Protein tyrosine phosphatase degraders and uses thereof

Abstract

Provided herein are degrader compounds, compositions, and methods useful for degrading protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1), and for treating related diseases, disorders, and conditions favorably responsive to PTPN1 or PTPN2 degrader treatment, e.g., a cancer or a metabolic disease.

Description

PROTEIN TYROSINE PHOSPHATASE DEGRADERS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application SerialNo. 63 / 517,192 filed August 2, 2023; which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Cancer im munotherapy regtmens tar geting im mume evasion mechanisms including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies) have been shown to be effective in treating in a variety of cancers, dramatically improving outcomes m some populations refractory to conventional therapies. However, incom plete clinical responses a nd the developm ent of intrinsic or a cquired resistna cee continue to iim it the patient populations who could benefit from checkpoint blockade.

[0003] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phospho-tyrosine specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells. In humans, PTPN2 expression is controlled post-transcripl tonally by the existence of two splice varia nts: a 45 kDa form that conta ins a nuclear localization signal at the C -terminus upstream of the splice junction, and a 48 kDa canonicalfonn which ha s a C -terminal ER retention motif. The 45 kDa isoform can passively transfuse into the cytosoiundercertain cellular stress conditions. Both isoforms share an N-tenninalphospho-tyrosine phospha tase catalytic domain. PTPN2 negatively regulates signaling of non-receptor tyrosine kinases (e.g., JAKl , JAK3), receptor tyrosine kinases (e.g., TNSR, EGFR, CSF1R. PDGFR), transcription factors (e.g., ST ATI , STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lek). As a critical negative regulator of the JAK- STAT pathway, PTPN2 functions to directly regulate signaling through cy tokine receptors, including IFNy. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also called FTP IB), and shares similar enzymatic kinetics. Data from a loss of function in vivo genetic screen using CRT SPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model show tha t deletion of Ptpn2 gene iti tumor cells improved response to the immunotherapy regimen of a GM-CSF secreting vaccine (GVAX) plus PD-1 checkpoint blockade. Loss of PTPN2 sensitized tumors to immunotherapy by enhancing IFNy-m edia ted effects on antigen presentation and growth suppression . The same screen also revealed that genes known to be involved in immune evasion. including PD-L1 and CD47, were also depleted under im munotherapy selective pressure, while genes involved in the IFNy signaling pathway, including IFNGR, JAKl, and STAT1, were enriched. These observations point to a putative role for therapeutic strategies that enhance IFNy sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens.

[0004] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phospha tase-lB (PTP1B), has been shown to play a key role in insulin and leptin signaling and is a primary mechanism for down -regulating both the insulin and leptin receptor signaling pathways. Animals deficient in PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with ahigh fat diet. Thus, PTP1B inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabohc syndrome.

[0005] One approach to externally impact protein activity is by decreasing levels of a particular protein by targeted protein degradation. Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin -pro tea some pathway (UPP). The UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycling, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neuralnetworks, modulation of cell surface receptors, ion channelsand the secretory pathway, the response to stress and extracellularmodulators, ribosome biogenesis and viral infection. Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin hgase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins. There are over 600 E3 ubiquitin hgases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RINGE3s and multi-subunit E3s. The first E3 hgase successfully targeted with a small molecule was SC Fβ TrC1’. using a hybrid of the small molecule MetAP2 inhibitor linked to a Ik Bα phosphopeptide epitope known to bind to the ubiquitin E3 hgase. (Sakamoto et al, PNAS 2001, 98 (15) 8554). Schneekloth et al. describe a degradation agent (PROTAC3) that targets the FK506 binding protein (FKBP12) and shows that both PROTAC2 and PROTAC3 hit their respective targets with green fluorescent protein (GFP) imaging. Schneekloth et al. (Chem Bio Chem 2005, 6, 40-46). In unrelated parallel research, scientists were investigating thahdomide toxicity, and discovered that cereblon is a thahdomide binding protein. Ito et al.(Science 2010, 327, 1345- 1350). Cereblon forms part of an E3 ubiquitin hgase protein complex which interacts with damaged DNA binding protein 1, forming an E3 ubiquitin hgase complex with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1) where it functions as a substrate receptor to select proteins for ubiquitination. The study revealed that thahdomide-cereblon binding in vivo may be responsible for thahdomide teratogenicity. After the discovery that thahdomide binds to the cereblon E3 ubiquitin hgase led to research to investigate incorporating thahdomide and certain derivatives into compounds for the targeted destruction of proteins. See G. Lu et al., (Science, 343, 305-309 (2014)); and J. Kronke et al., (Science, 343, 301-305 (2014)).

[0006] While progress has been made in the area of modulation of the UPP for in vivo protein degradation, there is a need for additional compounds and approaches to more fully harness the UPP for therapeutic treatments, forexample, forthe development of targeted PTPN1 or PTPN2 degraders useful for the treatment of cancer, type 2 diabetes, obesity, and metabohc syndrome.SUMMARY OF THE INVENTION

[0007] Disclosed herein are compounds, compositions, and methods that cause degradation of a protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 ((PTPN1), also known as protein tyrosine phosphatase-lB (PTP1B) via the ubiquitin proteasome pathway (UPP). In some embodiments, the compounds described herein comprise a “Targeting Ligand” that binds to a protein tyrosine phosphatase, a “Degron” which binds (e.g., non- covalently)to an E3 Ligase (e.g., the cereblon component) and a linker that covalently links the Targeting Ligand to the Degron.

[0008] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof :Formula (I) as disclosed herein.

[0009] Disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof :Formula (II) as disclosed herein.

[0010] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0011] Also disclosed herein is a method of trea ting cancer in a subject in need thereof, the method comprising administering to the subject a u effective amount of a compound d isclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0012] A method of trea ting cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0013] Also disclosed herein is a method of treating type-2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0014] Also disclosed herein is a method of treating type-2 diabetes in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0015] Also disclosed herein is a method of treatingand / orcontrollingobesity in a subject in need thereof, the method com prising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0016] Also d isclosed herein is a method of treatingand / orcontrollingobesity in a subject iti need thereof, the method comprising administering to the subject a pharmaceutical composition disclosed herein.

[0017] Also disclosed herein is a method of trea ting a metabolic disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0018] Also disclosed herein is a method of treating a metabolic disea se in a subject in need thereof, the method comprising adm inistering to the subject a pharmaceutical composition d isclosed herein.

[0019] In some embodiments, the method further com prises administering an additional therapeutic agent.

[0020] In some embodiments, the additional therapeutic agent is an anti-PD-1 antibody , an anti-PD-L1 antibody . or a n anti-CTL. A-4 antibody .

[0021] In some embodiments, the additional therapeutic agent is CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, or tisagenlecleucel.

[0022] Also disclosed herein is a method forproducinga leukocyte that ha san enhanced capacity forkilling a target cell, the method including contacting the leukocyte with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in conditions for enabling the degrader to inactivate PTPN2 in the leukocyte, thereby producing a leukocyte that has an enhanced capacity forkilling a target cell.

[0023] In som e embodiments, the leukocyte is contacted with the compound in the absence of a T helper cell.

[0024] In some embodiments, the leukocyte is derived from a subject having a cancer.

[0025] In some embodiments, the leukocyte is a neutrophil, eosinophil, basophil, monocyte, or lymphocyte.

[0026] In some embodiments, the lymphocyte is a tumor infiltrating lymphocyte.

[0027] In some embodiments, the leukocyte is conditioned or engineered to have specificity for a cancer antigen.

[0028] In some embodiments, the engineered specificity is provided by a recombinant chimeric receptor or T cell receptor that specifically binds to a cancer antigen.

[0029] In some embodiments, the target cell is a cancer cell.

[0030] Also disclosed herein is a method fortreatingca nccrincluding the steps of culturing a leukocytes from a cancer subject to be trea ted or a histocompatible donor to the cancer subject to be treated in the presence of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ex vivo in conditions for enabling the degraderto inactivate PTPN2 in the leukocytes, thereby forming a composition of cells with an enhanced capacity for killing a target cancer cell, administering the composition of cells to the subject, thereby treating cancer.

[0031] In some embodiments, the leukocyte is a neutrophil, eosinophil, basophil, monocyte, or lymphocyte.

[0032] In some embodiments, lymphocyte is a tumorinfiltrating lymphocyte, orperipheralblood lymphocyte.

[0033] In some embodiments, the leukocyte is conditioned or engineered to have specificity for the cancer to be treated.

[0034] In some embodiments, the engineered specificity is provided by a recombinant chimeric receptor or T cell receptor that specifically binds to a cancer antigen.INCORPORATION BY REFERENCE

[0035] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0036] In the following description, certain specific details are set forth in order to provide a thorough understandingof various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0037] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particularfeature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0038] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0039] “oxo” refers to =0.

[0040] “Amine” refers to -NH2.

[0041] “hydroxy” refers to -OH.

[0042] “Carboxyl” refers to -COOH.

[0043] “Alkyl” refers to a straight -chain orbranched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-m ethy 1-1 -propyl, 2-methy 1-2 -propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2- methy 1-3 -butyl, 2, 2-dimethy 1-1 -propyl, 2-m ethy 1-1 -pentyl, 3-methyl-l -pentyl, 4-m ethy 1-1 -pentyl, 2-methyl-2- pentyl, 3-methyl-2 -pentyl, 4-methyl-2 -pentyl, 2, 2 -dim ethy 1-1 -butyl, 3, 3 -dim ethy 1-1 -butyl, 2 -ethy 1-1 -butyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atomsor6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numericalrange is designated. In some embodiments, the alkylis a C1-C10 alkyl. In some embodiments, the alkyl is a C1-C6alkyl. In some embodiments, the alkyl is a C1-C5alkyl. In some embodiments, the alkyl is a C1-C4alkyl. In some embodiments, the alkyl is a C1-C3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylis optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe,1-OH, -OMe, -NH2, or -NO2. In some embodim ents, the alky lis optionally substituted with one or more halogen, - CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0044] “Alkenyl” refers to a straight-chain orbranched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1- propenyl(-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienylandthe like. Whenever it appears herein, a numericalrange such as“C2-C6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numericalrange is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0045] “ Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and havingfrom two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyland the like. Whenever it appears herein, a numericalrange such as “C2-C6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numericalrange is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0046] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, orheteroary 1, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0047] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionallysubstituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0048] “Aryl” refers to a radicalderivedfrom a hydrocarbon ringsy stem comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocychc, bicychc, tricyclic, ortetracychc ring system, which may include fused (when fused with a cycloalkyl or heterocycloalky 1 ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the arylis a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthraceny 1, naphthyl, phenanthrenyl, azulenyl, phenyl, chry senyl, fhioranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indeny 1, phenalenyl, phenanthrenyl, pleiadenyl,pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0049] “Arylene” refers to a divalent aryl as defined above. Unless stated otherwise specifically in the specification, an arylene may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the arylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the arylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the arylene is optionally substituted with halogen.

