Technologies targeting cell states

Abstract

Among other things, the present disclosure provides technologies targeting KAT2. In some embodiments, the present disclosure provides technologies for reducing levels of KAT2 polypeptides in various systems. In some embodiments, the present disclosure provides technologies for treating various diseases, disorders, or conditions, including those associated, with a KATZ polypeptide such as various cancers.

Description

TECHNOLOGIES TARGETING CELL STATES RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application No. 63 / 460,764, filed April 20, 2023, U.S. Application No. 63 / 561,294, filed March 4, 2024, U.S. Application No.63 / 575,594, filed April 5, 2024, and International Application No. PCT / US2023 / 031835, filed September 1, 2023, the entire contents of each of which are hereby incorporated by reference. BACKGROUND

[0002] KAT2A (also referred to as general control non-depressible 5 (GCN5)) and KAT2B (also referred to as p300 / CBP-associated factor (PCAF)) are both multidomain proteins, which contain an acetyltransferase domain and a bromodomain. KAT2A and KAT2B are reported to function as epigenetic proteins, as they are both reported to be capable of modifying histones and recognizing modified histones. They are reported to be involved in various cellular pathways, including cell proliferation and differentiation, metabolic regulation, and DNA damage repair. See, e.g., Bassi, Z.I., et al. ACS Chem. Biol., 2018, 13, 2862-67. Both KAT2A and KAT2B have been implicated in certain diseases, disorders, and conditions, such as cancers, neurodegenerative diseases, and inflammation. See, e.g., Humphreys, P.G., et al., J. Med. Chem., 2017, 60, 695-709. Conditional knockout of KAT2A in mice bearing an additional mutation that causes acute myeloid leukemia has been reported to delay development of leukemia, deplete leukemia stem cells, and shift leukemia cell fate out of self- renewal into differentiation, causing the disease to become less aggressive. See, e.g., Domingues A. P., et al., eLife 9:e51754, 2020. SUMMARY

[0003] Among other things, the present disclosure encompasses the recognition that various conditions, disorders or diseases are associated with certain cell states. For example, while many types of normal cells typically go through a proliferative, plastic cell state and then terminally differentiate and are committed to particular cell states and stop proliferating, many cancer cells reside in a plastic and proliferative state (which may be referred to as a plastic state), e.g., through blocking differentiation, de-differentiation, and / or trans- differentiation. In some embodiments, plastic states of cancer cells are associated with aggressive tumors, e.g., aggressive and / or metastatic tumors which can be resistant to reported therapies. In some embodiments, the present disclosure provides technologies for preventing and / or treating conditions, disorders or diseases by targeting their associates cell states. In some embodiments, the present disclosure provides technologies for targeting plastic states of cancer cells. In some embodiments, the present disclosure identifies drivers associated with plastic states of cancer cells. In some embodiments, a driver locks cancer cells in a plastic and proliferative state. In some embodiments, a driver contributes to maintain cancer cells in a plastic and proliferative state. In some embodiments, provided technologies revert cancer cells to normal cell states and / or inhibit their growthand proliferation.

[0004] In some embodiments, KAT2A and / or KAT2B are identified as driver(s) for plastic states of various cancer cells, e.g., those of small cell lung cancer, neuroendocrine prostate cancer and acute myeloid leukemia. In some embodiments, the present disclosure provides compounds useful to regulate KAT2 (KAT2A and / or KAT2B), for example to reduce KAT2 activity, for example by degrading (e.g., increasing degradation of) KAT2 (e.g., KAT2A and / or KAT2B). I In some embodiments, provided technologies (e.g., compounds, compositions or methods) can reduce level of a KAT2 protein. In some embodiments, provided technologies can reduce level of KAT2A. In some embodiments, provided technologies can reduce level of KAT2B. In some embodiments, provided technologies can reduce levels of KAT2A and KAT2B. In some embodiments, provided technologies can selectively reduce level of one of KAT2A and KAT2B over the other. In some embodiments, provided technologies can selectively reduce level of KAT2A over KAT2B. In some embodiments, provided compounds are useful for, among other things, treating and / or preventing diseases, disorders, or conditions associated with KAT2 (e.g., KAT2A and / or KAT2B), e.g., with level and / or activity of KAT2 (e.g., KAT2A and / or KAT2B) protein. In some embodiments, the provided technologies provides technologies for preventing or treating conditions, disorders or diseases associated with KAT2A and / or KAT2B. In some embodiments, the provided technologies provides technologies for preventing or treating conditions, disorders or diseases associated with KAT2A. In some embodiments, the provided technologies provides technologies for preventing or treating conditions, disorders or diseases associated with KAT2B.

[0005] In some embodiments, provided compounds comprise a protein binding moiety capable of binding a KAT2 protein (e.g., KAT2A and / or KAT2B) and an E3 ligase binding moiety capable of binding an E3 ubiquitin ligase. In some embodiments, a protein binding moiety binds to a bromodomain of KAT2A and / or KAT2B. In some embodiments, provided compounds may recruit a KAT2 protein to an E3 ubiquitin ligase, thereby promoting degradation of (or otherwise inhibiting) the KAT2 protein (e.g., KAT2A and / or KAT2B). In some embodiments, provided compounds promote ubiquitination of KAT2A and / or KAT2B. In some embodiments, provided compounds promote degradation of KAT2A and KAT2B.

[0006] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein PBM, linker, and LBM are as defined herein. In some embodiments, a provided compound is a compound of formula II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5 or IIA- 6, or a salt thereof. In some embodiments, a provided compound is a compound of formula IX, IXA, IXB, IXC or IXD, or a salt thereof.

[0007] In some embodiments, a provided compound is a compound of formula III or a salt thereof. In some embodiments, a provided compound is a compound of formula IIIA or a salt thereof. In some embodiments, a provided compound is a compound of formula IIIB, IIIB-1 or IIIB-2, or a salt thereof. In some embodiments, a provided compound is a compound of formula IIIC or a salt thereof. In some embodiments, aprovided compound is a compound of formula IIID or a salt thereof. In some embodiments, a provided compound is a compound of formula IV, IVA or IVA-1, or a salt thereof. In some embodiments, a provided compound is a compound of formula V, VA, VA-1, VB or VB-1, or a salt thereof. In some embodiments, a provided compound is a compound of formula VI, VIA or VIA-1, or a salt thereof. In some embodiments, a provided compound is a compound of formula VII or VIIA, or a salt thereof. In some embodiments, a provided compound is a compound of formula VIII or VIIIA, or a salt thereof. In some embodiments, a provided compound is a compound of formula X, XA, XA-1, XA-2 or XB, or a salt thereof. In some embodiments, a provided compound is a compound of formula XI or XIA, or a salt thereof. In some embodiments, a provided compound is a compound of formula XII, XIIA, XIIB or XIIB-1, or a salt thereof. In some embodiments, a provided compound is a compound of formula XIII or XIIIA, or a salt thereof. In some embodiments, a provided compound is a compound of formula XIV or a salt thereof. In some embodiments, a provided compound is a compound of formula XV or a salt thereof. In some embodiments, a salt is a pharmaceutically acceptable salt. In some embodiments, such a compound can bind KAT2A and / or KAT2B, and an E3 ligase. In some embodiments, such a compound promotes ubiquitination of KAT2A and / or KAT2B. In some embodiments, such a compound promotes degradation of KAT2A and / or KAT2B. In some embodiments, such a compound reduces level of KAT2A and / or level of KAT2B. In some embodiments, such a compound is useful for preventing and / or treating a condition, disorder or disease associated with KAT2A and / or KAT2B.

[0008] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a provided compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0009] In some embodiments, the present disclosure provides technologies (e.g., compounds or methods) for manufacturing provided compounds.

[0010] In some embodiments, the present disclosure provides methods for preventing a condition, disorder or disease comprising administering or delivering to a subject susceptible thereto an effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods for treating a condition, disorder or disease comprising administering or delivering to a subject suffering therefrom an effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition is administered to administer or deliver a provided compound or a salt thereof. In some embodiments, a condition, disorder or disease is associated with KAT2A and / or KAT2B. In some embodiments, a condition, disorder or disease is cancer. In some embodiments, a condition, disorder or disease is small-cell lung cancer. In some embodiments, a condition, disorder or disease is neuroendocrine prostate cancer. In some embodiments, a condition, disorder or disease is acute myeloid leukemia. BRIEF DESCRIPTION OF DRAWING

[0011] Figure 1. Provided compounds can provide various activities including inhibiting tumor growth in vivo. (A): Provided compounds can inhibit tumor growth in vivo. Nude Balb / c mice were inoculated withNCI-H1048 cells in Matrigel. Tumors were allowed to grow up to about 200 mm3and mice were then randomized into two groups. Mice were dosed intraperitoneally (i.p.) once per week with vehicle or 30 mg / kg compound 22. Tumor size was measured every three to four days and mice were sacrificed once vehicle tumors reached 2000 mm3. Error bar is SEM. Dosing started at day 17 post tumor inoculation. (B): Provided technologies can reduce KAT2A and KAT2B levels and histone acetylation levels. As shown, western blot data of small cell lung cancer NCI-H1048 cells treated 24h with compound 22 at various concentrations confirm such reduction. Vehicle is DMSO. (C): Provided technologies can inhibit cell growth. Cell count data relative to DMSO control after 8 days of treatment with compound 22 are presented as examples to confirm inhibition. GI50 = 6 nM. (D): Provided technologies can inhibit tumor growth in vivo. Nude balb / c mice inoculated with H1048 tumors were dosed intraperitoneally once per week (qw i.p.) with vehicle (HbCD) or compound 22. Average tumor volumes + / -SEM from 6 mice are represented. Significant tumor growth inhibition of 70% at 30mg / kg was observed and the treatment was well tolerated. See also (A). (E): Provided technologies are well tolerated. Certain body weights relative to starting weight are presented as examples to confirm tolerability and safety. (F): Provided technologies can reduce KAT2A and KAT2B levels and histone acetylation levels in tumor in vivo. Western blots from tumor 168 hours post last dose showed significant reduction of KAT2A and KAT2B and histone acetylation. (G): Provided technologies can modulate cell states and induce differentiation. Box plot of epithelial GSEA demonstrated significant upregulation in tumors treated with compound 22 as compared to vehicle.

[0012] Figure 2. Provided compounds can provide various activities. (A): Provided technologies can reduce KAT2A and KAT2B levels and histone acetylation levels. As shown, western blot data of acute myeloid leukemia MOLM-13 cells treated 48 hour with compound 22 confirm such reduction. (B): Provided technologies can inhibit cell growth. Cell count data after 8 days of treatment with compound 22 relative toDMSO control are presented as examples to confirm inhibition. GI50=1.2 nM. (C): Provided technologies canmodulate cell states and induce differentiation. CD86 was analyzed by flow cytometry at 48 hours and monocytic differentiation was observed. EC50 = 0.3nM.

