Acyclic glutarimide compounds, compositions comprising same, and methods of use thereof

Abstract

In one aspect, the disclosure relates to compounds of Formula (I) comprising a cereblon degrader precursor comprising an acyclic glutarimide moiety. In certain embodiments, the acyclic glutarimide moiety7 converts to a glutarimide moiety7 upon exposure to a stimulus. In certain embodiments, the compound of Formula (I) comprises at least one selected from the group consisting of a Proteolysis Targeting Chimera (PROTAC). degrader antibody conjugate (DAC), and / or Immunomodulatory Imide Drug (IMiD). In another aspect, the disclosure relates to methods of use of the compounds described herein for the treatment of a disease or disorder, including but not limited to cancer.

Description

[0001]Attorney Docket No.047162-7520WO1(02652) TITLE OF THE INVENTION Acyclic Glutarimide Compounds, Compositions Comprising Same, and Methods of Use Thereof STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under CA197589 awarded by National Institutes of Health. The government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.63 / 684,705, filed August 19, 2024, which is incorporated herein by reference in its entirety. BACKGROUND Targeted protein degradation (TPD) has recently emerged as a promising therapeutic approach combatting fatal diseases and cancers. By hijacking the cell’s own machinery, small molecules can either initiate non-native protein-protein interactions (PPIs) or stabilize existing ones to target and degrade specific proteins of interest. In eukaryotic cells, protein regulation primarily occurs through two recycling machineries, the proteasome and lysosome. TPD has predominantly focused on small molecule-based therapies that exploit the ubiquitin-proteasome system (UPS) to degrade target proteins. The UPS comprises an activating enzyme (E1), a conjugating enzyme (E2), and a ligase (E3). These components work together with other proteins to facilitate the ubiquitination of proteins. The polyubiquitinated protein is subsequently recognized and degraded by the 26S proteosome. Most TPD strategies target the E3 ligase, as this component binds to the target protein while the E2 enzyme mediates the ubiquitination process. Although there are over 600 E3 ligases capable of initiating protein degradation, only two (i.e., cereblon (CRBN) and von-Hippel- Lindau tumor suppressor (VHL)) are commonly utilized in TPD. CRBN is notably versatile, modulating proteins through both recruitment of non-native PPIs and stabilization of native PPIs. Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that consist of two distinct ligands connected by a linker; one ligand binds the E3 ligase and the other binds to the target protein. By virtue of these distinct ligands, PROTACs can recruit - 1 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) proteins to the E3 ligase that would not typically interact. Conversely, immunomodulatory imide drugs (IMiDs) bind to the E3 ligase and stabilize its interaction with the target protein. This prolonged induced proximity with the ligase leads to the polyubiquitination and degradation of the target protein. Both TPD technologies have shown considerable promise, with PROTACs ARV-110, ARV-471 and NX-2127 entering clinical trials, and IMiDs including thalidomide, lenalidomide, and pomalidomide having received FDA approval, with additional IMiDs in clinical trials. While cereblon ligands have demonstrated utility in both PROTAC and IMiD therapeutic applications, the limited reactivity of the requisite glutarimide moiety in such compounds limits the scope of conjugation techniques and / or masking group approaches that can be utilized. Stimulus-sensitive technologies, such as antibody drug conjugates (ADCs) and degrader antibody conjugates (DACs), rely on drug or degrader conjugation to a cleavable linker, yet many drug moieties and / or CRBN-recruiting degraders are not suitable for conjugation to the glutarimide through traditional methods. Consequently, permissive chemical modifications must be introduced elsewhere in the degrader or drug, often compromising potency and necessitating extensive optimization. Thus, there is a need in the art for cereblon ligands, or precursors thereof, which permit alternative conjugation techniques and / or masking group approaches, and methods of using thereof. The disclosure addresses this need. BRIEF SUMMARY In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or isotopologue thereof: , wherein: T is absent or selected from the group consisting of Ab and D; Ab, if present, is a cell and / or antigen binding domain, optionally wherein the cell and / or antigen binding domain is an antibody; D, if present, is a protein of interest-binding moiety; L is absent or each occurrence of L is independently a linker covalently conjugated to T and cDp; each occurrence of cDp is independently a cereblon degrader precursor of structure: - 2 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) , wherein each L, covalently conjugated to cDp via a covalent - , R1, or R2; l is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; m is 0 or 1; each occurrence of ring A is independently selected from the group consisting of optionally substituted C3-C20 heterocyclyl and optionally substituted C6-C10 aryl; each occurrence of R1is selected from the group consisting of H and a selectively cleavable protecting group; and each occurrence of R2is a leaving group. In another aspect, the disclosure provides a pharmaceutical composition comprising the compound of Formula (I) and a pharmaceutically acceptable carrier. In another aspect, the disclosure provides a method for inducing degradation of a target protein in a cell. In certain embodiments, the method comprises contacting the cell with a therapeutically effective amount of the compound of Formula (I) or a pharmaceutical composition thereof. In another aspect, the disclosure provides a method for treating, preventing, and / or ameliorating a disease or disorder in a subject. In certain embodiments, the method comprises contacting the cell with a therapeutically effective amount of the compound of Formula (I) or a pharmaceutical composition thereof. In certain embodiments, the disease or disorder is cancer. BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. FIG.1 depicts structures of certain exemplary, non-limiting cereblon (CRBN) ligands featuring different core scaffolds wherein the glutarimide moiety is retained in each of scaffolds A-H. FIG.2 depicts structures of certain exemplary, non-limiting cereblon (CRBN) ligands featuring different core scaffolds wherein the glutarimide moiety is retained in each - 3 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) compound. FIG.3A depicts the chemical structures of certain exemplary compounds comprising cyclized glutarimide (Compound 1-1) and acyclic glutarimide precursors or pro-degrons (Compounds 1-2 and 1-3) and DC50values thereof (R = 5-(substituted oxy)-isoindolin-1-one- 2-yl). FIG.3B provides a graph depicting HiBit degradation of Compounds 1-1 to 1-3. FIG. 3C provides a graph depicting the HiBit degradation profile of Compound 1-3 + / 1 CRBN (+ / - ), wherein CRBN (-) was KO using a CRBN-degrading PROTAC. Compound 1-1 (DHC- 286); compound 1-2 (DHC-291); compound 1-3 (DHC-287). FIG.4 provides a graph depicting results of a HiBit assay which shows SAR studies toward the optimization of potent degradation for certain pro-degrons of the disclosure. Compound 1-6 (DHC-562); compound 1-7 (DHC-563); compound 1-8 (DHC-564); compound 1-9 (DHC-565); compound 1-10 (DHC-575). FIG.5 provides the chemical structure of lenalidomide and Compound 1-15 as well as the SALL4 degradation profile for both compounds after 48 h. FIG.6 provides the chemical structure of masked amide Compound 1-16, which liberates Compound 1-3 following stimulation with UV light, and further provides a graph depicting percentage release of Compound 1-3 after 0, 0.5, 1.0, and 4.0 min exposure with 365 nm light. FIGs.7A-7C depict non-limiting exemplary acyclic glutarimide precursors (FIG.7A) and masking group strategies (FIG.7B-7C). FIG.8: Examples of the shared glutarimide motif in CRBN ligands and their mechanism of action. Graphical representation of the mechanism by which degraders induce the degradation of POIs. FIGs.9A-9H: Prodegraders cyclize in cellulo to degrade GSPT1. FIG.9A: Chemical structure of parent GSPT1 degrading IMiD, DHC-286, containing glutarimide (red). Chemical structure of DHC-286 analogs DHC-287 and DHC-291 containing prodegraders (blue) in the place of the glutarimide. FIGs.9B-9C: Normalized to DMSO. GSPT1HiBiTdegradation kinetics of DHC-286 (FIG.9B) and DHC-287 (FIG.9C), 4 to 48 hours. Normalized to DMSO. FIG.9D: ITC binding of DHC-286 to CRBNMidi*shown as raw titration data and plotted curve depicting a KD = 2.4 ± 1.4 µM. FIG.9E: ITC raw binding data depicting no binding of DHC-287 to CRBNMidi*. FIG.9F: Table with ITC KDvalues for DHC-286 and DHC-287. FIG.9G: Schematic of the experimental design for intracellular accumulation assay using HEK293T GSPT1HiBiTcells. FIG.9H: Chemical structures of the desired cyclized product, DHC-286, and hydrolysis product, DHC-289. Graph depicting the - 4 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) presence of the shown products at various time points (0-48 hours) after treatment with DHC- 287. FIGs.10A-10G: Optimization of prodegrader cyclization to enhance GSPT1 degradation. FIG.10A: SAR table depicting the chemical structure of a-branched prodegrader analogs and their respective GSPT1HiBiTDC50 (8 and 24 hours) in HEK293T GSPT1HiBiTcells. FIG.10B: Corresponding graphs for the analogs DC50at 8 hours; 24 hours (FIG.4). Normalized to DMSO. FIG.10C: SAR table depicting the chemical structure of g- branched prodegrader analogs and their respective GSPT1HiBiTDC50(24 hours) in HEK293T GSPT1HiBiTcells. FIG.10D: Corresponding graph of GSPT1HiBiTdegradation for DHC-286 DHC-562, DHC-582, DHC-564, and DHC-583 at 24 hours. Normalized to DMSO. FIG.10E In vitro cyclization of the ester analogs into DHC-286 after incubation at 37 °C in aqueous buffer. FIG.10F: Cell viability of DHC-562 compared to DHC-286 at 24 hours (left). Cell viability of DHC-562 compared to DHC-286 at 72 hours (right). Conducted with HEK293T GSPT1HiBiTcells. Normalized to DMSO. FIG.10G: Corresponding table depicting DC50s (24, 48, and 72 hours) and IC50s (48, 72, and 96 hours) for DHC-286 and DHC-562. FIGs.11A-11D: Prodegraders can be applied to other CRBN-recruiting scaffolds and degraders. FIG.11A: Chemical structure of 5-HT and prodegrader analog DHC-749. Compounds resulting SALL4NLucdegradation in H1299 SALL4-NanoLuc cells after 24 hours. Normalized to DMSO. FIG.11B: Chemical structure of SJF-620 and prodegrader analog DHC-753. FIG.11C: Western blot and quantification depicting BTK degradation by SJF-620 (10, 100, 1000 nM) and DHC-753 (100, 1000, 5000 nM) in NAMALWA cells after 24 hours. Quantification of western blot (right). Normalized to DMSO. FIG.11D: Dose response for cell viability of SJF-620 and DHC-753 in TMD8 cells after 72 hours. FIGs.12A-12F: CRBN-recruiting prodegraders enable generalizable conjugation strategies. FIG.12A: Depiction of the unstable glutarimide conjugation via a carbamate linker. FIG.12B: Chemical structure of two DAC’s incorporating chemical modifications to known degraders, CC-885 (DAC: ORUM-5029) and ARV-825 (BRD4 PROTAC DAC), to allow for conjugation. FIG.12C: Schematic depicting the proposed linker conjugation to the prodegraders that was more challenging with glutarimides. FIG.12D: UV triggered release of DHC-287 when DHC-585 is exposed to 365 UV light (0-4 minutes). FIG.12E: General structure of DAC. Schematic depicting the cleavage of the linker with cathepsin B and the resulting self-immolation to release the attached cytotoxic drug. FIG.12F: Incubation of DHC-683 with cathepsin B (0-150 minutes) results in the release of prodegrader, DHC-282. - 5 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) FIG.13: Western blot depicting dose-dependent degradation of GSPT1 by DHC-287 after a 24 hour treatment of 293T cells that stably express GSPT1HiBiT(293T-GSPT1-HiBiT). FIG.14: GSPT1HiBiTdegradation by α-branched analog DHC-287 and ^-branched analog DHC- 549 in 293T-GSPT1-HiBiTcells after 24 hours. Luminescence results were normalized to DMSO vehicle. FIG.15: LCMS measurements of the quantity of prodegrader (DHC-562, DHC-563, DHC-564, DHC-565, DHC-575α) converted to cyclized product (DHC-286) and hydrolysis product (DHC-289) over the course of incubation in 20 mM potassium phosphate buffer (pH 7.4) at 37 °C. FIG. 16:LCMS measurements of the quantity of prodegrader DHC-562 and DHC-565converted to cyclized product (DHC-286) and hydrolysis product (DHC-289) over the course of incubation in 20 mM ammonium acetate buffer (pH 7.4) at 37 °C. FIG.17: Degradation of GSPT1HiBiTin 293T-GSPT1-HiBiTcells by the degrader DHC- 286 and the prodegrader DHC-562 after 48 hour treatment. Luminescence results were normalized to DMSO vehicle. FIG. 18: Cell viability of 293TGSPT1-HiBiTcells treated with DHC-286 and DHC-562 at 48 (left), 72 (middle) and 96 (right) hours. Measured with CellTiter- Glo 2.0. Relative to DMSO. FIG.19: Degradation of GSPT1HiBiTin 293T-GSPT1-HiBiTcells by the (S)-enantiomer, DHC-781, and the racemic degrader, DHC-286, in addition to the (S)-enantiomer, DHC- 562, and the racemic prodegraders, DHC-800 after 4, 24 and 48 hour treatment. Luminescence results were normalized to DMSO vehicle. FIG. 20: SALL4NanoLucdegradation of 5-hydroxythalidomide (5-HT) andprodegrader DHC- 749 in H1299SALL4-NanoLuccells after 24-hour treatment. Luminescence results were normalized to DMSO vehicle. FIG. 21: CK1αNanoLucdegradation of lenalidomide and prodegrader DHC-608in K562CK1α - NanoLuccells after 24 hour treatment. Luminescence results were normalized to DMSO vehicle. FIG.22: Western blot depicting BTK degradation by SJF-620 (10, 100 nM) and DHC- 753 (10, 100, 1000 nM) in NAMALWA cells after 24 hours (top) and 48 hours (bottom). Quantification of western blot is to the right of their respective blots. Normalized to DMSO vehicle. - 6 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) FIG.23: LCMS measurements of the quantity of prodegrader IMiD DHC-562 (left) and PROTAC DHC-753 (right) converted to cyclized product (red) and their hydrolysis product (white) over the course of incubation in 20 mM potassium phosphate buffer (pH 7.4) at 37 °C. FIG.24: (left) Western blot depicting GSPT1 degradation by DHC-286 (100, 500 nM) and DHC-562 (100, 500 nM) in TMD8 cells after 24 hours. Quantification of western blot is beneath the respective blot. Normalized to DMSO vehicle. (right) Dose response for cell viability of GSPT1 degrader DHC-286 and prodegrader DHC-562 in TMD8 cells after 72 hours. Measured with CellTiter-Glo 2.0. Normalized to DMSO vehicle. FIG.25: LCMS measurements of the quantity of glutarimide prodegrader DHC-562 (left) and aspartimide prodegrader DHC-788 (right) converted to cyclized product (red) and their hydrolysis product (white) over the course of incubation in 20 mM potassium phosphate buffer (pH 7.4) at 37 °C. FIG.26: Degradation of GSPT1HiBiTin 293T-GSPT1-HiBiTcells by the glutarimide-based degrader DHC-286 and the aspartimide-based prodegrader DHC-791, along with their respective methyl ester prodegraders DHC-562 and DHC-795 after 4, 24 and 48 hour treatment. Luminescence results were normalized to DMSO vehicle. FIG.27: LCMS UV traces (254 nm) measuring UV-triggered release of prodegrader. The stacked traces depict the depletion of photolabile protected compound, DHC-585, and increase in prodegrader (DHC-287) formation in a time dependent manner when exposed to UV light (365 nm). FIG.28: LCMS UV traces (254 nm) measuring cathepsin B triggered release of prodegrader. The stacked traces depict the decrease of DHC-631 and its DTT adduct (through conjugation to maleimide) in a time dependent manner when exposed to cathepsin B to release the prodegrader DHC-282. Peaks in the 150 min spectra are shifted as a result of instrumental variability. FIG.29: Synthesis of GSPT1-degrading IMiD DHC-286. FIG.30: Synthesis of GSPT1 prodegrader DHC-291. FIG.31: Synthesis of GSPT1 prodegraders DHC-562, DHC-563, DHC-564, DHC- 565, and DHC-575. FIG.32: Synthesis of GSPT1 prodegraders DHC-582 and DHC-583 from the intermediate, DHC-549. FIG.33: Synthesis of DHC-562 and DHC-725 using enantiopure starting material. %ee was determined by SFC / MS and is listed underneath each compound. - 7 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) FIG.34: Synthesis of (S)-DHC-286, DHC-781, and the racemic DHC-562, DHC-800. The listed %ee for DHC-781 was determined by SFC / MS. FIG.35: Synthesis of prodegrader DHC-749. FIG.36: Synthesis of prodegrader DHC-608. FIG.37: Synthesis of prodegrader BTK-targeting PROTAC DHC-753. FIG.38: Synthesis of aspartimide based methyl ester prodegrader DHC-788. FIG.39: Synthesis of aspartimide-based analog of DHC-286. FIG.40: Synthesis of aspartimide based prodegrader DHC-795. FIG.41: Synthesis of DHC-585. FIG.42: Synthesis of DHC-683. DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement "about X to Y" has the same meaning as "about X to about Y," unless indicated otherwise. Likewise, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z," unless indicated otherwise. In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B." In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information - 8 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Description Proteolysis Targeting Chimeras (PROTACs) and immunomodulatory imide drugs (IMiDs) targeting CRBN all feature the conserved glutarimide ring (FIGs.1-2). Thalidomide was among the first compounds identified to bind and interact with the E3 ligase CRBN, thus many IMiDs and PROTACs contain its phthalimide or related isoindoline substructures. Additionally, novel CRBN binding modalities that diverge from the traditional thalidomide analogs have emerged, exemplified by the IMiDs CC-122 and CFT7455. PROTACs demonstrated greater structural diversity from the traditional phthalimide substructure, leading to enhanced stability and reduced off-target interactions. Fewer IMiD scaffolds have been developed, likely due to the distinct mechanisms of action and binding modes of IMiDs versus PROTACs, with IMiDs being more sensitive towards structural modifications. Interestingly, the glutarimide moiety of both IMiDs and PROTACs is conserved across all listed compounds. This underscores the critical binding role of the glutarimide to CRBN, consistent with the crystal structure or thalidomide. In the thalidomide:CRBN cocrystal structure, the two carbonyl groups and nitrogen of the glutarimide engage in strong interactions with the CRBN backbone. Limited modifications of the glutarimide moiety have been explored, except for ligands incorporating a dihydrouracil, yet all three key interactions remain unaltered. While thalidomide was serendipitously discovered as a CRBN ligand, the natural substrate for CRBN remains unknown. Without wishing to be bound by any theory, it has been proposed that C-terminal glutarimide moieties might arise from post-translational modifications, leading to ubiquitination and subsequent protein degradation. Thus, it has been hypothesized that glutarimides could function as natural occurring degrons involved protein regulation. Their studies demonstrated that glutarimides could form through intramolecular attack by the amide - 9 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) group of an asparagine or glutamine residue on the protein backbone, cleaving the protein in a manner analogous to inteins, leaving a glutarimide present at the C-terminus. To observe glutarimide formation and cleaved proteins, LCMS was employed and an in-vitro time-course experiment was conducted. However, glutarimide levels were found to be extremely low (<1%) at all pH’s tested and after 250 hours. In one aspect, the disclosure describes the use of IMiDs to optimize glutarimide cyclization and demonstrate rapid and efficient cyclization to form the glutarimide. By modifying IMiDs with an open-form glutarimide, equipotent degradation of target proteins has been achieved, as compared to the parent compounds containing the cyclic glutarimide. This “pro-degron” approach can be applied to other IMiDs and PROTACs, given their shared glutarimide moiety. Since the cyclization process is highly efficient and does not affect compound potency, the uncyclized glutarimide can serve as an alternative attachment point for release of unmodified degraders. As demonstrated herein, the pro-degrons can be attached to stimulus recognizing agents through the formation of N-acyl carbamates, whereas the cyclic glutarimide counterpart cannot. Furthermore, efficient cleavage and release of the pro- degron compounds occur following stimulus treatment. The developed pro-degron represents an attractive alternative for the attachment and delivery of CRBN-based degraders. In one aspect, the disclosure relates to the unexpected discovery that the acyclic glutarimide precursors of the disclosure readily undergo cyclization to form active cereblon degrader moieties. Thus, in one aspect, the disclosure demonstrates that acyclic glutarimide precursors of the disclosure, upon activation by demasking to form cereblon degraders comprising an intact glutarimide, can be achieved in situ, and this strategy is applicable to PROTACs, IMiDs, and / or DACs. The disclosures of U.S. Patent Application Publication No. US20190233433A1 are incorporated herein in their entireties by reference. Definitions The term "about" as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. - 10 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term “alkyl” as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “alkylene” or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, inter alia). In certain embodiments, the term may be regarded as a moiety derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g., - CH2-) different (e.g., -CH2CH2-) carbon atoms. The term “alkynyl” as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C^CH, -C^C(CH3), -C^C(CH2CH3), -CH2C^CH, -CH2C^C(CH3), and -CH2C^C(CH2CH3) - 11 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) among others. The term “amine” as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also includes ammonium ions as used herein. The term “amino group” as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. The term “antibody,” as used herein, refers to an immunoglobulin molecule, which specifically binds with an antigen. Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins. Antibodies are typically tetramers of immunoglobulin molecules. The antibodies in the present invention may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab)2, as well as single chain antibodies and humanized antibodies (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426). The term “antibody fragment” refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab’, F(ab’)2, and Fv fragments, linear antibodies, scFv antibodies, and multispecific antibodies formed from antibody fragments. An “antibody heavy chain,” as used herein, refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. An “antibody light chain,” as used herein, refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring - 12 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) conformations. ^ and ^ light chains refer to the two major antibody light chain isotypes. By the term “synthetic antibody” as used herein, is meant an antibody, which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage. The term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art. The term should also be construed to mean an antibody, which has been generated by the synthesis of an RNA molecule encoding the antibody. The RNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the RNA has been obtained by transcribing DNA (synthetic or cloned) or other technology, which is available and well known in the art. The term “antigen” or “Ag” as used herein is defined as a molecule that provokes an adaptive immune response. This immune response may involve either antibody production, or the activation of specific immunogenically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA or RNA. A skilled artisan will understand that any DNA or RNA, which comprises a nucleotide sequences or a partial nucleotide sequence encoding a protein that elicits an adaptive immune response therefore encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a biological fluid. The term “aralkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl - 13 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. The term “cell binding domain” and “antigen binding domain” are used herein to refer to any molecular structure or entity, naturally occurring or synthetically engineered, that has the capacity to specifically recognize and bind to a target molecule, such as an antigen on the surface of a cell or within a biological environment. Non-limiting examples include traditional immunoglobulin-based antibodies (e.g., monoclonal and polyclonal antibodies), Designed Ankyrin Repeat Proteins (DARPINs), aptamers, nanobodies (single-domain antibodies), and any other peptide, protein, or nucleic acid-based compositions engineered or selected for specific binding affinity and specificity to a target molecule. These binding domains may function as part of a larger molecule or independently. The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group. - 14 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) The term “cycloalkylene” or “cycloalkylenyl” as used herein refers to a bivalent saturated cycloalkyl radical (e.g., , , , , and , inter alia). In certain embodiments, the term may be regarded as a product of two hydrogen atoms from the corresponding cycloalkane (e.g., cyclobutyl) by hydrogen atoms from the same (e.g., ) different (e.g., and ) carbon atoms. “degrader” as to a chemical compound or moiety which to a target recruitment of an E3 ubiquitin ligase (e.g., cereblon). In certain embodiments, the “degrader” promotes ubiquitination and subsequent proteasomal degradation of the target protein, thereby reducing its cellular levels as part of a targeted protein degradation strategy. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. A disease or disorder is “ameliorated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced. As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- - 15 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) difluoropropyl, perfluorobutyl, and the like. The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), - 16 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. The term “heteroarylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein. The term “heteroarylene” or “heteroarylenyl” as used herein refers to a bivalent heteroaryl radical (e.g., 2,4-pyridylene). In certain embodiments, the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from one or more rings of a heteroaryl moiety, wherein the hydrogen atoms may be removed from the same or different rings, preferably the same ring. The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. A heterocycloalkyl can include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom can be optionally substituted. Representative heterocycloalkyl groups include, but are not limited, to the following exemplary groups: pyrrolidinyl, pyrazolinyl, - 17 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. The term heterocycloalkyl group can also be a C2 heterocycloalkyl, C2-C3 heterocycloalkyl, C2-C4 heterocycloalkyl, C2-C5heterocycloalkyl, C2-C6heterocycloalkyl, C2-C7heterocycloalkyl, C2-C8 heterocycloalkyl, C2-C9 heterocycloalkyl, C2-C10 heterocycloalkyl, C2-C11 heterocycloalkyl, and the like, up to and including a C2-145heterocycloalkyl. For example, a C2 heterocycloalkyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocycloalkyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, and the like. It is understood that a heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. The heterocycloalkyl group can be substituted or unsubstituted. The term “heterocycloalkylene” or “heterocycloalkylenyl” as used herein refers to a bivalent saturated cycloalkyl radical , and , inter alia). In certain embodiments, the of removal of two hydrogen atoms from the corresponding heterocycloalkane (e.g., piperidine) by removal of two hydrogen atoms from the same (e.g., ) different (e.g., and ) carbon atom(s) and / or heteroatom(s). The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic - 18 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. The term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term “hydrocarbyl” refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations. The term “leaving group” as used herein has the same meaning understood by those of ordinary skill in the art (Organic Chemistry, Fifth Edition by Marc Loudon; 2009, pages 98-100 and 1013) and refers to a group containing an atom that accepts an electron pair from - 19 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) one of its bonds which is broken during a nucleophilic addition reaction. In certain embodiments, the “leaving group” is a “good leaving group.” In certain embodiments, a “leaving group” is “good” where the displaced group is a weak base and / or the leaving group has a low energy barrier for displacement. Non-limiting examples of suitable “leaving groups” include halogens (e.g., F, Cl, Br, and I; preferably Cl, Br, or I), alkoxides, tosylate, mesylate, triflate, acetate, camphorsulfonate, and aryloxides. The term “linker” as used herein refers to an organic moiety that connects two parts of a compound (e.g., two small molecule drugs, or a small molecule drug and an antibody). The linker can be, in non-limiting examples, a direct bond, a single atom (e.g., -O-), a peptide, or a substituted or unsubstituted alkylene or heteroalkylene moiety (e.g., polyethylene glycol). One skilled in the art would be apprised of the common linkers suitable for use in antibody drug conjugates and methods of preparation thereof. The terms “masking group,” “protecting group,” and “blocking group” are used interchangeably herein to refer to the chemical modification or “blocking” of an integral functional group by attachment of a second moiety to disguise the chemical reactivity of the functional group and prevent it from reacting in an undesired manner during reactions at other sites in the molecule. Such modification is reversible, and allows subsequent conversion back to the original functional group by suitable treatment. In many cases, such masking formally interconverts structural functionality (e.g., a primary amine masked by acetylation becomes a substituted amide which can be later converted back to the primary amine by appropriate hydrolysis). In certain embodiments, the “masking group,” “protecting group,” or “blocking group” are selectively removed in response to stimuli (e.g., exposure to UV light, pH changes, and exposure to oxidants or reductants, inter alia). The term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. The term “organic group” as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- - 20 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C100)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted. The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic - 21 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. The term “phenylene” or “phenylenyl” as used herein refers to a bivalent phenyl - 22 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) radical (e.g., 1,4-phenylene). In certain embodiments, the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from a benzene moiety. The term “precursor” as used herein refers to a compound or moiety that participates in a chemical reaction to produce a desired compound or moiety. In certain embodiments, the desired compound or moiety possesses biological activity. In certain embodiments, the chemical reaction occurs spontaneously or requires stimulation. In one non-limiting embodiment, methyl 5-amino-5-oxopentanoate is a “precursor” to piperidine-2,6-dione, as the methyl 5-amino-5-oxopentanoate can undergo intramolecular [1,2]-carbonyl addition of the amide nitrogen to the methyl ester to form piperidine-2,6-dione. The term “room temperature” as used herein refers to a temperature of about 15 °C to 28 °C. The term “solvent” as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids. The term “specifically binds”, or “specifically binds”, or the like, means that a small molecule, an antibody, and / or antigen-binding fragment forms a complex with a target and / or an antigen that is relatively stable under physiological conditions. The specific bond can be characterized by an equilibrium dissociation constant (for example, a smaller KD denotes a firmer bond). Methods for determining whether two molecules specifically bind to each other are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term “substantially free of” can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term “substituted” as used herein in conjunction with a molecule or an organic - 23 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1- C100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. The terms “treat,” “treating” and “treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject. Compounds and Compositions In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or isotopologue thereof: , - 24 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) wherein: T is absent or selected from the group consisting of Ab and D; Ab, if present, is a cell and / or antigen binding domain, optionally wherein the cell and / or antigen binding domain is an antibody; D, if present, is a protein of interest-binding moiety; L is absent or each occurrence of L is independently a linker covalently conjugated to T and cDp; each occurrence of cDpis independently a cereblon degrader precursor of structure: , wherein each L, if covalently conjugated to cDpvia a covalent bond to ring A, -NH-, R1, or R2; l is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; m is 0 or 1; each occurrence of ring A is independently selected from the group consisting of optionally substituted C3-C20 heterocyclyl and optionally substituted C6-C10 aryl; each occurrence of R1is selected from the group consisting of H and a selectively cleavable protecting group; and each occurrence of R2is a leaving group. In certain embodiments, the compound of Formula (I) is a compound of Formula (Ia): . In certain embodiments, (I) is a compound of Formula (Ib): (Ib). In certain embodiments, the compound of Formula (I) is a compound of Formula (Ic): . In certain In certain embodiments, cDp is - - 56067759.3 Attorney Docket No.047162-7520WO1(02652) R1. isisis - 26 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) is is certain embodiments, one occurrence ofis - 27 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) embodiments, one occurrence of is certain embodiments, one occurrence ofL cDp is is In certain embodiments, In certain embodiments, ring A - 28 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) . In certain embodiments, ring embodiments, is . In certain embodiments, ring A embodiments, certain embodiments, ring A is certain embodiments, ring A embodiments, . In certain occurrence of R3is independently selected from the group consisting of H, halogen, CN, NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2- C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10 heteroaryl, ORA, N(RA)(RB), Si(RA)3, C(=O)ORA, C(=O)RA, C(=N-N(RA)(RB))RC, C(=O)N(RA)(RB), - 29 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) N(RA)S(=O)2N(RB)(RC). In certain embodiments, each occurrence of R4is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10aryl, optionally substituted C2-C10heteroaryl, Si(RA)3, C(=O)ORA, C(=O)RA, C(=N-N(RA)(RB))RC, C(=O)N(RA)(RB), S(=O)2N(RA)(RB), S(=O)2RA, and C N . from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1- C6heteroalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10heteroaryl. In certain embodiments, R3is NH2. In certain embodiments, R3is F. In certain embodiments, R3is CH3. In certain embodiments, R4is H. In certain embodiments, R4is CH3. In certain embodiments, R1is H. In certain embodiments, the selectively cleavable protecting group comprises a photocleavable moiety. In certain embodiments, the selectively cleavable protecting group comprises a pH-sensitive moiety. In certain embodiments, the selectively cleavable protecting group comprises a redox-sensitive moiety. In certain embodiments, the selectively cleavable protecting group comprises a thermally-sensitive moiety. In certain embodiments, the selectively cleavable protecting group comprises an oxygen-sensitive moiety (e.g., hypoxia- sensitive). In certain embodiments, the selectively cleavable protecting group comprises an electrochemically-sensitive moiety. In certain embodiments, the selectively cleavable protecting group comprises an enzymatically cleavable moiety. In certain embodiments, the enzymatically cleavable moiety comprises a cathepsin cleavable moiety. In certain embodiments, R1comprises an optionally substituted benzylcarboxymoiety. In certain embodiments, R1 comprises a hydrazone moiety ( ). In certain embodiments, R1 comprises a 1,2,4-trioxolane ). In certain embodiments, - 30 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) ). In certain embodiments, R1. In certain embodiments, R1is is of OH. In certain embodiments, R2is optionally substituted C1-C6alkoxy. In certain embodiments, R2is optionally substituted C3-C8 cycloalkoxy. In certain embodiments, R2is optionally substituted C2-C8heterocycloalkoxy. In certain embodiments, R2is optionally substituted C2-C8heteroaryloxy. In certain embodiments, R2is optionally substituted C6-C10 aryloxy. In certain embodiments, R2is optionally substituted C1-C6alkylamino. In certain embodiments, R2is optionally substituted C3-C8 cycloalkylamino. In certain embodiments, R2is optionally substituted C2-C8heterocycloalkylamino. In certain embodiments, R2is optionally substituted C2-C8 heteroarylamino. In certain embodiments, R2is optionally substituted C6-C10 arylamino. In certain embodiments, R2is optionally substituted C2-C8heteroaryl. In certain embodiments, R2is halogen. In certain embodiments, R2is OCH3. In certain embodiments, R2is OCH2CH3. In certain embodiments, R2is OC(CH3)3. In certain embodiments, R2is OCF3. In certain - 31 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) embodiments, R2is OCH2CF3. In certain embodiments, R2is OPh. In certain embodiments, R2is 4-nitro-phenoxy. In certain embodiments, R2is F. In certain embodiments, R2is Cl. In certain embodiments, R2is Br. In certain embodiments, R2is I. In certain embodiments, R2is imidazolyl. In certain embodiments, occurrence of L independently comprises o occurrences of L1, p occurrences of L2, and q instances of L3, wherein: each occurrence of L1is independently selected from the group consisting of optionally substituted C1-C6alkylenyl, optionally substituted C1-C6heteroalkylenyl, and optionally substituted C2-C6 alkenylenyl; each occurrence of L2is independently selected from the group consisting of - O-, -S-, and -N(RD)-; each occurrence of L3is independently selected from the group consisting of - C(=O)-, -S(=O)-, and -S(=O)2-; o, p, and q are each independently an integer ranging from 0 to 20; each occurrence of RDis independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl; and wherein L1, L2, and L3are selected such that no two occurrences of L1, L2, and L3are adjacent (i.e., no covalent bonds between two occurrences of L1, L2, or L3). In certain embodiments, the protein of interest-binding moiety targets a protein selected from the group consisting of 1KZF3, AKT (e.g., AKT1, AKT2, or AKT3), ALK, androgen receptor (AR), ARAF, AURORA-A, BCL2, BCL6, a BET protein (e.g., BRD2, BRD3, BRD4, BRD7, or BRD9), BTK, CBL-B, CDK (e.g., CDK2, CDK4, CDK6, CDK8, or CDK9), CDK4, CDK6, CK1alpha, EGFR, EP300, estrogen receptor (ER), EZH2, FAK, FKBP12, GSPT1, HPK1, HSP90, HTT, IKZF1, IRAK4, KRAS, LRRK2, Mcl-1, MDM2, mdm2, MEK (e.g., MEK1 or MEK2), METTL3, METTL14, PARP1, PBMR1, PD-1 / PD-L1, p300 / CBP, PRC2, PRMT5, RIPK2, SALL4, SGK-3, SF3B1, SMARCA2, SMARCA4, STING, STAT (e.g., STAT3 or STAT5), STAT6, Tau, TRIM24, Tyk2, ZFP91, ZFP98, ZNF276, ZNF653, ZNF692, ZNF827, and α-synuclein. In certain embodiments, the protein of interest-binding moiety comprises ABT-263, - 32 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Acalabrutinib, Afatinib, Alectinib, Alpelisib, AMG 510, Apalutamide, AZD5363, Bortezomib, Brigatinib, Capmatinib, Ceritinib, Copanlisib, Crizotinib, Dabrafenib, Dasatinib, Enzalutamide, Entrectinib, Erlotinib, Fulvestrant, Gefitinib, Gilteritinib, Ibrutinib, Imatinib, Ivosidenib, JQ1, Lapatinib, Lorlatinib, Nutlin-3, Nintedanib, Osimertinib, Palbociclib, Panobinostat, Ruxolitinib, Selpercatinib, Sorafenib, Sunitinib, SNS-032, Trametinib, Venetoclax, Vemurafenib, and Vorinostat, or derivative or analogue thereof. In certain embodiments, D . In certain embodiments, D is L to form . containing antibody. In certain embodiments, the antibody binds to a tumor-associated antigen or cell-surface receptor. In certain embodiments, the tumor associated antigen or cell-surface receptor is selected from the group consisting of AXL, B7-H4, CA125, CA19-9, CD19, CD20, CD22, CD30, CD33, CD38, CD40, CD44, CD52, CD56, CD70, CD74, CD79b, CD80, CD123, CD138, CD147, CD200, CD276 (B7-H3), CD319 (SLAMF7), CD324 (E-cadherin), CD366 (TIM-3), CEA (Carcinoembryonic Antigen), EGFR (Epidermal Growth Factor Receptor), EpCAM (Epithelial Cell Adhesion Molecule), FAP (Fibroblast Activation Protein), GD2, GD3, GPC3 (Glypican-3), HER2 (Human Epidermal Growth Factor Receptor 2), HER3, HER4, IGF-1R (Insulin-like Growth Factor 1 Receptor), IL-6R (Interleukin-6 Receptor), IL-13Rα2 (Interleukin-13 Receptor Alpha 2), L1CAM (L1 Cell Adhesion Molecule), Mesothelin, MET - 33 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) (Hepatocyte Growth Factor Receptor), MUC1, Nectin-4, PD-L1 (Programmed Death-Ligand 1), PSMA (Prostate-Specific Membrane Antigen), ROR1 (Receptor Tyrosine Kinase-Like Orphan Receptor 1), ROR2, TROP2, and VEGFR (Vascular Endothelial Growth Factor Receptor). In certain embodiments, each occurrence of optionally substituted C1-C6 alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C1-C6alkylenyl, optionally substituted C1-C6 heteroalkylenyl, optionally substituted C2-C6 alkenylenyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10heteroaryl is independently optionally substituted with one or more Ra. In certain embodiments, each occurrence of Rais independently selected from the group consisting of H, halogen, CN, NO2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2- C6alkynyl, C3-C8cycloalkyl, C2-C10heterocycloalkyl, C6-C10aryl, C2-C10heteroaryl,ORx, N(Rx)(Ry), Si(Rx)3, C(=O)ORx, C(=O)Rx, C(=N-N(Rx)(Ry))Rz, C(=O)N(Rx)(Ry), S(=O)2N(Rx)(Ry), S(=O)2Rx, C(=NRx)N(Ry)(Rz), N(Rx)C(=O)Ry, N(Rx)S(=O)2Ry, and N(Rx)S(=O)2N(Ry)(Rz). In certain embodiments, each occurrence of Rx, Ry, and Rzis independently selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, and C2-C10 heteroaryl. In certain embodiments, each occurrence of C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, or C2-C10 heteroaryl encompassed by Rais independently optionally substituted with one or more Rb. In certain embodiments, each occurrence of Rbis independently selected from the group consisting of H, halogen, CN, NO2, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6 alkynyl, C3-C8 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, C2-C10 heteroaryl, ORx, N(Rx)(Ry), Si(Rx)3, C(=O)ORx, C(=O)Rx, C(=N-N(Rx)(Ry))Rz, C(=O)N(Rx)(Ry), S(=O)2N(Rx)(Ry), S(=O)2Rx, C(=NRx)N(Ry)(Rz), N(Rx)C(=O)Ry, N(Rx)S(=O)2Ry, and N(Rx)S(=O)2N(Ry)(Rz). In certain embodiments, each occurrence of C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C10heterocycloalkyl, C6-C10aryl, or C2-C10heteroaryl encompassed by Rbis independently optionally substituted with one or more Rc. In certain embodiments, each occurrence of Rcis independently selected from the group consisting of H, halogen, CN, NO2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2- - 34 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) C6 alkynyl, C3-C8 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, C2-C10 heteroaryl, ORx, N(Rx)(Ry), Si(Rx)3, C(=O)ORx, C(=O)Rx, C(=N-N(Rx)(Ry))Rz, C(=O)N(Rx)(Ry), S(=O)2N(Rx)(Ry), S(=O)2Rx, C(=NRx)N(Ry)(Rz), N(Rx)C(=O)Ry, N(Rx)S(=O)2Ry, and N(Rx)S(=O)2N(Ry)(Rz). In certain embodiments, each occurrence of C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C10heterocycloalkyl, C6-C10aryl, or C2-C10heteroaryl encompassed by Rcis independently optionally substituted with one or more Rd. In certain embodiments, each occurrence of Rdis independently selected from the group consisting of H, halogen, CN, NO2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2- C6alkynyl, C3-C8cycloalkyl, C2-C10heterocycloalkyl, C6-C10aryl, C2-C10heteroaryl,ORx, N(Rx)(Ry), Si(Rx)3, C(=O)ORx, C(=O)Rx, C(=N-N(Rx)(Ry))Rz, C(=O)N(Rx)(Ry), S(=O)2N(Rx)(Ry), S(=O)2Rx, C(=NRx)N(Ry)(Rz), N(Rx)C(=O)Ry, N(Rx)S(=O)2Ry, and N(Rx)S(=O)2N(Ry)(Rz). In certain embodiments, each occurrence of C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, or C2-C10 heteroaryl encompassed by Rdis independently optionally substituted with one or more Re. In certain embodiments, each occurrence of Reis independently selected from the group consisting of H, halogen, CN, NO2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2- C6alkynyl, C3-C8cycloalkyl, C2-C10heterocycloalkyl, C6-C10aryl, C2-C10heteroaryl,ORx, N(Rx)(Ry), Si(Rx)3, C(=O)ORx, C(=O)Rx, C(=N-N(Rx)(Ry))Rz, C(=O)N(Rx)(Ry), S(=O)2N(Rx)(Ry), S(=O)2Rx, C(=NRx)N(Ry)(Rz), N(Rx)C(=O)Ry, N(Rx)S(=O)2Ry, and N(Rx)S(=O)2N(Ry)(Rz). In certain embodiments, each occurrence of C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, or C2-C10 heteroaryl encompassed by Reis independently optionally substituted with one or more Rf. In certain embodiments, each occurrence of Rfis independently selected from the group consisting of H, halogen, CN, NO2, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6 alkynyl, C3-C8 cycloalkyl, C2-C10 heterocycloalkyl, C6-C10 aryl, C2-C10 heteroaryl, ORx, N(Rx)(Ry), Si(Rx)3, C(=O)ORx, C(=O)Rx, C(=N-N(Rx)(Ry))Rz, C(=O)N(Rx)(Ry), S(=O)2N(Rx)(Ry), S(=O)2Rx, C(=NRx)N(Ry)(Rz), N(Rx)C(=O)Ry, N(Rx)S(=O)2Ry, and N(Rx)S(=O)2N(Ry)(Rz). In another aspect, the disclosure provides a pharmaceutical composition comprising at least one compound of the disclosure and at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises at least - 35 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) one additional therapeutically effective agent. The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. - 36 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as11C,18F,15O, and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent - 37 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t- butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC). Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective - 38 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. Methods In one aspect, the disclosure provides a method for inducing degradation of a target protein in a cell, the method comprising contacting the cell with a therapeutically effective amount of the compound of the disclosure or the pharmaceutical composition of the disclosure. In certain embodiments, target protein is at least one selected from the group consisting of 1KZF3, AKT (e.g., AKT1, AKT2, or AKT3), ALK, androgen receptor (AR), ARAF, AURORA-A, BCL2, BCL6, a BET protein (e.g., BRD2, BRD3, BRD4, BRD7, or BRD9), BTK, CBL-B, CDK (e.g., CDK2, CDK4, CDK6, CDK8, or CDK9), CDK4, CDK6, CK1alpha, EGFR, EP300, estrogen receptor (ER), EZH2, FAK, FKBP12, GSPT1, HPK1, HSP90, HTT, IKZF1, IRAK4, KRAS, LRRK2, Mcl-1, MDM2, mdm2, MEK (e.g., MEK1 or MEK2), METTL3, METTL14, PARP1, PBMR1, PD-1 / PD-L1, p300 / CBP, PRC2, PRMT5, RIPK2, SALL4, SGK-3, SF3B1, SMARCA2, SMARCA4, STING, STAT (e.g., STAT3 or STAT5), STAT6, Tau, TRIM24, Tyk2, ZFP91, ZFP98, ZNF276, ZNF653, ZNF692, ZNF827, and α-synuclein. In certain embodiments, the compound or composition is effective in degrading the target protein in the cell. In another aspect, the disclosure provides a method for treating, preventing, and / or ameliorating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of the disclosure or the pharmaceutical composition of the disclosure. In certain embodiments, the disease or disorder is cancer. In certain embodiments, the cancer is selected from the group consisting of squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non-Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; multiple myeloma, sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, - 39 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin’s disease, Wilms’ tumor, and teratocarcinomas. In certain embodiments, the cancer is at least one selected from the group consisting of T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML. In certain embodiments, the method further comprises exposing the compound or composition to a stimulus. In certain embodiments, the stimulus is at least one selected from the group consisting of light (e.g., UV light), a change in pH, a reducing agent, an oxidizing agent, a change in oxygen concentration, a temperature change, addition of a metal (e.g., Fe2+), and a change in electric potential. Administration / Dosage / Formulations In certain embodiments, the pharmaceutical compositions of the disclosure comprise an antibody-drug conjugate (ADC) or degrader-antibody conjugate (DAC). In certain embodiments, the ADCs or DACs of the disclosure administered parenterally (e.g., by intravenous infusion or subcutaneous injection). In certain embodiments, the ADCs or DACs of the disclosure are administered by a route of administration selected from the group consisting of intramuscular, intratumoral, intravenous, and intraperitoneal. In certain embodiments, a therapeutically effective amount of an ADC or DAC may be expressed as mg / kg of antibody or mg / m2of body surface area. Dosing schedules may include administration at intervals ranging from weekly to once every four weeks, optionally with loading doses followed by maintenance dosing. In certain embodiments, treatment may be administered in cycles (e.g., repeated every 2-6 weeks, inter alia). Dose selection may be guided by conventional methods including dose-escalation studies, determination of maximum tolerated dose, and therapeutic monitoring. In certain embodiments, ADCs or DACs of the disclosure are formulated as a lyophilized powder for reconstitution or as sterile liquid formulations (e.g., aqueous buffer solutions). In certain embodiments, formulations may include pharmaceutically acceptable excipients such as buffers (e.g., phosphate, citrate, - 40 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) histidine), tonicity agents (e.g., sodium chloride and mannitol), stabilizers (e.g., trehalose, sucrose, and one or more amino acids), and surfactants (e.g., polysorbate 20 and polysorbate 80). In certain embodiments, formulations are stored at refrigerated temperatures (e.g., 2-8 °C) and subjected to repeated freeze-thaw cycles. The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of the disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or disorder in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non- limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. - 41 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound. In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a - 42 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account. The compound(s) described herein for administration may be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, or reduce one or more - 43 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) symptoms of a disease or disorder in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to - 44 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their - 45 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage - 46 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein. Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects. Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled-release component” is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma - 47 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound or conjugate (e.g., ADC or DAC) described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of the disease or disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday - 48 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection. The compounds described herein can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, - 49 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein. EXAMPLES Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Materials and Methods Cell culture HEK293T cells stably expressing GSPT1HiBiT(293TGSPT1-HiBit) were provided by Halda Therapeutics™ and were cultured in DMEM (Gibco) supplemented with 10% FBS and 1% penicillin-streptomycin. H1299 cells expressing SALL4-ANanoLucand Firefly luciferase (H1299SALL4- NLuc) were used. K562 cells stabling expressing CK1αNanoLucand Firefly luciferase (K562CK1α-NLuc) were generated through lentiviral transduction. H1299SALL4-NLucand K562CK1α-NLucwere cultured in RPMI-1640 (Gibco) with 10% FBS and 1% penicillin- streptomycin. NAMALWA cells were purchased from ATCC and cultured in RPMI 1640 (Gibco) supplemented with 7.5% FBS, 4.5 g / L glucose, 1% penicillin- streptomycin, 200 mM L-glutamine, 10 mM HEPES pH 7.5, and 10 mM sodium pyruvate. TMD8 cells were cultured in RPMI 1640 (Gibco) supplemented with 10% FBS, 2 mM GlutaMAX™, 1% penicillin-streptomycin. All cells were kept at 37°C in a standard 5% CO2 incubator. Cell viability 293TGSPT1-HiBitand TMD8 cells were plated at 500 and 5000 cells, respectively, per well in 96-well plate 24 hours prior to treatment. Compounds were added at various - 50 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) concentrations through a 9- point dose-response. Cell viability was assessed with CellTiter- Glo 2.0 luminescent assay (Promega G9243). Luminescence was quantified using a Spark Cyto plate reader (Tecan). SALL4 and CK1α degradation H1299SALL4-NLucwere seeded in 96-well plates at 5,000 cells per well 24 hours before treatment. K562CK1α-NLucwere seeded in 96-well plates at 10,000 cells per well 24 hours before treatment. Compounds were added at various concentrations, and generally, a 9-point dose-response was performed and normalized to DMSO. Nano-Glo Dual-Luciferase Reporter Assay System (Promega N1650) was used to measure NanoLuc and Firefly luciferase levels according to the manufacturer’s protocol. Luminescence was quantified using a Spark Cyto plate reader (Tecan). GSPT1 degradation 293TGSPT1-HiBitwere seeded in 96-well plates at 5,000 cells per well 24 hours before treatment. Compounds were added at various concentrations, and generally, a 9-point dose- response was performed and normalized to DMSO. Nano-Glo HiBiT Lytic Detection System (Promega N3030) was used to measure GSPT1-HiBiT levels according to the manufacturer's protocol. Luminescence was quantified using a Spark Cyto plate reader (Tecan). PROTAC and IMiD treatment for immunoblotting experiments 293TGSPT1-HiBit, NAMAWLA and TMD8 cells were plated in 24-well plates at 1x106cells / mL. Cells were treated with DMSO vehicle and respective compounds (0.1% final) for 24-48 hours at 37˚C, 5% CO2. Immunoblotting and Antibodies Cells were treated with compounds at indicated concentrations for 24 hours. Cells were lysed in ice-cold RIPA buffer (25 mM Tris-HCl pH 7.6, 150 mMNaCl, 1% NP-40, 1% sodium deoxycholate) with 1x complete Protease Inhibitor cocktail (Roche 11697498001) and lysates were clarified at 4°C at 15,000 xg for 30 min. Protein levels were quantified using a Pierce BCA Protein Assay using BSA (Sigma) as a standard curve. Absorbance values at 560 nm were read on a Tecan Spark Cyto plate reader.20 µg of protein was separated using a 26-well Criterion TGX precast 4- 20% gradient midi gel. Following appropriate separation, proteins were transferred to a 0.45 µM PVDF membrane using Biorad’s Trans-Blot Turbo - 51 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Transfer system. Blots were blocked in 5% milk in Tris-buffered saline with Tween-20 (TBST; 20 mM Tris, 150 mM NaCl, 0.02 % Tween-20) for over an hour. Blots were then incubated in primary antibody overnight at 4˚C with mild rocking at the manufacturer’s indicated dilution in 5% milk in TBST. Blots were washed in TBST for 10 min thrice. After washing, blots were incubated with 1:5,000 – 1:10,000 of donkey anti-rabbit (GE Life Sciences; NA934) or sheep anti-mouse (GE Life Sciences; NA931). In 5% milk in TBST for one hour at room temperature with mild rocking. Blots were again washed in TBST for 10 min thrice. Membranes were imaged using Bio-Rad Image Lab software using ECL prime detection reagent (GE Healthcare, RPN2232 or ThermoScientific, 34095). Primary antibodies used were: anti-GSPT1 (Cell Signaling Technology; Cat. No.14980), anti-cereblon (Cell Signaling Technology; Cat. No.71810), anti-BTK (Cell Signaling Technology; Cat. No. 8547S), anti-B-actin (Cell Signaling Technology; Cat. No.4970), anti-GAPDH (Cell Signaling Technology; Cat. No.2118), and anti-Vinculin (Cell Signaling Technology; Cat. No.13901). Plasmid design CRBNMidi*was cloned into pOP5MP (Addgene #112612) with MBP removed and expressed with a N-terminal 6xHis-tag and HRV3C cleavage site. CRBNMidi*was designed with stabilizing mutations described in the art, except that T359 was not mutated. Recombinant expression in E. coli pOP5MP-HRV-CRBNMidi*was transformed into BL21(DE3) (New England Biolabs) and grown at 37˚C on LB-agar plates with 100 ug / mL of carbenicillin. Transformants were scraped into 100 mL of LB containing 100 ug / mL of carbenicillin, grown at 37 °C with 125 rpm shaking until OD600of 0.6.2L LB baffled flasks with 100 ug / mL of carbenicillin and 0.005% Antifoam 204 (Millipore Sigma) was inoculated with 50 mL of starter culture. The 2L cultures were grown at 37 °C with 125 rpm shaking until OD600of 0.6.50 µM zinc sulfate was added immediately prior to induction with 0.5 mM IPTG. Cultures were shaken at 18 °C overnight. The following day, cultures were centrifuged at 4000 rcf for 30 min (JLA-9.1000 rotor in Avanti J-25), and pellets were frozen at -80 °C. CRBNMidi*purification Pellets for CRBNMidi*were resuspended in 50 mL lysis buffer (50 mM HEPES, 300 mM NaCl, 1 mM TCEP, 20 mM imidazole, pH 7.5, 0.5 mg / mL lysozyme from chicken egg - 52 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) white (GoldBio), and cOmplete EDTA-free tablet (Roche) using a Dounce homogenizer and incubated on ice for 30 min. The lysate was sonicated (Branson 450) in 4 x 1-minute intervals at 50% duty cycle with 3 minute rests in between. Lysate was centrifuged at 18000 rpm for 50 min at 4 °C (JA-20 Avanti J- 25), and supernatant was filtered with a 0.45 µm PVDF syringe filter (Millipore Sigma). The clarified lysate was purified using a 5 mL HisTrap HP column on an AKTA Pure 25 (Cytiva). The HisTrap column was pre-equilibrated with 5 CV of binding buffer (50 mM HEPES, 300 mM NaCl, 1 mM TCEP, 20 mM imidazole, pH 7.5), sample was injected, column was washed with 15 CV of binding buffer, and protein was eluted with a 10 CV gradient of 0-100% elution buffer (50 mM HEPES, 300 mM NaCl, 1 mM TCEP, 300 mM imidazole, pH 7.5). Fractions containing His-MBP-CRBNMidi*were pooled, mixed with His-NT*-HRV3C (Addgene #162795), and dialyzed overnight at 4 °C into 25 mM HEPES, 500 mM NaCl, 0.5 mM TCEP, pH 7.5. Cleaved CRBNMidi*was isolated by passing the cleavage reaction over HisTrap 5 mL and collecting the flow through. Fractions containing CRBNMidi*were concentrated using a 15 mL Amicon Ultra centrifugal filter 10 kDa MWCO (Millipore Sigma) and injected onto a HiLoad S7516 / 600 (Cytiva) pre- equilibrated with 25 mM HEPES, 500 mM NaCl, 0.5 mM TCEP, pH 7.5. Fractions containing CRBNMidi*were concentrated to 3 mg / mL and flash frozen with liquid nitrogen until further use. ITC measurements Titrations were performed at 25 °C with an Affinity ITC (TA Instruments). Small molecules and CRBNMidi*were prepared in 25 mM HEPES, 500 mM NaCl, 0.5 mM TCEP, pH 7.5 + 4% DMSO. Syringe stir rate was set to 125 rpm, and injection delay was set to 120- 300 sec.350 µL of 20 µM of CRBNMidi*was loaded into the active cell, and 100-200 µM IMiD was titrated (20-30 injections of 2.5 µL). Background heat was subtracted, and data was fit to an independent binding model using NanoAnalyze (TA Instruments). Intracellular accumulation HEK 293T WT cells were treated with DHC-287 (5 µM) for 0, 2, 4, 8, 24, and 48 hours. Cell pellets were collected, washed 2x with PBS and the residual PBS was aspirated. Cell pellets were weighed (>30 mg) and analyzed by Drumetix Laboratories (Greensboro, NC). In vitro cyclization - 53 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) The prodegraders were incubated in 20 mM potassium phosphate buffer (8% acetonitrile, 1.25% DMSO, pH 7.4) at a final concentration of 250 µM. Samples were shaken at 37 °C, and LCMS measurements were taken for each sample at t = 1 h, 2 h, 5h, and 24 h. Waters SQD2, reverse- phase C18 column (1.7 µM particle size, 2.1 x 50 mm), 4-minute gradient, (0-0.5 min, 5% 0.1% formic acid / acetonitrile in 0.1% formic acid / water; 0.5−2.5 min, 5−95%; 2.5−3.5 min, 95%; 3.50−3.51 min, 95-5%; 3.50−3.51 min, 95-5%; 3.51−4.0 min, 5%. For each compound, the peak areas (at 254 nm) for the original compound, the cyclized product (DHC-286) and the hydrolyzed product (DHC-289), were integrated and used to calculate the percent of released product relative to starting material. A standard curve of DHC-286 was generated for quantification of the free drug. UV-light cleavage Four vials (A, B, C, D) were prepared with DHC-585 (5 µL, 20 µM stock in DMSO) diluted in 20 mM ammonium acetate buffer (355 µL) and acetonitrile (40 µL) at pH 7.4 (final concentration 250 µM). The samples were place in an analytikjena UV crosslinker (CL- 1000L Model). Vial A was not exposed to UV light, vial B was exposed to 365 UV light for 0.5 minutes, vial C was exposed to 365 UV light for 1 minute, vial D was exposed to 365 UV light for 4 minutes. The samples were then injected onto the LCMS, Waters SQD2, reverse- phase C18 column (1.7 µM particle size, 2.1 x 50 mm), 4-minute gradient, (0-0.5 min, 5% 0.1% formic acid / acetonitrile in 0.1% formic acid / water; 0.5−2.5 min, 5−95%; 2.5−3.5 min, 95%; 3.50−3.51 min, 95-5%; 3.50−3.51 min, 95-5%; 3.51−4.0 min, 5%. The peak areas (at 254 nm) of DHC-585 and the released product (DHC- 287) were integrated and used to calculate the percent of released product relative to starting material. Cathepsin B cleavage Human cathepsin B, (His Tag), was obtained from Acro Biosystems (Cat No. CTB- H522). Cathepsin B (2.5 µL, 11.7 µM stock) was activated by incubation with 10 µL of 30 mM DTT / 15 mM EDTA (pH 5) for 30 minutes at 37 °C. The mixture was then diluted with 285 µL of 25 mM sodium acetate / 1 mM EDTA (pH 5) (final concentration 100 nM). DHC- 683 (2.5 µL, 5 mM stock) (final concentration 40 µM) was added to the cathepsin B solution and 40 µL of the mixture were taken at 0, 30, 60 and 150 minutes and injected directly onto the LCMS. Waters SQD2, reverse- phase C4 column (300Å, 1.7 µM particle size, 2.1 x 100 mm), 9-minute gradient, (0-1.0 min, 5- 20% 0.1% formic acid / acetonitrile in 0.1% formic acid / water; 1.0−6.0 min, 20−70%; 6.0−7.0 min, 70%, 7.00−7.01 min, 70-5%; 7.01−9.0 min, - 54 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 5%.). The peak areas of DHC-683, DHC-683 + DTT (from addition to maleimide) and the released product (DHC-282) were integrated and used to calculate the percent of released product relative to starting material. Chemistry Unless otherwise indicated, common reagents or starting materials were obtained from a commercial source and used without further purification. Flash column chromatography was performed using a Biotage Isolera One purification machine equipped with pre-packed SiliCycle SiliaSep™ PREMIUM flash chromatography cartridges (25 µm, 90 Å). Preparative and analytical thin-layer chromatography (PTLC and TLC) was carried out on Merck silica gel plates with a QF- 254 indicator and visualized by using UV light or KMnO4 staining.1H and13C nuclear magnetic resonance (NMR) spectra were recorded on an Agilent DD2500 (500 MHz1H; 125 MHz13C), Agilent DD2600 (600 MHz1H; 150 MHz13C), or Agilent DD2400 (400 MHz1H; 100 MHz13C) spectrometers at room temperature. NMR chemical shifts are reported in parts per million (ppm) relative to the residual solvent peaks, i.e., CDCl3 (1H NMR: δ = 7.26 ppm;13C NMR: δ = 77.16 ppm), CD2Cl2 (1H NMR: δ = 5.32 ppm;13C NMR: δ = 53.84 ppm) or DMSO-d6 (1H NMR: δ = 2.50 ppm;13C NMR: δ = 39.5 ppm). NMR data are reported as follows: chemical shift, multiplicity, (s: singlet, d: doublet, br: broad signal), coupling constants (J, Hz), and integration. High- Resolution Mass Spectrometric (HRMS) was performed using electrospray ionization (ESI) in the positive ionization mode employing a Shimadzu Scientific Instruments QToF 9030 LC–MS system, equipped with a Nexera LC-40D xs UHPLC, consisting of a CBM-40 Lite system controller, a DGU-405 degasser unit, two LC-40D XS UHPLC pumps, a SIL-40C XS autosampler, and a column oven CTO-40S. UV data was collected with a Shimadzu Nexera HPLC / UHPLC photodiode array detector SPD M- 40 in the range of 190–800 nm. Mass spectra were subsequently recorded with the quadrupole time-of-flight (QToF) 9030 mass spectrometer. HRMS data are presented as a mass-to-charge ratio (m / z). Chiral SFC analyses were performed with a Waters Heartcutting 2D UPLC / SFC-MS. Column: Chiralpak IB-N, 4.6 × 150 mm, 3 µm; mobile phase: A = CO2, B = 90:10 MeOH:water 1% formic acid (FA); temperature: 40 °C; flow rate: 3.0 mL / min; gradient: 0.0 – 4.0 min = 0 – 50% B, 4.0 – 5.0 min = 50% B, 5.0 – 6.0 = 50 – 0% B. DMSO = Dimethyl Sulfoxide; DCM = Dichloromethane; DMF = Dimethylformamide; EtOAc = Ethyl Acetate; MeOH = Methanol; TFA = Trifluoroacetic acid; TBSCl = tert-Butyldimethylsilyl chloride; Et2O = Diethyl ether; - 55 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) MeCN = Acetonitrile; NBS = N-bromosuccinimide; AIBN = Azobisisobutyronitrile; DIPEA = diisopropylethylamine. Compound Synthesis tert-Butyl 2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxyacetate (Compound 1) To a solution of 3- 2,6-dione (500 mg, 1.92 mmol) and tert- in DMF (10 mL) was added KHCO3 (577 mg, 5.76 mmol) at room temperature. The reaction mixture was stirred for 24h at room temperature before being diluted with EtOAc, washed with a mixture of brine: water (1:1, 4x), dried over anhydrous Na2SO4, and concentrated under vacuum. Crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 336 mg (47% yield) of the product (1).1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 7.03 –6.97 (m, 1H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.73 (s, 2H), 4.40 – 4.17 (m, 2H), 2.92 – 2.80 (m, 1H), 2.55 (d, J = 17.5 Hz, 1H), 2.37 – 2.28 (m, 1H), 1.99 – 1.89 (m, 1H), 1.39 (s, 9H).13C NMR (151 MHz, DMSO-d6) δ 173.35, 171.59, 168.21, 167.92, 161.25, 144.72, 125.16, 124.76, 115.71, 109.32, 82.06, 65.64, 51.96, 47.42, 31.67, 28.15, 22.93. HRMS (ESI); m / z [M+1]+; Calcd. C19H23N2O6, 375.1478. Found 375.1540. 