[0050] “Cycloalkyl” refers to a partially or fully saturated, monocychc, orpolycychc carbocychc ring, which may include fused (when fused with an arylor a heteroarylring, the cycloalkylis bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15fully saturated cycloalkylorC3-C15cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8fully saturated cycloalkylor C3-C8cycloalkenyl), from three to six carbon atoms (e.g., C3-C6fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (e.g., C3-C5fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4fully saturated cycloalkyl or C3-C4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalky l is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6- membered cycloalkenyl. Monocychc cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycychc cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo [3 ,2.2]nonyl, and bicyclo[3.3.2]decyl,bicy clo[l .1. I]pentyl, bicyclo[3.1.0]hexyl, bicyclo [3.1. l]hepty 1, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, spiro [4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -C00H, -COOMe, -CF3, -OH, -OMe, -NH2, or - NO2. In some embodiments, a cycloalkylis optionally substituted with one or more oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0051] “Cycloalkylene” refers to a divalent cycloalkyl as defined above. Unless stated otherwise specifically in the specification, a cycloalkylene may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the cycloalkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the cycloalkylene is optionally substituted with halogen.

[0052] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0053] “Haloalky 1” refers to an alky 1 radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2- difluoroethyl, 2-fluoroethyl, 3-bromo-2 -fluoropropyl, 1,2-dibromoethyl, and the like.

[0054] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0055] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxy alkyl includes, for example, hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0056] “Aminoalkyl” refers to an alkylradical, as defined above, thatis substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0057] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkylis substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkylis substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0058] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalky lis attachedto the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms otherthan carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkylwherein the heteroalky lis comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfurwherein the heteroalkylis attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, - CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalky 1, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0059] “Heterocycloalkyl” refersto a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocychc, bicychc, tricychc, or tetracychc ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkylor C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydro pyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkylis not the same as the totalnumber of atoms (including the heteroatoms)thatmake up the heterocycloalkyl(i.e. skeletal atoms ofthe heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkylis a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6- membered heterocycloalkyl. In some embodiments, the heterocycloalkylis a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkylis a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or - NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0060] “Heterocycloalkylene” refers to a divalent heterocycloalkyl as defined above. Unless stated otherwise specifically in the specification, an heterocycloalkylene may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heterocycloalkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkylene is optionally substituted with one or more halogen, -CN, -OH, or - OMe. In some embodiments, the heterocycloalkylene is optionally substituted with halogen.

[0061] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocychc, bicychc, tricychc, or tetracychc ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroarylradicalmay be optionally oxidized; the nitrogen atom may be optionally quatemized. Insome embodiments, the heteroarylis a 5- to 10-membered heteroaryl. In some embodiments, the heteroarylis a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6- membered ring comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, iso thiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydro quinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0062] “Heteroarylene” refers to a divalentheteroarylasdefined above. Unless stated otherwise specifically in the specification, an heteroarylene may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalky 1, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroarylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroarylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the heteroarylene is optionally substituted with halogen.

[0063] The term “optional” or“optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un -substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and / or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0064] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0065] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammahan subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0066] “Treatment” of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceuticalcomposition, subsequentto the initiation of a pathologic event or contact with an etiologic agent and includes stabilization ofthe condition (e.g., condition does not worsen) or alleviation of the condition.

[0067] “Synergy” or“synergize” refers to an effect of a combination that is greaterthan additive of the effects of each component alone at the same doses.

[0068] As used herein, the term “PTPN2 -mediated” disorder or disease or alternatively “disease or disorder associated with PTPN2” means any disease or other deleterious condition in which PTPN2 or a mutant thereof is known to play a role. Accordingly, in some embodiments, the methods relate to treating or lessening the severity of one or more diseases in which PTPN2, or a mutant thereof, is known to play a role.

[0069] As used herein, the term “PTPN1 -mediated” disorder or disease or alternatively “disease or disorder associated with PTPN1” means any disease or other deleterious condition in which PTPN1 or a mutant thereof is known to play a role. Accordingly, in some embodiments, the methods relate to treating or lessening the severity of one or more diseases in which PTPN1, or a mutant thereof, is known to play a role.Compounds

[0070] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, that are PTPN1 / PTPN2 degraders.

[0071] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof : wherein:Ring A is a heterocycloalkyl or heteroaryl;each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1on the same atom are taken together to form an oxo; or two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; n is 0, 1, 2, 3, or 4; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR5-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, - NR5C(=O)-, -NR5C(=O)NR5-, -S(=O)2NR5-, -NR5S(=O)2-, -NR5S(=O)2NR5-, Ci-Cioalkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; each R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more R; s is 1-20;M is an E3 hgase targeting agent;L2is -O-, -S-, -S(=O)-, -S(=O)2-, -NR2-, -[C(R3)2]m-, -O[C(R3)2]m-, -NR2[C(R3)2]m-, -[C(R3)2]mO-, or - [C(R3)2]mNR2-;R2is hydrogen, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6dcutcroalkyl. C1-C6hydroxyalkyl. C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalky 1 is independently optionally substituted with one or more R; or two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; m is 1, 2, 3, or 4; each R4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, C1-C6dcutcroalkyl. C1-C6hydroxyalkyl. C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 0, 1, or 2;W is CRWorN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L -cyclo alkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6halo alky 1, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalky Independently optionally substituted with one or more R;L is absent or Ci-Csalkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, or C1-C3heteroalkyl; or two R on the same atom are taken together to form an oxo.

[0072] In some embodiments of a compound of Formula (I), Ring A is a 4- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from O, S, and N.

[0073] In some embodiments of a compound of Formula (I), Ring A is a 4-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N.

[0074] In some embodiments of a compound of Formula (I), Ring A is a 5-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N.

[0075] In some embodiments of a compound of Formula (I), Ring A is a 5-membered heterocycloalkyl comprising 1 heteroatom selected from O and N.

[0076] In some embodiments of a compound of Formula (I), Ring A is a 5-membered heterocycloalkyl comprising 1 heteroatom that is N.

[0077] In some embodiments of a compound of Formula (I), Ring A is a 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from O, S, and N.

[0078] In some embodiments of a compound of Formula (I), Ring A is a 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from O and N.

[0079] In some embodiments of a compound of Formula (I), Ring A is a 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms that are N.

[0080] In some embodiments of a compound of Formula (I), n is 0. In some embodiments of a compound of Formula (I), n is 1.

[0081] In some embodiments of a compound of Formula (I),

[0082] In some embodiments of a compound of Formula (I), each R3is hydrogen.

[0083] In some embodiments of a compound of Formula (I), m is 1 . In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 3.

[0084] In some embodiments of a compound of Formula (I), p is 0. In some embodiments of a compound of Formula (I), p is 1.

[0085] In some embodiments of a compound of Formula (I), W is N.

[0086] Also disclosed is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof :wherein:Ring A is a 7- to 15-membered cycloalkyl or a 7- to 15 -membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR5-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, - NR5C(=O)-, -NR5C(=O)NR5-, -S(=O)2NR5-, -NR5S(=O)2-, -NR5S(=O)2NR5-, Ci-Cioalkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; each R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; s is 1-20;M is an E3 hgase targeting agent;X is CRxorN;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYorN;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWorN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L -cyclo alkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, C 1 -C ehalo alky 1, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalky Independently optionally substituted with one or more R;L is absent or Ci-Csalkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, or Ci-Csheteroalkyl; or two R on the same atom are taken together to form an oxo.

[0087] In some embodiments of a compound of Formula (II), Ring A is a 7-membered cycloalkyl. In some embodiments of a compound of Formula (II), Ring A is a 8-membered cycloalkyl.

[0088] In some embodiments of a compound of Formula (II), Ring A is a 7-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, andN. In some embodiments of a compound of Formula (II), Ring A is a 7-memberedheterocycloalkylcomprising 1 heteroatom selected from O andN. In some embodiments of a compound of Formula (II), Ring A is a 7-membered heterocycloalkyl comprising 1 heteroatom that is N.

[0089] In some embodiments of a compound of Formula (II), Ring A is a 8-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, andN. In some embodiments of a compound of Formula (II), Ring A is a 8-memberedheterocycloalkylcomprising 1 heteroatom selected from O andN. In some embodiments of a compound of Formula (II), Ring A is a 8-membered heterocycloalkyl comprising 1 heteroatom that is N.

[0090] In some embodiments of a compound of Formula (II), n is 0. In some embodiments of a compound of Formula (II), n is 1 .

[0091] In some embodiments of a compound of Formula (II), X is CRX.

[0092] In some embodiments of a compound of Formula (II), Rxis halogen.

[0093] In some embodiments of a compound of Formula (II), Y is CRY.

[0094] In some embodiments of a compound of Formula (II), RYis -OH.

[0095] In some embodiments of a compound of Formula (II), Z is CRZ.

[0096] In some embodiments of a compound of Formula (II), Rzis hydrogen.

[0097] In some embodiments of a compound of Formula (II), W is N.

[0098] Also disclosed herein is a compound of Formula (III), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof :Formula (III), wherein:Ring A is a 6- to 15-membered bicychc cycloalkyl or a 6- to 15-membered bicychc heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR5-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, - NR5C(=O)-, -NR5C(=O)NR5-, -S(=O)2NR5-, -NR5S(=O)2-, -NR5S(=O)2NR5-, Ci-Cioalkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; each R5is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more R; s is 1-20;M is an E3 ligase targeting agent;X is CRxorN;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYorN;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRzor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWorN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L -cyclo alkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, C 1 -C ehalo alky 1, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalky Independently optionally substituted with one or more R;L is absent or Ci-Csalkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, or Ci-Csheteroalkyl; or two R on the same atom are taken together to form an oxo.

[0099] In some embodiments of a compound of Formula (III), Ring A is a 6- to 15-membered bicyclic cycloalkyl. In some embodiments of a compound of Formula (III), Ring A is a 6- to 10-membered bicyclic cycloalkyl.

[0100] In some embodiments of a compound of Formula (III), Ring A is a 6- to 15-membered bicyclic heterocycloalkylcomprising 1 to 4 heteroatoms selected from O, S, andN. In some embodiments of a compound of Formula (III), Ring A is a 6- to 15-membered bicyclic heterocycloalkylcomprising 1 or 2 heteroatoms selected from O and N. In some embodiments of a compound of Formula (III), Ring A is a 6- to 10-membered bicychc heterocycloalkyl comprising 1 or 2 heteroatoms selected from O and N.

[0101] In some embodiments of a compound of Formula (III), n is 0. In some embodiments of a compound of Formula (III), n is 1.

[0102] In some embodiments of a compound of Formula (III), X is CRX.

[0103] In some embodiments of a compound of Formula (III), Rxis halogen.

[0104] In some embodiments of a compound of Formula (III), Y is CRY.

[0105] In some embodiments of a compound of Formula (III), RYis -OH.

[0106] In some embodiments of a compound of Formula (III), Z is CRZ.