[0013] Figure 3. Provided compounds can provide various activities. (A): Provided technologies can reduce KAT2A and KAT2B levels and histone acetylation levels. As shown, western blot of neuroendocrine prostate cancer LASCPC-01 cells treated 24 hours with compound 22 confirm such reduction. (B): Provided technologies can inhibit cell growth. Cell viability (Cell Titer Glo) data relative to DMSO control after 7 days of treatment with compound 22 are presented as examples to confirm inhibition. GI50= 5 nM. (C): Provided technologies can modulate cell states and induce differentiation. Box plot of epithelial GSEA demonstrated significant upregulation in cells treated with compound 22 as compared to DMSO. (D): Provided technologies can reduce KAT2A and KAT2B levels and histone acetylation levels including in neuroendocrine prostate cancer primary patient organoid. As shown, western blot of NEPC primary patient organoid treated with compound 22 for 72 hours confirmed such reductions. Concentrations are nM. (E): Provided technologies can inhibit cell growth. Cell viability data relative to DMSO control after 21 days of treatment with compound 22are presented as examples to confirm inhibition. GI50= 3 nM. (F): Provided technologies can modulate cell states and induce differentiation. Box plot of microglial GSEA demonstrated significant upregulation (both epithelial and neural components). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0014] Certain provided technologies of the disclosure, e.g., compounds, compositions, methods, include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. Definitions

[0015] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0016] Unless otherwise indicated, structures depicted herein are meant to represent all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, where a stereocenter is present, in some embodiments, the R and / or S configurations of such stereocenter are contemplated as part of the disclosure. Therefore, in some embodiments, single stereochemical isomers, and / or enantiomeric, diastereomic, and / or geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some case, Table 1 and Table 2 show one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise indicated, tautomeric forms of provided compounds are within the scope of the disclosure.

[0017] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0018] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”). Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms(e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation.

[0019] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1- 4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1- 10,C1-8,C1-6,C1-4,C1- 3, or C1- 2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0020] Carbocyclyl: The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C5-C10(e.g., C7-C10or C8- C10) bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3–6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0021] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12,C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0022] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0023] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but is not limitedto, phenyl, naphthyl, and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.

[0024] Heteroaliphatic: The term “heteroaliphatic”, as used herein, is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). In some embodiments, one or more units selected from C, CH, CH2, and CH3are independently replaced by one or more heteroatoms (including oxidized and / or substituted forms thereof). In some embodiments, a heteroaliphatic group is heteroalkyl. In some embodiments, a heteroaliphatic group is heteroalkenyl.

[0025] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 ʌ^electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0026] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0027] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. In some embodiments, they refer to a 3- to 8- membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).

[0028] Partially Unsaturated: As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0029] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0030] Specific binding: As used herein, the term “specific binding” refers to an ability to discriminate between possible binding partners in the environment in which binding is to occur. A binding agent that interacts with one particular target when other potential targets are present is said to "bind specifically" to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining degree and / or rate of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining degree and / or rate of dissociation of a binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or determining ability of the binding agent to compete an alternative interaction between its partner and another entity. In some embodiments, specific binding is assessed by performing such detections or determinations across a range of concentrations.

[0031] Substituted or optionally substituted: As described herein, compounds of this disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitablesubstituent (i.e., as described below for optionally substituted groups). “Substituted” applies to one or more 1 hydrogens that are either explicit or implicit from the structure (e.g.,refers to at least; NH R1NH 1 N R1R1NH R R1and refers to at least , ,NH, or ). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0032] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4Rq; –(CH2)0–4ORq; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(ORq)2; –(CH2)0–4SRq; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(Rq)2; –(CH2)0–4N(Rq)C(O)Rq; –N(Rq)C(S)Rq; –(CH2)0–4N(Rq)C(O)NRq2; -N(Rq)C(S)NRq2; –(CH2)0–4N(Rq)C(O)ORq; - N(Rq)N(Rq)C(O)Rq; -N(Rq)N(Rq)C(O)NRq2; -N(Rq)N(Rq)C(O)ORq; –(CH2)0–4C(O)Rq; –C(S)Rq; –(CH2)0–4C(O)ORq; –(CH2)0–4C(O)SRq; -(CH2)0–4C(O)OSiRq3; –(CH2)0–4OC(O)Rq; –OC(O)(CH2)0–4SR°; –(CH2)0– 4SC(O)Rq; –(CH2)0–4C(O)NRq2; –C(S)NRq2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NRq2; -C(O)N(ORq)Rq; –(CH2)0–4OS(O)2Rq; –S(O)2NRq2; -(CH2)0–4S(O)(NH)Rq^ -(CH2)0–4S(O)Rq; -N(Rq)S(O)2NRq2; –N(Rq)S(O)2Rq; –N(ORq)Rq; –C(NH)NRq2; –P(O)2Rq; -P(O)Rq2; -OP(O)Rq2; –OP(O)(ORq)2; –SiRq3; –(C1–4straight or branched alkylene)O–N(Rq)2; or –(C1–4 straight or branched alkylene)C(O)O–N(Rq)2, wherein each Rq may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rq, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0033] Suitable monovalent substituents on Rq (or the ring formed by taking two independent occurrencesof Rq together with their intervening atoms), are independently halogen, –(CH2)0–2Rz, –(haloRz), –(CH2)0–2OH, –(CH2)0–2ORz, –(CH2)0–2CH(ORz)2, -O(haloRz), –CN, –N3, –(CH2)0–2C(O)Rz, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)ORz, –(CH2)0–2SRz, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHRz, –(CH2)0–2NRz2, –NO2, –SiRz3, – OSiRz3, -C(O)SRz,–(C1–4straight or branched alkylene)C(O)ORz, or –SSRzwherein each Rzis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of Rq include =O and =S.

[0034] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–,wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on the aliphatic group of R*include halogen, –Rz, -(haloRz), -OH, –ORz, – O(haloRz), –CN, –C(O)OH, –C(O)ORz, –NH2, –NHRz, –NRz2, or –NO2, wherein each Rzis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, – C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on the aliphatic group of R†are independently halogen, –Rz, -(haloRz), –OH, –ORz, –O(haloRz), –CN, –C(O)OH, –C(O)ORz, –NH2, –NHRz, –NRz2, or -NO2, wherein each Rzis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder, and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.

[0039] As used in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprise”, “comprising”, “include” and “including” (whether used with “not limited to” or not (whether used with “not limited to” or not) may be understood to encompass itemized component(s) or step(s) whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included. Unless otherwise clear from context, isomers of compounds are included. As those skilled in the art appreciate, compounds may be provided, administered, or delivered in various forms, e.g., salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, esters, prodrugs, tautomers, etc. Certain Compounds

[0040] In some embodiments, the present disclosure provides compounds useful for preventing or treating various conditions, disorders or diseases including cancer. In some embodiments, the present disclosure provides compounds useful for inhibiting cell proliferation, e.g., cancer cell proliferation. In some embodiments, the present disclosure provides compounds useful for reducing tumor growth. In some embodiments, the present disclosure provides compounds useful for reducing level of KAT2A and / or level of KAT2B. In some embodiments, the present disclosure provides compounds useful for inhibiting one or more functions of KAT2A and / or KAT2B. In some embodiments, the present disclosure provides compounds that can bind to KAT2A and / or KAT2B, and can bind to an E3 ligase. Certain compounds are described below as examples.

[0041] In some embodiments, the present disclosure provides KAT2 degrader compounds, comprising a KAT2 protein binding moiety, a linker, and an E3 ubiquitin ligase binding moiety.

[0042] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: PBM is a KAT2 protein binding moiety, or isr; linker is an optional linking moiety, or is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or -Cy-; and , ,wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; L3, L4, and L5are each independently a covalent bond or an optionally substituted bivalent C1-6hydrocarbon chain; each R8is independently -R’; R9is -R’; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; O Ring E is, or an optionally substituted group selected fromand; Y is N or CH; each Rais independently halogen, -CN or -R’; linker is attached to the bracketed moiety at one of Rd, Re, Rf, or Rg, or linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together; each Rdthat is not the point of attachment for the linker is independently -R’, or two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each Rethat is not the point of attachment for the linker is independently -R; Rf, when it is not the point of attachment for the linker, is -R; each Rgthat is not the point of attachment for the linker is independently halogen, -CN, R or -OR; p is 0, 1, 2, or 3; Rhis halogen, or -R; each Rithat is not the point of attachment of the linker is independently halogen, -R, -C(O)N(R’)2, or - N(R)C(O)R, or two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S; Rjis -R, or Rjcombines with one instance of Ri, together with their intervening atoms, to form an optionally substituted 5- to 7-membered ring having 1-2 heteroatoms independently selected from N, O, and S; Rkis -R; r is 1, 2, 3, 4, or 5; q is 1 or 2;Rmis -R; each of Rn, Rp, Rq, Rr, Rs, and Ruis independently halogen, -CN, -R or -OR; s is 0, 1, 2, 3, 4, or 5; t is 0, 1, 2, 3, 4, or 5; each u is independently 0, 1, 2, 3, 4, or 5; each Rtis independently R, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered ring having 0-2 heteroatoms independently selected from N, O, and S; each Rvis independently halogen, -CN, -R or -OR, or one instance of Ruand Rv, together with their intervening atoms, combine to form an optionally substituted 3- to 7-membered ring having 0-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -CN, -R or -OR, or one instance of Ruand Rw, together with their intervening atoms, combine to form an optionally substituted 3- to 7-membered ring having 0-2 heteroatoms independently selected from N, O, and S; each v is independently 0, 1, 2, 3, 4, or 5; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0043] In some embodiments, the present disclosure provides a compound of Formula I: PBM – linker – LBM I or a pharmaceutically acceptable salt thereof, wherein: PBM is a KAT2 protein binding moiety; linker is an optional linking moiety; and LBM is an E3 ubiquitin ligase binding moiety.

[0044] In some embodiments, PBM is or, and,, s v. In somembodiments, PBM is R9e , and LBM is,In someR9embodiments, PBM is , and LBM is

[0045] In some embodiments, a compound comprises a moiety, e.g., PBM, that can bind a KAT2 protein or a fragment (e.g., bromodomain) thereof. In some embodiments, PBM-H or a salt thereof can bind a KAT2 protein or a fragment (e.g., bromodomain) thereof. In some embodiments, PBM-H or a salt thereof binds KAT2A or a fragment (e.g., bromodomain) thereof. In some embodiments, PBM-H or a salt thereof binds KAT2B or a fragment (e.g., bromodomain) thereof. In some embodiments, PBM-H or a salt thereof binds KAT2A or a fragment (e.g., bromodomain) thereof, and KAT2B or a fragment (e.g., bromodomain) thereof. In some embodiments, PBM-linker-H or a salt thereof can bind a KAT2 protein or a fragment (e.g., bromodomain) thereof. In some embodiments, PBM-linker-H or a salt thereof binds KAT2A or a fragment (e.g., bromodomain) thereof. In some embodiments, PBM-linker-H or a salt thereof binds KAT2B or a fragment (e.g., bromodomain) thereof. In some embodiments, PBM-linker-H or a salt thereof binds KAT2A or a fragment (e.g., bromodomain) thereof, and KAT2B or a fragment (e.g., bromodomain) thereof. In some embodiments, H-LBM or a salt thereof can bind an E3 ligase (e.g., CRBN, VHL, IAP, or MDM2). In some embodiments, H-LBM or a salt thereof bind CRBN. In some embodiments, H-LBM or a salt thereof bind VHL. In some embodiments, H-linker-LBM or a salt thereof can bind an E3 ligase (e.g., CRBN, VHL, IAP, or MDM2). In some embodiments, H- linker-LBM or a salt thereof bind CRBN. In some embodiments, H- linker- LBM or a salt thereof bind VHL.

[0046] In some embodiments, the present disclosure provides a compound of Formula II:II or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is a 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or a bivalent C1-3 straight or branched hydrocarbon chain; each R1is independently optionally substituted C1-6 aliphatic or optionally substituted C3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R4is hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S;each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety.

[0047] In some embodiments, the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is a 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or a bivalent C1-3 straight or branched hydrocarbon chain; each R1is independently optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally andindependently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety.

[0048] In some embodiments, the present disclosure provides a compound of Formula IIA:or a pharmaceutically acceptable salt thereof, wherein Ring A, L1, R1, R9, n, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0049] In some embodiments, the present disclosure provides a compound of Formula IIA-1, IIA-2, IIA- 3, or IIA-4:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R9, X, Z, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.In some embodiments, the present disclosure provides a compound of Formula IIA-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IIA-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IIA-3, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IIA-4, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the present disclosure provides a compound of Formula IIA-1:IIA-1 or a pharmaceutically acceptable salt thereof, wherein: R1is optionally substituted C1-6aliphatic; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen or halogen; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R9is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-; each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or optionally substituted C1-6 aliphatic;; Ring C is an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S;each Rais hydrogen; L2is a covalent bond, -CH2-, –O-, or -N(R)-; and Y is N or CH.