2-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxy-N-[[2- (trifluoromethyl)phenyl]methyl] acetamide (DHC-286) O O CF3NH O A solution of isoindolin-5- yl]oxyacetate (1) (765.0 mg, 2.04 mmol) in a mixture of DCM:TFA (4:2 mL) was stirred at room temperature for 2h. The solvent was removed in vacuo and the crude product was dried under high vacuum for 1h and used in the next step without any further purification (2). To a stirred suspension of 5-amino-5- oxo-4-[1-oxo-5- [2-oxo-2-[[ 2-(trifluoromethyl)phenyl] methylamino] ethoxy] isoindolin-2- yl]pentanoic acid (2) (650 mg, 2.04 mmol) in anhydrous - 56 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) DMF (10 mL) was added [2-(trifluoromethyl)phenyl]methanamine (715 mg, 4.08 mmol), HATU (1.165 g, 3.06 mmol), and DIPEA (1.05 mL, 6.13 mmol) at room temperature. After stirring for 12h at room temperature, water was added to the reaction mixture to precipitate the product. The solid was collected by vacuum filtration and the filtrate was diluted with EtOAc, washed with water:brine (1:1) 4x, and the organic layer was dried and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane). The purified material and collected solid was combined to give 703 mg (72% yield) of the product (DHC-286).1H NMR (400 MHz, DMSO- d6) δ 10.96 (s, 1H), 8.78 (t, J = 6.1 Hz, 1H), 7.66 (dd, J = 8.1 7.57 (t, J = 7.6 Hz, 1H), 7.46 – 7.35 (m, 2H), 7.17 (s, 1H), 7.10 (d, J = 8.7 , J = 13.3, 5.1 Hz, 1H), 4.71 (s, 2H), 4.49 (d, J = 5.9 Hz, 2H), 4.37 (d, J = 17.3 Hz, 1H), 4.24 (d, J = 17.3 Hz, 1H), 2.95 –2.81 (m, 1H), 2.56 (d, J = 17.1 Hz, 1H), 2.35 (qd, J = 13.7, 4.9 Hz, 1H), 1.99 – 1.92 (m, 1H).13C NMR (151 MHz, DMSO-d6) δ 173.35, 171.59, 168.23, 161.25, 144.76, 137.69, 133.03, 128.65, 127.80, 126.67 (q, J = 30 Hz), 126.15 (q, J = 6 Hz), 125.27, 124.89 (q, J = 274 Hz), 124.82, 123.98, 116.21, 109.43, 67.57, 51.97, 47.45, 38.80, 31.67, 22.94. HRMS (ESI); m / z [M+1]+; Calcd. C23H21F3N3O5, 476.1355. Found 476.1419. methyl 4-[tert-butyl(dimethyl)silyl]oxy-2-methyl-benzoate (Compound 3) O To a solution of methyl 4- (500 mg, 3.01 mmol) in dry DMF (20 mL) were added imidazole (512 mg, 7.52 mmol) and TBSCl (544 mg, 0.0361 mmol) under an argon atmosphere at 0°C. The reaction was stirred for 2h at room temperature, then quenched with aqueous saturated NH4Cl solution and diluted with Et2O. The aqueous layer was extracted 3x with Et2O and the organic layers were combined, dried, and concentrated. The crude product was purified via column chromatography (20% EtOAc in Hexanes) to give 806 mg (95% yield) of product (3).1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J = 8.0, 2.4 Hz, 1H), 7.31 – 7.12 (m, 2H), 4.42 (d, J = 2.4 Hz, 3H), 3.13 (d, J = 2.4 Hz, 3H), 1.55 (d, J = 2.3 Hz, 9H), 0.79 (d, J = 2.6 Hz, 6H).13C NMR (151 MHz, CDCl3) δ 167.97, 159.29, 143.35, 133.14, 123.46, 122.72, 117.50, 51.89, 25.97 (q, J = 26.0 Hz), 22.47,18.59, -4.00 (q, J = 34.1 Hz). HRMS (ESI); m / z [M+1]+; Calcd. C15H25O3Si, 281.1495.Found 281.1154. - 57 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) methyl 2-(bromomethyl)-4-[tert-butyl(dimethyl)silyl]oxy-benzoate (Compound 4) To a round bottom flask 6-methyl-benzoate (3) (1g, 3.57 mmol) in CCl4 (20 mL) 3.74 mmol) and AIBN (58.6 mg, 0.357 mmol). The solution was warmed to 80°C and stirred for 12h. The insoluble material was filtered out and washed with EtOAc. The filtrate was concentrated in vacuo and purified via flash chromatography (EtOAc 10% in Hexane) to give 990 mg (77% yield) of product (4).1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.7, 2.2 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.77 (dt, J = 8.6, 2.5 Hz, 1H), 4.90 (d, J = 2.3 Hz, 2H), 3.91 – 3.85 (m, 3H), 0.99 – 0.93 (m, 9H), 0.22 (d, J = 1.3 Hz, 6H).13C NMR (151 MHz, CDCl3) δ 166.58, 159.29, 141.63, 133.48, 123.19, 121.51, 119.69, 51.97, 31.68, 25.55, 18.21, -4.39. HRMS (ESI); m / z [M+1]+; Calcd. C15H24BrO3Si, 359.0510. Found 360.1585. tert-Butyl (S)-5-amino-4-(5-hydroxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (Compound 5) To a mixture of [tert-butyl(dimethyl)silyl]oxy- benzoate (4) (400 mg, 1.11 mmol) and tert-butyl 4,5-diamino-5-oxo-pentanoate; hydrochloride (399 mg, 1.67 mmol) in MeCN (10 mL) was added N-ethyl-N-isopropyl- propan-2-amine (0.582 mL, 3.34 mmol) at room temperature. The mixture was stirred at 80°C for 16h. The reaction mixture was then cooled to room temperature and concentrated to give a crude oil. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane). Any recovered TBS protected product was collected and exposed to 1M TBAF in THF 1 mL : 4 mL DCM for 1h and purified in the same manner. The collected fractions from the two purifications produced 320 mg (86% yield) of product (5).1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.11 (s, 1H), 6.90 (s, 1H), 6.86 – 6.79 (m, 1H), 4.69 – 4.59 (m, 1H), 4.46 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, - 58 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 1H), 2.09 (d, J = 11.2 Hz, 3H), 1.92 (t, J = 9.6 Hz, 1H), 1.31 (s, 9H).13C NMR (151 MHz, DMSO-d6) δ 172.51, 171.84, 168.38, 161.19, 145.20, 124.76, 123.30, 115.86, 110.02, 80.18, 53.58, 46.91, 32.16, 28.08, 25.27. HRMS (ESI); m / z [M+1]+; Calcd. C17H23N2O5, 335.1529. Found 335.1602. Chiral SFC / MS: 96% ee. tert-Butyl (S)-5-amino-4-[5-(2-methoxy-2-oxo-ethoxy)-1-oxo-isoindolin-2-yl]-5-oxo- pentanoate (Compound 6) (DHC-282) To a solution of 2-yl)-5-oxo- pentanoate (5) (220 mg, (101 mg, 0.658 mmol) in DMF (5 mL) was added KHCO3 (198 mg, 1.97 mmol) at room temperature. The reaction mixture was stirred for 24h at room temperature. The reaction mixture was then diluted with EtOAc, washed with a mixture of brine:water (1:1, 4x), dried, and concentrated under vacuum. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 150 mg (56% yield) of the product (6) (DHC-282).1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.13 (d, J = 2.7 Hz, 2H), 7.00 (dd, J = 8.4, 2.3 Hz, 1H), 4.87 (s, 2H), 4.69 – 4.61 (m, 1H), 4.55 – 4.31 (m, 2H), 3.67 (s, 3H), 2.15 – 2.04 (m, 3H), 1.98 – 1.86 (m, 1H), 1.29 (s, 9H).13C NMR (151 MHz, DMSO-d6) δ 171.95, 171.38, 168.90, 167.56, 160.53, 144.59, 125.09, 124.22, 115.06, 108.87, 79.75, 64.78, 53.33, 51.91, 46.71, 31.77, 27.66, 24.86. HRMS (ESI); m / z [M+1]+; Calcd. C20H27N2O7, 407.1740. Found 407.1813. Chiral SFC / MS: 96% ee. tert-Butyl (S)-5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2- (trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]pentanoate (DHC-287) To a mixture -1-oxo-isoindolin- 2-yl]-5-oxo- pentanoate (6) (DHC-282)(220 mg, 0.541 mmol) in MeOH (10 mL) was added 1M KOH (2.5mL) at room temperature. The reaction mixture was stirred at room temperature - 59 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) for 15 min before being diluted with water and washed with EtOAc (2x). The pH of the aqueous phase was acidified (pH~1) by the addition of 1N aqueous HCl solution, then extracted with EtOAc (3x). The organic layers were combined and concentrated and the crude product (7) was used in the next steps without further purification. To a stirred suspension of 2-[2-(4-tert-butoxy-1-carbamoyl-4-oxo- butyl)-1-oxo-isoindolin-5-yl]oxyacetic acid (7) (300 mg, 0.765 mmol) in anhydrous DMF (5.0 mL) was added [2- (trifluoromethyl)phenyl]methanamine (268 mg, 1.53 mmol), HATU (436 mg, 1.15 mmol), and DIPEA (0.654 mL, 3.82 mmol) at room temperature. After stirring for 12h at room temperature, the reaction mixture was diluted with EtOAc, washed with water:brine (1:1) 4x, the organic layer was dried and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 320 mg (76% yield) of the product (DHC-287).1H NMR (600 MHz, DMSO-d6) δ 8.79 (t, J = 5.9 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.68 – 7.58 (m, 2H), 7.56 (s, 1H), 7.49 – 7.41 (m, 2H), 7.22 – 7.13 (m, 2H), 7.11 (dd, J = 8.4, 2.2 Hz, 1H), 4.72 (s, 2H), 4.72 – 4.68 (m, 1H), 4.59 – 4.51 (m, 3H), 4.40 (d, J = 17.5 Hz, 1H), 2.18 –2.10 (m, 3H), 1.98 (qd, J = 10.7, 4.8 Hz, 1H), 1.33 (s, 9H).13C NMR (151 MHz, DMSO-d6) δ 172.40, 171.81, 168.23, 168.04, 161.09, 145.01, 137.70, 133.03, 128.69, 127.79, 126.47 (q, J = 30 Hz), 126.15 (q, J = 6 Hz), 125.50, 124.89 (q, J = 274 Hz), 124.67, 115.94, 109.37, 80.21, 67.56, 53.76, 47.17, 38.83, 32.23, 28.11, 25.33. HRMS methyl 2-[[5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2(trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]pentanoyl]amino]acetate (DHC-291) A solution isoindolin-5- yl]oxyacetate (7.0 mg, 0.0127 mmol) in DCM (2 mL) was added TFA (1 mL) and was stirred at room temperature for 2h. Solvent was removed in vacuo and crude product was dried under high vacuum for 1h and used in the next step without any further purification. To a stirred suspension of the crude 5-amino-5- oxo-4-[1-oxo-5-[2-oxo-2-[[2- (trifluoromethyl)phenyl]methylamino]ethoxy]isoindolin-2-yl]pentanoic acid (6.30 mg, 0.0128 mmol) in dry DMF (0.5 mL) was added methyl 2-aminoacetate (1.37 mg, 0.0153 mmol), HATU (5.83 mg, 0.0153 mmol), and DIPEA (0.0109 mL, 0.638 mmol) at room temperature. After stirring for 12h at room temperature, the reaction mixture was diluted with - 60 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) EtOAc, washed with water:brine (1:1) 4x, the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified via PTLC (5% MeOH in DCM) to give 1.40 mg (19.4% yield) of the product (DHC-291).1H NMR (600 MHz, DMSO-d6 ) δ 8.77 (t, J = 6.1 Hz, 1H), 8.27 (t, J = 5.9 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.54 (s, 1H), 7.48 –7.39 (m, 2H), 7.19 (d, J = 2.2 Hz, 1H), 7.13 (s, 1H), 7.08 (dd, J = 8.5, 2.2 Hz, 1H), 4.70 (s, 2H), 4.66 (dd, J = 10.5, 4.7 Hz, 1H), 4.59 (d, J = 17.5 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.39 (d, J = 17.5 Hz, 1H), 3.73 (d, J = 5.9 Hz, 2H), 3.57 (s, 3H), 2.17 – 2.02 (m, 3H), 1.95 (ddd, J = 16.3, 12.3, 8.4 Hz, 1H).13C NMR (151 MHz, DMSO-d6 ) δ 172.68, 172.17, 170.82, 168.24, 168.08, 161.08, 145.05, 137.69, 133.05, 128.68, 127.81, 126.46 (q, J = 30 Hz), 126.15 (q, J = 6 Hz), 125.56, 124.89 (q, J = 274 Hz), 124.66, 115.92, 109.36, 67.54, 54.05, 52.08, 47.25, 40.93, 38.81, 32.39, 26.16. HRMS (ESI); m / z [M+1]+; Calcd. C26H28F3N4O7, 565.1832. Found 565.1890. (S)-5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2- (trifluoromethyl)phenyl]methylamino]ethoxy] isoindolin-2-yl]pentanoic acid (DHC-289) A solution of [[2- (trifluoromethyl)phenyl] methylamino]ethoxy]isoindolin-2-yl]pentanoate (DHC-287) (100 mg, 0.182 mmol) in DCM (2 mL) was added TFA (1 mL) and stirred at room temperature for 2h. Solvent was removed in vacuo and crude product was dried under high vacuum and used in the next step without any further purification. HRMS (ESI); m / z [M+1]+; Calcd. C23H23F3N3O6, 494.1461. Found 494.1527. Dimethyl (S)-2-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl]methylamino]ethoxy] isoindolin-2-yl]pentanedioate (DHC-562) To a solution of [[2- (trifluoromethyl)phenyl] methylamino]ethoxy]isoindolin-2-yl]pentanoic acid (DHC-289) - 61 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) (15.0 mg, 0.0304 mmol) in methanol (0.25 mL) was added thionyl chloride (0.00887 mL, 0.122 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2h. The reaction was then quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc (3x), dried and concentrated. The resulting solid was then purified by PTLC (5% MeOH in DCM) to yield 9.60 mg (60% yield) of product (DHC-562).1H NMR (600 MHz, DMSO-d6) δ 8.80 (t, J = 6.1 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67 – 7.55 (m, 3H), 7.49 – 7.40 (m, 2H), 7.21 – 7.16 (m, 2H), 7.11 (dd, J = 8.5, 2.2 Hz, 1H), 4.75 – 4.69 (m, 3H), 4.60 – 4.51 (m, 3H), 4.40 (d, J = 17.4 Hz, 1H), 3.51 (d, J = 1.5 Hz, 3H), 2.31 – 2.22 (m, 2H), 2.22 – 2.15 (m, 1H), 2.07 – 1.99 (m, 1H).13C NMR (151 MHz, DMSO-d6) δ 172.97, 172.35, 168.24, 168.08, 161.10, 145.00, 137.69, 133.03, 128.67, 127.79, 126.47 (q, J = 30 Hz), 126.15 (q, J = 6 Hz), 125.42, 124.88 (q, J = 274 Hz), 124.69, 115.93, 109.37, 67.55, 53.68, 51.77, 47.16, 38.83, 30.81, 25.34. HRMS (ESI); m / z [M+1]+; Calcd. C24H25F3N3O6, 508.1617. Found 508.1690. Chiral SFC / MS: 96% ee. phenyl 5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]pentanoate (DHC-563) To a solution (trifluoromethyl)phenyl] methylamino] ethoxy]isoindolin-2-yl]pentanoic acid (DHC-289) (7.00 mg, 0.0142 mmol) in ethyl acetate (0.5 mL) was added phenyl carbonochloridate (2.44mg, 0.0156 mmol), TEA (0.00218 mL, 0.0156 mmol), and DMAP (0.173 mg, 0.00142 mmol). The reaction was stirred at r.t. overnight then diluted with saturated aqueous NaHCO3 solution, extracted with EtOAc, filtered, and concentrated. Crude material was purified by PTLC (DCM:MeOH:NH4OH, 97:2.5:0.5) to give 2.70 mg (33% yield) of product (DHC- 563).1H NMR (600 MHz, DMSO-d6) δ 8.78 (t, J = 6.0 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 16.5, 8.7 Hz, 2H), 7.45 – 7.39 (m, 2H), 7.37 – 7.32 (m, 2H), 7.23 – 7.16 (m, 3H), 7.10 (dd, J = 8.5, 2.3 Hz, 1H), 7.03 (d, J = 7.9 Hz, 2H), 4.79 (dd, J = 10.5, 5.1 Hz, 1H), 4.71 (s, 2H), 4.56 (d, J = 17.5 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.44 (d, J = 17.5 Hz, 1H), 2.56 – 2.49 (m, 2H), 2.27 (dq, J = 13.7, 6.9 Hz, 1H), 2.16 – 2.06 (m, 1H).13C NMR (151 MHz, DMSO-d6) δ 172.24, 171.44, 168.24, 168.16, 161.15, 150.88, 145.05, 137.69, 133.04, 129.81, 128.68, 127.79, 126.46 (q, J = 30 Hz), 126.18, 126.14 (q, J = 6 Hz), - 62 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 125.43, 124.89 (q, J = 274 Hz), 124.76, 122.22, 115.95, 109.43, 67.56, 53.58, 47.17, 38.83, 31.02, 25.13. HRMS (ESI); m / z [M+1]+; Calcd. C29H27F3N3O6, 570.1774. Found 570.1836. ethyl 5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2- (trifluoromethyl)phenyl]methylamino]ethoxy] isoindolin-2-yl]pentanoate (DHC-564) To a crude (trifluoromethyl) acid (DHC-289) (5.0 mg, 0.0101 mmol) was added thionyl chloride (0.00296 mL, 0.0405 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was then quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc (3x), dried and concentrated. The resulting solid was then purified by PTLC (5% MeOH in DCM) to yield 3.60 mg (68% yield) of product (DHC-564).1H NMR (600 MHz, DMSO-d6) δ 8.77 (t, J = 6.1 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.63 – 7.53 (m, 3H), 7.46 – 7.38 (m, 2H), 7.19 – 7.14 (m, 2H), 7.11 – 7.06 (m, 1H), 4.72 – 4.66 (m, 3H), 4.57 –4.48 (m, 3H), 4.37 (d, J = 17.4 Hz, 1H), 3.99 – 3.86 (m, 2H), 2.22 (p, J = 7.8 Hz, 2H), 2.18 – 2.11 (m, 1H), 1.99 (q, J = 7.5 Hz, 1H), 1.11 – 1.05 (m, 3H).13C NMR (151 MHz, DMSO-d6) δ 172.49, 172.36, 168.24, 168.06, 161.10, 145.00, 137.70, 133.03, 128.67, 127.79, 126.47 (q, J = 30 Hz), 126.14 (q, J = 6 Hz), 125.44, 124.89 (q, J = 274 Hz), 124.67, 115.93, 109.37, 67.55, 60.34, 53.71, 47.16, 38.80, 31.05, 25.33, 14.42. HRMS (ESI); m / z [M+1]+; Calcd. C25H27F3N3O6, 522.1774. Found 522.1839. 2,2,2-trifluoroethyl 5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl] methylamino]ethoxy]isoindolin-2-yl]pentanoate (DHC-565) To a (trifluoromethyl)phenyl] methylamino]ethoxy]isoindolin-2-yl]pentanoic acid (DHC-289) - 63 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) (30.0 mg, 0.0608 mmol) was added thionyl chloride (0.0177 mL, 0.243 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2h. The reaction was then quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc (3x), dried and concentrated. The resulting solid was then purified by PTLC (EtOAc w / 10% MeOH 1:1 Hexanes) to yield 9.2 mg (26% yield) of product (DHC-565).1H NMR (600 MHz, CD2Cl2) δ 7.72 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.04 (dd, J = 8.3, 2.1 Hz, 1H), 7.00 (s, 1H), 6.94 (d, J = 6.6 Hz, 1H), 6.20 (s, 1H), 5.40 (s, 1H), 4.87 (dd, J = 8.9, 6.1 Hz, 1H), 4.71 (d, J = 6.3 Hz, 2H), 4.60 (s, 2H), 4.48 – 4.44 (m, 2H), 4.43 (d, J = 12.2 Hz, 1H), 4.36 (d, J = 17.0 Hz, 1H), 2.52 (q, J = 7.7 Hz, 1H), 2.46 (dd, J = 7.9, 6.1 Hz, 1H), 2.44 – 2.39 (m, 1H), 2.21 – 2.13 (m, 1H).13C NMR (151 MHz, CD2Cl2) δ 171.05, 170.94, 168.47, 167.15, 160.42, 144.15, 136.20, 132.36, 130.22, 127.87 (q, J = 30 Hz), 127.74, 126.03 (q, J = 6 Hz), 125.60, 125.18, 124.48 (q, J = 274 Hz), 123.02 (q, J = 277 Hz), 115.62, 108.63, 67.56, 60.31 (q, J = 36 Hz), 53.50, 46.84, 39.54, 29.96, 23.69. HRMS (ESI): m / z [M+1]+; Calcd. C25H24F6N3O6, 576.1491. Found 576.1551. phenyl 5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]pentanoate (DHC-575) To a (trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]pentanoic acid (DHC-289) (5.00 mg, 0.0101 mmol) in ethyl acetate (0.5 mL) was added (4-nitrophenyl) carbonochloridate (2.25 mg, 0.0111 mmol), TEA (0.00155 mL, 0.0111 mmol), and DMAP (0.124 mg, 0.00101 mmol). The reaction was stirred at r.t. overnight then diluted with saturated aqueous NaHCO3 solution, extracted with EtOAc, filtered, and concentrated. Crude material was purified by PTLC (DCM:MeOH:NH4OH, 97:2.5:0.5) to give 3.30 mg (53% yield) of product (DHC-575).1H NMR (400 MHz, CD2Cl2) δ 8.23 (d, J = 9.1 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 2.7 Hz, 2H), 7.43 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H), 7.08 – 6.98 (m, 2H), 6.96 (s, 1H), 6.35 (s, 1H), 5.75 (s, 1H), 5.00 (dd, J = 9.0, 6.5 Hz, 1H), 4.71 (d, J = 6.2 Hz, 2H), 4.61 (s, 2H), 4.52 – 4.36 (m, 2H), 2.68 (td, J = 7.2, 3.2 Hz, 2H), 2.50 (dq, J = 14.3, 7.1 Hz, 1H), 2.24 (dq, J = 15.0, 7.5 Hz, 1H). - 64 - 56067759.3 Attorney Docket No.047162-7520WO1(02652)13C NMR (151 MHz, DMSO-d6 ) δ 172.16, 170.89, 168.24, 168.19, 161.18, 155.78, 145.04, 133.03, 128.68, 128.65, 127.79, 127.61, 126.47 (q, J = 30 Hz, 126.15 (q, J = 6 Hz), 125.64, 124.88 (q, J = 274 Hz), 125.36, 124.78, 123.60, 115.97, 109.41, 67.52, 53.47, 47.15, 38.81, 31.03, 24.97. HRMS (ESI); m / z [M+1]+; Calcd. C29H26F3N4O8, 614.1625. Found 615.1697. tert-Butyl 5-amino-2-(5-hydroxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (Compound 8) To a mixture of [tert-butyl(dimethyl)silyl]oxy- benzoate (4) (500 mg, 1.39 5-oxo- pentanoate;hydrochloride (498 mg, 2.09 mmol) in MeCN (10 mL) was added N-ethyl-N- isopropyl-propan-2-amine (0.727 mL, 4.17 mmol) at room temperature. The reaction mixture was stirred at 80°C for 16h. The reaction was then cooled to room temperature and the precipitated product was collected by vacuum filtration and washed with MeCN. The filtrate was concentrated and purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane). Any recovered TBS protected product was collected and exposed to TBAF (1M in THF) : DCM (1:4 mL) for 1h and purified in the same manner. The collected fractions and solid from the purifications produced 300 mg (65% yield) of product (8).1H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.47 (dd, J = 8.3, 1.2 Hz, 1H), 7.22 (s, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.84 (dt, J = 8.4, 1.6 Hz, 1H), 6.72 (s, 1H), 4.62 (dd, J = 10.9, 4.7 Hz, 1H), 4.33 (d, J = 3.8 Hz, 2H), 2.20 – 2.12 (m, 1H), 2.05 – 1.98 (m, 2H), 1.94 (dtd, J = 16.9, 9.4, 4.1 Hz, 1H), 1.36 (d, J = 1.3 Hz, 9H).13C NMR (151 MHz, DMSO-d6) δ 173.44, 170.58, 168.67, 161.39, 145.07, 124.89, 123.08, 116.03, 110.08, 81.74, 54.29, 46.86, 31.93, 28.04, 25.31. HRMS (ESI); m / z [M+1]+; Calcd. C17H23N2O5, 334.1529. Found 335.1602. tert-Butyl 5-amino-2-[5-(2-methoxy-2-oxo-ethoxy)-1-oxo-isoindolin-2-yl]-5-oxo- pentanoate (Compound 9) - 65 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) To a solution of isoindolin-2-yl)-5-oxo- pentanoate (8) (220 mg, (101 mg, 0.658 mmol) in DMF (5 mL) was added KHCO3 (198 mg, 1.97 mmol) at room temperature. The reaction mixture was stirred for 24h at room temperature then diluted with EtOAc, washed with a mixture of brine:water (1:1, 4x), dried, and concentrated under vacuum. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 210 mg (79% yield) of the product (9).1H NMR (400 MHz, CD2Cl2) δ 7.69 (d, J = 8.3 Hz, 1H), 6.97 (dd, J = 13.9, 3.8 Hz, 2H), 5.93 (s, 1H), 5.42 (s, 1H), 4.95 – 4.85 (m, 1H), 4.72 (s, 2H), 4.54 (d, J = 16.8 Hz, 1H), 4.32 (d, J = 16.8 Hz, 1H), 3.79 (t, J = 1.7 Hz, 3H), 2.32 (dd, J = 13.0, 6.5 Hz, 1H), 2.17 (td, J = 16.3, 5.7 Hz, 3H), 1.43 (t, J = 1.6 Hz, 9H).13C NMR (126 MHz, CD2Cl2) δ 173.56, 169.73, 168.77, 168.70, 160.99, 144.37, 125.43, 124.96, 115.10, 108.49, 82.16, 65.30, 54.18, 52.19, 46.66, 32.04, 27.68, 25.42. HRMS (ESI); m / z [M+1]+; Calcd. C20H27N2O7, 407.1740. Found 407.1813. tert-Butyl 5-amino-5-oxo-2-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]pentanoate (DHC-549) O O To a mixture -1-oxo-isoindolin- 2-yl]-5-oxo- pentanoate (9) (210 mg, 0.517 mmol) in MeOH (10 mL) was added a 1M aqueous solution of KOH (2.5mL) was added. The mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with water and washed with EtOAc (2x) and the pH of the aqueous phase was acidified 1N aqueous HCl solution then extracted with EtOAc (3x). The organic layers were combined and concentrated and the crude product (DHC-548) was used in the next steps without further purification. To a stirred suspension of 2-[2-(4- amino-1-tert-butoxycarbonyl-4-oxo-butyl)- 1-oxo-isoindolin-5-yl]oxyacetic acid (DHC-548) (60 mg, 0.153 mmol) in dry DMF (1.0 mL) was added [2- - 66 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) (trifluoromethyl)phenyl]methanamine (53.6 mg, 0.306 mmol), HATU (87.2 mg, 0.229 mmol), and DIPEA (0.105 mL, 0.612 mmol) at room temperature. After stirring for 12 hours at room temperature, the reaction mixture was diluted with EtOAc, washed with water:brine (1:1) 4x, the organic layer was dried and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 30 mg (36% yield) of the product (DHC-549).1H NMR (600 MHz, DMSO-d6 ) δ 8.78 (t, J = 6.0 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 23.8, 8.0 Hz, 2H), 7.46 – 7.39 (m, 2H), 7.23 (s, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.4, 2.3 Hz, 1H), 6.73 (s, 1H), 4.72 (s, 2H), 4.65 (dd, J = 10.7, 4.8 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H), 4.40 (s, 2H), 2.23 – 2.14 (m, 1H), 2.00 (ddd, J = 26.4, 14.1, 7.4 Hz, 3H), 1.36 (s, 9H).13C NMR (151 MHz, DMSO-d6 ) δ 173.41, 170.46, 168.31, 168.23, 161.25, 144.88, 137.69, 133.03, 128.69, 127.80, 126.47 (q, J = 30 Hz), 126.16 (q, J = 6 Hz), 125.23, 124.89 (q, J = 274 Hz), 124.81, 116.08, 109.43, 81.84, 67.52, 47.12, 38.81, 31.91, 31.14, 28.04, 25.25. HRMS (ESI); m / z [M+1]+; Calcd. C27H31F3N3O6, 550.2087. Found 550.2160. dimethyl 2-[1-oxo-5-[2-oxo-2-[[2- (trifluoromethyl)phenyl]methylamino]ethoxy]isoindolin-2- yl]pentanedioate (DHC-582) A solution of [[2- (trifluoromethyl)phenyl] methylamino]ethoxy]isoindolin-2-yl]pentanoate (DHC-549) (62.4 mg, 0.114 mmol) in a mixture DCM:TFA (2:1 mL) was stirred at room temperature for 2h. The solvent was removed in vacuo and crude product was dried under high vacuum for 1h and used in the next step without any further purification. To a solution of crude 5-amino-5- oxo-4-[1-oxo-5-[2-oxo-2-[[2- (trifluoromethyl)phenyl] methylamino]ethoxy]isoindolin-2- yl]pentanoic acid (10.0 mg, 0.0203 mmol) was added methanol (0.25 mL) was added thionyl chloride (0.00591 mL, 0.00811 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2h. The reaction was then quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc (3x), dried and concentrated. The resulting solid was then purified by PTLC (5% MeOH in DCM) to yield 5.40 mg (51% yield) of product (DHC-582).1H NMR (600 MHz, CD2Cl2) δ 7.71 (dd, J = 8.4, 1.6 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.06 – 6.95 (m, 3H), 5.86 – - 67 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 5.70 (m, 1H), 5.41 – 5.33 (m, 1H), 5.07 – 5.00 (m, 1H), 4.71 (d, J = 6.3 Hz, 2H), 4.60 (d, J = 1.6 Hz, 2H), 4.51 (d, J = 16.7 Hz, 1H), 4.36 (d, J = 16.7 Hz, 1H), 3.71 (d, J = 1.7 Hz, 3H), 2.43 – 2.36 (m, 1H), 2.27 – 2.16 (m, 3H).13C NMR (151 MHz, CD2Cl2) δ 173.36, 171.04, 168.59, 167.26, 160.35, 144.45, 136.23, 132.36, 130.13, 127.84 (q, J = 30 Hz), 127.72, 126.03 (q, J = 6 Hz), 125.60, 125.19, 124.49 (q, J = 274 Hz), 115.47, 108.56, 67.56, 53.32, 52.31, 46.73, 39.50, 31.84, 25.25. HRMS (ESI); m / z [M+1]+; Calcd. C24H24F3N3O6, 508.1617. Found 508.1690. ethyl 5-amino-5-oxo-2-[1-oxo-5-[2-oxo-2-[[2- (trifluoromethyl)phenyl]methylamino]ethoxy] isoindolin-2-yl]pentanoate (DHC-583) To a crude [2- (trifluoromethyl)phenyl] methylamino]ethoxy]isoindolin-2-yl]pentanoic acid (10.0 mg, 0.0203 mmol) (Synthesized in procedure for DHC-582) was added methanol (0.25 mL) was added thionyl chloride (0.00591 mL, 0.00811 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was then quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc (3x), dried and concentrated. The resulting solid was then purified by PTLC (5% MeOH in DCM) to yield 5.0 mg (47% yield) of product (DHC-583).1H NMR (600 MHz, CD2Cl2) δ 7.72 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.03 (dd, J = 8.4, 2.2 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.98 (t, J = 6.5 Hz, 1H), 5.76 (s, 1H), 5.31– 5.25 (m, 1H), 5.02 (dd, J = 10.8, 4.5 Hz, 1H), 4.71 (d, J = 6.3 Hz, 2H), 4.54 (d, J = 16.7 Hz, 1H), 4.36 (d, J = 16.