[0107] In some embodiments of a compound of Formula (III), Rzis hydrogen.

[0108] In some embodiments of a compound of Formula (III), W is N.

[0109] Also disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof :Formula (IV), wherein:Ring A is a 3- to 15-membered cycloalkyl or a 3- to 15-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR5-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, - NR5C(=O)-, -NR5C(=O)NR5-, -S(=O)2NR5-, -NR5S(=O)2-, -NR5S(=O)2NR5-, Ci-Cioalkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R;each R5is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more R; s is 1-20;M is an E3 hgase targeting agent;X is CRxorN;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYorN;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWorN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L -cyclo alkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, C 1 -C ehalo alky 1, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalky Independently optionally substituted with one or more R;L is absent or Ci-Csalkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, or Ci-Csheteroalkyl; or two R on the same atom are taken together to form an oxo.

[0110] In some embodiments of a compound of Formula (IV), Ring A is a 3- to 15-membered cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is a 3- to 10-membered cycloalkyl. In some embodiments of a compound of Formula (IV), Ring A is a 3- to 6-membered cycloalkyl.

[0111] In some embodiments of a compound of Formula (IV), Ring A is a 3- to 15-membered heterocycloalkylcomprising 1 to 4 heteroatoms selected from O, S, andN. In some embodiments of a compound of Formula (IV), Ring A is a 3- to 15 -membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O and N. In some embodiments of a compound of Formula (IV), Ring A is a 3- to 10-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O and N. In some embodiments of a compound of Formula (IV), Ring A is a 3- to 6-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O and N.

[0112] In some embodiments of a compound of Formula (IV), n is 0. In some embodiments of a compound of Formula (IV), n is 1.

[0113] In some embodiments of a compound of Formula (IV), X is CRX.

[0114] In some embodiments of a compound of Formula (IV), Rxis halogen.

[0115] In some embodiments of a compound of Formula (IV), Y is CRY.

[0116] In some embodiments of a compound of Formula (IV), RYis -OH.

[0117] In some embodiments of a compound of Formula (IV), W is N.

[0118] Also disclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof :Formula (V), wherein: each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4; p is 1, 2, or 3; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR5-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, - NR5C(=O)-, -NR5C(=O)NR5-, -S(=O)2NR5-, -NR5S(=O)2-, -NR5S(=O)2NR5-, Ci-Cioalkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R;each R5is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more R; s is 1-20;M is an E3 hgase targeting agent;X is CRxorN;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYorN;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWorN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L -cyclo alkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, C 1 -C ehalo alky 1, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalky Independently optionally substituted with one or more R;L is absent or Ci-Csalkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, or Ci-Csheteroalkyl; or two R on the same atom are taken together to form an oxo.

[0119] In some embodiments of a compound of Formula (V), m is 0. In some embodiments of a compound of Formula (V), m is 1.

[0120] In some embodiments of a compound of Formula (V), p is 0. In some embodiments of a compound of Formula (V), p is 1 .

[0121] In some embodiments of a compound of Formula (V), X is CRX.

[0122] In some embodiments of a compound of Formula (V), Rxis halogen.

[0123] In some embodiments of a compound of Formula (V), Y is CRY.

[0124] In some embodiments of a compound of Formula (V), RYis -OH.

[0125] In some embodiments of a compound of Formula (V), Z is CRZ.

[0126] In some embodiments of a compound of Formula (V), Rzis hydrogen.

[0127] In some embodiments of a compound of Formula (V), W is N.

[0128] Also disclosed herein is a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof :Formula (VI), wherein: each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4;R3is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cealkyl(cycloalkyl), Ci-Cealkyl(heterocycloalkyl), Ci-Cealkyl(aryl), or Ci-Cealkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3a; each R3ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R3aon the same atom are taken together to form an oxo;p is 1 -3 ; each L1is independently -0-, -S-, -S(=0)-, -S(=0)2-, -NR5-, -C(=0)-, -0C(=0)-, -C(=0)0-, -C(=O)NR5-, - NR5C(=O)-, -NR5C(=O)NR5-, -S(=O)2NR5-, -NR5S(=O)2-, -NR5S(=O)2NR5-, Ci-Cioalkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; each R5is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more R; s is 1-20;M is an E3 hgase targeting agent;X is CRxorN;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYorN;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWorN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L -cyclo alkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, C i -C ehalo alky 1, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalky Independently optionally substituted with one or more R;L is absent or Ci-Csalkylene independently optionally substituted with one or more R; andeach R is independently deuterium, halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, or Ci-Csheteroalkyl; or two R on the same atom are taken together to form an oxo.

[0129] In some embodiments of a compound of Formula (VI), m is 0. In some embodiments of a compound of Formula (V), m is 1.

[0130] In some embodiments of a compound of Formula (VI), p is 0. In some embodiments of a compound of Formula (V), p is 1 .

[0131] In some embodiments of a compound of Formula (VI), R3is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (VI), R3is hydrogen. In some embodiments of a compound of Formula (VI), R3is Ci-Cealkyl.

[0132] In some embodiments of a compound of Formula (VI), X is CRX.

[0133] In some embodiments of a compound of Formula (VI), Rxis halogen.

[0134] In some embodiments of a compound of Formula (VI), Y is CRY.

[0135] In some embodiments of a compound of Formula (VI), RYis -OH.

[0136] In some embodiments of a compound of Formula (VI), Z is CRZ.

[0137] In some embodiments of a compound of Formula (VI), Rzis hydrogen.

[0138] In some embodiments of a compound of Formula (VI), W is N.

[0139] In some embodiments of a compound of Formula (I)-(VI), each L1is independently -O-, -NR5-, - C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, -NR5C(=O)-, Ci-Cioalkylene, C2-C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

[0140] In some embodiments of a compound of Formula (I)-(VI), each L1is independently -O-, -NR5-, - C(=O)NR5-, -NR5C(=O)-, Ci-Cioalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

[0141] In some embodiments of a compound of Formula (I)-(VI), each L1is independently -NR5-, - C(=O)NR5-, -NR5C(=O)-, Ci-Cioalkylene, arylene, or heteroarylene; wherein each alkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

[0142] In some embodiments of a compound of Formula (I)-(VI), each L1is independently -NR5-, - C(=O)NR5-, -NR5C(=O)-, Ci-Cioalkylene, or arylene; wherein each alkylene, and arylene is independently optionally substituted with one or more R.

[0143] In some embodiments of a compound of Formula (I)-(VI), each L1is independently -NR5-, - C(=O)NR5-, -NR5C(=O)-, Ci-Cioalkylene; wherein each alkylene is independently optionally substituted with one or more R.

[0144] In some embodiments of a compound of Formula (I)-(VI), each R5is independently hydrogen or Ci-C6alkyl.

[0145] In some embodiments of a compound of Formula (I)-(VI), s is 1-15. In some embodiments of a compound of Formula (I)-(VI), s is 1-10. In some embodiments of a compound of Formula (I)-(VI), s is 1-5. In some embodiments of a compound of Formula (I)-(VI), s is 5-10. In some embodiments of a compound of Formula (I)-(VI), s is 5-15. In some embodiments of a compound of Formula (I)-(VI), s is 5-20. In some embodiments of a compound of Formula (I)-(VI), s is 2. In some embodiments of a compound of Formula (I)- (VI), s is 3. In some embodiments of a compound of Formula (I)-(VI), s is 4. In some embodiments of a compound of Formula (I)-(VI), s is 5. In some embodiments of a compound of Formula (I)-(VI), s is 6. In some embodiments of a compound of Formula (I)-(VI), s is 7. In some embodiments of a compound of Formula (I)- (VI), s is 8. In some embodiments of a compound of Formula (I)-(VI), s is 9. In some embodiments of a compound of Formula (I)-(VI), s is 10. In some embodiments of a compound of Formula (I)-(VI), s is 11. In some embodiments of a compound of Formula (I)-(VI), s is 12. In some embodiments of a compound of Formula (I)- (VI), s is 13. In some embodiments of a compound of Formula (I)-(VI), s is 14. In some embodiments of a compound of Formula (I)-(VI), s is 15. In some embodiments of a compound of Formula (I)-(VI), s is 16. In some embodiments of a compound of Formula (I)-(VI), s is 17. In some embodiments of a compound of Formula (I)- (VI), s is 18. In some embodiments of a compound of Formula (I)-(VI), s is 19. In some embodiments of a compound of Formula (I)-(VI), s is 20.

[0146] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Cioalkylene-NR5C(=0)-Ci- Csalkylene-.

[0147] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -C4-Cioalkylene-NR5C(=0)-Ci- Csalkylene-.

[0148] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -Ci-Csalkylene-NR5C(=O)-Ci- Csalkylene-.

[0149] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -Ci-Cioalkylene-NR5C(=0)- Ci alkylene-.

[0150] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -C4-Cioalkylene-NR5C(=0)- Ci alkylene-.

[0151] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-NR5C(=O)- Ci alkylene-.

[0152] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-Ci-Cioalkylene-NR5C(=0)- Ci-Csalkylene-.

[0153] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-C4-Cioalkylene-NR5C(=0)- Ci-Csalkylene-.

[0154] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-Ci-Csalkylene-NR5C(=O)- Ci-Csalkylene-.

[0155] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-Ci-Cioalkylene-NR5C(=0)- Ci alkylene-.

[0156] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-C4-Cioalkylene-NR5C(=0)- Ci alkylene-.

[0157] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-Ci-Csalkylene-NR5C(=O)- Ci alkylene-.

[0158] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Cioalkylene-.

[0159] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Csalkylene-.

[0160] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-C4-Cioalkylene-.

[0161] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5C(=0)-Ci-Cioalkylene-.

[0162] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5C(=O)-Ci-Csalkylene-.

[0163] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5C(=0)-C4-Cioalkylene-.

[0164] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Cioalkylene-.

[0165] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-.

[0166] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Cr-Cioalkylene-.

[0167] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -Ci-Cioalkylene-cycloalkylene-Ci- C i oa Iky lene -NR5C (=O)-C i -C3 a Iky lene -.

[0168] In some embodimentsofa compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-cycloalkylene -Ci- C 5 a Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0169] In some embodimentsofa compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-cycloalkylene -Ci- C3 a Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0170] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Cioalkylene- heterocycloalkylene-Ci-Cioalkylene-NR5C(=0)-Ci-C3alkylene-.

[0171] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene- heterocycloalkylene -Ci-C5alkylene-NR5C(=O)-Ci-C3alkylene-.

[0172] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene- heterocycloalkylene -Ci-C3alkylene-NR5C(=O)-Ci-C3alkylene-.

[0173] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Cioalkylene-arylene-Ci-C 1 oa Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0174] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-arylene-Ci-C 5 a Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0175] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-arylene-Ci-C3 a Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0176] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -Ci-Cioalkylene-heteroarylene-Ci- C 1 oa Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0177] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -Ci-Csalkylene-heteroarylene-Ci- C 5 a Iky lene -NR5C (=O)-C i -C3 a Iky lene

[0178] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -Ci-Csalkylene-heteroarylene-Ci- C3 a Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0179] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Cioalkylene- cy clo a Iky lene -C 1 -C 1 oa Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0180] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-Ci-C5alkylene-cycloalkylene -C 1 -C 5 a Iky lene -NR5C (=O)-C 1 -Csa Iky lene -.