[0051] In some embodiments, the present disclosure provides a compound of Formula IIA-1:IIA-1 or a pharmaceutically acceptable salt thereof, wherein: R1is C1-6alkyl; Z is N or CR3; R2is hydrogen, halogen, -CN, C1-6alkyl, or C3-6cycloalkyl; each R3is independently hydrogen or halogen; R4is C1-6alkyl; R9is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-; each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or C1-6alkyl;; Ring C is an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; each Rais hydrogen; L2is a covalent bond, -CH2-, –O-, or -N(R)-; and Y is N or CH.

[0052] In some embodiments, the present disclosure provides a compound of Formula IIA-5: linker LBMIIA-5 or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0053] In some embodiments, the present disclosure provides a compound of Formula IIA-6:IIA-6 or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0054] In some embodiments, the present disclosure provides a compound of Formula II-1:II-1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R;each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; LBM is an E3 ubiquitin ligase binding moiety; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0055] In some embodiments, the present disclosure provides a compound of Formula III:III or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is a 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; each R1is independently optionally substituted C1-6aliphatic or optionally substituted-6cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6 aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R9is hydrogen or optionally substituted C1-6 aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated orunsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; L2is a covalent bond or a straight or branched C1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; Y is N or CH; each Rais independently hydrogen or an optionally substituted C1-6 aliphatic, or two Ragroups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0056] In some embodiments, the present disclosure provides a compound of Formula IIIA:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; andm is 0, 1, 2, or 3.

[0057] In some embodiments, the present disclosure provides a compound of Formula IIIB:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Rb, Rc, m, and linker are as defined above for Formula IIIA and described in classes and subclasses herein, both singly and in combination.

[0058] In some embodiments, the present disclosure provides a compound of Formula IIIB-1 or IIIB-2:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIIB-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IIIB-2, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the present disclosure provides a compound of Formula IIIC:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, L2, R1, R9, Y, n, and linker are as defined above for Formula III and described in classes and subclasses herein, both singly and in combination;and each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0060] In some embodiments, the present disclosure provides a compound of Formula IIID:or a pharmaceutically acceptable salt thereof, wherein Ring A, B, L2, R1, R9, Rc, Y, m, and linker are as defined above for Formula IIIC and described in classes and subclasses herein, both singly and in combination.

[0061] In some embodiments, the present disclosure provides a compound of Formula IIID:or a pharmaceutically acceptable salt, wherein: Ring A is; R1is optionally substituted C1-6aliphatic; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen or halogen; R4is optionally substituted C1-6 aliphatic; R9is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-; each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or optionally substituted C1-6aliphatic; L2is a covalent bond, -CH2-, –O-, or -N(R)-; Y is N or CH; each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; and m is 0, 1, 2, or 3.

[0062] In some embodiments, the present disclosure provides a compound of Formula IIID:IIID or a pharmaceutically acceptable salt, wherein: Ring A is; R1is C1-6 alkyl; Z is N or CR3; R2is hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl; each R3is independently hydrogen or halogen; R4is C1-6 alkyl; R9is hydrogen; linker; L6and L7are both a covalent bond;Cy is is selected from:, , , , ,, , , ; the moietyL2is a covalent bond; Y is CH; each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -O(C1-6 alkyl), and C1-6 alkyl; and m is 0, 1, 2, or 3.

[0063] In some embodiments, the present disclosure provides a compound of Formula III-1:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R;each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is, or an optionally substituted group selected fromand; Y is N or CH; each Rais independently halogen, -CN or -R’; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0064] In some embodiments, the present disclosure provides a compound of Formula IIIE:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, orR2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is N or CH; each Rais independently halogen, -CN or -R’; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0065] In some embodiments, the present disclosure provides a compound of Formula IIIF:IIIF or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is N or CH; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0066] In some embodiments, the present disclosure provides a compound of Formula IIIG:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independentlyselected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; L6is a covalent bond, -C(O)- or optionally substituted -CH2-; Cy is an optionally substituted, 3- to 16-membered bivalent ring system having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is, or an optionally substituted group selected from Oand; Y is N or CH; each Rais independently halogen, -CN or -R’; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0067] In some embodiments, the present disclosure provides a compound of Formula IIIH:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, orR2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; L6is a covalent bond, -C(O)- or optionally substituted -CH2-; Cy is an optionally substituted, 3- to 16-membered bivalent ring system having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is N or CH; each Rais independently halogen, -CN or -R’; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0068] In some embodiments, the present disclosure provides a compound of Formula IIIJ:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; L6is a covalent bond, -C(O)- or optionally substituted -CH2-; Cy is an optionally substituted, 3- to 16-membered bivalent ring system having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6heteroatoms independently selected from N, O, and S; each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is N or CH; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0069] In some embodiments, the present disclosure provides a compound of Formula IIIK:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3;R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; L6is a covalent bond, -C(O)- or optionally substituted -CH2-; Cy is an optionally substituted, 3- to 16-membered bivalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0070] In some embodiments, the present disclosure provides a compound of Formula IIIL:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-,-SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rband Rb1is independently halogen, -CN, -R’ or -OR; t’ is 0, 1, 2, or 3; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is, or an optionally substituted group selected fromand; Y is N or CH; each Rais independently halogen, -CN or -R’; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0071] In some embodiments, the present disclosure provides a compound of Formula IIIM:IIIMor a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; L6is a covalent bond, -C(O)- or optionally substituted -CH2-; Cy is an optionally substituted, 3- to 16-membered bivalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rband Rb1is independently halogen, -CN, -R’ or -OR; t’ is 0, 1, 2, or 3; L2is a covalent bond or an optionally substituted C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is O, or an optionally substituted group selected fromand; Y is N or CH; each Rais independently halogen, -CN or -R’; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0072] In some embodiments, the present disclosure provides a compound of Formula IIIN:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain;each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; L6is a covalent bond, -C(O)- or optionally substituted -CH2-; Cy is an optionally substituted, 3- to 16-membered bivalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rband Rb1is independently halogen, -CN, -R’ or -OR; t’ is 0, 1, 2, or 3; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is N or CH; each Rais independently halogen, -CN or -R’; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, andS, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0073] In some embodiments, the present disclosure provides a compound of Formula IV:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one of Rd, Re, Rf, or Rg; each Rdthat is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6aliphatic, or two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each Rethat is not the point of attachment for the linker is independently hydrogen or optionally substituted C1-6aliphatic; Rf, when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6 aliphatic; each Rgthat is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic; Rhis hydrogen, halogen, or optionally substituted C1-6 aliphatic; and p is 0, 1, 2, or 3.

[0074] In some embodiments, the present disclosure provides a compound of Formula IVA:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, Rd, Re, Rf, Rg, Rh, p, n, and linker are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0075] In some embodiments, the present disclosure provides a compound of Formula IVA-1:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Rd, Re, Rf, Rg, Rh, p, and linker are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0076] In some embodiments, the present disclosure provides a compound of Formula IV-1:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’;R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; linker is attached to the bracketed moiety at one of Rd, Re, Rf, or Rg; each Rdthat is not the point of attachment for the linker is independently -R’, or two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each Rethat is not the point of attachment for the linker is independently -R; Rf, when it is not the point of attachment for the linker, is -R; each Rgthat is not the point of attachment for the linker is independently halogen, -CN, R or -OR; p is 0, 1, 2, or 3; Rhis halogen, or -R; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, andS, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0077] In some embodiments, a compound of formula IV-1 is a compound of formula IVD:wherein the variables are as defined above for Formula IVB and described in classes and subclasses herein, both singly and in combination.

[0078] In some embodiments, the present disclosure provides a compound of Formula V:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together; each Rithat is not the point of attachment of the linker is independently halogen, optionally substituted C1-6 aliphatic, -C(O)N(R)2, or -N(R)C(O)R, or two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Rjis an optionally substituted group selected from C1-6 aliphatic and C3-7 cycloaliphatic, or Rjcombines with one instance of Ri, together with the atoms to which they are attached, to form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S; Rkis an optionally substituted C1-6 aliphatic; r is 1, 2, 3, 4, or 5; and q is 1 or 2.

[0079] In some embodiments, the present disclosure provides a compound of Formula VA:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, Ri, Rj, Rk, n, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.

[0080] In some embodiments, the present disclosure provides a compound of Formula VA-1:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Ri, Rj, Rk, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.

[0081] In some embodiments, the present disclosure provides a compound of Formula VB:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R, R1, R9, Ri, Rj, Rk, n, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.

[0082] In some embodiments, the present disclosure provides a compound of Formula VB-1:VB-1 or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R, R1, R9, Rj, Rk, n, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.

[0083] In some embodiments, the present disclosure provides a compound of Formula V-1:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’;linker is a covalent bond or an optionally substituted bivalent C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together; each Rithat is not the point of attachment of the linker is independently halogen, -R, -C(O)N(R’)2, or - N(R)C(O)R, or two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S; Rjis -R, or Rjcombines with one instance of Ri, together with the atoms to which they are attached, to form an optionally substituted 5- to 7-membered ring having 1-2 heteroatoms independently selected from N, O, and S; Rkis -R; r is 1, 2, 3, 4, or 5; q is 1 or 2. each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0084] In some embodiments, a compound of formula V-1 is of formula VC:wherein the variables are as defined above for Formula V-1 and described in classes and subclasses herein, both singly and in combination.

[0085] In some embodiments, a compound of formula V-1 is of formula VD:wherein the variables are as defined above for Formula V-1 and described in classes and subclasses herein, both singly and in combination.

[0086] In some embodiments, a compound of formula V-1 is of formula VE:wherein the variables are as defined above for Formula V-1 and described in classes and subclasses herein, both singly and in combination.

[0087] In some embodiments, the present disclosure provides a compound of Formula VI:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and Rmis optionally substituted C1-6 aliphatic;each Rnis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; and s is 0, 1, 2, 3, 4, or 5.

[0088] In some embodiments, the present disclosure provides a compound of Formula VIA: sor a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, Rm, Rn, n, s, and linker are as defined above for Formula VI and described in classes and subclasses herein, both singly and in combination.

[0089] In some embodiments, the present disclosure provides a compound of Formula VIA-1: sVIA-1 or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Rm, Rn, s, and linker are as defined above for Formula VI and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula VI-1: sVI-1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain; each R1is independently -R;n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; Rmis R; each Rnis independently halogen, -CN, -R or -OR; s is 0, 1, 2, 3, 4, or 5; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0090] In some embodiments, the present disclosure provides a compound of Formula VIB:VIB or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above for Formula VI-1 and described in classes and subclasses herein, both singly and in combination.

[0091] In some embodiments, the present disclosure provides a compound of Formula VII:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each Rpis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rqis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rris independently hydrogen or optionally substituted C1-6aliphatic; each Rsis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5.

[0092] In some embodiments, the present disclosure provides a compound of Formula VIIA:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Rp, Rq, Rr, Rs, u, t, and linker are as defined above for Formula VII and described in classes and subclasses herein, both singly and in combination.

[0093] In some embodiments, the present disclosure provides a compound of Formula VII-1: or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20hydrocarbon chain, wherein one ormore methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S; each Rpis independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic; each Rqis independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic; each Rris independently hydrogen or optionally substituted C1-6 aliphatic; each Rsis independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5.

