted with one or more R.

88. The conjugate of claim 82, or a pharmaceutically acceptable salt thereof, wherein each M is independently -C(=O)-, -C(=O)NRM-, -NRMC(=O)-, Ci-C2oalkylene, or Ci- C2oheteroalkylene; wherein each alkylene and heteroalkylene is optionally and independently substituted with one or more R.

89. The conjugate of any one of claims 82-88, or a pharmaceutically acceptable salt thereof, wherein each RMis independently hydrogen or Ci-C4alkyl.

90. The conjugate of any one of claims 82-88, or a pharmaceutically acceptable salt thereof, wherein each RMis hydrogen.

91. The conjugate of any one of claims 82-88, or a pharmaceutically acceptable salt thereof, wherein n is 1-10.

92. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,377. 379.wherein S2is or and m is 1-15.

93. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,382.

383. WSGR Docket No. 68195-704.60194. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,385.N387.

388. and m is 1-15.

95. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,391.

96. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,395.

396. 1-15.

97. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,398.N N N N H H399.N N N N401.

402. H H H H403.and each m is independently 1- 15.

98. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,405.N N H H406.N N408.

409. H H410.and each m is independently 1-15.

99. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,413.

100. The conjugate of any one of claims 92-99, or a pharmaceutically acceptable salt thereof, wherein each m is independently 4-12.

101. The conjugate of any one of claims 92-99, or a pharmaceutically acceptable salt thereof, wherein each m is independently 1-5.WSGR Docket No. 68195-704.601102. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,418.° ° / U U \ wherein S419. 420.2isqorqand q is 1-10.

103. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof,423.

104. The conjugate of any one of claims 1-91, or a pharmaceutically acceptable salt thereof;426.°.tO427.wherein S428. 429.2, is vAMor AMv and q is 1-10.

105. The conjugate of any one of claims 102-104, or a pharmaceutically acceptable salt thereof, wherein q is 1-5.

106. The conjugate of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, wherein S2is:

433.

434.

107. The conjugate of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, wherein S2is:

436.

437. WSGR Docket No. 68195-704.601438.o o440.

441. or108. The conjugate of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, wherein S2is absent.

109. The conjugate of any one of claims 1-108, or a pharmaceutically acceptable salt445.

110. The conjugate of any one of claims 1-108, or a pharmaceutically acceptable salt thereof, wherein AB is449.

450. WSGR Docket No. 68195-704.601452.

453.

111. The conjugate of any one of claims 1-108, or a pharmaceutically acceptable salt or454.

455.

112. The conjugate of any one of claims 1-111, or a pharmaceutically acceptable salt I— S2-AB456.thereof, wherein457.

458. I is WSGR Docket No. 68195-704.601460.

461. WSGR Docket No. 68195-704.601463.

464.

113. The conjugate of any one of claims 1-111, or a pharmaceutically acceptable salt465.I— S2-AB thereof, wherein I is466.

467. WSGR Docket No. 68195-704.601469.

470. WSGR Docket No. 68195-704.601472.

473.

114. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a conjugate found in Table 1, Table 2, Table 3, or Table 4.

115. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

476.

477. WSGR Docket No. 68195-704.601479.

480. WSGR Docket No. 68195-704.601481.R482.R484.

485. or a pharmaceutically acceptable salt thereof,486.wherein R487.

488. is116. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:490.H2NX^° HN492.

493. WSGR Docket No. 68195-704.601494.wherein R is495.

496. WSGR Docket No. 68195-704.601498.

499. or a pharmaceutically acceptable salt thereof.

117. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

502.

503. WSGR Docket No. 68195-704.601505.

506. or a pharmaceutically acceptable salt thereof,507.wherein R508.

509. is118. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:WSGR Docket No. 68195-704.601512.

513. WSGR Docket No. 68195-704.601515.

516. or a pharmaceutically acceptable salt thereof,517.wherein R518.

519. is119. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:521.H2NX^° HN523.

524. WSGR Docket No. 68195-704.601526.

527. or a pharmaceutically acceptable salt thereof.

120. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

530.

531. WSGR Docket No. 68195-704.601532.H2NS-^°534.

535. wherein R is '; or a pharmaceutically acceptable salt thereof.

121. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

538.

539. or a pharmaceutically acceptable salt thereof.

122. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:WSGR Docket No. 68195-704.601542.

543. ; or WSGR Docket No. 68195-704.601545.

546. or a pharmaceutically acceptable salt thereof,547.wherein R548.

549. is123. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

552.

553. or a pharmaceutically acceptable salt thereof, WSGR Docket No. 68195-704.601555.

124. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

559.

560. wherein R is or a pharmaceutically acceptable salt thereof.

125. The conjugate of any one of claims 1-108, or a pharmaceutically acceptable salt thereof; wherein AB comprises a maleimide derivative.

126. The conjugate of any one of claims 1-108, or a pharmaceutically acceptable salt thereof; wherein AB comprises maleimide.

127. The conjugate of any one of claims 1-108, or a pharmaceutically acceptable salt564.thereof; wherein565.

566. AB is128. The conjugate of any one of claims 1-108, or a pharmaceutically acceptable salt568.thereof, wherein569.

570. WSGR Docket No. 68195-704.601571.o573.

130. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a conjugate found in Table 5, Table 6, Table 7, or Table 8.

131. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:WSGR Docket No. 68195-704.601578.

579. WSGR Docket No. 68195-704.601581.

582. WSGR Docket No. 68195-704.601584.

585. or a pharmaceutically acceptable salt thereof,587.

132. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

591.

592. or a pharmaceutically acceptable salt thereof, WSGR Docket No. 68195-704.601594.

133. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

598.

599.

134. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from: WSGR Docket No. 68195-704.601600.\ or a pharmaceutically acceptable salt602.

603.

135. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

605.

606. ; or or a pharmaceutically acceptable salt thereof,607.wherein R608.

609. is WSGR Docket No. 68195-704.601136. A conjugate, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

612. 614.or a pharmaceutically acceptable salt thereof,616.

137. A pharmaceutical composition comprising a conjugate of any one of claims 1-136, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

138. A method of treating cancer in a subject, comprising administering to the subject a conjugate of any one of claims 1-136, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 137.

139. A method of:621.enhancing transport of a protein degrader to a tumor in a mammal;622.increasing the accumulation of a heterobifunctional protein degrader in a tumor of a mammal; or623.improving the pharmacokinetic profile of a heterobifunctional protein degrader in a mammal; or a combination thereof,624.wherein the method comprises administering to the mammal a compound of any one of claims 1-136, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 137.

140. The method of claim 139, wherein the protein is bromodomain-containing protein 4 (BRD4), estrogen receptor (ER), Myc, fibroblast growth factor receptor 2 (FGFR2), or receptor-interacting protein kinase 2 (RIPK2).WSGR Docket No. 68195-704.601141. The method of claim 139, wherein the protein is estrogen receptor (ER), Myc, fibroblast growth factor receptor 2 (FGFR2), or receptor-interacting protein kinase 2 (RIPK2)142. The method of any one of claims 139-141, wherein the method comprises administering to the mammal a compound of any one of claims 109-124.

143. The method of any one of claims 139-141, wherein the method comprises administering to the mammal a compound of any one of claims 125-136.

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