[0181] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-Ci-C3alkylene-cycloalkylene -Ci-C3alkylene-NR5C(=O)-Ci-C3alkylene-.

[0182] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Cioalkylene- heterocycloalkylene-Ci-Cioalkylene-NR5C(=0)-Ci-C3alkylene-.

[0183] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Csalkylene- heterocycloalkylene -Ci-C5alkylene-NR5C(=O)-Ci-C3alkylene-.

[0184] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-C3alkylene- heterocycloalkylene -Ci-C3alkylene-NR5C(=O)-Ci-C3alkylene-.

[0185] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Cioalkylene-arylene-Ci- C 1 oa Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0186] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Csalkylene-arylene-Ci- C 5 a Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0187] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-C3alkylene-arylene-Ci- C3 a Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0188] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Cioalkylene- heteroarylene-Ci-Cioa Iky lene-NR5C(=O)-Ci-C3alky lene-.

[0189] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Csalkylene- heteroa ry lene -C 1 -C 5 a Iky lene -NR5C (=O)-C 1 -C3 a Iky lene -.

[0190] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-C3alkylene- heteroarylene-Ci-C3alkylene-NR5C(=O)-Ci-C3alkylene-.

[0191] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -O-Ci-Cioheteroalkylene-.

[0192] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -O-Ci-Csheteroalkylene-.

[0193] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -O-Cr-Cioheteroalkylene-.

[0194] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -O-Ci-Cioheteroalkylene-NR5C (=O)-C 1 -C3 a Iky lene -.

[0195] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -O-Ci-Csheteroalkylene-NR5C (=O)-C 1 -C3 a Iky lene -.

[0196] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -0-C4-Cioheteroalkylene- NR5C(=O)-Ci-C3alkylene-.

[0197] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -0-Ci-Cioheteroalkylene-NR5-Ci- Csalkylene-.

[0198] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -O-Ci-C5heteroalkylene-NR5-Ci- Csalkylene-.

[0199] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -0-C4-Cioheteroalkylene-NR5-Ci- Csalkylene-.

[0200] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Cioheteroalkylene-.

[0201] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-C5heteroalkylene-.

[0202] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-C4-Cioheteroalkylene-.

[0203] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-Cioheteroalkylene-NR5C (=O)-C i -C3 a Iky lene

[0204] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-C5heteroalkylene- NR5C(=O)-Ci-C3alkylene-.

[0205] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-C4-Cioheteroalkylene-NR5C (=O)-C 1 -C3 a Iky lene

[0206] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-Ci-Cioheteroalkylene-NR5- Ci-Csalkylene-.

[0207] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -NR5-Ci-C5heteroalkylene-NR5- Ci-Csalkylene-.

[0208] In some embodiments of a compound of Formula (I)-(VI), -(L1^- is -NR5-C4-Cioheteroalkylene-NR5- Ci-Csalkylene-.

[0209] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Cioalkylene-NR5-Ci- Cioa Iky lene-.

[0210] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-NR5-Ci- Csalkylene-.

[0211] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-C3alkylene-NR5-Ci- Csalkylene-.

[0212] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Cioalkylene-O-Ci- Cioa Iky lene-.

[0213] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-O-Ci-Csalkylene-.

[0214] In some embodiments of a compound of Formula (I)-(VI), -(L^s- is -Ci-Csalkylene-O-Ci-Csalkylene-.

[0224] In some embodiments of a compound of Formula (I)-(VI), the E3 ligase targeting agent is a cereblon E3 ligase, a VH L E3 ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, or an IAP ligase.

[0226] In some embodiments of a compound of Formula (I)-(VI), the E3 ligase targeting agent is

[0227] In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or Ci-Cehaloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl.

[0228] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-CealkylorCi-Cehaloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen orCi-Cealky 1. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl.

[0229] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl or Ci-Cehaloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen orCi-Cea Iky 1. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cealkyl.

[0230] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R.

[0231] In some embodiments of a compound disclosed herein, L is Ci-C3alkylene independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is Ci-C3alkylene. In some embodiments of a compound disclosed herein, L is Ci-C2alkylene. In some embodiments of a compound disclosed herein, L is Cialkylene. In some embodiments of a compound disclosed herein, L is C2alkylene. In some embodiments of a compound disclosed herein, L is C3alkylene. In some embodiments of a compound disclosed herein, L is absent.

[0232] In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, - CN, -OH, -OCi-C3alkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, - C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, or Ci-C3heteroalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, or Ci-C3heteroalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3haloalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -NH2, Ci-C3alkyl, orC1-C3haloalkyl; or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C3alkyl, or C1-C3haloalkyl; or two R on the same atom are taken together to form an oxo.

[0233] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0234] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0235] In some embodiments, the compound disclosed herein is a compound selected from the group consisting of:Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0236] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include alldia stereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments ofthe compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the apphcations described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, orpreferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0237] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically -labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically -labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically -labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or massnumber differentfrom the atomic mass ormassnumber usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically -labeled compounds, forexample those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability . Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

[0238] In some 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. Pharmaceutically acceptable salts

[0239] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0240] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolationand purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0241] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, Υ-hydroxy butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1 -napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propio late, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicy late, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0242] Further, the compoundsdescribedherein canbe prepared aspharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glyco lic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandehc acid, arylsulfonic acid, methane sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4’- methy lenebis-(3 -hydroxy -2 -ene-1 -carboxy lic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, saheyhe acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxa lic while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0243] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, orwith a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkalior alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI-C4 alky 4)4 hydroxide, and the like.

[0244] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understoodthat the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization. Solvates

[0245] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0246] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Tautomers

[0247] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and one ormore adjacent double bonds. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.Method of Treatment

[0248] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN1 / PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0249] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN1 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN1 is beneficial is cancer or a metabohc disease.

[0250] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN2 is beneficial is cancer.Cancer

[0251] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is used to treat cancer.

[0252] As used herein, “cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including so and and lymphoid cancers.

[0253] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase ornon-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, erythroleukemia, Gross' leukemia, hairy -cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0254] The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumo r sarcoma, endometrial sarcoma, endothehosarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, osteogenic sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0255] The term “carcinoma” refers to a malignant new growth made up of epithe lial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell care inoma, basalcell carcinoma, carcinoma basocellula re, basaloid carcinoma, basosquamous cell carcinoma, bileduct carcinoma, bladder carcinoma, breast carcinoma, Brenner carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, branchiogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocellular carcinoma, chordoma, chorionic carcinoma, clear cell carcinoma, colloid carcinoma, colon carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cy lindricalcell carcinoma, cystadenocarcinoma, duct carcinoma, ductalcarcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, endometrioid carcinoma, epiermoid carcinoma, epithehal carcinoma, carcinoma epithehale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatinifomi carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermalcarcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, hpomatous carcinoma, lobular carcinoma, lungcarcinoma, lymphoepithelialcarcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma my xomatodes, nasopharyngeal carcinoma, nonpapillary renal cell carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, ovarian carcinoma, pancreatic ductal carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, sebaceous gland carcinoma, seminoma, serous carcinoma, signet- ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, undifferentiated carcinoma, verrucous carcinoma, or carcinoma villosum.

[0256] In some embodiments, the cancer is acoustic neuroma, adrenal cortical cancer, adrenal gland cancer, astrocytoma, benign monoclonal gammopathy, biliary tract cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchus cancer, cancer of the hematological tissues, cancer of the hepatic stellate cells, cancer of the oral cavity or pharynx, cancer of the pancreatic stellate cells, carcinoma, central nervous system cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, ductalcarcinoma, endocrine system cancer, endometrial cancer, ependymoma, epithehalovarian cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, ghobla stoma multiforme, ghoma, gynecologic cancers, head and neck cancer, hemangioblastoma, Hodgkin's Disease, immunocytic amyloidosis, kidney cancer, laryngeal cancer, leukemia, hver cancer (including hepatocarcinoma), lobular carcinoma, lung cancer, lymphoma , malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulanoma, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, meso thehoma, multiple myeloma, myeloma, neoplasms of the endocrine or exocrine pancreas, neuroblastoma, non-Hodgkin's Lymphoma, ohgodendroghoma, oral cancer, ovarian cancer, Paget' s Disease of the Nipple, pancreatic cancer, papillary thyroid cancer, peripheral nervous system cancer, Phyllodes Tumors, pinealoma, premalignant skin lesions, primary macro globulinemia, primary thrombocytosis, prostate cancer, renal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small bowel or appendix cancer,stomach cancer, testicular cancer, thyroid cancer, urinary bladder cancer, uterine cancer, Waldenstrom’s m a cro globulinem ia .

[0257] Disclosed herein is a method for producing a leukocy te that has an enhanced capacity for killing a target cell, the method including contacting the leukocyte with a PTPN2 degrader disclosed herein in conditions for enabling the inhibitor to inactivate PTPN2 in the leukocyte, thereby producing a leukocyte that has an enhanced capacity for killing a target cell. Preferably, the leukocyte is contacted with the PTPN2 inhibitor in the absence of a T helper cell.

[0258] Disclosed herein is a method forproducinga leukocyte cell that ha san enhanced capacity for killing a target cell, the method including contacting the leukocyte ex vivo with a PTPN2 degrader disclosed herein for a sufficient time and under conditions for inactivation of PTPN2 in the leukocyte, thereby producing a leukocyte cell that has an enhanced capacity for killing a target cell. Preferably, the leukocyte is not contacted ex vivo with a CD4 T helper cell.

[0259] Disclosed herein is a method for prepa ring an ex vivo population of T cells exhibiting at least one property of a cytotoxic T cell including culturing I cells in the presence of a PTPN2 degrader disclosed herein.

[0260] Disclosed herein is a method for preparing an ex vivo population of T cells exhibiting at least one property of a cytotoxic T cell including the steps of: culturing a T cell population from a biological sample in the presence of a PTPN2 degrader disclosed herein; expanding the cells in culture; thereby preparing an ex vivo population of T cells exhibiting cytotox ic properties. In som e embodim cuts, the biological sa mple is derived from a subject having a cancer or have been conditioned or engineered to have specificity for a cancer.

[0261] Disclosed herein is an ex vivo method forpreparinga composition including antigen-specific cytotoxic I cells ex vivo including: providing a biological sample containing I cells; co-culturing antigenic material with the T ceil popula non in the presence of a PTPN2 degrader disclosed herein; and expanding the cells in culture, thereby preparing a composition including antigen-specific cytotoxic T cells ex vivo.