[0094] In some embodiments, the present disclosure provides a compound of Formula VIIB:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Rp, Rq, Rr, Rs, u, t, and linker are as defined above for Formula VII-1 and described in classes and subclasses herein, both singly and in combination.

[0095] In some embodiments, the present disclosure provides a compound of Formula VIII:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each Rtis independently hydrogen or optionally substituted C1-6 aliphatic, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Ruis independently hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic; each Rvis independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic, or one instance of Ruand Rv, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic, or one instance of Ruand Rw, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; and each v is independently 0, 1, 2, 3, 4, or 5.

[0096] In some embodiments, the present disclosure provides a compound of Formula VIIIA:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Rt, Ru, Rv, Rw, v, and linker are as defined above for Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0097] In some embodiments, the present disclosure provides a compound of Formula VIII-1:or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-,-SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S; each Rtis independently hydrogen or optionally substituted C1-6 aliphatic, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Ruis independently hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic; each Rvis independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic, or one instance of Ruand Rv, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic, or one instance of Ruand Rw, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; and each v is independently 0, 1, 2, 3, 4, or 5.

[0098] In some embodiments, the present disclosure provides a compound of Formula VIIIB:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring F, R1, R9, Rt, Ru, Rv, Rw, v, and linker areas defined above for Formula VIII-1 and described in classes and subclasses herein, both singly and in combination.

[0099] In some embodiments, the present disclosure provides a compound of Formula IX:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; L3, L4, and L5are each independently a covalent bond or an optionally substituted bivalent C1-6 straight or branched hydrocarbon chain; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; each R8is independently hydrogen or optionally substituted C1-6aliphatic; R9is hydrogen or optionally substituted C1-6 aliphatic;linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety.

[0100] In some embodiments, the present disclosure provides a compound of Formula IX, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; L3, L4, and L5are each independently a covalent bond or an optionally substituted bivalent C1-6 straight or branched hydrocarbon chain; Z is N or CR3; R2is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, orR4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; each R8is independently hydrogen or optionally substituted C1-6aliphatic; R9is hydrogen or optionally substituted C1-6 aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety.

[0101] In some embodiments, the present disclosure provides a compound of Formula IXA, IXB, IXC, or IXD:or a pharmaceutically acceptable salt thereof, wherein L3, L4, L5, R2, R3, R4, R5, R6, R8, R9, X, Z, linker, andLBM are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IXA, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IXB, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IXC, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IXD, or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the present disclosure provides a compound of Formula IX-1:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5LV^KDORJHQ^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; L3, L4, and L5are each independently a covalent bond or an optionally substituted bivalent C1-6hydrocarbon chain;each R8is independently -R’; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; LBM is an E3 ubiquitin ligase binding moiety; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

[0103] In some embodiments, the present disclosure provides a compound of Formula X:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each Rais independently hydrogen or an optionally substituted C1-6 aliphatic, or two Ragroups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L2is a covalent bond or a straight or branched C1-3 hydrocarbon chain wherein one methylene isoptionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; and Y is N or CH.

[0104] In some embodiments, the present disclosure provides a compound of Formula XA:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0105] In some embodiments, the present disclosure provides a compound of Formula XA-1 or XA-2:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula XA-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula XA-2, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the present disclosure provides a compound of Formula XB:or a pharmaceutically acceptable salt thereof, wherein Ring A, L2, L3, L4, L5, R8, R9, Y, and linker are as defined above for Formula X and described in classes and subclasses herein, both singly and in combination; and each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0107] In some embodiments, the present disclosure provides a compound of Formula X-1, X-2, or X-3:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I or IIIL and described in classes and subclasses herein, both singly and in combination.

[0108] In some embodiments, the present disclosure provides a compound of Formula XA’:or a pharmaceutically acceptable salt thereof, wherein each Rcis independently selected from halogen, -OR, - N(R)2, -CN, and -R; m is 0, 1, 2, or 3; and the other variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, Ring A is selected from:; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5is halogen^^í&1^^RU^-R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; R9is -R’; L3, L4, and L5are each independently a covalent bond or an optionally substituted bivalent C1-6hydrocarbon chain; each R8is independently -R’; Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or linker is a covalent bond or an optionally substituted bivalent C1-C20 hydrocarbon chain, wherein one or moremethylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C3-10 cycloaliphatic, C1-C8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S; each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; and m is 0, 1, 2, or 3.

[0109] In some embodiments, the present disclosure provides a compound of Formula XA-1’ or XA-2’:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments, Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula X-1 and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula XA-1’, ora pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula XA-2’, or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the present disclosure provides a compound of Formula XB’:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring F, L2, L3, L4, L5, R8, R9, Y, and linker are as defined above for Formula X-1 and described in classes and subclasses herein, both singly and in combination; and each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0111] In some embodiments, the present disclosure provides a compound of Formula XI:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one of Rd, Re, Rf, or Rg; each Rdthat is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6aliphatic, or two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each Rethat is not the point of attachment for the linker is independently hydrogen or optionally substituted C1-6 aliphatic; Rf, when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6aliphatic; each Rgthat is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; Rhis hydrogen, halogen, or optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3.

[0112] In some embodiments, the present disclosure provides a compound of Formula XIA:XIA or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, Rd, Re, Rf, Rg, Rh, p, and linker are as defined above for Formula XI and described in classes and subclasses herein, both singly and in combination.

[0113] In some embodiments, the present disclosure provides a compound of Formula XI-1:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination.

[0114] In some embodiments, the present disclosure provides a compound of Formula XIB:XIB or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination.

[0115] In some embodiments, the present disclosure provides a compound of Formula XII:XII or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together; each Rithat is not the point of attachment of the linker is independently halogen, optionally substituted C1-6aliphatic, -C(O)N(R)2, or -N(R)C(O)R, or two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Rjis an optionally substituted group selected from C1-6 aliphatic and C3-7 cycloaliphatic, or Rjcombines with one instance of Ri, together with the atoms to which they are attached, to form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S; Rkis an optionally substituted C1-6 aliphatic; r is 1, 2, 3, 4, or 5; and q is 1 or 2.

[0116] In some embodiments, the present disclosure provides a compound of Formula XIIA:XIIA or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, Ri, Rj, Rk, q, r, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.

[0117] In some embodiments, the present disclosure provides a compound of Formula XIIB:XIIB or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R, R8, R9, Ri, Rj, Rk, q, r, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.

[0118] In some embodiments, the present disclosure provides a compound of Formula XIIB-1:XIIB-1 or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R, R8, R9, Rj, Rk, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.

[0119] In some embodiments, the present disclosure provides a compound of Formula XII-1:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination.

[0120] In some embodiments, the present disclosure provides a compound of Formula XIIA’:XIIA’ or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination.

[0121] In some embodiments, the present disclosure provides a compound of Formula XIIB’:XIIB’ or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination.

[0122] In some embodiments, the present disclosure provides a compound of Formula XIIB-1’:XIIB-1’ or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination.

[0123] In some embodiments, the present disclosure provides a compound of Formula XIII: sXIII or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and Rmis optionally substituted C1-6 aliphatic; each Rnis independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic; and s is 0, 1, 2, 3, 4, or 5.

[0124] In some embodiments, the present disclosure provides a compound of Formula XIIIA: sXIIIA or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, Rm, Rn, s, and linker are as defined above for Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0125] In some embodiments, the present disclosure provides a compound of Formula XIII-1: sXIII-1 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination.

[0126] In some embodiments, the present disclosure provides a compound of Formula XIIIB: sXIIIB or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring F, L3, L4, L5, R8, R9, Rm, Rn, s, and linker are as defined above for Formula XIII-1 and described in classes and subclasses herein, both singly and in combination.

[0127] In some embodiments, the present disclosure provides a compound of Formula XIV:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each Rpis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rqis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rris independently hydrogen or optionally substituted C1-6aliphatic; each Rsis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic;t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5.

[0128] In some embodiments, the present disclosure provides a compound of Formula XIV-1:XIV-1 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination.

[0129] In some embodiments, the present disclosure provides a compound of Formula XV:XV or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each Rtis independently hydrogen or optionally substituted C1-6aliphatic, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Ruis independently hydrogen, halogen, -CN, or optionally substituted C1-6aliphatic; each Rvis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rv, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rw, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S;each v is independently 0, 1, 2, 3, 4, or 5.

[0130] In some embodiments, the present disclosure provides a compound of Formula XV-1:XV-1 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined as in formula I and described in classes and subclasses herein, both singly and in combination. PBM

[0131] In some embodiments of any Formula described herein, PBM is a KAT2 protein binding moiety, i.e., is a moiety that is capable of binding a KAT2 protein. In some embodiments, a PBM is a KAT2A protein binding moiety, i.e., is a moiety that is capable of binding a KAT2A protein. In some embodiments, a PBM is a KAT2B protein binding moiety, i.e., is a moiety that is capable of binding a KAT2B protein. Typically, a PBM is considered to be capable of binding a KAT2 protein (e.g., KAT2A and / or KAT2B) if it specifically (i.e., preferentially) associates with the KAT2 protein when contacted with the KAT2 protein in the presence of at least one other protein. In some embodiments, a PBM is considered to be capable of binding a KAT2 protein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo).

[0132] In some embodiments, a PBM shares significant structural identity with a reference compound or moiety thereof that is capable of binding a KAT2 protein. For example, in some embodiments, a PBM comprises the same or similar structure as a reference compound, except that a PBM comprises a point of attachment to a linker. In some embodiments, a reference compound is characterized by a Kdof less than 1 µM in a biophysical assay, such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). In some embodiments, a reference compound is characterized by a IC50of less than 1 µM in a competition or functional assay, such as time-resolved fluorescence resonance energy transfer (TR-FRET). In some embodiments, a reference compound is characterized by an DC50of less than 30 nM in the Western Blot assay of Example B1. In some embodiments, a reference compound binds to a KAT2 protein but does not cause KAT2 degradation when assessed, e.g., as described in Example B1. In some embodiments, a reference compound has the structure of PBM-H or a salt thereof. In some embodiments, a reference compound is a compound described in WO 2016 / 036954, WO 2016 / 036873, WO 2016 / 112298, Chaikuad, A., et al., J. Med. Chem., 2016, 59, 1648-53, Humphreys, P.G., et al., J. Med. Chem., 2017, 60, 2, 695-709, Moustakim, M., et al., Angew. Chem. Int. Ed., 2017, 56, 827-31, the entire contents of each of which are hereby incorporated byreference. A reference compound can be useful for assessing the binding properties of a PBM of the present disclosure, e.g., by comparison of binding data of a PBM of the present disclosure with binding data of a reference compound. In some embodiments, a reference compound can be incorporated as a PBM (see, e.g., GSK4027 incorporated into various compounds as PBM). In some embodiments, a PBM is as described in WO 2024 / 003533, US20230391745, WO2017 / 197046, or Bassi, Z., et al., ACS Chem. Biol. 2018, 13, ^^^^í^^^^^^ the entirety of each of which is incorporated herein by reference. In some embodiments, technologies for identifying or assessing PBM are described in one or more of such references. In some embodiments, an PBM is considered to be capable of binding a KAT2A protein if a compound of PBM-H or a salt thereof, or PBM-linker-H or a salt thereof, has a KD toward a KAT2A protein of about or less than about 1 uM in an assay such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). In some embodiments, a compound of PBM-H or a salt thereof, or PBM-linker-H or a salt thereof, has an IC50 of about or less than about 1 uM in a competition or functional assay, such as time-resolved fluorescence resonance energy transfer (TR-FRET).

[0133] In some embodiments, a reference compound is GSK4027:. In some embodiments, a reference compound is:.