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.44 – 2.36 (m, 1H), 2.26 – 2.14 (m, 3H), 1.25 (t, J = 7.1 Hz, 3H).13C NMR (151 MHz, CD2Cl2) δ 173.30, 170.54, 168.60, 167.25, 160.32, 144.47, 136.24, 132.36, 130.14, 127.85 (q, J = 30 Hz), 127.72, 126.03 (q, J = 6 Hz), 125.66, 125.17, 124.49 (q, J = 274 Hz),115.44, 108.56, 67.56, 61.54, 53.43, 46.69, 39.52, 31.92, 25.32, 13.91. HRMS (ESI); m / z [M+1]+; Calcd. C25H27F3N3O6, 522.1774. Found 522.1849. (3S)-3-(5-hydroxy-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (Compound 10) - 68 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) O O NH N O To a round bottom 2-(bromomethyl)-3-[tert- butyl(dimethyl)silyl]oxy- and (3S)-3-aminopiperidine-2,6- dione;hydrochloride (34.4 mg, 0.209 mmol) in MeCN (10 mL). N-ethyl-N-isopropyl-propan- 2- amine (0.0727 mL, 0.417 mmol) was added and the reaction was stirred at 80°C for 16 hours. The reaction was cooled to room temperature and concentrated to give a crude oil. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane). Any recovered TBS protected product was collected and exposed to TBAF for 1h and purified in the same manner. The collected fractions from the two purifications produced 20 mg (55% yield) of product (10). NMR consistent with the commercially reported 3-(1,3- Dihydro-5-hydroxy-1-oxo-2H- isoindol-2-yl)-2,6-piperidinedione. HRMS (ESI); m / z [M+1]+; Calcd. C13H12N2O4, 261.0797. Found 261.0869. Chiral SFC / MS: 13% ee. tert-Butyl 2-[2-[(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxyacetate (Compound 11) Compound 11 (20 mg) according to the same experimental procedure as 1. The1H and13C NMR data for 11 are consistent with that observed for 1. HRMS (ESI); m / z [M+1]+; Calcd. C19H23N2O6, 374.1478. Found 375.1545. Chiral SFC / MS: 13% ee. 2-[2-[(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxy-N-[[2- (trifluoromethyl)phenyl] methyl]acetamide (DHC-725) DHC-725 (5.0 according to the same experimental procedure as DHC-286. The1H and13C NMR data for DHC-725 are consistent - 69 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) with that observed for DHC-286. HRMS (ESI); m / z [M+1]+; Calcd. C23H21F3N3O5, 476.1355. Found 476.1422. Chiral SFC / MS: 14% ee. 2-[2-((3S)-2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxy-N- [[2(trifluoromethyl)phenyl] methyl]acetamide (DHC-781) To a solution of 2-[[2- (trifluoromethyl) (10.0 mg, 0.0182 mmol) in MeCN (1 mL) was added benzenesulfonic acid (5.76 mg, 0.0364 mmol) and the reaction mixture was heated at reflux temperature for 16h. The mixture was then concentrated and purified by PTLC (5% MeOH in DCM) to give 6.40 mg (72% yield) of product (DHC- 781). The1H and13C NMR data for DHC- 725 are consistent with that observed for DHC- 286.1H NMR (600 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.77 (t, J = 6.2 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 8.4, 2.3 Hz, 1H), 5.06 (dd, J = 13.4, 5.1 Hz, 1H), 4.72 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 4.37 (d, J = 17.2 Hz, 1H), 4.25 (d, J = 17.2 Hz, 1H), 2.88 (ddd, J = 18.3, 13.9, 5.4 Hz, 1H), 2.57 (d, J = 17.5 Hz, 1H), 2.36 (qd, J = 13.3, 4.5 Hz, 1H), 2.00 – 1.93 (m, 1H). HRMS (ESI): m / z [M+1]+; Calcd. C23H20F3N3O5, 476.1355. Found 476.1412. Chiral SFC / MS: 94% ee. tert-butyl 5-amino-4-(5-hydroxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (Compound 12) Compound 12 (62.0 4 (100.0 mg) according to the same experimental procedure as 5. The 1H and 13C NMR data for 12 are consistent with that observed for 5.1H NMR (600 MHz, CD2Cl2) δ 7.49 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 6.84 (d, J = 6.8 Hz, 2H), 6.33 (s, 1H), 4.86 (dd, J = 9.3, 5.6 Hz, 1H), 4.35 (d, J = 17.2 Hz, 1H), - 70 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 4.25 (d, J = 17.1 Hz, 1H), 2.29 – 2.20 (m, 3H), 2.10 – 2.02 (m, 1H), 1.37 (s, 9H). HRMS (ESI): m / z [M+1]+; Calcd. C17H22N2O5, 335.1529. Found 335.1605. tert-butyl 5-amino-4-[5-(2-methoxy-2-oxo-ethoxy)-1-oxo-isoindolin-2-yl]-5-oxo- pentanoate (Compound 13) Compound 13 mg) according to the same experimental consistent with that observed for 6.1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.13 (d, J = 3.6 Hz, 2H), 7.00 (dd, J = 8.4, 2.3 Hz, 1H), 4.87 (s, 2H), 4.69 – 4.61 (m, 1H), 4.51 (d, J = 17.5 Hz, 1H), 4.35 (d, J = 17.6 Hz, 1H), 3.67 (d, J = 2.5 Hz, 3H), 2.09 (d, J = 10.7 Hz, 3H), 1.93 (t, J = 9.3 Hz, 1H), 1.29 (s, 9H). HRMS (ESI): m / z [M+1]+; Calcd. C20H26N2O7, 407.1740. Found 407.1815. tert-butyl 5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]pentanoate (Compound 15) Compound according to the same experimental procedure as DHC-287. The1H and13C NMR data for 15 are consistent with that observed for DHC-287.1H NMR (400 MHz, DMSO-d6) δ 8.77 (t, J = 6.0 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.46 – 7.37 (m, 2H), 7.16 (t, J = 4.3 Hz, 2H), 7.07 (dd, J = 8.4, 2.2 Hz, 1H), 4.71 – 4.64 (m, 3H), 4.57 – 4.46 (m, 3H), 4.36 (d, J = 17.5 Hz, 1H), 2.11 (s, 3H), 1.95 (s, 1H), 1.30 (s, 9H). HRMS (ESI): m / z [M+1]+; Calcd. C27H30F3N3O6, 550.2087. Found 550.2168. methyl 5-amino-5-oxo-4-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl] methylamino] ethoxy]isoindolin-2-yl]pentanoate (DHC-800) - 71 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Compound 15 (4.8 mg) according to the same experimental data for DHC-800 are consistent with that observed for DHC-562.1H NMR (400 MHz, DMSO-d6) δ 8.77 (t, J = 6.0 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.58 (dd, J = 15.6, 8.8 Hz, 3H), 7.47 – 7.36 (m, 2H), 7.16 (s, 2H), 7.11 – 7.04 (m, 1H), 4.72 – 4.64 (m, 3H), 4.57 – 4.46 (m, 3H), 4.36 (d, J = 17.5 Hz, 1H), 3.47 (d, J = 1.5 Hz, 3H), 2.21 (d, J = 8.0 Hz, 2H), 2.15 (dd, J = 13.5, 7.0 Hz, 1H), 2.00 (d, J = 12.5 Hz, 1H). HRMS (ESI): m / z [M+1]+; Calcd. C24H24F3N3O6, 508.1617. Found 508.1704. methyl 5-amino-4-(5-hydroxy-1,3-dioxo-isoindolin-2-yl)-5-oxo-pentanoate (DHC-749) A mixture of 5- mg, 0.152 mmol) and methyl 4,5-diamino- 5-oxo-pentanoate (32.9 mg, 0.168 mmol) in acetic acid (2.0 mL) was heated under reflux for 3 days. The reaction mixture was quenched with NaHCO3 and extracted with EtOAc (3x), dried, and concentrated. The mixture was purified via PTLC (5% MeOH in DCM) to give 2.4 mg (5% yield) of product (DHC-749).1H NMR (600 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.69 – 7.64 (m, 1H), 7.52 (s, 1H), 7.13 , 7.10 (d, J = 6.8 Hz, 2H), 4.50 (dd, J = 10.5, 4.3 Hz, 1H), 3.43 (s, 3H), 2.38 – 2.32 (m, 1H), 2.26 – 2.18 (m, 3H).13C NMR (101 MHz, DMSO-d6) δ 173.02, 170.30, 167.89, 167.83, 163.64, 134.95, 125.67, 122.38, 120.73, 110.08, 52.32, 51.68, 30.94, 24.00. HRMS (ESI); m / z [M+1]+; Calcd. C14H15N2O6, 307.0852. Found 307.0925. methyl 5-amino-4-(4-amino-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (DHC-608) - 72 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) To a mixture of methyl 2-(bromomethyl)-3-nitro-benzoate (50 mg, 0.182 mmol), methyl 4,5- diamino-5-oxo-pentanoate;hydrochloride (53.8 mg, 0.274 mmol) in MeCN (2.5 mL) was added N,N-diethylethanamine (0.0953 mL, 0.547 mmol) at room temperature. The reaction mixture was brought 80°C and stirred for 16h. The reaction was cooled to room temperature and the crude product (12) subjected to the next reaction. HRMS (ESI); m / z [M+1]+; Calcd. C14H16N3O6, 322.0961. Found 322.1035. To the crude material (12) was added MeOH (2 mL) and Pd / C (10%w / w Pd; 82.8 mg, 0.778 mmol) H2 gas was bubbled through the black suspention for 15 min. The reaction mixture was then stirred for 3h under and H2 atmosphere. The reaction mixture was the filtered through celite, concentrated and purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 6.2 mg (14% yield) of product (DHC- 608).1H NMR (400 MHz, CD2Cl2) δ 7.29 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.27 (s, 1H), 5.39 (s, 1H), 4.90 (dd, J = 9.2, 5.5 Hz, 1H), 4.33 (d, J = 16.5 Hz, 1H), 4.26 (d, J = 16.5 Hz, 1H), 3.62 (s, 3H), 2.45 – 2.28 (m, 3H), 2.24 – 2.12 (m, 1H).13C NMR (101 MHz, CD2Cl2) δ 172.88, 171.38, 169.53, 141.59, 132.56, 129.35, 126.27, 117.61, 113.41, 53.59, 51.59, 44.90, 30.25, 24.01. HRMS (ESI); m / z [M+1]+; Calcd. C14H18N3O4, 292.1219. Found 292.1292. methyl 5-amino-4-[5-[2-[2-[2-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4- d]pyrimidin-1- yl]-1-piperidyl]ethoxy]ethoxy]ethoxy]-1-oxo-isoindolin-2-yl]-5-oxo- pentanoate (DHC-753) phenoxyphenyl)pyrazolo[3,4- d]pyrimidin-1-yl]-1-piperidyl]ethoxy]ethoxy]ethoxy]-1-oxo- isoindolin-2-yl]-5-oxo-pentanoic acid (13) (10.0 mg, 0.0128 mmol) (synthesized according to previous reports)2in methanol (0.25 mL) was added thionyl chloride (1M in DCM) (0.0257 mmol, 0.0257 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was then quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc (3x), dried and concentrated. The resulting solid was then - 73 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) purified by PTLC (DCM:MeOH:NH4OH, 97:2.5:0.5) to give 6.6 mg (65% yield) of product (DHC-753).1H NMR (500 MHz, DMSO-d6) δ 8.20 (d, J = 1.4 Hz, 1H), 7.67 – 7.59 (m, 2H), 7.58 – 7.50 (m, 2H), 7.44 – 7.36 (m, 2H), 7.19 – 7.07 (m, 7H), 7.00 (dd, J = 8.5, 2.1 Hz, 1H), 4.66 (td, J = 12.0, 5.1 Hz, 2H), 4.56 – 4.46 (m, 1H), 4.38 – 4.29 (m, 1H), 4.15 (t, J = 4.6 Hz, 2H), 3.76 (t, J = 4.6 Hz, 2H), 3.57 (dt, J = 21.9, 4.9 Hz, 6H), 3.46 (d, J = 1.5 Hz, 3H), 3.05 (s, 2H), 2.55 (s, 2H), 2.31 – 2.08 (m, 7H), 2.02 – 1.83 (m, 3H).13C NMR (126 MHz, DMSO-d6) δ 172.94, 172.33, 168.14, 161.93, 158.59, 157.51, 156.71, 155.89, 154.09, 145.08, 143.29, 130.56, 130.44, 128.50, 124.78, 124.61, 124.23, 119.44, 119.36, 115.59, 109.02, 97.88, 70.32, 70.13, 69.22, 68.10, 57.30, 53.64, 52.96, 51.72, 47.10, 30.79, 28.04, 25.34. HRMS (ESI); m / z [M+1]+; Calcd. C42H49N8O8, 793.3595. Found 793.3668. benzyl 4-amino-3-(5-hydroxy-1-oxo-isoindolin-2-yl)-4-oxo-butanoate (Compound 19) To a mixture of butyl(dimethyl)silyl]oxy- benzoate (4) (100 mg, 0.278 mmol) and benzyl 3,4-diamino-4-oxo-butanoate;hydrochloride (108 mg, 0.417 mmol) in MeCN (3 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.145 mL, 0.835 mmol) at room temperature. The mixture was stirred at 80°C for 16h. The reaction mixture was then cooled to room temperature and concentrated to give a crude oil. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane). Any recovered TBS-protected product was collected and exposed to 1M TBAF in THF 1 mL : 4 mL DCM for 1h and purified in the same manner. The collected fractions from the two purifications produced 73 mg (74% yield) of product (19).1H NMR (600 MHz, DMSO-d6) δ 10.12 (s, 1H), 7.51 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.26 – 7.22 (m, 5H), 7.20 (s, 1H), 6.87 (s, 1H), 6.83 (dd, J = 8.2, 2.1 Hz, 1H), 5.05 – 5.03 (m, 1H), 5.02 (s, 2H), 4.36 – 4.26 (m, 2H), 3.03 (dd, J = 15.9, 6.5 Hz, 1H), 2.78 (dd, J = 15.9, 8.6 Hz, 1H).13C NMR (151 MHz, DMSO-d6) δ 171.33, 170.70, 167.97, 161.29, 145.01, 136.38, 128.73, 128.34, 128.18, 124.83, 123.30, 115.92, 110.01, 66.11, 51.52, 47.44, 34.90. HRMS (ESI): m / z [M+1]+; Calcd. C19H18N2O5, 355.1216. Found 355.1288. dimethyl 2-(5-hydroxy-1-oxo-isoindolin-2-yl)butanedioate (DHC-788) - 74 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) To a solution of benzyl isoindolin-2-yl)-4-oxo- butanoate (19) (20 mg, 0.0564 Pd / C (12 mg, 0.0113 mmol) and was placed under hydrogen atmosphere for 2h. The reaction mixture was then filtered through celite and washed with 10% MeOH in DCM. The filtrate was concentrated and subsequently used in the next step without further purification. To a crude solution of 4- amino-3-(5-hydroxy-1-oxo-isoindolin-2-yl)-4-oxo- butanoic acid (14.9 mg, 0.0564 mmol) was added methanol (0.5 mL) and brought to 0°C. Thionyl chloride (0.0165 mL, 0.226 mmol) was added and the reaction was allowed to come to room temperature for 2h. The reaction was then quenched with NaHCO3 and extracted with EtOAc (3x), dried and concentrated. The resulting solid was then purified by PTLC (10% MeOH in DCM) to yield 6.30 mg (38% yield) of product (DHC-788).1H NMR (600 MHz, DMSO-d6) δ 10.11 (d, J = 2.1 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.18 (s, 1H), 6.89 (s, 1H), 6.82 (dd, J = 8.6, 2.1 Hz, 1H), 4.99 (t, J = 7.5 Hz, 1H), 4.32 (d, J = 3.7 Hz, 2H), 3.52 (s, 3H), 3.03 – 2.93 (m, 1H), 2.70 (dd, J = 16.0, 8.2 Hz, 1H).13C NMR (151 MHz, DMSO-d6) δ 171.34, 171.26, 167.93, 161.28, 145.03, 124.81, 123.28, 115.93, 110.02, 51.98, 51.45, 47.45, 34.62. HRMS (ESI): m / z [M+1]+; Calcd. C13H14N2O5, 279.0903. Found 279.0973. 3-(5-hydroxy-1-oxo-isoindolin-2-yl)pyrrolidine-2,5-dione (Compound 20) To a mixture of methyl -3-[tert-butyl(dimethyl)silyl]oxy- benzoate (4) (100 mg, 0.278 mmol) and 3-aminopyrrolidine-2,5-dione;hydrochloride (62.9 mg, 0.417 mmol) in MeCN (3 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.145 mL, 0.835 mmol) at room temperature. The mixture was stirred at 80°C for 16 h. The reaction mixture was then cooled to room temperature and concentrated to give a crude oil. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane). Any recovered TBS-protected product was collected and exposed to 1M TBAF in THF 1 mL : 4 mL DCM for 1h and purified in the same manner. The collected fractions from the two purifications produced 60.0 mg (88% yield) of product (20).1H NMR (400 MHz, - 75 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) DMSO-d6) δ 11.26 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.90 – 6.80 (m, 2H), 5.13 (dd, J = 9.2, 6.1 Hz, 1H), 4.46 (d, J = 17.0 Hz, 1H), 4.20 (d, J = 16.9 Hz, 1H), 2.87 (qd, J = 17.8, 7.7 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 177.33, 176.54, 168.28, 161.56, 144.84, 124.90, 122.70, 116.21, 110.14, 52.40, 48.07, 34.92. HRMS (ESI): m / z [M+1]+; Calcd. C12H10N2O4, 247.0641. Found 247.0711. tert-butyl 2-[2-(2,5-dioxopyrrolidin-3-yl)-1-oxo-isoindolin-5-yl]oxyacetate (Compound 21) To a solution of 3- 2,5-dione (35.0 mg, 0.142 mmol) and tert-butyl mg, mmol) in DMF (2 mL) was added KHCO3 (42.7 mg, 0.426 mmol) at room temperature, then the reaction mixture was stirred at room temperature for 24h. The reaction mixture was diluted with EtOAc, washed with a mixture of brine: water (1:1, 4x), dried, and concentrated under vacuum. Crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 20.2 mg (39% yield) of the product (21).1H NMR (600 MHz, DMSO-d6) δ 10.22 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.3, 1.1 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.86 (dt, J = 8.2, 1.6 Hz, 1H), 5.36 (dd, J = 9.4, 5.7 Hz, 1H), 4.52 (d, J = 16.7 Hz, 1H), 4.12 (s, 3H), 3.17 – 3.10 (m, 1H), 3.05 – 2.98 (m, 1H), 1.40 (d, J = 1.2 Hz, 9H).13C NMR (151 MHz, DMSO-d6) δ 175.21, 174.53, 168.29, 166.20, 161.67, 144.66, 125.05, 122.40, 116.29, 110.20, 82.62, 50.81, 47.22, 40.67, 33.40, 28.02. HRMS (ESI): m / z [M+1]+; Calcd. C18H20N2O6, 361.1321. Found 361.1394. 2-[2-(2,5-dioxopyrrolidin-3-yl)-1-oxo-isoindolin-5-yl]oxy-N-[[2-(trifluoromethyl)phenyl] methyl]acetamide (DHC-791) A solution of oxo-isoindolin-5- yl]oxyacetate (21) (20.0 mg, 0.0555 mmol) in a mixture DCM:TFA (1:0.5 mL) was stirred at room temperature for 2h. Solvent was removed in vacuo and crude product was dried under - 76 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) high vacuum for 1h and used in the next step without any further purification (quantitative yield). To a stirred suspension of the crude 2-[2-(2,5-dioxopyrrolidin-3-yl)-1-oxo-isoindolin- 5-yl]oxyacetic acid (22) (650 mg, 2.04 mmol) in dry DMF (1 mL) was added [2- (trifluoromethyl)phenyl]methanamine (19.5 mg, 0.111 mmol), HATU (31.7 mg, 0.0833. mmol), and DIPEA (0.0285 mL, 0.167 mmol) at room temperature. After 12 hours the mixture was diluted with EtOAc and washed with washed with water:brine (1:1) 4x, and the organic layer was dried and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 20.6 mg (80% yield) of the product (DHC-791).1H NMR (600 MHz, DMSO-d6) δ 10.22 (d, J = 2.1 Hz, 1H), 8.72 (t, J = 5.9 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.50 – 7.43 (m, 3H), 6.89 (s, 1H), 6.85 (dd, J = 8.3, 2.1 Hz, 1H), 5.34 (dd, J = 9.4, 5.5 Hz, 1H), 4.50 (d, J = 17.0 Hz, 1H), 4.46 (t, J = 6.8 Hz, 2H), 4.20 – 4.14 (m, 3H), 3.15 – 3.10 (m, 1H), 2.97 (dd, J = 18.1, 5.4 Hz, 1H).13C NMR (151 MHz, DMSO-d6) δ 175.08, 174.47, 167.94, 165.83, 161.21, 144.34, 136.91, 132.69, 128.55, 127.53, 126.17 (q, J = 30.3 Hz), 125.75 (q, J = 4.6 Hz), 124.55, 124.39 (d, J = 274.1 Hz), 121.95, 115.81, 109.71, 59.74, 50.45, 33.20, 20.76, 14.07. HRMS (ESI): m / z [M+1]+; Calcd. C22H18F3N3O5, 462.1199. Found 462.1262. benzyl 4-amino-3-[5-(2-tert-butoxy-2-oxo-ethoxy)-1-oxo-isoindolin-2-yl]-4-oxo- butanoate (Compound 23) To a solution 2-yl)-4-oxo- butanoate (20.0 mg, 0.0564 mmol) and tert-butyl 2-bromoacetate (19) (11.0 mL, 0.0564 mmol) in DMF (1 mL) was added KHCO3 (17 mg, 0.169 mmol) at room temperature, then the reaction mixture was stirred for 24h at room temperature. The reaction mixture was diluted with EtOAc, washed with a mixture of brine: water (1:1, 4x), dried, and concentrated under vacuum. Crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 18 mg (68% yield) of the product (23).1H NMR (600 MHz, DMSO-d6) δ 7.59 – 7.53 (m, 2H), 7.27 – 7.18 (m, 6H), 7.07 (d, J = 2.3 Hz, 1H), 6.99 (dd, J = 8.5, 2.3 Hz, 1H), 5.03 (d, J = 14.3 Hz, 3H), 4.73 (s, 2H), 4.42 – 4.31 (m, 2H), 3.05 (dd, J = 16.0, 6.4 Hz, 1H), 2.82 (dd, J = 15.9, 8.8 Hz, 1H), 1.41 (s, 9H).13C NMR (151 MHz, DMSO-d6) δ 171.23, 170.69, 167.94, 167.62, 161.15, 144.81, 136.35, 128.74, 128.35, 128.17, 125.37, - 77 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 124.68, 115.51, 109.20, 82.05, 66.13, 65.61, 51.63, 47.70, 34.90, 28.15. HRMS (ESI): m / z [M+1]+; Calcd. C25H28N2O7, 469.1897. Found 469.1963. benzyl 4-amino-4-oxo-3-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]butanoate (Compound 25) A solution of -1-oxo-isoindolin-2- yl]-4-oxo- butanoate (1:0.5 mL) was stirred at room temperature for 2h. Solvent was removed in vacuo and crude product was dried under high vacuum for 1h and used in the next step without any further purification (quantitative yield). To a stirred suspension of the crude 2-[2-(3-benzyloxy-1-carbamoyl-3- oxo-propyl)-1-oxo-isoindolin-5-yl]oxyacetic acid (24) (15.8 mg, 0.0383 mmol) in dry DMF (1 mL) was added [2-(trifluoromethyl)phenyl]methanamine (13.4 mg, 0.0766 mmol), HATU (21.9 mg, 0.0575 mmol), and DIPEA (0.0197 mL, 0.115 mmol) at room temperature. After 12h the mixture was diluted with EtOAc and washed with washed with water:brine (1:1) 4x, and the organic layer was dried and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc w / 10% MeOH 1:1 Hexane) to give 18.6 mg (85% yield) of the product (25).1H NMR (600 MHz, DMSO- d6) δ 8.77 (t, J = 6.1 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 6.9 Hz, 2H), 7.46 – 7.39 (m, 2H), 7.24 (s, 6H), 7.15 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.4, 2.3 Hz, 1H), 5.06 (dd, J = 8.8, 6.5 Hz, 1H), 5.02 (s, 2H), 4.71 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 4.39 (q, J = 17.2 Hz, 2H), 3.07 (dd, J = 15.9, 6.4 Hz, 1H), 2.84 (dd, J = 15.9, 8.8 Hz, 1H).13C NMR (151 MHz, DMSO-d6) δ 171.24, 170.68, 168.24, 167.65, 161.16, 144.84, 137.69, 136.35, 133.05, 128.74, 128.68, 128.36, 128.19, 127.80, 126.46 (d, J = 30.1 Hz), 126.14 (d, J = 5.8 Hz), 125.47, 124.89 (d, J = 274.0 Hz), 124.73, 115.99, 109.31, 67.54, 66.14, 51.63, 47.70, 38.84, 34.91. HRMS (ESI): m / z [M+1]+; Calcd. C29H26F3N3O6, 570.1774. Found 570.1835. methyl 4-amino-4-oxo-3-[1-oxo-5-[2-oxo-2-[[2-(trifluoromethyl)phenyl]methylamino] ethoxy]isoindolin-2-yl]butanoate (DHC-795) - 78 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) To a solution of 2-[[2- (trifluoromethyl) (25) (16 mg, 0.0281 mmol) in MeOH was added Pd / C (5.98 mg, 0.00562 mmol) and was placed under hydrogen atmosphere. The mixture was stirred under hydrogen atmosphere for 2h where it was then filtered, washed with 5% MeOH in DCM and concentrated. The crude material was used in the next step without further purification (quantitative yield). To a crude solution of 4-amino- 4-oxo-3-[1-oxo-5-[2-oxo-2-[[2- (trifluoromethyl)phenyl]methylamino]ethoxy]isoindolin-2- yl]butanoic acid (13.5 mg, 0.0282 mmol) was added methanol (0.25 mL) and brought to 0°C. Thionyl chloride (0.00822 mL, 0.113 mmol) was added and let stir for 2 hours 0°C - r.t.. The reaction was then quenched with NaHCO3 and extracted with EtOAc (3x), dried and concentrated. The resulting solid was then purified by PTLC (5% MeOH in DCM) to yield 6.60 mg (48% yield) of product (DHC-795).1H NMR (600 MHz, DMSO-d6) δ 8.77 (t, J = 6.1 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.55 (s, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 8.4, 2.2 Hz, 1H), 5.02 (dd, J = 8.4, 6.6 Hz, 1H), 4.70 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.44 – 4.35 (m, 2H), 3.53 (s, 3H), 3.00 (dd, J = 16.0, 6.6 Hz, 1H), 2.76 (dd, J = 16.0, 8.5 Hz, 1H).13C NMR (151 MHz, DMSO-d6) δ 171.25, 171.24, 168.23, 167.61, 161.15, 144.86, 137.69, 133.04, 128.67, 127.80, 126.46 (d, J = 30.1 Hz), 126.15 (d, J = 5.8 Hz), 125.45, 124.88 (d, J = 274.0 Hz), 124.71, 116.00, 109.34, 67.53, 52.01, 51.57, 47.71, 38.81, 34.63. HRMS (ESI): m / z [M+1]+; Calcd. C23H22F3N3O6, 494.1461. Found 494.1530. tert-Butyl 5-[(4,5-dimethoxy-2-nitro-phenyl)methoxycarbonylamino]-5-oxo-4-[1-oxo-5- [2- oxo-2-[[2-(trifluoromethyl)phenyl]methylamino]ethoxy]isoindolin-2-yl]pentanoate (DHC- 585) - 79 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) A (DHC-287) (5.0 mg, 0.0091 mmol) in anhydrous THF (0.25 mL) was brought to -78 °C under and Ar atmosphere. (4,5-dimethoxy-2-nitro- phenyl)methyl carbonochloridate (2.51 mg, 0.00910 mmol) was then added, followed by the slow addition of LHMDS (1M in DCM) (0.0091 mL, 0.0091 mmol). The solution was stirred for 2 hours at -78 °C then quenched with water, extracted with EtOAc, dried, and concentrated. The crude material was purified by PTLC (5% MeOH in DCM) to yield 0.60 mg (7% yield) of product (DHC- 585).1H NMR (600 MHz, CD2Cl2) δ 8.89 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 1.3 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 7.0 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.22 (s, 1H), 7.09 – 7.02 (m, 1H), 7.01 (s, 1H), 6.92 (s, 1H), 5.57 (s, 2H), 4.95 (s, 1H), 4.71 (d, J = 6.3 Hz, 2H), 4.60 (d, J = 1.2 Hz, 2H), 4.47 (d, J = 16.9 Hz, 1H), 4.42 (d, J = 16.8 Hz, 1H), 3.94 (d, J = 1.2 Hz, 3H), 3.91 (d, J = 1.3 Hz, 3H), 2.31 (ddd, J = 27.6, 14.7, 5.8 Hz, 3H), 2.19 – 2.14 (m, 1H), 1.41 (d, J = 1.3 Hz, 9H). HRMS (ESI); m / z [M+1]+; Calcd. C37H40F3N4O12, 789.2517. Found 789.2589. tert-Butyl 5-[[4-[[(2R)-2-[[(2R)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methyl- butanoyl]amino]-5-ureido-pentanoyl]amino]phenyl]methoxycarbonylamino]-4-[5-(2- methoxy-2-oxo-ethoxy)-1,3-dioxo-isoindolin-2-yl]-5-oxo-pentanoate (DHC-563) - 80 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) To a solution of tert-butyl 5-amino-4-[5-(2-methoxy-2-oxo-ethoxy)-1-oxo-isoindolin- 2-yl]-5-oxo-pentanoate (6) (DHC-282) (5.00 mg, 0.0123 mmol) in DCE (0.5 mL) at 0°C was added oxalyl chloride (2M in DCM) (0.0615 mL, 0.123 mmol). The solution was allowed to stir for 5 min at room temperature, then heated at 60°C for 1 h. To the reaction mixture was cooled to room temperature and 6-(2,5-dioxopyrrol-1-yl)-N-[(1R)-1-[[(1R)-1-[[4- (hydroxymethyl)phenyl]carbamoyl]-4-ureido- butyl]carbamoyl]-2-methyl- propyl]hexanamide (7.75 mg, 0.0135 mmol) was added. The reaction mixture was brought back to 60 °C for 1 hour. The reaction mixture was cooled and concentrated in vacuo. The crude mixture was purified by HPLC (MeCN (0.1% FA) : H2O (0.1% FA) 20:80 – 60:40 over 30 minutes to give 0.541 mg (5% yield) of product (DHC-683).1H NMR (600 MHz, DMSO-d6 ) δ 10.96 (s, 1H), 9.99 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.58 (t, J = 7.8 Hz, 3H), 7.31 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.4, 2.3 Hz, 1H), 6.97 (d, J = 0.9 Hz, 2H), 5.94 (d, J = 6.4 Hz, 1H), 5.38 (s, 2H), 5.04 (s, 2H), 4.88 (s, 3H), 4.59 (d, J = 17.2 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.35 (q, J = 7.3 Hz, 1H), 4.16 (dd, J = 8.7, 6.8 Hz, 1H), 3.68 (s, 3H), 3.34 (d, J = 7.1 Hz, 2H), 2.99 (dq, J = 13.3, 6.7 Hz, 1H), 2.91 (dt, J = 13.3, 6.5 Hz, 1H), 2.16 (dt, J = 14.0, 7.4 Hz, 3H), 2.09 (q, J = 6.9 Hz, 2H), 2.02 (dt, J = 14.8, 7.5 Hz, 1H), 1.94 (dt, J = 13.6, 6.7 Hz, 1H), 1.68 – 1.63 (m, 1H), 1.56 (dd, J = 9.3, 4.8 Hz, 1H), 1.45 (p, J = 8.0 Hz, 5H), 1.29 (s, 10H), 1.15 (t, J = 7.6 Hz, 2H), 0.82 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H). HRMS (ESI): m / z [M+1]+; Calcd. C49H64N8O15, 1005.4491. Found 1005.4564. Example 1: Design, preliminary evaluation, and optimization of pro-degron cyclization to prepare immunomodulatory imide drugs (IMiDs) It has been demonstrated that glutarimides can form through the intramolecular cyclization of an amino acid and the protein backbone. However, this process was shown to be slow and inefficient, thus it has been hypothesized that substituting the electrophilic amide with an ester might enhance the conversion efficiency. To test this hypothesis, conversion of an uncyclized pro-degron to the glutarimide was monitored by assessing the degradation of a target protein. The cyclized IMiD (Compound 1-1) achieved potent degradation of the target protein with a DC50 of 2.1 nM (FIGs.3A-3C). Degradation was also observed for the IMiD mimicking the amide backbone (Compound 1-2), albeit at significantly higher concentrations, consistent with the slow conversion reported in the literature. In alignment with the hypothesis, the compound with a tert-butyl ester as the electrophile (Compound 1-3) exhibited improved potency compared to the amide-based - 81 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) compound. In addition to HiBiT assays used to quantify degradation, these results were validated by western blot analysis. To confirm that the degradation was mediated by CRBN, it was demonstrated that no degradation occurred when cells were pretreated with a CRBN- degrading PROTAC (FIG.3C). Having established that the pro-degron containing IMiDs can undergo cyclization to induce degradation, a structure-activity relationship study was conducted to identify attractive leaving groups that would maximize cyclization and degradation (FIG.4 and Table 1). Following the evaluation of the tert-butyl ester, alternative leaving groups were evaluated, including methyl (Compound 1-6) and ethyl (Compound 1-8) esters, which demonstrated improved cyclization. Phenol (Compound 1-7), trifluoroethoxy (Compound 1-9), and para- nitro phenol (Compound 1-10) leaving groups were also evaluated. Surprisingly, all of these leaving groups significantly enhanced degradation, with Compound 1-6 demonstrating equipotent degradation after 24 hours. Table 1. Pro-degron SAR studies Compound R224 h DC50 (nM) 1-3 2500 (DHC-287) 1-4 >10000(DHC-289) 1-5 6500 (DHC-291)1-6 1.8(DHC-562) 1-7 2.3 (DHC-563)1-8 8.4(DHC-564) - 82 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 1-9 3.4 pro- achieving levels comparable to those of the cyclized IMiD. Although the glutamine analog (i.e., branched alpha to the amide) used in the pro-degron produced the desired glutarimide product, it did not fully mimic the structure of the glutamine (Table 2). Therefore, IMiDs incorporating L-glutamine, which is branched alpha to the ester, were synthesized and the effectiveness of the methyl (Compound 1-13) and ethyl ester (Compound 1-14) were compared (Table 2). These compounds exhibited potency equivalent to their counterparts, indicating that the branching of the amino acid does not significantly impact cyclization. Table 2. Pro-degron cyclization studies 2 24 h DC50R (nM) (nM) 1-3 1-11 2500  5200 (DHC-287) (DHC-549) 1-4 >10000  1-12 NA(DHC-289) 1-6 1-13 1.8  3.2 (DHC-562) (DHC-582) 1-8 8.4 1-14 10.3- 83 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) (DHC-564) (DHC-583) approach was applied using other known CRBN degraders. Lenalidomide, a well-known SALL4 degrader, was modified to incorporate the methyl ester pro-degron. Following a 48 hour treatment, equipotent SALL4 degradation was observed, demonstrating that the pro- degron approach is applicable to other glutarimide-bearing compounds targeting different proteins of interest. Example 2: Cleavable protecting groups permit masking of the glutarimide moiety of celebron ligands and novel conjugation techniques for PROTACs, DACS, and / or IMiDs CRBN-based degraders constitute a large portion of the degraders currently in clinical trials. These degraders, including both PROTACs and IMiDs, vary in their CRBN ligand but consistently feature a glutarimide moiety. The development of alternative methods for achieving glutarimide formation within cells expands their potential application, not only for standalone dosing but also for innovative conjugation techniques. Degrader antibody conjugates (DACs) are an emerging therapeutic strategy that uses antibodies to specifically delivery degraders to tumor cells. This approach is analogous to antibody-drug conjugates (ADCs), but the cytotoxic drug is replaced with a degrader (which may also possess cytotoxic properties). Conjugation involving the glutarimide would be ideal for this technique, as it would allow for the release of an unmodified degrader, maximizing its potency. However, the glutarimide is not amenable to facile conjugation through popular techniques, such as carbamates or benzyl attachments, leading to degraders being modified with functional groups more conducive for conjugation. Such modification can significantly reduce the degrader’s potency, and identifying a functional group that does not interfere with degradation can be a challenging and time-consuming process. To determine whether the pro-degron could enable conjugation techniques not feasible with cyclized glutarimides, Compound 1-16 (DHC-585), where the amide of the uncyclized glutamine is conjugated to a UV-labile group via a carbamate, was synthesized (FIG.6). A similar reaction with the cyclized glutarimide yielded no product, indicating that - 84 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) the amides are amenable to carbamate formation, whereas glutarimides are not. Exposure of Compound 1-16 with 365 nm UV light from 30 seconds to 4 minutes triggered the release of the amide-bearing degrader, demonstrating that the pro-degron compounds can be conjugated and released in a manner not achievable with that the glutarimides. Thus, the pro-degron can be masked using various linkage types (FIG.7A). As previously demonstrated, carbamate formation can be achieved with the amide of glutamine and can be applied to both analogs regardless of branched location. As reported in the literature, asparagine can also undergo the same intramolecular cyclization to yield the cyclic aspartimide. Thus the amide groups of both glutamine and asparagine can be masked via carbamates for release of degraders. An alternative conjugation technique involves masking the carboxylic acid groups of the glutamine and asparagine analogs with a stimulus- responsive group via a carboxylic acid linkage. Examples of masked CRBN degraders are shown in FIGs.7B-7C: the first depicts a hydrogen peroxide sensitive masking group attached via a carbamate, while the second depicts a DAC that releases the amide following enzymatic cleavage. Recent studies have explored innovative conjugation strategies to glutarimide, such as a carbamates or carbonates with methene spacers and methyleneoxy phosphates. If proven effective, these methods could also be applied to conjugate the pro-degron. Additionally, given the ability of the amide to form conjugates, it can be utilized in other stimulus- responsive techniques such as ultraviolet light, H2O2, phosphatase nitroreductase, trans- cyclooctene, NAD-(P)H quinone dehydrogenase, sulfamate acetamides, and methyl acrylamides. In summary, the disclosure describes the design and validation of degron cyclization of glutarimide precursors, enabling equipotent protein degradation. Additionally, these pro- degrons grant access to conjugation techniques not applicable to the cyclic degrons so they can be employed in stimulus-responsive settings. Example 3: Development and validation of prodegraders capable of intramolecular cyclization It has been previously demonstrated that in vitro glutarimide formation within a synthetic, glutamine-containing peptide substrate was slow and inefficient, with less than 1% detected by Liquid Chromatography Mass Spectrometry (LCMS) after multiple days. Despite the low conversion rate, it was hypothesized that this naturally occurring intramolecular reaction was not exclusive to peptide substrates and could be integrated into an IMiD-based - 85 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) scaffold. Specifically, it was proposed that replacing the glutarimide with a glutamine analog mimicking the peptide backbone, or an optimized analog, would facilitate cyclization, thereby transforming an inactive prodegrader into an active, glutarimide-bearing degrader. To test this, a prodegrader mimicking a peptide backbone was synthesized and in cellulo degradation of HiBiT-tagged GSPT1 was measured as the primary readout of prodegrader activity, albeit with low efficacy. Intracellular glutarimide formation of glutamine analog- containing prodegraders were validated with LCMS, and it was confirmed by ITC that prior to cyclization, prodegraders do not bind to CRBN. GSPT1 is an essential protein involved in protein translation termination and was chosen as the target neosubstrate to test the prodegrader strategy. Several GSPT1 degraders have been developed for clinical applications, such as CC-885 and CC-90009 for treatment of acute myeloid leukemia (AML), as well as MRT-2359 for treatment of MYC-driven solid tumors. A potent, GSPT1-targeting IMiD, DHC-286, (FIG.9A) (FIG.29) was used as the parent IMiD for the development of the prodegrader analogs. Adegrader with a low nanomolar half-maximal degradation concentration (DC50), would induce measurable degradation even if only a small quantity of the prodegrader cyclized (i.e., 1% cyclization of an IMiD with a DC50 = 10 nM would result in a DC50 = 1 µM). To implement this strategya prodegrader analog of DHC-286 featuring an electrophilic amide designed to mimic the peptide backbone was first synthesized, with the aim of replicating native-like glutarimide cyclization. The amide analog (DHC-291) was synthesized from the α-branched tert-butyl ester-protected glutamine, DHC-287 (FIG.9A) (FIG.30). The α-branched glutamine analog was chosen over the naturally occurring ^-branched analog, as it was hypothesized the α- branching would have minimal effect on cyclization efficiency. The cyclized parent IMiD (DHC-286), the amide analog (DHC-291), and the tert-butyl ester intermediate (DHC-287) were tested for GSPT1HiBiTdegradation in HEK293T cells stably expressing the GSPT1HiBiTreporter protein. Encouragingly, GSPT1HiBiTdegradation was observed for the peptide backbone mimic prodegrader, DHC-291, (DC50 = 6.5 ± 1.7 µM), though this was ~1000-fold less potent than DHC-286 (DC50 = 5.6 ± 3.2 nM) (FIG.3B). The intermediate, DHC-287, exhibited slightly higher degradation (DC50= 2.5 ± 0.6 µM) than the amide (DHC-291) analog, suggesting that cyclization is tunable and dependent on the electrophilicity of the carbonyl. GSPT1 degradation of DHC-287 was further validated by western blot (FIG.13). GSPT1HiBiTlevels in DHC-287 treated cells were rescued upon chemical CRBN knockdown through pretreatment with a CRBN-degrading PROTAC, confirming that the mechanism of - 86 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) GSPT1 degradation was CRBN-mediated. To investigate degradation kinetics, the degradation of GSPT1HiBiTby DHC-286 and DHC-287 was monitored over 48 hours. The cyclized IMiD, DHC-286, rapidly decreases GSPT1HiBiTlevels, reaching a maximal DC50 within 12 hours (FIG.9B). In contrast, the DC50of DHC-287 improved over 48 hours, suggesting prolonged cyclization and gradual formation of the active degrader (FIG.9C). It was next sought to demonstrate that the prodegrader analogs could not bind CRBN to induce GSPT1 degradation prior to cyclization. Isothermal titration calorimetry (ITC) confirmed that DHC-286 exhibited a KDof 2.4 ± 1.4 µM (FIG.9D), consistent with reported ITC KD values for IMiDs binding to CRBNMidi*, whereas DHC-287 did not measurably bind to CRBNMidi*(FIGs.9E-9F) To further validate intramolecular cyclization, HEK293T cells expressing GSPT1HiBiTcells were treated with DHC-287 for various durations, following which intracellular concentrations of the cyclized product (DHC-286) and the hydrolyzed product (DHC-289) were quantified via mass spectrometry (FIG.9H). DHC-289 can form via hydrolysis of the tert-butyl ester or glutarimide, which is a common decomposition product for thalidomide analogs. While DHC-286 and DHC-289 were only present in trace quantities after 4 hours, the formation of both the cyclized and hydrolyzed products were observed at later time points (FIG.9H). These findings demonstrate that DHC-287 undergoes intramolecular cyclization in cellulo within the degradation timeframe, supporting the hypothesis that prodegraders cyclize to form glutarimide-bearing active compound. Example 4: Optimization of prodegraders to enable potent degradation It was next sought to optimize the cyclization rates of the prodegraders to enhance degradation kinetics and potency. Given that the bulky tert-butyl ester analog DHC-287 was more potent than the amide analog DHC-291, ester-containing prodegraders were pursued. Esters are generally more amenable to nucleophilic substitution than amides and are commonly used in prodrug design. Less bulky methyl (DHC-562) and ethyl (DHC-564) ester prodegraders were synthesized, in addition to more activated esters such as phenyl (DHC- 563), trifluoroethyl (DHC-565), and p-nitrophenyl ester (DHC-575) (FIG.10A andFIG.31). GSPT1HiBiTdegradation was measured at 8- and 24-hours for these ester analogs (FIG.10B). Within 8 hours, nearly all analogs exhibited potencies within 5-fold of the parent degrader, representing a significant improvement over DHC-287, which was ~1000x weaker. Structure- activity relationships (SAR) indicated that at 8 hours, the more activated esters (DHC-563, DHC-565, and DHC-575) were more potent than the methyl and ethyl esters, likely due to their faster cyclization. By 24 hours, however, the methyl ester DHC-562 emerged as the - 87 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) most potent prodegrader, nearly equipotent with DHC-286. From 8- to 24- hours, DHC-286 and the activated esters exhibited, at most, a 2-fold increase in degradation (DC50), whereas DHC-562 and DHC-564 had a 6-fold and 4-fold increase in DC50 values, respectively. It was speculated that these differences arise from the latter having slower cyclization and hydrolysis rates, exemplified by DHC-287 exhibiting generation of the active IMiD over a prolonged period (FIG.9C). In conjunction, ^-branched tert-butyl (DHC-549), ethyl (DHC-583) and methyl (DHC-582) ester analogs were synthesized and evaluated for GSPT1 degradation at 24 hours to investigate whether the branching of the glutamine moiety modulates cyclization rate and influences target degradation (FIG.10C, FIG.14, and FIG 32). Compared to their α-branched counterparts (FIG.10D), no sizeable differences in potency were observed for ^-branched glutamine esters, suggesting that both glutamine analog series have similar cyclization kinetics. Additionally, since the inductive effects of the amide in the isoindolone ring at the α- or γ-position did not impact degradation, it was anticipated that a broad range of chemical matter, including alternative CRBN-binding scaffolds, may be tolerated. To further explore the observed discrepancies in DC50 fold changes from 8 hours to 24 hours, the intramolecular cyclization rates of the GSPT1 prodegraders were monitored in vitro. Compounds were incubated in 20 mM potassium phosphate buffer at 37 °C, and prodegrader conversion was analyzed via LCMS over a 24 hour period (FIG.10E). As expected, cyclization rates varied among the compounds, with the more activated esters (DHC-563, DHC-565, DHC-575) undergoing rapid cyclization, reaching a maximal conversion within 5 hours, after which the quantity of hydrolyzed, inactive product (DHC- 289) increased (FIG.15). In alignment with the degradation data, the methyl, DHC-562, and ethyl, DHC-564, esters cyclized more gradually over the 24 hours, with 42% and 21% conversion into the cyclized product, respectively. The cyclization rates were found to be dependent on the composition of the buffer; however, the relative rates between the compounds remained the same (FIG.16). These cyclization kinetics explain why activated esters exhibited more potent degradation at 8 hours, since most of the compounds had already cyclized, but displayed only a relatively small improvement in potency from the 8- to 24-hour time point. Conversely, DHC-562 and DHC-564, cyclized more gradually and produced lower levels of active degrader at 8 hours, exhibiting weaker GSPT1 degradation at this timepoint; however, their continued cyclization through 24 hours ultimately contributed to a larger fold increase in degradation potency, surpassing that of the activated esters. - 88 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Since DHC-562 progressively forms active degrader (DHC-286) over the course of 24 hours, it was sought to determine whether the DHC-562 DC50would continue to decrease at extended time points, as previously observed for DHC-287. GSPT1HiBiTdegradation of DHC- 286 and DHC-562, was monitored at 24, 48, and 72 hours (FIGs.10F-10G and FIG.17). The 24-hour time point was consistent with previous findings, with DHC-562 (DC50 = 15 nM) exhibiting slightly weaker potency than DHC-286 (DC50= 8.8 nM). As expected, the potency of the prodegrader DHC-562 increased from 24 to 48 hours (DC50 = 7.8 nM), whereas DHC- 286 remained unchanged (DC50= 6.9 nM), rendering the two compounds equipotent. However, beyond 48 hours, DHC-562 did not show further improvement, as the DC50 values for DHC-562 (DC50= 7.1 nM) and DHC-286 (DC50= 8.7 nM) remained the same at 72 hours (FIG.10G and FIG 17). As GSPT1 is an essential protein whose degradation induces cell death, it was hypothesized that DHC-286 and DHC-562 would exhibit similar half-maximal inhibitory concentrations (IC50) values. Indeed, cell viability measurements at 2, 3, 4 days post- treatment demonstrated equipotent cytotoxicity with DHC-286 and DHC-562 (FIG.18). These results highlight the utility of the prodegrader approach, demonstrating its ability to achieve degradation and cytotoxicity comparable to the parent glutarimide-containing IMiD. Thalidomide analogs are known to undergo rapid racemization at the stereocenter linking the glutarimide to the phthalimide or isoindolone core. The more potent (S)- enantiomer has been associated with teratogenic effects and enhanced CRBN binding. DHC- 286 was synthesized as a racemic mixture, whereas the prodegrader scaffolds were prepared from an enantiomerically pure precursor, potentially yielding the single (S)-enantiomer of DHC-562. To investigate the extent to which this stereochemistry was retained during prodegrader synthesis, Supercritical Fluid Chromatography Mass Spectrometry (SFC / MS) was performed to determine the enantiomeric excess (%ee) of DHC-286 and DHC-562. As expected, DHC-286 exhibited a 50 / 50 mixture of both enantiomers. On the other hand, DHC- 562 showed a 96% ee for the (S)-enantiomer. This suggests that the pKa of the α-hydrogen in the open, prodegrader form is not acidic enough to be