[0262] Disclosed herein is a method for increasin g the level of T ceils in a subject exhibiting an effector memory phenotype inchidin g the steps of: culturing a T cell population from a biological sa mple ex vivo in the presence of a PTPN2 degrader disclosed herein: expanding the cells in culture: administering the cultured cells to the subject: thereby increasing the level of T cells in a subject exhibiting an effector memory phenotype.

[0263] Disclosed herein is a method for forming an immune response in a subject suitable for the treatment of cancer including the steps of obtaining! cells from the subject or a histocompatible donor subject; culturing the I cells in the presence of a PTPN2 degrader disclosed herein ex vivo for a sufficient time and under conditions for to genera te a population of T cells exhibiting a t lea si one cy iotoxic T cell property, thereby form ing a population of cytotoxic T cells, administering the population of cy totoxlc T cells to the subject, thereby producing an immune response in a subjec t suitable for the treatment of cancer.

[0264] Disclosed herein is a method of increasing CD8+ I cell mediated immunity in a subject having a disease including: contacting CD8+ T cells with a PTPN2 degrader disclosed herein, ex vivo for a sufficient time and under conditions to generate a population of CD8-+ T cells exhibiting at least one property of a cytotoxic T cell; adm inistering the population of CD8+- T cells to the subject, thereby increa sing CD8+- T cell med ia ted immunity in a subject.

[0265] Disclosed herein is a method of increasing CD8+ T cell mediated immunity in a subject having a disease including: isolating a population of the subject's CD8-+ T cells: introducing a nucleic acid molecule encoding an siRNA or shRNA directed to PTPN2 into the isolated CD8+ T cells, thereby reducing the level of PTPN2 m a CD8+ T cell; and reintroducing the CD8+ T cells into said subject; thereby increasing the CD8+ T ceil mediated immunity in a subject.

[0266] Disclosed herein is a method of promoting regression of a cancer in a subject including the steps of: culturing T cells obtained from a subject in the presence of a PTPN2 degrader disclosed herein, administering the cultured T ceils to the subject, whereupon regression of the cancer is promoted.

[0267] Disclosed herein is a method of promoting regression of a cancer iti a subject having cancer including the steps of: culturing CAR T cells specific for a tumor antigen expressed by the cancer hi the presence of a PTPN2 degrader disclosed herein, administering the cultured CART cells to the subject, whereupon regression of the cancer is promoted. In some embodiments, the cancer is a Her-2 positive cancer and the CAR T ceil is specific for Her-2.

[0268] Disclosed herein is a method of prolonging survival of a subject having cancer including the steps of: culturing CAR T cells specific for a tumor antigen expressed by the cancer in the presence of a PTPN2 degrader disclosed herein, administering the cultured CAR T cells to the subject, whereupon survival of the subject is prolonged. Preferably, the cancer is a Her-2 positive cancer and the CAR T cell is specific for Her-2.

[0269] In some embodiments, the T cells is selected from the group consisting of tumor infiltrating lym phocytes, peripheral blood lymphocyte, genetically engineered to express a nti-tumor T cell receptors or ihimeric antigen receptors (CARs), yo T cells, enriched with mixed lymphocyte tumor cell cultures (MLTCs) or cloned using autologous antigen presenting cells and tumor derived peptides. In some embodiments, the lymphocytes is isolated from a histocompatible donor or from the cancer-bearing subject.

[0270] In some embodiments, the leukocytes or T cells are purified or substantially purified prior to culture hi the presence of a PTPN2 degrader disclosed herein. This step enriches the leukocytes orT cells by removing other cell types from the biological sample.

[0271] In some embodiments, the CAR T ceils are Her-2 specific CAR CD8+ T cells. In some embodiments, the T ceils are a popula lion that includes more tba ti one type of T cells, includ tng a ny one or more types described herein. For example, the population of T ceils may include naive, activated and / or memory T cells.Metabolic Diseases

[0272] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is used to treat a metabolic disease.

[0273] As used herein, the term “metabolic disease” refers to a disease or condition affecting a meta bolic process in a subject. Exemplary metabolic diseases include non-alcoholic steatohepatitis (NASH), non-alcoholic- fatty liver disease (NAFUD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Keams-Say re disease. In some embodiments, a compound disclosed herein, is used to treat a metabolic disease (e.g., a metabolic disease described herein) by decreasing or eliminating a symptom of the d isease. In some embodiments, the method of treatment comprises decreasing or eliminating a symptomcomprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.Dosing

[0274] In certain embodiments, the compositions containing the compound(s) described herein are administered fortherapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already sufferingfrom a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0275] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0276] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).

[0277] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.

[0278] The amount of a given a gent that corresponds to such an amount varies dependingupon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need oftreatment, but nevertheless is determined accordingto the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0279] In some embodiments, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mgper day. In some embodiments, the daily dosages appropriate forthe compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg / kgperbody weight. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.Routes of Administration

[0280] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal,transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0281] In certain embodiments, a compound as described herein is administered in a local ratherthan systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (forexample subcutaneously or intramuscularly) orby intramuscularinjection. Furthermore, in other embodiments, the drug is dehvered in a targeted drug delivery system, for example, in a hposome coated with organ specific antibody. In such embodiments, the hposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.Pharmaceutical Compositions / Formulations

[0282] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0283] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceuticalcompositions described herein can be found, forexample, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[0284] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.

[0285] The pharmaceutical formulations described herein include, but are not limited to, aqueous hquid dispersions, hquids, gels, syrups, elixirs, slurries, suspensions, self -emulsifying dispersions, sohd solutions, hposomal dispersions, aerosols, sohd oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.Combination

[0286] Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a PTPN2 / N1 degrader d isclosed herein; and (b) an additional therapeutic agent. In some embodiments, the combination therapy improves patient outcomes.

[0287] In some embodiments, the additional therapeutic agent is an anticancer agent.

[0288] In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. Use of immunotherapeutic agents in combination with other cancer treatment regimens has emerged as a promising approach to address limitations such as suboptimal efficacy, dose-dependent toxicity and acquired resistance while generating long-lasting anti-tumor immune responses and improving patient outcomes. In some embodiments, combining a PTPN2 / N1 degrader with a checkpoint inhibitor enhances therapeutic efficacy and improves tumor clearance in an in vivo tumor model. In some embodiments, there is a therapeutic benefit to combining a PTPN2 / N1 degrader disclosed herein with a clinically approved immune checkpoint inhibitor such as, but not limited to, atezolizumab, avelumab, cemipilimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toribalimab. Further examples of checkpoint inhibitors are AMG-404, camrelizumab, ezabenlimab, pidilizumab, or spartalizumab.

[0289] PTPN2 has emerged as a validated immunotherapy target as multiple published studies have demonstrated that PTPN2 deletion in either the turn or or in the immune compartment significantly enhanced antitumor immunity and sensitivity to other immunotherapies such as checkpoint inhibitors (Manguso et al. 2017; LaFleur et al. 2019; Weide et al. 2020). Emerging data have also shown that PTPN1 functions as an intracellular checkpoint and that PTPN1 deletion in T cells enhanced tumor clearance (Weide et al. 2022). Recently, it was shown that a smallmolecule PTPN2 / N1 inhibitor enhanced T cell activation andpro liferation and inhibited tumor growth in a murine syngeneic model (Liang et al. 2023).

[0290] In some embodiments, the additional therapeutic agent is chemotherapeutic agent. Chemotherapy induces cytotoxic effects on tumor cells but is also recognized for reinstating cancer cell immune surveillance and actingas an adjuvantforanti-tumor immunity (Liu et al. 2020). In some embodiments, chemotherapeutic agent includes, but is not limited to, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, methotrexate, oxaliplatin, paclitaxel, or vinblastine, or a combination thereof.

[0291] In some embodiments, the additional therapeutic agent is radiation therapy (RT). Radiation therapy (RT) can induce turn or cells to release antigens and trigger local or systemic anti-tumorimmunity (Demaria et al. 2016).

[0292] In some embodiments, the additional therapeutic agent is a VEGF inhibitor. Previous clinical studies demonstrated that the combination of an immune checkpoint inhibitor with an anti-angiogenic agent had synergistic effectsand severalof these combinations have recently been approved for the treatment of advanced renal cell carcinoma (Motzer et al. 2021 ; Makker et al. 2019; Jonasch et al. 2022). In some embodiments, the VEGF inhibitor includes, but is not limited to, aflibercept, axitinib, bevacizumab, cabozatinib, lenvatinib, pazopanib, ponatinib, ramucirumab, ramucirumab, regorafenib, sorafenib, sunitunib, tivozanib, and vandetanib, to potentially improve the clinical efficacy of these agents.

[0293] In some embodiments, the additional therapeutic agent is a bi-specific antibody or T cell engager.

[0294] In some embodiments, the bi-specific antibodies or T cell engagers is, but is not limited to, bintrafusp alia , blina turn omab, elranaiamab, epcoritamab, erfeonrilimab, glofitamab, mosunetuzumab, SHR-170I , tebentafusp, or teclistamab. In some embodiments, the combination disclosed herein enhances T cell mediated tumor immunity as most of these bi-specific antibodies are designed to redirect T cells.

[0295] In some embodiments, the additional therapeutic agent is CAR-T cell therapy. Wiede et al. recently demonstrated that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of CAR-T therapy by augmenting both CAR-T cell activation and homing to CXCL9 / CXCL10-expressing tumors via STAT5 signaling (Wiede et al. 2020). In some embodiments, the CAR-T cell therapy is, but is not limited to, axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, hsocabtagene maraleucel, ortisagenlecleucel. In some embodiments, the combination disclosed herein enhances the clinical efficacy of human CAR-T cells.

[0296] In some embodiments, the additional therapeutic agent is a KRAS G12C inhibitor. Recently, it was shown that the KRAS G12C inhibitor adagrasib sensitizes tumors to immunotherapy altering immune cell populations in the turn ormicroenvironm ent (Briere etal. 2021). In some embodiments, the KRAS G12C inhibitor is, but is not limited to, adagrasib or sotorasib. Further examples of KRAS G12C inhibitors are disclosed in WO2021 / 245051, WO2021 / 245055, and WO2023 / 099612, which are herein incorporated by reference in their entireties. In particular, further examples of KRAS G12C inhibitors that can be used according to the present invention are represented by compounds Ib-1 to lb- 16, Ic-1 to Ic-9, Id-1 to Id-9 and Ie-1 of WO2021 / 245051, compounds la-1 to la-170 of WO2021 / 245055 and compounds la-1 to la-4 and Ib-1 to Ib- 9 of WO2023 / 099612. Further examples of KRAS G12C inhibitors are compounds known as: divarasib (GDC-6036), opnurasib (also known as JDQ443), garsorasib (D-1553), glecirasib (JAC-21822), GFH925 / GF105 / IBI351, RMC-6291, LY3537982, JNJ-74699157 and LY3499446._In some embodiments, the combination disclosed herein potentiates anti-tumor immunity and potentially improve patient outcomes.