[0134] In some embodiments, a PBM has the structure, wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, Ring F is an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 5- to 10-(e.g., 5-8, 5-6, 3, 4, 5, 6, 7, 8, 9 or 10) membered ring having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 5-membered ring having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 6-membered ring having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted aromatic ring. In some embodiments, Ring F is an optionally substituted phenyl ring. In someembodiments, Ring F is an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O and S. In some embodiments, Ring F is an optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 5- to 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted monocyclic ring (e.g., 3-10, 5-8, 3, 4, 5, 6, 7, 8, 9 or 10 membered). In some embodiments, Ring F is an optionally substituted bicyclic ring (e.g., 6-10, 6, 7, 8, 9 or 10 membered). In some embodiments, Ring F is polycyclic.

[0135] In some embodiments, PBM is, wherein each variable are as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, a PBM has the following structure:, wherein Ring A, Ring B, L1, R1, R9, and n are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.

[0136] In some embodiments, a PBM has the following structure:, wherein Ring A, L1, R1, R9, and n are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.

[0137] In some embodiments, a PBM has the following structure:, wherein Ring A, R1, and R9are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.

[0138] In some embodiments, a PBM has the following structure:, wherein Ring A, R1, and R9are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.

[0139] In some embodiments, a PBM has the following structure:, wherein Ring A, R1, and R9are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.

[0140] In some embodiments, a PBM is selected from:wherein R1, R2, R3, R4, R5, R6, R9, X, and Z are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.

[0141] In some embodiments, a PBM has the following structure:, wherein Ring A, L3, L4, L5, R8, and R9are as defined herein for Formula IX and described in classes and subclasses herein, both singly and in combination.

[0142] In some embodiments, a PBM is selected from:wherein L3, L4, L5, R2, R3, R4, R5, R6, R8, R9, X, and Z are as defined herein for Formula IX and described in classes and subclasses herein, both singly and in combination.

[0143] In some embodiments, a PBM is selected from:.

[0144] In some embodiments, a PBM is selected from:.

[0145] In some embodiments of any Formula described herein (unless explicitly indicated otherwise, with or without “of any Formula described herein” or similar language, embodiments described, e.g., for variables or moieties, should apply to all suitable formulae, structures, etc., e.g., all of those comprising such variables or moieties), Ring A is. In some embodiments, Ring A is. In some embodiments, O 2 Ring A . In some embodiments, Ring A is In some embodiments, Ring A is. In some embodiments, Ring A is . In some embodiments, Ring A isIn some embodiments, Ring A is. In some O embodiments, Ring A isIn some embodiments, Ring A is selected from:,, and N. In some embodiments, Ring A is selected from:O

[0146] In some embodiments of any Formula described herein, Ring A is . In someembodiments, Ring. In some such embodiments, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, a formed ring is aromatic. In some embodiments, Ring. 5

[0147] In some embodiments of any Formula described herein, Ring. In some5embodiments, Ring. In some embodiments, Ring. In some such embodiments, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some such embodiments, R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, a formed ring is aromatic. In some embodiments, Ring A is selected from:.

[0148] In some embodiments of any Formula described herein, Ring. In some embodiments, Ring.

[0149] In some embodiments of any Formula described herein, Z is N or CH. In some embodiments, Z is N. In some embodiments, Z is CR3(e.g., CH). In some embodiments, Z is optionally substituted CH.

[0150] In some embodiments, Ring F is an optionally substituted 3- to 16-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 3-15, 3-10, 5-10, 3-8, 3-7, 5-6 membered) ring having 0-6 (e.g., 0, 1-6, 1-4, 1, 2, 3, 4, 5, or 6) heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is 3-10 membered. In some embodiments, it is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7- membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is aromatic. In some embodiments, it has 1-6, 1-5, 1-4, 1-3, 1, 2, 3, or 4 heteroatoms. In some embodiments, it has no heteroatom. In some embodiments, it is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, at least onemonocyclic ring unit is saturated. In some embodiments, at least one monocyclic ring unit is partially unsaturated. In some embodiments, at least one monocyclic ring unit is aromatic. In some embodiments, at least one monocyclic ring unit has a heteroatom. In some embodiments, at least one monocyclic ring unit has no heteroatom. In some embodiments, Ring F is an optionally substituted 5- to 6- membered ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted phenyl ring. In some embodiments, Ring F is an optionally substituted pyridine ring. In some embodiments, Ring F is an optionally substituted 5-membered ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is 3-10 membered. In some embodiments, it is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7-membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is aromatic. In some embodiments, it has 1-6, 1-5, 1-4, 1-3, 1, 2, 3, or 4 heteroatoms. In some embodiments, it has no heteroatom. In some embodiments, it is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, at least one monocyclic ring unit is saturated. In some embodiments, at least one monocyclic ring unit is partially unsaturated. In some embodiments, at least one monocyclic ring unit is aromatic. In some embodiments, at least one monocyclic ring unit has a heteroatom. In some embodiments, at least one monocyclic ring unit has no heteroatom.

[0151] In some embodiments, Ring F is optionally substituted with one or more halogens. In some embodiments, Ring F is optionally substituted with one or more C1-C6alkyl groups. In some embodiments, Ring F is optionally substituted with an optionally substituted -O(C1-C6alkyl) group. In some embodiments, Ring F issome embodiments, Ring F is optionally substituted 1,4-phenylene. In some embodiments, Ring F is 1,4-phenylene. In some embodiments, Ring F is. In some embodiments, Ring.

[0152] In some embodiments, R2is -R as described herein. In some embodiments, R2is -R but not hydrogen. In some embodiments of any Formula described herein, R2is hydrogen, halogen, -CN, or optionally substituted C1-6aliphatic. In some embodiments, R2is hydrogen, halogen, -CN, C1-6alkyl, or C3-6cycloalkyl.In some embodiments, R2is hydrogen, halogen, -CN, C1-6alkyl, C3-6cycloalkyl, or C6-10aryl. In some embodiments, R2is hydrogen, halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R2is hydrogen, halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R2is hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, R2is halogen or C1-6alkyl. In some embodiments, R2is chloro, bromo, or methyl. In some embodiments, R2is hydrogen. In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro. In some embodiments, R2is bromo. In some embodiments, R2is –CN. In some embodiments, R2is optionally substituted C1-6 aliphatic. In some embodiments, R2is optionally substituted C1-6 alkyl. In some embodiments, R2is C1-2 alkyl (e.g., methyl or ethyl). In some embodiments, R2is optionally substituted C3-6 cycloaliphatic. In some embodiments, R2is optionally substituted C3-6 cycloalkyl. In some embodiments, R2is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R2is C6-10 aryl. In some embodiments, R2is phenyl. In some embodiments, R2is naphthyl. In some embodiments, R2is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R2is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R2is 3- to 10-membered monocyclic heterocyclyl having 1- 5 heteroatoms independently selected from N, O, and S. In some embodiments, R2is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0153] In some embodiments, R3is -R as described herein. In some embodiments, R3is -R but not H. In some embodiments of any Formula described herein, each R3is independently hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, each R3is independently hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, each R3is independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, each R3is independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R3is independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R3is hydrogen. In some embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is optionally substituted C1-6aliphatic. In some embodiments, R3is optionally substituted C1-6alkyl. In some embodiments, R3is C1-2alkyl (e.g., methyl). In some embodiments, R3is optionally substituted C3-6cycloaliphatic. In some embodiments, R3is optionally substituted C3-6cycloalkyl. In some embodiments, R3is C6-10aryl. In some embodiments, R3is phenyl. In some embodiments, R3is naphthyl. In some embodiments, R3is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R3is 5- to 6-membered heteroarylhaving 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R3is 3- to 10- membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R3is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0154] In some embodiments, R4is -R as described herein. In some embodiments, R4is -R but not hydrogen. In some embodiments of any Formula described herein, R4is hydrogen or optionally substituted C1-6aliphatic. In some embodiments, R4is hydrogen. In some embodiments, R4is optionally substituted C1-6aliphatic. In some embodiments, R4is hydrogen. In some embodiments, R4is optionally substituted C1-6 aliphatic. In some embodiments, R4is optionally substituted C1-6 alkyl. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is optionally substituted C1-2 alkyl. In some embodiments, R4is C1-2 alkyl (e.g., methyl). In some embodiments, R3is methyl. In some embodiments, R4is optionally substituted C3-6 cycloaliphatic. In some embodiments, R4is optionally substituted C3-6 cycloalkyl. In some embodiments, R4is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R4is -C(O)R. In some embodiments, R4is - C(O)(C1-6 alkyl). In some embodiments, R4is -S(O)2R. In some embodiments, R4is -S(O)2(C1-6 alkyl).

[0155] In some embodiments, R5is -R as described herein. In some embodiments, R5is -R but is not hydrogen. In some embodiments of any Formula described herein, R5is hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, R5is hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, R5is hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, R5is hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R5is hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R5is hydrogen. In some embodiments, R5is halogen. In some embodiments, R5is fluoro. In some embodiments, R5is chloro. In some embodiments, R5is bromo. In some embodiments, R5is optionally substituted C1-6 aliphatic. In some embodiments, R5is optionally substituted C1-6 alkyl. In some embodiments, R5is C1-2 alkyl (e.g., methyl). In some embodiments, R5is optionally substituted C3-6 cycloaliphatic. In some embodiments, R5is optionally substituted C3-6cycloalkyl. In some embodiments, R5is C3-4cycloalkyl (e.g., cyclopropyl). In some embodiments, R5is C6-10aryl. In some embodiments, R5is phenyl. In some embodiments, R5is naphthyl. In some embodiments, R5is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R5is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R5is 3- to 10-membered monocyclic heterocyclyl having 1- 5 heteroatoms independently selected from N, O, and S. In some embodiments, R5is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0156] In some embodiments, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N,O, and S. In some embodiments, a formed ring is monocyclic. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it has 1-2 heteroatoms. In some embodiments, it has no heteroatoms. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is aromatic. In some embodiments, it is an optionally substituted heteroaryl ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments of any Formula described herein, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, R2and R5, together with the atoms to which they are attached, combine to form an 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S, and optionally substituted on a substitutable carbon atom with one or more halogen, –Rq, -ORq, -N(Rq)2, and –CN, and on a substitutable nitrogen atom with one or more –R†and –C(O)R†. In some embodiments, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5-membered aromatic ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R2and R5combine to form an optionally substituted pyrrole. In some embodiments, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, R2and R5combine to form an optionally substituted phenyl or pyridine. In some embodiments, R2and R5combine to form an optionally substituted phenyl ring. In some embodiments, R2and R5combine to form an optionally substituted pyridine ring. In some embodiments, R2and R5combine to form optionally substituted.

[0157] In some embodiments, R6is -R as described herein. In some embodiments, R6is -R but is not hydrogen. In some embodiments of any Formula described herein, R6is hydrogen or optionally substituted C1- 6 aliphatic. In some embodiments, R6is hydrogen. In some embodiments, R6is optionally substituted C1-6 aliphatic. In some embodiments, R6is optionally substituted C1-6 alkyl. In some embodiments, R6is C1-6 alkyl. In some embodiments, R6is optionally substituted C1-2 alkyl. In some embodiments, R6is C1-2 alkyl (e.g., methyl). In some embodiments, R6is methyl. In some embodiments, R6is optionally substituted C3-6 cycloaliphatic. In some embodiments, R6is optionally substituted C3-6 cycloalkyl. In some embodiments, R6is C3-4cycloalkyl (e.g., cyclopropyl). In some embodiments, R6is -C(O)R. In some embodiments, R6is - C(O)(C1-6alkyl). In some embodiments, R6is -S(O)2R. In some embodiments, R6is -S(O)2(C1-6alkyl).

[0158] In some embodiments of any Formula described herein, X is O. In some embodiments, X is NR7. In some embodiments, when X is NR7, then R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.