significantly epimerized during the synthesis of DHC-562, despite exposure to strong acids and bases. To investigate whether an enantiopure glutarimide starting material for DHC-286 would also tolerate these conditions, synthesis of its (S)-enantiomer, DHC-725, was attempted under reaction conditions similar to those used with DHC-562 (FIG.33). SFC / MS revealed that DHC-725 had only a 14 %ee. Further examination of the reaction intermediates indicated that epimerization occurred - 89 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) during the initial isoindolone core formation step, likely due to the presence of the base, diisopropylethylamine. Despite similar reaction conditions, the uncyclized glutamine analog was more resistant to epimerization under the basic conditions, suggesting that prodegraders are less prone to racemization to the less active enantiomer in cellulo prior to cyclization. As a result, preferential formation of the (S)-DHC-286 may occur upon cyclization within cells. To evaluate the impact of stereochemistry on degrader and prodegrader efficacy, the (S)-enantiomer of DHC-286 (DHC-781, 94% ee) and the racemic analog of DHC-562 were synthesized (DHC-800, FIG.34). The (S)-enantiomers and their corresponding racemates were then tested for their GSPT1HiBiTdegradation at 4, 24, and 48 hours (FIG.19). At the 4 hour timepoint, both the (S)-enantiomers – DHC-781 and DHC-562 – demonstrated only slightly greater potency than their racemic counterparts. By 24 hours, the differential narrowed further, with the (S)-enantiomers DHC-781 (DC50 = 3.1 nM) and DHC-562 (DC50 = 7.8 nM) displaying marginally improved potency compared to DHC-286 (DC50= 3.8 nM) and DHC-800 (DC50 = 11.5 nM), respectively. After 48 hours, all compounds demonstrated comparable potencies, with DC50 values in the 3-6 nM range. These results indicate that over time, the differences in activity between the (S)-enantiomer and their racemic counterparts diminishes. Notably, the similar shift in potency between the (S)-enantiomers and racemic compounds at the earlier timepoints for both degraders and prodegraders suggests that the enantiopure prodegraders preferentially cyclize to yield the (S)-enantiomer. Example 5: Application of prodegraders to other degraders Next, efforts were made to demonstrate that the prodegrader strategy could be applied to alternative cereblon binding scaffolds targeting unique POIs.5-hydroxy thalidomide (5- HT) is a known metabolite of thalidomide that contains a phthalimide scaffold and has been shown to degrade SALL4. The methyl ester prodegrader of 5-HT, DHC-749 was synthesized (FIG.35) and SALL4NLucdegradation was monitored in a SALL4-NanoLuc-expressing H1299 cell line at 24- and 48- hours posttreatment. Similarly to the GSPT1 prodegraders, the prodegrader DHC-749 showed improved potency over time, becoming equipotent (DC50= 95 nM) to the cyclized parent compound, 5-HT, (DC50 = 87 nM) after 48 hours (FIG.11A and FIG.20). Next, it was examined whether the prodegrader of yet another IMiD, lenalidomide, could confer equipotent degradation as its glutarimide counterpart. Lenalidomide is a known degrader of CK1α, so both it and its methyl ester prodegrader, DHC-608, were tested for target degradation in CK1α-NanoLuc-expressing K562 cells after 24- and 48- hours. After 48 - 90 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) hours, DHC-608 (DC50 = 73 nM) displayed nearly equipotent degradation to lenalidomide (DC50= 50 nM) (FIG.21), mirroring the trends observed for the SALL4 and GSPT1- targeting molecules. Having established prodegrader efficacy for IMiDs, their application to PROTACs was next explored. The potent BTK-degrading PROTAC, SJF-620, was selected to modify with the methyl ester prodegrader moiety, yielding DHC-753 (FIG.11B and FIG.37). BTK- dependent TMD8 cells were treated with SJF-620 and DHC-753 for 24 hours, after which BTK degradation was quantified through immunoblotting (FIG.11C). DHC-753 was able to induce BTK degradation, albeit at higher concentrations than the parent degrader SJF-620. BTK degradation by SJF-620 and DHC-753 was also tested in NAMALWA cells. A similar differential between the PROTAC SJF-620 and prodegrader DHC-753 was observed at 24 and 48 hours (FIG.22). To more accurately compare the cyclization and potency of the two compounds, determination of their ability to induce cell death in the BTK-dependent TMD8 cells was next sought. Following treatment with the BTK degrader SJF-620 and prodegrader DHC-753 for 72 hours, a 3-fold decrease in potency from DHC-753 (IC50 = 2.3 µM) to SJF- 620 (IC50 = 760 nM) was observed (FIG.11D). Without wishing to be bound by any theory, it was hypothesized that the discrepancy in potency is due to the distinct physicochemical properties of the larger, beyond the Rule of 5, PROTACs, as factors such as permeability and stability may be limiting their ability to capitalize on the gradual cyclization rate. Furthermore, in vitro incubation of PROTAC DHC-753 revealed a similar cyclization rate as the IMiD methyl ester prodegrader DHC-562, although the extent of conversion to the cyclized product was slightly lower after 24 hours (31% vs.42%, respectively, FIG.23). This modest discrepancy was attributed to the potential for intramolecular interactions or hydrophobic collapse within the larger PROTAC molecule, which may hinder its cyclization efficiency. To determine whether the difference in potency was not due to an effect of testing in an endogenous system, the GSPT1 degrader DHC-286 and prodegrader DHC-562 were tested in TMD8 cells to evaluate if the prodegrader would retain comparable potency to the degrader, as previously observed with exogenous GSPT1HiBiTdegradation. Following treatment of TMD8 cells with DHC-286 and DHC-562 for 72 hours, the observed IC50values confirmed that the two compounds were equipotent (FIG.24). This further suggests that the differential in PROTAC potency is due to the compounds physiochemical properties rather than the presence of the prodegrader moiety. Overall, these results demonstrate that prodegraders can be broadly applied to distinct CRBN targeting modalities such as IMiDs and PROTACs. - 91 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Glutarimides are almost exclusively employed across the diverse array of CRBN- recruiting ligands; however, recent studies have demonstrated that aspartimides are also capable of binding to CRBN and may be applicable in degrader technologies. Thus, it was sought to determine whether the prodegrader approach could be extended to aspartimide- based CRBN ligands. To this end, prodegrader DHC-788 (FIG.38) was synthesized, incorporating a methyl ester asparagine analog to compare its cyclization kinetics to that of a methyl ester glutamine analog. Cyclization to the 5-membered aspartimide ring was found to be significantly faster, reaching 72% after 2 hours compared to only 6% for the glutarimide analog DHC-562 (FIG.25). These results demonstrate that the prodegrader approach is applicable to asparagine analogs and that aspartimide formation is kinetically more favorable than glutarimide formation. Although aspartimides can bind CRBN, their incorporation in PROTACs has been less successful, as direct replacement of the glutarimide with an aspartimide often results in greatly diminished degradation efficacy. To determine if this limitation extends to the GSPT1 degraders, an aspartimide-containing analog of DHC-286 (DHC-791) was synthesized and its corresponding methyl ester prodegrader counterpart (DHC-796) As anticipated, neither compound induced GSPT1HiBiTdegradation at 4, 24 or 48 hours (FIG.26). These results further demonstrate that direct substitution of the glutarimide with an aspartimide abrogates degradation and illustrates the sensitivity of IMiDs to subtle structural modifications. Example 6: Prodegraders enable conjugation of CRBN-recruiting degraders While prodegraders are comparable to glutarimides for standalone dosing, it was hypothesized that the prodegrader scaffold provides linker attachment points, which are absent in glutarimides, that can expand degrader-conjugate technologies. DACs are an emerging therapeutic modality that harnesses antibodies to deliver degraders selectively to tumor cells, analogous to antibody-drug conjugates (ADCs). In DACs, the degrader payloads are conjugated to an antibody through a variety of linkers, and the most common linker is enzymatically cleaved by lysosomal proteases, such as cathepsin B, upon internalization in target cells. Ideally, for CRBN-recruiting degraders, conjugation would occur via the glutarimide to prevent premature activity, since N- modification of glutarimides abrogates CRBN binding, and ultimately releases an unmodified degrader. However, the glutarimide is not amenable to facile conjugation through popular techniques such as carbamate or benzyl attachments (FIG.12A), as evidenced by the lack of - 92 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) DACs using this strategy in the literature and patents. Consequently, CRBN-recruiting degraders require modifications to introduce conjugation handles, which can require extensive SAR campaigns to discover an analog that does not suffer from decreased potency and / or selectivity. This is exemplified by the recently disclosed DAC, ORUM-5029 (WO2021198965), which added a PEG-amine (FIG.12B) to the known IMiD GSPT1 degrader, CC-885, for conjugation. Similarly, the BRD4 degrading PROTAC, ARV-826, was modified by replacing an oxygen in the PEG linker with an amine to provide the conjugation handle (WO2019140003A1). It was hypothesized that the amide of the prodegrader could be used as a conjugation site via acyl carbamate formation (FIG.12C). Upon cleavage of the stimuli-responsive group, the prodegrader would undergo intramolecular cyclization to generate the active degrader. Since the glutarimide is a core feature of CRBN-based degraders, functionalization of the uncyclized glutarimide is (1) broadly applicable and (2) ensures no CRBN binding prior to payload release. To access this approach, DHC-585 was synthesized, where the amide of the uncyclized glutamine is conjugated to a nitrobenzyl photolabile-protecting group via a carbamate (FIG.41). A similar reaction with the cyclized glutarimide, DHC-286, yielded no product, confirming that amides are more amenable to carbamate formation than glutarimides. DHC-585 was then UV-irradiated, and the release of DHC-287 was monitored by LCMS. A time-dependent increase in abundance of DHC-287 was observed from 0.5 to 4 minutes (FIG.12D and FIG.27), demonstrating that prodegrader scaffolds can be masked with stimulus-sensitive groups and subsequently released upon activation. Encouraged by these results, the utility of prodegraders to DACs was investigated by conjugating a DAC linker to prodegrader DHC-282 and enzymatically cleaving the linker. Valine-citrulline-p- aminobenzylcarbamate (Val-Cit-PABC) is a commonly used amino acid-based linker in ADCs and DACs that contains the recognition elements (Val-Cit) for cathepsin B. Once endocytosed and localized to the lysosome, the amide bond between Cit-PABC is cleaved by cathepsin B to yield the primary aniline that rapidly initiates a 1,6 benzyl elimination to release from the carbamate, which spontaneously decomposes and liberates the drug payload (FIG.12E). DHC-683 was synthesized by conjugating the amide of DHC-282 to the Val-Cit-PAB linker (FIG.42). When DHC-683 (10 µM) was incubated with purified cathepsin B (250 nM) in ammonium acetate buffer, LCMS analysis revealed rapid cleavage of the linker, with 75% of DHC-282 released in just one hour (FIG.12F and FIG.28). Importantly, in the absence of cathepsin B, < 1% of DHC-282 was released. These results - 93 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) demonstrate that uncyclized glutarimide analogs of CRBN-based degraders can be successfully incorporated onto linkers for DAC development. Enumerated Embodiments The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1 provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or isotopologue thereof: (I), wherein: T is absent or selected from the group consisting of Ab and D; Ab, if present, is a cell and / or antigen binding domain, optionally wherein the cell and / or antigen binding domain is an antibody; D, if present, is a protein of interest-binding moiety; L is absent or each occurrence of L is independently a linker covalently conjugated to T and CDp; each occurrence of cDpis independently a cereblon degrader precursor of structure: , wherein each L, covalently conjugated to cDp via a covalent bond to ring A, -NH-, R1, or R2; l is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; m is 0 or 1; each occurrence of ring A is independently selected from the group consisting of optionally substituted C3-C20 heterocyclyl and optionally substituted C6-C10 aryl; each occurrence of R1is selected from the group consisting of H and a selectively cleavable protecting group; and each occurrence of R2is a leaving group. Embodiment 2 provides the compound of Embodiment 1, which is selected from the group consisting of: - 94 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) (Ia), (Ib), and (Ic). Embodiment 3 provides the compound of Embodiment 1 or 2, wherein cDpis selected from the group consisting of: each occurrence of , if present, is independently selected from the group consisting of: , , - 95 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) L R1N O - 96 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) each occurrence of R3is independently selected from the group consisting of H, halogen, CN, NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10 heteroaryl, ORA, N(RA)(RB), Si(RA)3, C(=O)ORA, C(=O)RA, C(=N-N(RA)(RB))RC, C(=O)N(RA)(RB), S(=O)2N(RA)(RB), S C N N C N S N S 2N ; substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10heteroaryl, Si(RA)3, C(=O)ORA, C(=O)RA, C(=N- N(RA)(RB))RC, C(=O)N(RA)(RB), S(=O)2N(RA)(RB), S(=O)2RA, and C(=NRA)N(RB)(RC); n is 0, 1, 2, 3, 4, or 5; and each occurrence of RA, RB, and RCis independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10heteroaryl. Embodiment 6 provides the compound of Embodiment 5, wherein R3is selected from the group consisting of NH2, F, and CH3. Embodiment 7 provides the compound of Embodiment 5 or 6, wherein R4is selected from the group consisting of H and CH3. Embodiment 8 provides the compound of any one of Embodiments 1-7, wherein R1is H. Embodiment 9 provides the compound of any one of Embodiments 1-7, wherein the selectively cleavable protecting group comprises a photocleavable moiety, a pH-sensitive moiety, a redox-sensitive moiety, a thermally-sensitive moiety, an oxygen-sensitive moiety (e.g., hypoxia-sensitive), and an electrochemically-sensitive moiety. Embodiment 10 provides the compound of any one of Embodiments 1-7 and 9, wherein R1comprises a moiety selected from the group consisting of an optionally substitutedbenzylcarboxy moiety ( ) , a hydrazone ), and a 1,2,4- - 97 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) trioxolane moiety ( ).the compound of any one of Embodiments 1-7 and 9-10, wherein R1is selected from the group . the compound of any one of Embodiments 1-11, wherein R2 is selected from the group consisting of OH, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8cycloalkoxy, optionally substituted C2-C8heterocycloalkoxy, optionally substituted C2-C8 heteroaryloxy, optionally substituted C6-C10 aryloxy, optionally substituted C1-C6alkylamino, optionally substituted C3-C8cycloalkylamino, optionally substituted C2-C8heterocycloalkylamino, optionally substituted C2-C8 heteroarylamino, optionally substituted C6-C10arylamino, optionally substituted C2-C8heteroaryl, and halogen. Embodiment 13 provides the compound of any one of Embodiments 1-12, wherein R2is selected from the group consisting of OH, OCH3, OCH2CH3, OC(CH3)3, OCF3, OCH2CF3, OPh, 4-nitro-phenoxy, F, Cl, Br, I, and imidazolyl. Embodiment 14 provides the compound of any one of Embodiments 1-13, wherein each occurrence of L independently comprises o occurrences of L1, p occurrences of L2, and q instances of L3, wherein: each occurrence of L1is independently selected from the group consisting of optionally substituted C1-C6 alkylenyl, optionally substituted C1-C6 heteroalkylenyl, and optionally substituted C2-C6 alkenylenyl; each occurrence of L2is independently selected from the group consisting of -O-, -S-, and -N(RD)-; each occurrence of L3is independently selected from the group consisting of -C(=O)-, -S(=O)-, and -S(=O)2-; o, p, and q are each independently an integer ranging from 0 to 20; each occurrence of RDis independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2- C10heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10heteroaryl; and wherein L1, L2, and L3are selected such that no two occurrences of L1, L2, - 98 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) and L3are adjacent (i.e., no covalent bonds between two occurrences of L1, L2, or L3). Embodiment 15 provides the compound of any one of Embodiments 1-14, wherein the protein of interest-binding moiety targets a protein selected from the group consisting of 1KZF3, AKT (e.g., AKT1, AKT2, or AKT3), ALK, androgen receptor (AR), ARAF, AURORA-A, BCL2, BCL6, a BET protein (e.g., BRD2, BRD3, BRD4, BRD7, or BRD9), BTK, CBL-B, CDK (e.g., CDK2, CDK4, CDK6, CDK8, or CDK9), CDK4, CDK6, CK1alpha, EGFR, EP300, estrogen receptor (ER), EZH2, FAK, FKBP12, GSPT1, HPK1, HSP90, HTT, IKZF1, IRAK4, KRAS, LRRK2, Mcl-1, MDM2, mdm2, MEK (e.g., MEK1 or MEK2), METTL3, METTL14, PARP1, PBMR1, PD-1 / PD-L1, p300 / CBP, PRC2, PRMT5, RIPK2, SALL4, SGK-3, SF3B1, SMARCA2, SMARCA4, STING, STAT (e.g., STAT3 or STAT5), STAT6, Tau, TRIM24, Tyk2, ZFP91, ZFP98, ZNF276, ZNF653, ZNF692, ZNF827, and α-synuclein. Embodiment 16 provides the compound of any one of Embodiments 1-15, wherein the protein of interest-binding moiety comprises a compound, or derivative or analogue thereof, selected from the group consisting of ABT-263, Acalabrutinib, Afatinib, Alectinib, Alpelisib, AMG 510, Apalutamide, AZD5363, Bortezomib, Brigatinib, Capmatinib, Ceritinib, Copanlisib, Crizotinib, Dabrafenib, Dasatinib, Enzalutamide, Entrectinib, Erlotinib, Fulvestrant, Gefitinib, Gilteritinib, Ibrutinib, Imatinib, Ivosidenib, JQ1, Lapatinib, Lorlatinib, Nutlin-3, Nintedanib, Osimertinib, Palbociclib, Panobinostat, Ruxolitinib, Selpercatinib, Sorafenib, Sunitinib, SNS-032, Trametinib, Venetoclax, Vemurafenib, and Vorinostat. Embodiment 17 provides the compound of any one of Embodiments 1-14, wherein the antibody is a thiol-containing antibody. Embodiment 18 provides the compound of any one of Embodiments 1-14 and 17, wherein the antibody binds to a tumor-associated antigen or cell-surface receptor. Embodiment 19 provides the compound of Embodiment 18, wherein the tumor associated antigen or cell-surface receptor is selected from the group consisting of AXL, B7- H4, CA125, CA19-9, CD19, CD20, CD22, CD30, CD33, CD38, CD40, CD44, CD52, CD56, CD70, CD74, CD79b, CD80, CD123, CD138, CD147, CD200, CD276 (B7-H3), CD319 (SLAMF7), CD324 (E-cadherin), CD366 (TIM-3), CEA (Carcinoembryonic Antigen), EGFR (Epidermal Growth Factor Receptor), EpCAM (Epithelial Cell Adhesion Molecule), FAP (Fibroblast Activation Protein), GD2, GD3, GPC3 (Glypican-3), HER2 (Human Epidermal Growth Factor Receptor 2), HER3, HER4, IGF-1R (Insulin-like Growth Factor 1 Receptor), IL-6R (Interleukin-6 Receptor), IL-13Rα2 (Interleukin-13 Receptor Alpha 2), L1CAM (L1 Cell Adhesion Molecule), Mesothelin, MET (Hepatocyte Growth Factor Receptor), MUC1, - 99 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) Nectin-4, PD-L1 (Programmed Death-Ligand 1), PSMA (Prostate-Specific Membrane Antigen), ROR1 (Receptor Tyrosine Kinase-Like Orphan Receptor 1), ROR2, TROP2, and VEGFR (Vascular Endothelial Growth Factor Receptor). Embodiment 20 provides a pharmaceutical composition comprising the compound of any one of Embodiments 1-19 and a pharmaceutically acceptable carrier. Embodiment 21 provides a method for inducing degradation of a target protein in a cell, the method comprising contacting the cell with a therapeutically effective amount of the compound of any one of Embodiments 1-19 or the pharmaceutical composition of Embodiment 20. Embodiment 22 provides the method of Embodiment 21, wherein the target protein is at least one selected from the group consisting of 1KZF3, AKT (e.g., AKT1, AKT2, or AKT3), ALK, androgen receptor (AR), ARAF, AURORA-A, BCL2, BCL6, a BET protein (e.g., BRD2, BRD3, BRD4, BRD7, or BRD9), BTK, CBL-B, CDK (e.g., CDK2, CDK4, CDK6, CDK8, or CDK9), CDK4, CDK6, CK1alpha, EGFR, EP300, estrogen receptor (ER), EZH2, FAK, FKBP12, GSPT1, HPK1, HSP90, HTT, IKZF1, IRAK4, KRAS, LRRK2, Mcl- 1, MDM2, mdm2, MEK (e.g., MEK1 or MEK2), METTL3, METTL14, PARP1, PBMR1, PD-1 / PD-L1, p300 / CBP, PRC2, PRMT5, RIPK2, SALL4, SGK-3, SF3B1, SMARCA2, SMARCA4, STING, STAT (e.g., STAT3 or STAT5), STAT6, Tau, TRIM24, Tyk2, ZFP91, ZFP98, ZNF276, ZNF653, ZNF692, ZNF827, and α-synuclein. Embodiment 23 provides the method of Embodiment 21 or 22, wherein the compound or composition is effective in degrading the target protein in the cell. Embodiment 24 provides a method for treating, preventing, and / or ameliorating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-19 or the pharmaceutical composition of Embodiment 20. Embodiment 25 provides the method of Embodiment 24, wherein the disease or disorder is cancer. Embodiment 26 provides the method of Embodiment 25, wherein the cancer is selected from the group consisting of squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non-Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; multiple myeloma, sarcomas, including Ewing’s sarcoma, - 100 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin’s disease, Wilms’ tumor, and teratocarcinomas. Embodiment 27 provides the method of Embodiment 25 or 26, wherein the cancer is at least one selected from the group consisting of T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T- cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML. Embodiment 28 provides the method of any one of Embodiments 24-27, wherein the method further comprises exposing the compound or composition to a stimulus. Embodiment 29 provides the method of Embodiment 28, wherein the stimulus is at least one selected from the group consisting of light, a change in pH, a reducing agent, an oxidizing agent, a change in oxygen concentration, a temperature change, addition of a metal (e.g., Fe2+), and a change in electric potential. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application. - 101 - 56067759.3