[0297] In some embodiments, the additional therapeutic agent is a cancer vaccine. Cancer vaccines such as, but not limited to, BCG, sipuleucel-T, and talimogene laherparepvec (T-VEC), where T-VEC is the oncolytic virus approved by the FDA, activate the immune response both locally and systemically ensuring better induction of tumor-specific effector T cell function (Vafaei at al., 2021, Ferrucci et al., 2021). Current clinical trials utilize the combination of DC -based mRNA vaccines in combination with ipilimumab to stimulate a strong T cell response (De Keersmaecker et al., 2020). In some embodiments, a combination disclosed herein promotes an additive or synergistic effect on anti-tumor immunity, thus potentially improves clinical outcomes.

[0298] In some embodiments, the additional therapeutic agent is a HER2 -targeted therapy. Recent reports have demonstrated that HER2 -targeted therapies can enhance anti-tumor immunity by enhancing expression of dendritic (DC) markers, boosting MHC I expression on cancer cells for ease of recognition by the immune system and enhancing recruitment of tumor-infiltrating CD4+ and CD8+ T cells (Iwata et al., 2018 & 2019). Consistent with this idea, HER2 -targeted therapies such as, but not limited to, lapatinib, margetuximab, neratinib, pertuzumab, trastuzumab em tansine (T-DM1), trastuzumab, tucatinib, and zongertinib could also be combined with a PTPN2 / N1 degrader to achieve more robust anti-tumor immune responses (Vafaei et al., 2022).

[0299] In some embodiments, the additional therapeutic agent is a CXCR4 antagonist. CXCR4 antagonists have been developed to impair pathological procedures and disrupt cancer cell adhesion to the stromal cells, facilitatingcancer cell release into circulation (Otsuka etal., 2008; Schrader et al., 2002). In some embodiments, the combination disclosed herein confers a strong immune response and attacks the circulating cancer cells to delay turn or development and enable tumor regression. In some embodiments, the CXCR4 antagonist is, but not limited to, plerixafor.

[0300] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.EXAMPLESProcedure for compound 1-2

[0301] To a solution of 1-1 (120 g, 508 mmol, 1 eq) in DMSO (1.67 L) was added 10MNaOH (100 mL, 2 eq) and allowed to stir at room temperature for 12 h. To this was then added IM HC1 (30 L) then extracted with ethyl acetate (10 Lx3). The combined organic phase was washed with brine (10 Lx2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification.Compound 1-2 (75 g, 320 mmol, 63% yield) was isolated as a crude yellow solid. LCMS (ESI-): m / z = 236.0 (M- H)-.JH NMR (400 MHz, CDCh) 5 10.62 (s, 1H), 7.20 (t, 7=1.90 Hz, 1H), 6.99 (dd, 7=10.64, 2.08 Hz, 1H).Procedure for compound 1-3

[0302] To a solution of 1-2 (100 g, 423 mmol, 1 eq) in CH2CI2 (1.52 L) was added triethylamine (64.3 g, 635 mmol, 88.4 mL, 1.5 eq) and 1 -(chloromethoxy )-2 -methoxy -ethane (58 mL, 508 mmol, 1.2 eq) at 0 °C under a N2 atmosphere. The reaction mixture was then allowed to stir at 0 °C for 2 h. The reaction mixture was then washed with H2O(5 L) and brine (2 L), dried with anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compound 1-3 (130 g, 397 mmol, 94% yield) was isolated as a crude yellow sohd. 'HNMR (400 MHZ, CDC13) 5 7.35 (t, 7=1.67 Hz, 1H), 7.09 (dd, 7=8.58,1.79 Hz, 1H), 5.35 (s, 2H), 3.83-3.88 (m, 2H), 3.55-3.59 (m, 2H), 3.39 (s, 3H).Procedure for compound 1-4

[0303] To a mixture of 1-3 (60 g, 185 mmol, 1 eq) in EtOH (600 mL) and H2O (600 mL) was added Fe (51.7 g, 925 mmol, 5 eq) and NH4CI (99 g, 1.85 mol, 10 eq) and allowed to stir for 1 h at 80 °C. The reaction mixture was then filtered and concentrated under reduced pressure to remove EtOH. The aqueous mixture was extracted with ethyl acetate (500 mL><3). The combined organic phase was then washed with brine (500 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compound 1-4 (38.5 g, 131 mmol, 70% yield) was isolated as a crude brown oil.1H NMR (400 MHz, CDCh) 5 6.98 (t, 7=1.75 Hz, 1H) 6.82 (dd, 7=9.88, 2.00 Hz, 1H) 5.21 (s, 2H) 3.75-3.79 (m, 2H) 3.49- 3.53 (m, 2H) 3.33 (s, 3H).Procedure for compound 1-6

[0304] To a solution of 1-4 (100 g, 340 mmol, 1 eq) in DMF (1 L) was added diisopropylethylamine (52.7 g, 408 mmol, 71.1 mL, 1.2 eq), sodium iodide (10.2 g, 68 mmol, 0.2 eq) and 1-5 (73 g, 374 mmol, 55.2 mL, 1.1 eq) then was allowed to stir for 6 h at 80 °C. The reaction mixture was then filtered and concentrated under reduced pressure. To the crude was added H2O (6 L) and extracted with ethyl acetate (1 L*3). The combined organic phase was then washed with brine (1 L*3), dried with anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=100 / l to 10 / 1) to afford 1-6 (89 g, 217 mmol, 64% yield) as brown oil. LCMS (ESI+): m / z = 410.1 (M+H)+.1H NMR (400 MHz, CDCh) 5 7.07 (t, 7=1.75 Hz, 1H) 6.88 (dd, 7=11.51 , 2.00 Hz, 1 H) 5.29 (s, 2H) 3.97 (dd, 7=6.07, 2.56 Hz, 2H) 3.82-3.87 (m, 2H) 3.56-3.60 (m, 2H) 3.39-3.42 (m, 3H) 1.46 (s, 9H).Procedure for compound 1-7

[0305] To a solution of Ar-(oxomethylene)sulfamoylchloride (48 g, 339 mmol, 29.5 mL, 1.15 eq) in CH2Ch (l L) was added prop-2 -en-l-ol (20 g, 343 mmol, 23.4 mL, 1.17 eq) at 0 °C and allowed to stir for 30 min under a N2 atmosphere. To this was then added a solution of 1-6 (120 g, 294 mmol, 1 eq) and triethylamine (89.2 g, 881 mmol, 122 mL, 3 eq) in CH2CI2 (200 mL) and allowed to stir an additional 30 mins. To the reaction mixture was added H2O (2 L) and extracted with CH2CI2 (500 mL><3). The combined organic phase was then washed with brine (1 L), dried with anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compound 1-7 (154 g, 269 mmol, 91% yield) was isolated as a crude yellow sohd. LCMS (ESI-): m / z = 570.8 (M-H)-.1H NMR (400 MHz, CDCh) 5 7.20 (t, 7=1.81 Hz, 1H) 6.94 (dd, 7=8.76, 2.13 Hz, 1H) 5.88-5.96 (m, 1H) 5.31-5.33 (m, 1H) 5.27 (d, 7=1.63 Hz, 2H) 5.16-5.21 (m, 1H) 4.83 (d,.7=17.76 Hz, 1H) 4.53-4.58 (m, 2H) 4.27 (d,J=l 7.76 Hz, 1H) 3.85-3.88 (m, 2H) 3.56 (dd, .7=5.32, 3.81 Hz, 2H) 3.38 (s, 3H) 1.38 (s, 9H).Procedure for compound 1-8

[0306] To a solution of 1-7 (180 g, 315 mmol, 1 eq) in MeOH (1.3 L) was added NaOMe (170 g, 945 mmol, 30% purity, 3 eq) then was degassed in vacuo and purged with N2 gas. Degassing and purging was repeated a totalof 3 times. To the reaction mixture was then added Pd(PPh3)4 (3.64 g, 3.15 mmol, 0.01 eq) and degassed and purged with N2 gas an additional times. The reaction mixture was then heated to 60 °C and allowed to stir for 2 h. The reaction mixture was then filtrated and concentrated under reduced pressure. To the reaction mixture was added 1M HC1(4 L) and extracted with ethyl acetate (1 L*5). The combined organic phasewasthen washed with brine (500 mL), dried with anhydrous Na2SOr, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compound 1-8 (100 g, 242 mmol, 77% yield) was isolated as a crude yellow sohd. LCMS (ESI-): m / z = 413.1 (M-H)'.XH NMR (400 MHz, CD3OD) 5 7.31 (t, .7=1.81 Hz, 1H) 7.16 (dd, .7=8.94, 2.06 Hz, 1H) 5.35 (s, 2H) 4.45 (s, 2H) 3.82-3.85 (m, 2H) 3.54-3.57 (m, 2H) 3.32-3.34 (m, 3H).Procedure for compound 1-10

[0307] To a mixture of 1-8 (20 g, 48 mmol, 1 eq) and 1-9 (9.6 g, 48.40 mmol, 1 eq) in DME (2 L) and H2O (200 mL) was added K2CO3 (20 g, 145 mmol, 3 eq) and Pd(dppf)Ch (708 mg, 968 pmol, 0.02 eq) then was allowed to stir for 1 h at95°C. The reaction mixture was filtered, then added IM HCI (1.5 L), and extracted with ethyl acetate (500 mL><3). The combined organic phase was then washed with brine (500 mL), dried with anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compound 1-10 (17.5 g, 43.4 mmol, 90% yield) was isolated as a crude yellow sohd. LCMS (ESI-): m / z = 403.2 (M-H)'.1H NMR (400 MHz, CDC13) 5 6.96 (d, .7=12.9 Hz, 1H), 6.78 (s, 1H), 6.55 (d, .7=10.4 Hz, 1H), 5.65 (d, .7=12.8 Hz, 1H), 5.21 (s, 2H), 4.39-4.18 (m, 2H), 3.96-3.80 (m, 2H), 3.72 (s, 2H), 3.47-3.34 (m, 2H), 3.32-3.16 (m, 3H), 1.32 (t, .7=7.0 Hz, 3H).Procedure for compound 1-11

[0308] To a solution of 1-10 (310 mg, 766 pmol, 1 eq) in acetonitrile (6 mL) was added 12M HCI (0.6 mL, 9.4 eq) and allowed to stir for 20 mins at 0 °C. To the reaction mixture was added diisopropylethylamine to adjust pH=8-9. The mixture was then concentrated andused in the next step directly without purification. Compound 1- 11 (280 mg, 743 pmol, 97% yield) was isolated as a yellow hquid. LCMS (ESI-): m / z = 375.2 (M-H)'.Example 1: 2-((S)-l-(4-(l,l-dioxido-4-oxo-l,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenethyl) pyrrolidin-3-yl)-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)methyl)benzyl) acetamideProcedure for compound 1-14A

[0309] To a solution of 1-12 (1.5 g, 5.43 mmol, 1 eq) and 1-13 (5.97 mmol, 1.1 eq) in NMP (15 mL) was added diisopropylethylamine (1.9 mL, 10.86 mmol, 2 eq) then heated to 90 °C and allowed to stir for 12 hr. To this was then added H2O (100 mL) then extracted with ethyl acetate (50 mL><3). The combined organic layers were washed with brine (50 mL><2), dried over Na2SC>4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiCh, petroleum ether / ethylacetate=l / O to 10 / 1 to 1 / 1) to give 1-14A (2.6 g, 1.62 mmol, 30% yield) as a yellow oil. LCMS (ESI+): m / z = 493.2 (M+H)+.XH NMR (400 MHz, CD3OD) 5 7.53 (d, 7=8.28 Hz, 1H), 6.97 (d, .7=2.01 Hz, 1H), 6.86 (dd, .7=8.41, 2.13 Hz, 1H), 5.02 (dd, .7=12.49, 5.46 Hz, 1H), 4.43 (s, 2H), 4.21 (d, .7=5.14 Hz, 2H), 2.59-2.80 (m, 3H), 2.33-2.39 (m, 5H), 2.03 (d, 7=8.03 Hz, 3H), 1.44 (s, 9H)

[0310] Intermediate 1-14B - 1-141 were prepared according to the procedures described in 1-14A using the appropriate intermediates.