[0159] In some embodiments, R7is -R as described herein. In some embodiments, R7is -R but is nothydrogen. In some embodiments of any Formula described herein, R7is hydrogen or optionally substituted C1-6alkyl. In some embodiments, R7is hydrogen. In some embodiments, R7is optionally substituted C1-6aliphatic. In some embodiments, R7is optionally substituted C1-6alkyl. In some embodiments, R7is C1-6alkyl. In some embodiments, R7is optionally substituted C1-2alkyl. In some embodiments, R7is C1-2alkyl (e.g., methyl). In some embodiments, R7is optionally substituted C3-6 cycloaliphatic. In some embodiments, R7is optionally substituted C3-6cycloalkyl. In some embodiments, R7is C3-4cycloalkyl (e.g., cyclopropyl). In some embodiments, R7is -C(O)R. In some embodiments, R7is -C(O)(C1-6alkyl). In some embodiments, R7is - S(O)2R. In some embodiments, R7is -S(O)2(C1-6 alkyl).

[0160] In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, a formed ring is monocyclic. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it has 2 heteroatoms. In some embodiments, it has 3 heteroatoms. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is aromatic. In some embodiments of any Formula described herein, R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form a 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S, and optionally substituted on a substitutable carbon atom with one or more halogen, –Rq, -ORq, -N(Rq)2, and –CN, and on a substitutable nitrogen atom with one or more –R†and –C(O)R†. In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form a 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S, and optionally substituted with one or more C1-6 alkyl. In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form a 5-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R4and R7combine to form an optionally substituted triazole. In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form a 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, a formed ring is optionally substituted. In some embodiments, a formed ring.

[0161] In some embodiments, R9is -R as described herein. In some embodiments, R9is -R but is not hydrogen. In some embodiments of any Formula described herein, R9is hydrogen or optionally substituted C1-6alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is optionally substituted C1-6aliphatic.In some embodiments, R9is optionally substituted C1-6alkyl. In some embodiments, R9is C1-6alkyl. In some embodiments, R9is optionally substituted C1-2alkyl. In some embodiments, R9is C1-2alkyl (e.g., methyl). In some embodiments, R9is methyl. In some embodiments, R9is optionally substituted C3-6cycloaliphatic. In some embodiments, R9is optionally substituted C3-6cycloalkyl. In some embodiments, R9is C3-4cycloalkyl (e.g., cyclopropyl). In some embodiments, R9is -C(O)R. In some embodiments, R9is -C(O)(C1-6 alkyl). In some embodiments, R9is -S(O)2R. In some embodiments, R9is -S(O)2(C1-6alkyl).

[0162] In some embodiments, Ring B is an optionally substituted 5-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is an optionally substituted 5-membered saturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is an optionally substituted 5-membered partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is an optionally substituted 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is an optionally substituted 9-membered saturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is an optionally substituted 5-membered partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B has at least one nitrogen atom. In some embodiments, Ring B is an optionally substituted piperidine ring. In some embodiments, Ring B is optionally substituted. In some embodiments, Ring. In some embodiments of any Formula described herein, Ring B is a 5- to 6-membered heterocyclyl having 1 heteroatom independently selected from N, O, and S. In some embodiments, Ring B is a 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N. In some embodiments, Ring B is a 5-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is a 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is piperidine. In some embodiments,some embodiments,

[0163] In some embodiments of any Formulae described herein, L1is a covalent bond. In some embodiments, L1is an optionally substituted bivalent C1-3hydrocarbon chain. In some embodiments, L1is an optionally substituted bivalent saturated C1-3hydrocarbon chain. In some embodiments, L1is an optionally substituted bivalent partially unsaturated C1-3hydrocarbon chain. In some embodiments, L1is an optionally substituted bivalent linear C1-3 hydrocarbon chain. In some embodiments, L1is an optionally substituted bivalent branched C1-3hydrocarbon chain. In some embodiments, L1is a bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L1is a bivalent C1-3straight hydrocarbon chain. In some embodiments, L1is a bivalent C1-2 straight hydrocarbon chain. In some embodiments, L1is optionally substituted In some embodiments, L1is –CH2-.

[0164] In some embodiments, R1is -R as described herein. In some embodiments, R1is -R but not hydrogen. In some embodiments of any Formulae described herein, each R1is independently optionally substituted C1-6 alkyl or optionally substituted C3-6 cycloalkyl. In some embodiments, each R1is independently hydrogen or an optionally substituted group selected from C1-8 aliphatic, C6-10 aryl, C3-10 cycloaliphatic, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and a 3- to 10- membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R1is optionally substituted C1-6 aliphatic. In some embodiments, R1is optionally substituted C1- 6 alkyl. In some embodiments, R1is C1-6 alkyl. In some embodiments, R1is optionally substituted C1-2 alkyl. In some embodiments, R1is C1-2 alkyl (e.g., methyl). In some embodiments, R1is methyl. In some embodiments, R1is optionally substituted C3-6 cycloaliphatic. In some embodiments, R1is optionally substituted C3-6 cycloalkyl. In some embodiments, R1is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R1LV^í&+2- C3-6 cycloaliphatic. In some embodiments, R1LV^í&+2-cyclopropyl. In some embodiments, R1is C6-10 aryl. In some embodiments, R1is phenyl. In some embodiments, R1is naphthyl. In some embodiments, R1is 5- to 10- membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R1is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R1is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R1is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0165] In some embodiments of any Formulae described herein, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0166] In some embodiments, L3is an optionally substituted bivalent straight C1-6(e.g., C1-3, C1, C2, C3, C4, C5or C6) hydrocarbon chain. In some embodiments, L3is an optionally substituted bivalent branched C1-6(e.g., C1-3, C1, C2, C3, C4, C5or C6) hydrocarbon chain. In some embodiments of any Formulae described herein, L3is a covalent bond or an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L3is a covalent bond. In some embodiments, L3is a bivalent C1-6straight or branched hydrocarbon chain. In some embodiments, L3is an optionally substituted bivalent C1-3straight or branchedhydrocarbon chain. In some embodiments, L3is a bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L3is optionally substituted -CH2-. In some embodiments, L3is selected from -CH2- and – CH(CH3)-. In some embodiments, a chain is saturated. In some embodiments, it is partially unsaturated. In some embodiments, L3is -CH2-.

[0167] In some embodiments, L4is an optionally substituted bivalent straight C1-6 (e.g., C1-3, C1, C2, C3, C4, C5or C6) hydrocarbon chain. In some embodiments, L4is an optionally substituted bivalent branched C1-6(e.g., C1-3, C1, C2, C3, C4, C5or C6) hydrocarbon chain. In some embodiments of any Formulae described herein, L4is a covalent bond or an optionally substituted bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L4is a covalent bond. In some embodiments, L4is an optionally substituted bivalent C1-6 straight or branched hydrocarbon chain. In some embodiments, L4is a bivalent C1-6 straight or branched hydrocarbon chain. In some embodiments, L4is an optionally substituted bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L4is a bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L4is optionally substituted -CH2-. In some embodiments, L4is selected from –CH2- and – CH(CH3)-. In some embodiments, L4is -CH2-.

[0168] In some embodiments, L5is an optionally substituted bivalent straight C1-6 (e.g., C1-3, C1, C2, C3, C4, C5 or C6) hydrocarbon chain. In some embodiments, L5is an optionally substituted bivalent branched C1-6 (e.g., C1-3, C1, C2, C3, C4, C5 or C6) hydrocarbon chain. In some embodiments of any Formulae described herein, L5is a covalent bond or an optionally substituted bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L5is a covalent bond. In some embodiments, L5is an optionally substituted bivalent C1-6 straight or branched hydrocarbon chain. In some embodiments, L5is a bivalent C1-6 straight or branched hydrocarbon chain. In some embodiments, L5is an optionally substituted bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L5is a bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L5is optionally substituted -CH2-. In some embodiments, L5is selected from -CH2- and – CH(CH3)-. In some embodiments, L5is -CH2-.

[0169] In some embodiments, R8is -R as described herein. In some embodiments, R8is -R but is not hydrogen. In some embodiments of any Formulae described herein, each R8is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is optionally substituted C1-6aliphatic. In some embodiments, R8is optionally substituted C1-6alkyl. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is optionally substituted C1-2alkyl. In some embodiments, R8is C1-2alkyl (e.g., methyl). In some embodiments, R8is optionally substituted C3-6cycloaliphatic. In some embodiments, R8is optionally substituted C3-6cycloalkyl. In some embodiments, R8is C3-4cycloalkyl (e.g., cyclopropyl). In some embodiments, R8is -C(O)R. In some embodiments, R8is -C(O)(C1-6alkyl). In some embodiments, R8is -S(O)2R. In some embodiments, R8is -S(O)2(C1-6alkyl). In some embodiments, the two R8groups are the same. In some embodiments, they are different. In some embodiments, two R8together with the nitrogen atom to which they are attached, combine to form an optionally substituted 3-16 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 3-15, 3-10, 5-10, 3-8, 3-7, or 5-6) membered ring having 1-5 (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, a formed ring is 3-10 membered. In some embodiments, a formed ring is 3-6 membered. In some embodiments, a formed ring is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, it is saturated or at least one monocyclic unit is saturated. In some embodiments, it is partially unsaturated or at least one monocyclic unit is partially unsaturated. In some embodiments, it is aromatic or at least one monocyclic unit is aromatic. In some embodiments, it is heteroaromatic or at least one monocyclic unit is heteroaromatic. Linker

[0170] In some embodiments of any Formulae described herein, linker is a linking moiety (i.e., any suitable bivalent moiety that connects a PBM to a LBM). In some embodiments, linker is a covalent bond. In some embodiments, linker is an optionally substituted bivalent C1-C20 (e.g., C1-C15, C1-C10, C1-C6, C1-C4, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, or C20) hydrocarbon chain (which can be straight or branched, and saturated or partially unsaturated, and can comprise one or more (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) hydrocarbon rings), wherein one or more (e.g., 1-10, 1-8, 1-6, 1-5, 1-3, 1-2, 2-10, 2-5, 2-3, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, various linkers described herein can provide superior properties, e.g., improved potency, improved half-life, improved stability, and / or decreased toxicity.

[0171] In some embodiments, linker is a particular length (e.g., as measured by number of atoms). It will be appreciated that when the length of linker is described, the longest contiguous chain of atoms is used. For example, in some embodiments, linker has the following structure, which is 14 atoms in length (counted as shown with italicized numbers):.

[0172] In some embodiments, a linker is 2-16 atoms in length. In some embodiments, a linker is 2-13 atoms in length. In some embodiments, a linker is 2-10 atoms in length. In some embodiments, a linker is 2-8 atoms in length. In some embodiments, a linker is 2-7 atoms in length. In some embodiments, a linker is 0-16 atoms in length. In some embodiments, a linker is 0-13 atoms in length. In some embodiments, a linker is 0- 10 atoms in length. In some embodiments, a linker is 0-7 atoms in length. In some embodiments, a linker is 4- 16 atoms in length. In some embodiments, a linker is 4-13 atoms in length. In some embodiments, a linker is4-10 atoms in length. In some embodiments, a linker is 4-8 atoms in length. In some embodiments, a linker is 4-7 atoms in length. In some embodiments, a linker is less than 14 atoms in length. In some embodiments, a linker is less than 11 atoms in length. In some embodiments, a linker is less than 9 atoms in length. In some embodiments, a linker is less than 8 atoms in length.