Claims

1. Attorney Docket No.047162-7520WO1(02652) CLAIMS What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or isotopologue thereof: , wherein: T is absent or selected Ab and D; Ab, if present, is a cell and / or antigen binding domain, optionally wherein the cell and / or antigen binding domain is an antibody; D, if present, is a protein of interest-binding moiety; L is absent or each occurrence of L is independently a linker covalently conjugated to T and cDp; each occurrence of cDpis independently a cereblon degrader precursor of structure: , wherein each L, covalently conjugated to cDpvia a covalent bond to ring A, -NH-, R1, or R2; l is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; m is 0 or 1; each occurrence of ring A is independently selected from the group consisting of optionally substituted C3-C20heterocyclyl and optionally substituted C6-C10aryl; each occurrence of R1is selected from the group consisting of H and a selectively cleavable protecting group; and each occurrence of R2is a leaving group.

2. The compound of claim 1, which is selected from the group consisting of: (Ia), (Ib), and (Ic). - 102 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 3. The compound of claim 1 or 2, wherein cDp is selected from the group consisting of:

4. The compound of any one of claims 1-3, wherein each occurrence of , if present, is independently selected from the group consisting of: , , - 103 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) L R1N O , 5. The compound of any one of claims 1-4, wherein ring A is selected from the group consisting of: - 104 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) wherein: each occurrence of R3is independently selected from the group consisting of H, halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10aryl, optionally substituted C2-C10heteroaryl, ORA, N(RA)(RB), Si(RA)3, C(=O)ORA, C(=O)RA, C(=N-N(RA)(RB))RC, C(=O)N(RA)(RB), S(=O)2N(RA)(RB), S C N N C N S N S2N ; substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted C6-C10aryl, optionally substituted C2-C10 heteroaryl, Si(RA)3, C(=O)ORA, C(=O)RA, C(=N- N(RA)(RB))RC, C(=O)N(RA)(RB), S(=O)2N(RA)(RB), S(=O)2RA, and C(=NRA)N(RB)(RC); n is 0, 1, 2, 3, 4, or 5; and each occurrence of RA, RB, and RCis independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl.

6. The compound of claim 5, wherein R3is selected from the group consisting of NH2, F, and CH3.

7. The compound of claim 5 or 6, wherein R4is selected from the group consisting of H and CH3.

8. The compound of any one of claims 1-7, wherein R1is H.

9. The compound of any one of claims 1-7, wherein the selectively cleavable protecting group comprises a photocleavable moiety, a pH-sensitive moiety, a redox-sensitive moiety, a thermally-sensitive moiety, an oxygen-sensitive moiety (e.g., hypoxia-sensitive), an enzymatically cleavable moiety, and an electrochemically-sensitive moiety. - 105 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 10. The compound of any one of claims 1-7 and 9, wherein R1comprises a moiety selected from the group consisting of an optionally substituted benzylcarboxy moiety ( ). from the is 12. The compound of any one of claims 1-11, wherein R2is selected from the group consisting of OH, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkoxy, optionally substituted C2-C8heterocycloalkoxy, optionally substituted C2-C8heteroaryloxy, optionally substituted C6-C10 aryloxy, optionally substituted C1-C6 alkylamino, optionally substituted C3-C8cycloalkylamino, optionally substituted C2-C8- 106 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) heterocycloalkylamino, optionally substituted C2-C8 heteroarylamino, optionally substituted C6-C10arylamino, optionally substituted C2-C8heteroaryl, and halogen.

13. The compound of any one of claims 1-12, wherein R2is selected from the group consisting of OH, OCH3, OCH2CH3, OC(CH3)3, OCF3, OCH2CF3, OPh, 4-nitro-phenoxy, F, Cl, Br, I, and imidazolyl.

14. The compound of any one of claims 1-13, wherein each occurrence of L independently comprises o occurrences of L1, p occurrences of L2, and q instances of L3, wherein: each occurrence of L1is independently selected from the group consisting of optionally substituted C1-C6alkylenyl, optionally substituted C1-C6heteroalkylenyl, and optionally substituted C2-C6 alkenylenyl; each occurrence of L2is independently selected from the group consisting of -O-, -S-, and -N(RD)-; each occurrence of L3is independently selected from the group consisting of -C(=O)-, -S(=O)-, and -S(=O)2-; o, p, and q are each independently an integer ranging from 0 to 20; each occurrence of RDis independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C10 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10heteroaryl; and wherein L1, L2, and L3are selected such that no two occurrences of L1, L2, and L3are adjacent (i.e., no covalent bonds between two occurrences of L1, L2, or L3).

15. The compound of any one of claims 1-14, wherein the protein of interest-binding moiety targets a protein selected from the group consisting of 1KZF3, AKT (e.g., AKT1, AKT2, or AKT3), ALK, androgen receptor (AR), ARAF, AURORA-A, BCL2, BCL6, a BET protein (e.g., BRD2, BRD3, BRD4, BRD7, or BRD9), BTK, CBL-B, CDK (e.g., CDK2, CDK4, CDK6, CDK8, or CDK9), CDK4, CDK6, CK1alpha, EGFR, EP300, estrogen receptor (ER), EZH2, FAK, FKBP12, GSPT1, HPK1, HSP90, HTT, IKZF1, IRAK4, KRAS, LRRK2, Mcl-1, MDM2, mdm2, MEK (e.g., MEK1 or MEK2), METTL3, METTL14, PARP1, PBMR1, PD-1 / PD-L1, p300 / CBP, PRC2, PRMT5, RIPK2, SALL4, SGK-3, SF3B1, - 107 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) SMARCA2, SMARCA4, STING, STAT (e.g., STAT3 or STAT5), STAT6, Tau, TRIM24, Tyk2, ZFP91, ZFP98, ZNF276, ZNF653, ZNF692, ZNF827, and α-synuclein.

16. The compound of any one of claims 1-15, wherein the protein of interest-binding moiety comprises a compound, or derivative or analogue thereof, selected from the group consisting of ABT-263, Acalabrutinib, Afatinib, Alectinib, Alpelisib, AMG 510, Apalutamide, AZD5363, Bortezomib, Brigatinib, Capmatinib, Ceritinib, Copanlisib, Crizotinib, Dabrafenib, Dasatinib, Enzalutamide, Entrectinib, Erlotinib, Fulvestrant, Gefitinib, Gilteritinib, Ibrutinib, Imatinib, Ivosidenib, JQ1, Lapatinib, Lorlatinib, Nutlin-3, Nintedanib, Osimertinib, Palbociclib, Panobinostat, Ruxolitinib, Selpercatinib, Sorafenib, Sunitinib, SNS-032, Trametinib, Venetoclax, Vemurafenib, and Vorinostat.

17. The compound of any one of claims 1-14, wherein the antibody is a thiol-containing antibody.

18. The compound of any one of claims 1-14 and 17, wherein the antibody binds to a tumor-associated antigen or cell-surface receptor.

19. The compound of claim 18, wherein the tumor associated antigen or cell-surface receptor is selected from the group consisting of AXL, B7-H4, CA125, CA19-9, CD19, CD20, CD22, CD30, CD33, CD38, CD40, CD44, CD52, CD56, CD70, CD74, CD79b, CD80, CD123, CD138, CD147, CD200, CD276 (B7-H3), CD319 (SLAMF7), CD324 (E- cadherin), CD366 (TIM-3), CEA (Carcinoembryonic Antigen), EGFR (Epidermal Growth Factor Receptor), EpCAM (Epithelial Cell Adhesion Molecule), FAP (Fibroblast Activation Protein), GD2, GD3, GPC3 (Glypican-3), HER2 (Human Epidermal Growth Factor Receptor 2), HER3, HER4, IGF-1R (Insulin-like Growth Factor 1 Receptor), IL-6R (Interleukin-6 Receptor), IL-13Rα2 (Interleukin-13 Receptor Alpha 2), L1CAM (L1 Cell Adhesion Molecule), Mesothelin, MET (Hepatocyte Growth Factor Receptor), MUC1, Nectin-4, PD- L1 (Programmed Death-Ligand 1), PSMA (Prostate-Specific Membrane Antigen), ROR1 (Receptor Tyrosine Kinase-Like Orphan Receptor 1), ROR2, TROP2, and VEGFR (Vascular Endothelial Growth Factor Receptor).

20. A pharmaceutical composition comprising the compound of any one of claims 1-19 and a pharmaceutically acceptable carrier. - 108 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) 21. A method for inducing degradation of a target protein in a cell, the method comprising contacting the cell with a therapeutically effective amount of the compound of any one of claims 1-19 or the pharmaceutical composition of claim 20.

22. The method of claim 21, wherein the target protein is at least one selected from the group consisting of 1KZF3, AKT (e.g., AKT1, AKT2, or AKT3), ALK, androgen receptor (AR), ARAF, AURORA-A, BCL2, BCL6, a BET protein (e.g., BRD2, BRD3, BRD4, BRD7, or BRD9), BTK, CBL-B, CDK (e.g., CDK2, CDK4, CDK6, CDK8, or CDK9), CDK4, CDK6, CK1alpha, EGFR, EP300, estrogen receptor (ER), EZH2, FAK, FKBP12, GSPT1, HPK1, HSP90, HTT, IKZF1, IRAK4, KRAS, LRRK2, Mcl-1, MDM2, mdm2, MEK (e.g., MEK1 or MEK2), METTL3, METTL14, PARP1, PBMR1, PD-1 / PD-L1, p300 / CBP, PRC2, PRMT5, RIPK2, SALL4, SGK-3, SF3B1, SMARCA2, SMARCA4, STING, STAT (e.g., STAT3 or STAT5), STAT6, Tau, TRIM24, Tyk2, ZFP91, ZFP98, ZNF276, ZNF653, ZNF692, ZNF827, and α-synuclein.

23. The method of claim 21 or 22, wherein the compound or composition is effective in degrading the target protein in the cell.

24. A method for treating, preventing, and / or ameliorating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-19 or the pharmaceutical composition of claim 20.

25. The method of claim 24, wherein the disease or disorder is cancer.

26. The method of claim 25, wherein the cancer is selected from the group consisting of squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non-Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; multiple myeloma, sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, - 109 - 56067759.3 Attorney Docket No.047162-7520WO1(02652) oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin’s disease, Wilms’ tumor, and teratocarcinomas.

27. The method of claim 25 or 26, wherein the cancer is at least one selected from the group consisting of T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre- B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

28. The method of any one of claims 24-27, wherein the method further comprises exposing the compound or composition to a stimulus.

29. The method of claim 28, wherein the stimulus is at least one selected from the group consisting of light, a change in pH, a reducing agent, an oxidizing agent, a change in oxygen concentration, a temperature change, addition of a metal (e.g., Fe2+), and a change in electric potential. - 110 - 56067759.3

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