[0339] To a solution of 16-3 (13 g, 36.27 mmol, 1 eq) in MeOH (180 mL), THF (180 mL) and H2O (180 mL) was added LiOH-H2O(3.04 g, 72.54 mmol, 2 eq) then allowed to stir for 12 h at room temperature. The reaction mixture was then concentrated under reduced pressure and resuspended in 0.1M NaOH (1 L). The aqueous mixture acidified to pH=l with IM HClthen extracted with ethyl acetate (500 mL><3). The combined organic phase wasthen washed with brine (1 L), dried with anhydrous Na2SOr, filtered, and concentrated under reduced pressure. The crude was used in the next step without further purification. Compound 16-4 (11.3 g, 32.9 mmol, 90% yield) was obtained as a colorless oil.XHNMR (400MHz, CD3OD) 54.61-4.43 (m, 2H), 4.30 (s, 1H), 3.90- 3.73 (m, 2H), 2.34-2.24 (m, 1H), 2.06 (ddd, 7=4.5, 9.1, 13.4 Hz, 1H), 1.44 (s, 9H), 1.03 (s, 9H).Procedure for Compound 16-7

[0340] To a solution of 16-5 (10 g, 33.31 mmol, 1 eq), potassium acetate (6.54 g, 66.62 mmol, 2.00 eq), and Pd(OAc)2(74.79 mg, 333.12 pmol, 0.01 eq) in DMA (65 mL) was added 16-6 (6.61 g, 66.62 mmol, 6.06 mL, 2.00 eq) then heated to 120 °C under N2atmosphere for 2 h. To this was then added H2O (500 ml) which caused the formation of a precipitate. The precipitate was filtered then washed with an additional H2O (500 ml). The precipitate was isolated, dried, and purified via column chromatography (SiO2, petroleum ether / ethyl acetate=99 / l to 87 / 13) to give 16-7 (27.9 g, 87.6 mmol, 87% yield) as a light yellow sohd.XH NMR (400 MHz, DMSO-de) 5 8.15 (s, 1H) 6.40-6.73 (m, 5H) 3.76-3.94 (m, 1H) 1.63 (s, 3H) 0.45-0.62 (m, 12H).Procedure for Compound 16-8

[0341] To a solution of 16-7 (4.65 g, 14.6 mmol, 1 eq) in CH2C12(320 mL) was added 4M HC1 (Dioxane solution, 53.5 mL, 14.65 eq) and allowed to stir for 3 h at room temperature. To the reaction mixture was then added MTBE (200ml) which caused the formation of a precipitate. The precipitate was isolated and dried under reduced pressure. The crude product was used into the next step without furtherpurification. Compound 14-8 (2.9 g, 11.6 mmol, 80% yield) was obtained as a yellow sohd.1H NMR (400 MHz, DMSO-de) 59.15 (s, 1H) 7.66 (d, 7=8.34 Hz, 2H) 7.56 (d, 7=8.23 Hz, 2H) 4.44 (br d, 7=3.46 Hz, 1H) 2.47 (s, 3H) 1.55 (d, 7=6.79 Hz, 3H).Procedure for Compound 16-9

[0342] To a solution of 16-4 (2.1 g, 6.3 mmol, 1 eq) and 16-8 (2 g, 6.28 mmol, 1 eq) in CH2C12(80 mL) was added HATU (3.6 g, 9.4 mmol, 1.5 eq) and diisopropylethylamine (4.06 g, 31.4 mmol, 5.4 mL, 5 eq) then allowed to stir for 20 h atroom temperature. The reaction mixture was washed with citric acid (aq) (5%, 200 mL), IM NaOH (500 mL*2) and brine (300 mL). The organic layer was then dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was then dissolved with MeOH (minimal amount) then followed by the addition of H2O which caused the formation of a precipitate. The precipitate was isolated then dried underreduced pressure and used into the next step without further purification. Compound 16-9 (2.9 g, 5.4 mmol, 86% yield) was obtained as a white sohd.XH NMR (400 MHz, CDCI3) 5 8.68 (s, 1H) 7.61 (d, 7=7.75 Hz, 1H) 7.32-7.46 (m, 4H) 5.21-5.35 (m, 1H) 5.08 (quin, 7=7.06 Hz, 1H) 4.77 (s, 1H) 4.50 (s, 1H) 4.23 (d, 7=9.30 Hz, 1H) 4.09 (d,7=l 1.44 Hz, 1H) 3.58 (dd, 7=11.44, 3.34 Hz, lH)2.44-2.62 (m, 4H) 1.98-2.15 (m, 1H) 1.29-1.55 (m, 12H) 0.92-1.12 (m, 9H).Procedure for Compound 16-10

[0343] To a solution of 16-9 (3.7 g, 6.79 mmol, 1 eq) in CH2C12(24 mL) was added 4M HC1 (Dioxane solution, 24 mL, 14.1 eq) then was allowed to stir for 15 min atroom temperature. To this was then added MeOH (18 mL) and allowed to stir for an additional 30 min. The reaction mixture was then concentrated under reducedmixture was then extracted with ethylacetate (100 mL><2). The combined organic layers were washed with water (lOO mL) and brine (100 mL), dried over Na2SO4, then filtered and concentrated underreduced pressure to give a crude. The crude was then purified by HPLC to give 25-5 (1 g, 4.10 mmol, 17% yield) as a white sohd.NMR (CD3OD) 5 7.31-7.27 (m, 2H), 3.33-3.29 (m, 4H), 3.22-3.17 (m, 4H).Procedure for compound 25-6

[0375] To a solution of 25-5 (0.5 g, 2.05 mmol, 1 eq) in CH2CI2 (5 mL) was added BOC2O (894mg, 4.1 mmol, 941, 2 eq) and DMAP (25.02 mg, 204.83 pmol, 0.1 eq) then allowed to stir at room temperature for 12 h. The resulting suspension was quenched with a mixture of sat. NELClcaq) and lMNa2S2O3 (aq) (l : l, lO mL) and allowed to stir for5 minutes at25 °C. The resulting reaction mixture was then extracted with ethyl acetate (10 mL><2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried overNa2SO4, then filtered and concentrated underreduced pressure to give a crude. The crude was then purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / O to 0 / 1) to give 25-6 (0.7 g, 2.03 mmol, 99% yield) as a yellow oil. NMR (CDCI3) 5 7.12-7.07 (m, 2H), 3.59-3.50 (m, 4H), 2.94-2.86 (m, 4H), 1.48 (s, 9H).Procedure for compound 25-7

[0376] To a solution of 25-6 (0.7 g, 2.03 mmol, 1 eq) in 1,4-dioxane (10 mL) was added 25-7 (1.03 g, 4.07 mmol, 2 eq), Pd(dppf)C12 (148mg, 203pmol, 0.1 eq) and KOAc (798 mg, 8.1 mmol, 4 eq) then heated to 90 °C for 2 h under N2. The resulting suspension was quenched with a mixture of sat. NHqCltaq) and IM Na2S2C>3 (aq) (1 : 1, 10 mL) and allowed to stir for 5 minutes at 25°C. The resulting reaction mixture was then extracted with ethyl acetate (10 mL><2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SOr, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / O to 0 / 1) to give 25-8 (1 .3 g, crude) as yellow sohd. m NMR (CDCI3) 5 7.34-7.30 (m, 2H), 3.57-3.51 (m, 4H), 2.99-2.90 (m, 4H), 1.33 (s, 9H), 1.26 (s, 12H).Procedure for compound 25-9

[0377] To a solution of 25-8 (1.2 g, 3.07 mmol, 1 eq) in acetone (20 mL) was added oxone (3.77 g, 6.13 mmol, 2 eq) in H2O (20 mL) and allowed to stir at 0 °C for 0.5 h. To this was then added H2O (50 mL) then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / O to 0 / 1) to give 25-9 as colorless oil.JH NMR (CDCI3) 5 6.49-6.43 (m, 2H), 3.58-3.50 (m, 4H), 2.89-2.82 (m, 4H), 1.49 (s, 9H).Procedure for compound 25-10

[0378] To a solution of 25-9 (0.7 g, 2.49 mmol, 1 eq) in THF (10 mL) was added NaH (199 mg, 4.9 mmol, 60% purity, 2 eq) then was allowed to stir at 0 °C for 0.5 h under N2. To the reaction mixture was then added MEMCI (464 mg, 3.73 mmol, 426 pL, 1.5 eq) then allowed to warm to 25 °C and stirred for an additional 12 hr. The resulting suspension was quenched with a mixture of sat. NLLClcaq) and IM Na2S2C>3 (aq) (1 : 1, 20 mL) and allowed to stir for 5 minutes at 25°C. The resulting reaction mixture was then extracted with ethyl acetate (10 mL><2). The combined organic layers were washed with water (20 mL) and brine (30 mL), dried overNa2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / O to 0 / 1) to give 25-10 (0.7 g, 1.89 mmol, 76% yield) asyellow solid. ' H NMR (CDCI3) 5 6.69-6.61 (m, 2H), 5.23 (s, 2H), 3.83-3.80 (m, 2H), 3.59-3.49 (m, 6H), 3.39 (s, 3H), 2.87 (br d, J= 4.8 Hz, 4H), 1.49 (s, 9H).Procedure for compound 25-11