[0173] Alternative or additionally, in some embodiments, the shortest-path length of a linker (the number of atoms in the chain from one end of a linker to the other following the shorted path (the shortest path chain)) is about 0-16 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 3-15, 3-10, 5-10, 3-8, 3-7, or 5-6) atoms. In some embodiments, it is 0. In some embodiments, it is about 1-16 atoms. In some embodiments, it is about 1-10 atoms. In some embodiments, it is 1 atom. In some embodiments, it is about or no more than about 2 atoms. In some embodiments, it is about or no more than about 2 atoms. In some embodiments, it is about or no more than about 3 atoms. In some embodiments, it is about or no more than about 4 atoms. In some embodiments, it is about or no more than about 5 atoms. In some embodiments, it is about or no more than about 6 atoms. In some embodiments, it is about or no more than about 7 atoms. In some embodiments, it is about or no more than about 8 atoms. In some embodiments, it is about or no more than about 9 atoms. In some embodiments, it is about or no more than about 10 atoms. In some embodiments, it is about or no more than about 11 atoms. In some embodiments, it is about or no more than about 12 atoms. In some embodiments, it is about or no more than about 13 atoms. In some embodiments, it is about or no more than about 14 atoms.

[0174] In some embodiments of any Formulae described herein, linker is a covalent bond.

[0175] In some embodiments of any Formulae described herein, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)- , -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)- , -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, - C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0176] In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally andindependently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)- , -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, - N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, - C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)- , -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0177] In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O- , -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

[0178] In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10(e.g., C1-C8, C1-C6, C1-C5, C1-C4, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10) hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)- , -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

[0179] As exemplified herein, in various embodiments, linkers in provided compounds are short (e.g., with lengths and / or shortest path lengths about or no more than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 atoms; in many cases about or no more than about 8, 9 or 10 atoms) and provide rigidity (e.g., with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring consecutive sp3atoms in the shortest path chain, with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring consecutive atoms in the shortest path chain, with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring sp3atoms in the shortest path chain, with about or no more than about 0, 1, 2, 3, 4 or5 non-ring atoms in the shortest path chain, with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring consecutive sp3atoms in the shortest path chain each atom of which is independently C, N, O or S, with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring consecutive atoms in the shortest path chain each atom of which is independently C, N, O or S, with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring sp3C, N, O or S atoms in the shortest path chain, or with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring C, N, O or S atoms in the shortest path chain). In some embodiments, the number of non-ring consecutive sp3atoms in the shortest path chain of a linker is about or no more than about 5. In some embodiments, the number of non-ring consecutive sp3atoms in the shortest path chain of a linker is about or no more than about 4. In some embodiments, the number of non-ring consecutive sp3atoms in the shortest path chain of a linker is about or no more than about 3. In some embodiments, the number of non-ring consecutive sp3atoms in the shortest path chain of a linker is about or no more than about 2. In some embodiments, the number of non-ring sp3atoms in the shortest path chain of a linker is about or no more than about 5. In some embodiments, the number of non- ring sp3atoms in the shortest path chain of a linker is about or no more than about 4. In some embodiments, the number of non-ring sp3atoms in the shortest path chain of a linker is about or no more than about 3. In some embodiments, the number of non-ring sp3atoms in the shortest path chain of a linker is about or no more than about 2. In some embodiments, the number of non-ring sp3atoms in the shortest path chain of a linker is about or no more than about 1. In some embodiments, the number of non-ring sp3atoms in the shortest path chain of a linker is 0. In some embodiments, the number of non-ring sp3C, O, and S atoms in the shortest path chain of a linker is about or no more than about 5. In some embodiments, the number of non-ring sp3C, O, and S atoms in the shortest path chain of a linker is about or no more than about 4. In some embodiments, the number of non-ring sp3C, O, and S atoms in the shortest path chain of a linker is about or no more than about 3. In some embodiments, the number of non-ring sp3C, O, and S atoms in the shortest path chain of a linker is about or no more than about 2. In some embodiments, the number of non-ring sp3C, O, and S atoms in the shortest path chain of a linker is about or no more than about 1. In some embodiments, the number of non-ring sp3C, O, and S atoms in the shortest path chain of a linker is 0. In some embodiments, the number of non-ring C, O, and S atoms in the shortest path chain of a linker is about or no more than about 5. In some embodiments, the number of non-ring C, O, and S atoms in the shortest path chain of a linker is about or no more than about 4. In some embodiments, the number of non-ring C, O, and S atoms in the shortest path chain of a linker is about or no more than about 3. In some embodiments, the number of non-ring C, O, and S atoms in the shortest path chain of a linker is about or no more than about 2. In some embodiments, the number of non-ring C, O, and S atoms in the shortest path chain of a linker is about or no more than about 1. In some embodiments, the number of non-ring atoms in the shortest path chain of a linker is 0. In some embodiments, the number of non- ring atoms in the shortest path chain of a linker is about or no more than about 5. In some embodiments, the number of non-ring atoms in the shortest path chain of a linker is about or no more than about 4. In some embodiments, the number of non-ring atoms in the shortest path chain of a linker is about or no more than about 3. In some embodiments, the number of non-ring atoms in the shortest path chain of a linker is about or nomore than about 2. In some embodiments, the number of non-ring atoms in the shortest path chain of a linker is about or no more than about 1. In some embodiments, the number of non-ring atoms in the shortest path chain of a linker is 0. As those skilled in the art appreciate, there can be one or more shortest path chains of a linker. In some embodiments, a linker comprises one or more (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) -Cy-. In some embodiments, a linker comprises one or more (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) -Cy- in its shortest path chain. In some embodiments, each -Cy- is independently in the shortest path chain of a linker. In some embodiments, -Cy- is monocyclic. In some embodiments, -Cy- is bicyclic. In some embodiments, -Cy- is spiro-bicyclic. In some embodiments, -Cy- is polycyclic. In some embodiments, -Cy- is saturated. In some embodiments, -Cy- is partially unsaturated. In some embodiments, -Cy- is aromatic. In some embodiments, -Cy- is 3-10 (e.g., 3- 8, 3-6, 3-5, 5-6, 3, 4, 5, 6, 7, 8, 9 or 10) membered and is monocyclic. In some embodiments, -Cy- is 6-16 (e.g., 6-15, 7-15, 10-15, 10-16, 11-16, 11-15, 10-11, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) membered and is bicyclic. In some embodiments, -Cy- is 6-16 (e.g., 6-15, 7-15, 10-15, 10-16, 11-16, 11-15, 10-11, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) membered and is spiro-bicyclic. In some embodiments, -Cy- is 10-12 membered and is bicyclic. In some embodiments, -Cy- is 10-12 membered and is spiro-bicyclic. In some embodiments, -Cy- is 11-membered and is bicyclic. In some embodiments, -Cy- is 11-membered and is spiro-bicyclic. In some embodiments, each monocyclic ring unit in -Cy- is independently 3-10 (e.g., 3-8, 3-6, 3-5, 5-6, 3, 4, 5, 6, 7, 8, 9 or 10) membered. In some embodiments, each monocyclic ring unit in -Cy- is independently 3-8 (e.g., 3-6, 3-5, 5-6, 3, 4, 5, 6, 7, 8, 9 or 10) membered. In some embodiments, each monocyclic ring unit in -Cy- is independently 3-6 (e.g., 3-5, 5-6, 3, 4, 5, 6, 7, 8, 9 or 10) membered. In some embodiments, each monocyclic ring unit in -Cy- is independently 5- or 6-membered. In some embodiments, a monocyclic ring unit in -Cy- is saturated. In some embodiments, a monocyclic ring unit in -Cy- is partially unsaturated. In some embodiments, a monocyclic ring unit in -Cy- is aromatic. In some embodiments, each monocyclic ring unit in -Cy- is independently saturated or partially unsaturated. In some embodiments, each monocyclic ring unit in -Cy- is saturated. In some embodiments, the number of N, O or S heteroatoms in each monocyclic ring unit in -Cy- is independently 0-4 (e.g., 0, 1-4, 1-2, 1, 2, 3, or 4). In some embodiments, the number of N, O or S heteroatoms in each monocyclic ring unit in -Cy- is independently 0-2. In some embodiments, the number of N, O or S heteroatoms in each monocyclic ring unit in -Cy- is independently 0-1. In some embodiments, -Cy- comprises at least one nitrogen. In some embodiments, each heteroatom in -Cy- is nitrogen. In some embodiments, it was observed that spirocyclic rings in linkers can provide various benefits and advantages including high potency. In some embodiments, the number of basic nitrogen atoms can be utilized to modulate compound properties and / or potency, e.g., pharmacokinetic properties. In some embodiments, it was observed that basic nitrogen atoms in linkers, e.g., in -Cy- (e.g., in piperidine and / or piperazine rings) can provide improved solubility, improved dissolution rate, and / or longer T1 / 2, e.g., when assessed in rodent PK assays. Various embodiments of linkers are described herein as examples, e.g., below or in various compounds.

[0180] In some embodiments, a linker is an optionally substituted bivalent C1-C5(e.g., C1-C4, C1-C3, C1-C2, C1, C2, C3, C4, or C5) hydrocarbon chain (which can be straight or branched, and saturated or partiallyunsaturated), wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, a linker is an optionally substituted bivalent C1-C3 (e.g., C1-C2, C1, C2, or C3) hydrocarbon chain (which can be straight or branched, and saturated or partially unsaturated), wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, - N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, - C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, a linker is an optionally substituted bivalent straight C1-C3 (e.g., C1-C2, C1, C2, or C3) hydrocarbon chain, wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)- , -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, a linker is an optionally substituted bivalent straight C1-C3 (e.g., C1-C2, C1, C2, or C3) alkylene chain, wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(NR)-, or -Cy-. In some embodiments, a linker is an optionally substituted bivalent straight C1 or C2 alkylene, wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(NR)-, or -Cy-. In some embodiments, a linker further has limited number of non-ring atoms in its shortest path chain as described herein, e.g., the number of non-ring atoms in its shortest path chain is about or no more than about 0, 1, 2, 3, 4 or 5 (as illustrated herein, in various embodiments, about or no more than about 2, and in various embodiments, about or no more than about 1). For example, in some embodiments, a linker is -C(O)-Cy-, wherein -C(O)- is bonded to PBM; in some embodiments, a linker is -CH2-Cy-, wherein -CH2- is bonded to PBM; in some embodiments, a linker is -CH2-O-, wherein -CH2- is bonded to PBM; in some embodiments, a linker is -Cy-O-, wherein -Cy- is bonded to PBM.

[0181] In some embodiments, about or no more than about 1-10 (e.g., 1-10, 1-8, 1-6, 1-5, 1-3, 1-2, 2-10, 2-5, 2-3, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) methylene units are independently replaced as described herein. In some embodiments, about or no more than about 5 methylene units are independently replaced as described herein. In some embodiments, about or no more than about 4 methylene units are independently replaced as described herein. In some embodiments, about or no more than about 3 methylene units are independently replaced as described herein. In some embodiments, about or no more than about 2 methylene units are independently replaced as described herein. In some embodiments, about or no more than about 1 methylene unit is replaced as described herein.

[0182] In some embodiments, linker comprises an ether moiety (e.g., -O-). In some embodiments, linkeris an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -O-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -O-.

[0183] In some embodiments, linker comprises an amine moiety (e.g., -N(R)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)- (e.g., -NH- or –N(C1-6alkyl)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)- (e.g., -NH- or –N(C1-6alkyl)-). In some embodiments, a methylene unit is replaced by -NH-.

[0184] In some embodiments, linker comprises a carbonyl moiety. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-.

[0185] In some embodiments, linker comprises an ester moiety. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-.

[0186] In some embodiments, linker comprises an amide moiety. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)- (e.g., -C(O)NH- or –C(O)N(C1-6 alkyl)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)- (e.g., -C(O)NH- or - C(O)N(C1-6 alkyl)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein at least one methylene unit is replaced by - N(R)C(O)- (e.g., -N(H)C(O)- or –N(C1-6alkyl)C(O)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)C(O)- (e.g., -N(H)C(O)- or -N(C1-6alkyl)C(O)-). In some embodiments, In some embodiments, a methylene unit is replaced by -C(O)NH-.