[0379] To a solution of 2,2,6,6-Tetramethylpiperidine (497 mg, 3.5 mmol, 597 pL, 2 eq) in THF (6 mL) was added 2.5M n-BuLi (1.41 mL, 2 eq) dropwise at 0 °C then was allowed to stir for 0.5 h under N2. The reaction mixture was then cooled to -78 °C then added 25-10 (0.65 g, 1.76 mmol, 1 eq) in THF (3 mL) followed by tetramethylethylenediamine (306 mg, 2.64 mmol, 398pL, 1.5 eq) and allowed to stir for an additional 2 h. To this was then added h (1.12 g, 4.4 mmol, 886 pL, 2.5 eq) in THF (1.5 mL). The reaction mixture was then allowed to warm to 25 °C and allowed to stir for an additional 1 h. The resulting suspension was quenched with a mixture of sat.NH4Cl(aq)and lMNa2S2O3 (aq)(l : 1, 10 mL) and allowed to stir for 5 minutes at 25 °C. The resulting reaction mixture was then extracted with ethyl acetate (10 mL><2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried overNa2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified via column chromatography to give 25-11 (0.71 g, 1.43 mmol, 81% yield) as a yellow sohd. ' H NMR (CDCI3) 5 6.73 (s, 1H), 5.32 (s, 2H), 3.90-3.84 (m, 2H), 3.59-3.49 (m, 6H), 3.38 (s, 3H), 2.96-2.85 (m, 4H), 1.48 (s, 9H).Procedure for compound 25-13

[0380] To a solution of 25-11 (0.65 g, 1.31 mmol, 1 eq) in 1,4-dioxane (7 mL) was added 25-12 (258 mg, 1.97 mmol, 1.5 eq), CS2CO3 (1.28 g, 3.94 mmol, 3 eq), XPhos (125.12 mg, 262.46 pmol, 0.2 eq) and BrettPhos Pd G3 (118 mg, 131 pmol, 0.1 eq) then heated to 90 °C for 48 h under N2. The resulting suspension was quenched with a mixture of sat. NH4Cl(aq) and IM Na2S2C>3 (aq) (1 : 1, 15 mL) and allowed to stir for 5 minutes at 25 °C. The resulting reaction mixture was then extracted with ethyl acetate (10 mL><2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried overNa2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / O to 0 / 1) to give 25-13 (0.5 g, 1 .0 mmol, 76% yield) as a yellow oil.XH NMR (CDCI3) 5 6.70 (br s, 1H), 5.26 (br s, 2H), 3.95 (br s, 2H), 3.91-3.80 (m, 2H), 3.64-3.48 (m, 6H), 3.47-3.33 (m, 3H), 3.07-2.64 (m, 4H), 1.67-1.41 (m, 18H).Procedure for compound 25-14

[0381] To a solution of 7V-(oxomethylene)sulfamoyl chloride (191 mg, 1.35 mmol, 117 pL, 1.5 eq) in CH2CI2 (5 mL) was added prop-2 -en-l-ol (157 mg, 2.7 mmol, 184 pL, 3 eq) and stirred at 0 °C for 0.5 h. The reaction mixture was then allowed to warm to at 25 °C then was added 25-13 (0.45 g, 902 pmol, 1 eq) and diisopropylethylamine (116 mg, 902 pmol, 157 pL, 1 eq) in CH2CI2 (2 mL) and allowed to stir for an additional 1 h. To the reaction mixture was then added H2O (5 mL) then extracted with CH2CI2 (5 mL*2). The combined organic layers were washed with brine (lO mL), dried overNa2SO4, then filtered and concentrated under reduced pressure to give 25-14 (0.5 g, crude) as a yellow oil.Procedure for compound 25-15

[0382] To a solution of 25-14 (0.3 g, 453 pmol, 1 eq) in MeOH (3 mL) was added NaOMe (408 mg, 2.27 mmol, 30% purity, 5 eq) and Pd(PPh3)4 (52 mg, 45 pmol, 0.1 eq) then heated to 60 °C for 1 h under N2. To the reaction mixture was then added H2O (5 mL) then extracted with CH2CI2 (5 mL><2). The combined organic layers were washed with brine (10 mL), dried overNa2SO4, then filtered and concentrated under reduced pressure to

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a heterocycloalkyl or heteroaryl; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1on the same atom are taken together to form an oxo; or two R1on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R1on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; n is 0, 1, 2, 3, or 4; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR5-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, - NR5C(=O)-, -NR5C(=O)NR5-, -S(=O)2NR5-, -NR5S(=O)2-, -NR5S(=O)2NR5-, Ci-Cioalkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; each R5is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more R; s is 1-20;M is an E3 hgase targeting agent;L2is -O-, -S-, -S(=O)-, -S(=O)2-, -NR2-, -[C(R3)2]m-, -O[C(R3)2]m-, -NR2[C(R3)2]m-, -[C(R3)2]mO-, or - [C(R3)2]mNR2-;R2is hydrogen, -C(=O)Ra, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedcutcroalkyl. Ci -Cehydroxyalkyl. Ci-C 6 aminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalky 1 is independently optionally substituted with one or more R;or two R3are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; m is 1, 2, 3, or 4; each R4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CedeuteroalkybCi-Cehydroxyalkyl, Ci-C 6 aminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl; p is 0, 1, or 2;W is CRWorN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L -cyclo alkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, C 1 -C ehalo alky 1, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalky Independently optionally substituted with one or more R;L is absent or Ci-Csalkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, or Ci-Csheteroalkyl; or two R on the same atom are taken together to form an oxo.2 The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 4- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from O, S, and N.3 The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 4-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N.4 The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 5-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N.

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from O, S, and N.

6. The compoundof any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.

7. The compoundof any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L2is -[C(R3)2]m-.8 The compoundof any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R3is hydrogen.9 The compoundof any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 2.10 The compoundof any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 3.11 The compoundof any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0.12 The compoundof any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.13 A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein:Ring A is a 7- to 15-membered cycloalkyl or a 7- to 15 -membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R1on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR5-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, - NR5C(=O)-, -NR5C(=O)NR5-, -S(=O)2NR5-, -NR5S(=O)2-, -NR5S(=O)2NR5-, Ci-Cioalkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; each R5is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;s is 1-20;M is an E3 ligase targeting agent;X is CRxorN;Rxis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Y is CRYorN;RYis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Z is CRZor N;Rzis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;W is CRWorN;Rwis hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-C ehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L -cyclo alkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, C 1 -C ehalo alky 1, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalky Independently optionally substituted with one or more R;L is absent or Ci-Csalkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, or Ci-Csheteroalkyl; or two R on the same atom are taken together to form an oxo.

14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 7-membered cycloalkyl.

15. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 7-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N.

16. The compound of any one of claims 13-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.

17. The compound of any one of claims 13-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is CRX.

18. The compound of any one of claims 13-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Rxis halogen.

19. The compound of any one of claims 13-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is CRY.

20. The compound of any one of claims 13-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RYis -OH.

21. The compound of any one of claims 13-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is CRZ.

22. The compound of any one of claims 13-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Rzis hydrogen.

23. The compound of any one of claims 13-22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.

24. The compoundof any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each L1is independently -O-, -NR5-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR5-, - NR5C(=O)-, Ci-Cioalkylene, C2-C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

25. The compoundof any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each L1is independently -O-, -NR5-, -C(=O)NR5-, -NR5C(=O)-, Ci-Cioalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

26. The compoundof any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each L1is independently -NR5-, -C(=O)NR5-, -NR5C(=O)-, Ci-Cioalkylene, arylene, or heteroarylene; wherein each alkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

27. The compoundof any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each L1is independently -NR5-, -C(=O)NR5-, -NR5C(=O)-, Ci-Cioalkylene, or arylene; wherein each alkylene, and arylene is independently optionally substituted with one or more R.

28. The compoundof any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R5is independently hydrogen or Ci-Cealkyl.

29. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 1-15.

30. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 1-10.

31. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 1 -5.

32. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 5-10.

33. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 5-15.

34. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 5-20.

35. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 2.

36. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 3.

37. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 4.

38. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 5.

39. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 6.

40. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 7.

41. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 8.

42. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 9.

43. The compoundof any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 10.

44. The compoundof any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the E3 hgase targeting agent is a cereblon E3 hgase, a VHL E3 hgase, a MDM2 hgase, a TRIM24 hgase, a TRIM21 hgase, a KEAP1 hgase, or an IAP hgase.49, A method of treating cancer in a subject hi need thereof, the method comprising administering to the subject a pharmaceutical composition of claim 47.

50. A method of treatingtype-2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

51. A method of treating type-2 diabetes in a subject in need thereof, the method coinprisingadministeringto the subject a pharmaceutical composition of claim 47.

52. A method of treating and / or controlling obesity in a subject in need thereof, the method comprising administering to the subject an effective a mount of a compound of any one of cla im s I -46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

53. A method of treating and / or controlling obesity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of claim 47.

54. A method of treating a metabolic disease in a subject in need thereof, the method comprising adm inistering io the subject an effective a mount of a compound of any one of claim s I -46. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

55. A method of treating a metabolic disease in a subject in need thereof, the method comprising adm inistering to the subject a pharmaceutical composition of claim 47.

56. The method of a ny one of claims 48-55, further comprising administering an additional therapeutic agent.

57. The method of claim 56, wherein the additional therapeutic agent is an anti-PD-1 antibody, an anti-PD- Li antibody, or an anti-CTLA-4 antibody.

58. The method of claim 56, wherein the additional therapeutic agent is CAR-T cell therapy,59. The method of cla im 58. wherein the CAR-T cell therapy is axicabtagene ciloleucel, brexueabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, hsocabtagene maraleucel, or tisagenlecleucel.

60. A method for producing a leukocyte that has an enhanced capacity for killing a target cell, the method including contacting the leukocyte with a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in conditions for enabling the degrader to inactivate PTPN2 in the leukocyte, thereby producing a leukocyte that has an enhanced capacity for killing a target cell.

61. The method of claim 60, wherein the leukocyte is contacted with the compound in the absence of a T helper cell.

62. The method of claim 60, wherein the leukocyte is derived from a subject having a cancer.

63. The method of claim 60, wherein the leukocyte is a neutrophil, eosinophil, basophil, monocyte, or lymphocyte.

64. The method of claim 63, wherein the lymphocyte is a tumor infiltrating lymphocyte.

65. The method of claim 60, wherein the leukocyte is conditioned or engineered to have specificity for a cancer antigen.

66. The method of claim 65, wherein the engineered specificity is provided by a recombinant chimeric receptor or T cell receptor that specifically binds to a cancer antigen.

67. The method of claim 60, wherein the target cell is a cancer cell.

68. A method for treating cancer including the steps of culturing a leukocytes from a cancer subject to be treated ora histocompatible donor to the cancer subject to be treated in the presence of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ex vivo in conditions for enabling the degrader to inactivate PTPN2 in the leukocytes, thereby forming a composition of cells with an enhanced capacity for killing a target cancer cell, administering the composition of cells to the subject, thereby treating cancer.

69. The method of claim 68, wherein the leukocyte is a neutrophil, eosinophil, basophil, monocyte, or lymphocyte.

70. The method of claim 69, wherein lymphocyte is a tumor infiltrating lymphocyte, or peripheral blood lymphocyte.

71. The method of claim 68, wherein the leukocyte is conditioned or engineered to have specificity for the cancer to be treated.

72. A method of claim 71, wherein the engineered specificity is provided by a recombinant chimeric receptor or T cell receptor that specifically binds to a cancer antigen.

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