[0187] In some embodiments, linker comprises a bivalent ring moiety (e.g., -Cy-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. In some such embodiments, Cy is not phenyl.

[0188] In some embodiments, linker comprises a triple bond. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C20hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, - N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C10hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C20 hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C10hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

[0189] In some embodiments of any Formulae described herein, linker has the following structure: M1L6Cy L7M2, wherein Cy is as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and: M1and M2are each independently absent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0190] In some embodiments of any Formulae described herein, linker has the following structure:, wherein Cy is as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and: M1and M2are each independently absent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; andL6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C5(e.g., C1-C4, C1-C3, C1-C2, C2-C4, C1, C2, C3, C4, or C5) hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, - N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0191] In some embodiments of any Formulae described herein, linker is selected from: ,

[0192] In some embodiments of any Formulae described herein, linker isor L6Cy L7O .

[0193] In some embodiments of any Formulae described herein, linker is selected from: ,.

[0194] In some embodiments of any Formulae described herein, linker has the following structure: wherein:M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0195] In some embodiments of any Formulae described herein, linker is selected from:

[0196] In some embodiments of any Formulae described herein, linker has the following structure: wherein:M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; andL8is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2- , -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0197] In some embodiments of any Formulae described herein, linker is selected from:.

[0198] In some emERGLPHQWV^^OLQNHU^LV^í01í / 6í / 7í02í^

[0199] In some embodiments of any Formulae described herein, M1is –CH2-, –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, M1is absent. In some embodiments, M1is optionally substituted -CH2-. In some embodiments, M1is –CH2-. In some embodiments, M1is -O-. In some embodiments, M1is -N(R)- (e.g., -N(H)- or –N(CH3)-). In some embodiments, M1is -C(O)-. In some embodiments, M1is -OC(O)-. In some embodiments, M1is -C(O)O-. In some embodiments, M1is -C(O)N(R)- (e.g., -C(O)N(H)- or –C(O)N(CH3)-). In some embodiments, M1is -N(R)C(O)- (e.g., -N(H)C(O)- or – N(CH3)C(O)-). In some embodiments, a variable is a covalent bond, and as those of ordinary skill in the art appreciate, it can be properly considered as absent. In some embodiments, M1is bonded to PBM.

[0200] In some embodiments of any Formulae described herein, M2is –CH2-, –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, M2is absent. In some embodiments, M2is –CH2-. In some embodiments, M2is –O-. In some embodiments, M2is -N(R)- (e.g., -N(H)- or –N(CH3)- ). In some embodiments, M2is -C(O)-. In some embodiments, M2is -OC(O)-. In some embodiments, M2is - C(O)O-. In some embodiments, M2is -C(O)N(R)- (e.g., -C(O)N(H)- or –C(O)N(CH3)-. In some embodiments, M2is -N(R)C(O)- (e.g., -N(H)C(O)- or –N(CH3)C(O)-). In some embodiments, M2is bonded to LBM.

[0201] In some embodiments of any Formulae described herein, L6is a covalent bond.

[0202] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-.

[0203] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, - N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

[0204] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or - N(R)C(O)-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0205] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-.

[0206] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straightor branched, saturated C1-C10hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated C1-C6hydrocarbon chain.

[0207] In some embodiments, L6is optionally substituted -CH2-. In some embodiments, L6is -CH2-. In some embodiments, L6is -C(O)-. In some embodiments, L6is bonded to PBM.

[0208] In some embodiments of any Formulae described herein, L7is a covalent bond.

[0209] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-.

[0210] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, - N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

[0211] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or - N(R)C(O)-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0212] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –.

[0213] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated C1-C10hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated C1-C6hydrocarbon chain.

[0214] In some embodiments, L7is bonded to LBM.

[0215] In some embodiments of any Formulae described herein, both L6and L7are a covalent bond.

[0216] In some embodiments of any Formulae described herein, L8is a covalent bond.

[0217] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-.

[0218] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched,saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by –O-, - N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

[0219] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or - N(R)C(O)-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0220] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain, wherein at least two methylene units are replaced by –O-.

[0221] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated C1-C15 hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated C1-C6hydrocarbon chain.

[0222] In some embodiments of any Formulae described herein, linker is selected from:,,

[0223] As described herein and exemplified in various compounds, various linkers are of short lengths (e.g., shortest path chain lengths are about or no more than about 8, 9 or 10 atoms) and / or contain few conformationally flexible chain atoms, e.g., they contain about or no more than about 1, 2, 3, 4, or 0, non-ring sp3C, N, O, or S atoms in its shortest path chain. In some embodiments, there are about or no more than about 1, 2 or 3 non-ring atoms in its shortest path chain. In some embodiments, there are about or no more than about 2 non-ring atoms in its shortest path chain. In some embodiments, there is about or no more than about 1 non- ring atom in its shortest path chain (e.g., as in, , ,In some embodiments, the number of bonds between two non-ring sp3atom in the shortest path chain of a linker is about or no more than 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5; in some embodiments, it is 0 (e.g., as inin some embodiments, it is 1 (e.g., as in . Among other things, such linkers can provideincreased conformational rigidity, and / or can provide various benefits and advantages. In some embodiments, rings are monocyclic or bicyclic, in many cases spiro-bicyclic, and each monocyclic ring unit is independently about 3-, 4-, 5- or 6-membered. In some embodiments, rings independently contain 1, 2, or 3 heteroatoms. In some embodiments, one or more heteroatoms are nitrogen. In some embodiments, each heteroatom is nitrogen. In some embodiments, linker comprises one or more basic nitrogen atoms, e.g., in its shortest path chain. For O example, in some embodiments, linker isIn some embodiments, linker is. In some embodiments, linker is. In some embodiments, linker is . In some embodiments, linker is. In some embodiments, linker isO . In some embodiments, linker is. In some embodiments, linker is. In some embodiments, linker is. In some embodiments, linker isO . In some embodiments, linker is. In someembodiments, linker is. In some embodiments, linker is. In some embodiments, linker is. In some embodiments, -C(O)- in linker is bonded to PBM. In some embodiments, linker is -CH2-O-. In some embodiments, linker is. In some embodiments, linker is bonded to LBM at O.

[0224] In some embodiments of any Formulae described herein, linker is not:.

[0225] In some embodiments of any Formulae described herein, each Cy is independently an optionally substituted, mono- or bicyclic, 3- to 11-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently an optionally substituted group selected from phenyl, C9-10 bicyclic aryl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic C3-7 cycloaliphatic, 5- to 10-membered bicyclic cycloaliphatic, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently an optionally substituted group selected from phenyl, 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0226] In some embodiments, Cy is optionally substituted phenyl. In some embodiments, Cy is phenyl. In some embodiments, Cy is not phenyl.

[0227] In some embodiments, Cy is optionally substituted C9-10bicyclic aryl. In some embodiments, Cy is optionally substituted C13-16polycyclic aryl.

[0228] In some embodiments, Cy is optionally substituted 5- to 6-membered monocyclic heteroaryl having1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted triazole. In some embodiments, Cy is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted pyridine, pyridazine, or pyrimidine.

[0229] In some embodiments, Cy is an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

[0230] In some embodiments, Cy is an optionally substituted monocyclic C3-7 cycloaliphatic. In some embodiments, Cy is an optionally substituted monocyclic C3-7 cycloalkyl. In some embodiments, Cy is an optionally substituted monocyclic C4-6 cycloalkyl (e.g., cyclobutane, cyclopentane, or cyclohexane).

[0231] In some embodiments, Cy is an optionally substituted 5- to 10-membered bicyclic cycloaliphatic. In some embodiments, Cy is an optionally substituted 6- to 10-membered bicyclic cycloaliphatic. In some embodiments, Cy is an optionally substituted bicyclic 6- to 10-membered bridged, fused, or spirocyclic cycloaliphatic.

[0232] In some embodiments, Cy is an optionally substituted monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 4-membered heterocyclyl having 1 heteroatom independently selected from N, O, and S. In some embodiments, Cy is azetidine. In some embodiments, Cy is an optionally substituted monocyclic 5-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is pyrrolidine. In some embodiments, Cy is an optionally substituted monocyclic 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is piperidine or piperazine. In some embodiments, Cy is an optionally substituted monocyclic 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, at least one heteroatom is N; in some embodiments, each is N.

[0233] In some embodiments, Cy is an optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 6- to 11-membered bridged, fused, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7- to 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered bridged heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 8-membered spirocyclic heterocyclyl having 1-3heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 9-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 10-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted group selected from, ,, , , , ,some embodiments, Cy is selectede embodiments, Cy is an optionally substituted bicyclic 10- to 16-membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, -Cy- is spiro-bicyclic. In some embodiments, -Cy- is optionally substituted spiro-bicyclic diamine. In some embodiments, -Cy- is optionally substituted spiro-bicyclic diamine boned to the rest of a compound at the two amino groups.

[0234] In some embodiments, Cy is an optionally substituted group selected from, ,, , , , ,, . In some embodiments, Cy is selected from:,, , , , , ,, , , , ,. In some embodiments, linker comprises -Cy-. In some embodiments, linker is -Cy-.

[0235] Rings are utilized in many formulae and compounds of the present disclosure. In some embodiments, each monocyclic ring unit in a ring (e.g., -Cy-, certain R embodiments, Ring B, Ring C, or Ring F) is independently 3-10 membered (e.g., 3-8, 3-6, 3-5, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9 or 10), is independently saturated, partially unsaturated or aromatic, and has independently 0-4 (e.g., 0, 1-4, 1-2, 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, each monocyclic ring unit is independently 3-8 membered. In some embodiments, each monocyclic ring unit is independently 3-6 membered. In some embodiments, each monocyclic ring unit is independently 5-6 membered. In some embodiments, a monocyclic ring unit is 3-membered. In some embodiments, a monocyclic ring unit is 4- membered. In some embodiments, a monocyclic ring unit is 5-membered. In some embodiments, a monocyclic ring unit is 6-membered. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, each is saturated. In some embodiments, a monocyclic ring unit is partially unsaturated. In some embodiments, a monocyclic ring unit is aromatic. In some embodiments, a monocyclic ring unit is heteroaromatic. In some embodiments, a ring is saturated. In some embodiments, a ring is partially unsaturated. In some embodiments, a ring is aromatic. In some embodiments, a ring is heteroaromatic. In some embodiments, a monocyclic ring unit has no heteroatom. In some embodiments, a monocyclic ring unit has 1-4 (e.g., 1-3, 1-2, 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, each monocyclic ring unit independently has 1-4 (e.g., 1-3, 1-2, 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, a monocyclic ring unit has a nitrogen atom. In some embodiments, each monocyclic ring unit independently has a nitrogen atom.

[0236] Various variables can be R’ as described herein. In some embodiments, R’ is hydrogen.

[0237] In some embodiments, R’ is -R as described herein. In some embodiments, R’ is íC(O)R wherein 5^LV^DV^GHVFULEHG^KHUHLQ^^^,Q^VRPH^HPERGLPHQWV^^5¶^LV^í&^2^25^ZKHUHLQ^5^LV^DV^GHVFULEHG^KHUHLQ^^^,Q^VRPH^ HPERGLPHQWV^^5¶^LV^í6^2^2R wherein R is as described herein. In some embodiments, two R’ groups, or two groups that are or can be R’, on the same atom can be taken together with the atom to form an optionally substituted ring as described herein. In some embodiments, two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3-16 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 3-15, 3-10, 5-10, 3-8, 3-7 or 5-6) membered ring having 1-5 (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, two R’ groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3- 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 5-10, 3-8, 3-7 or 5-6) membered ring having, in additionto the atom, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, a formed ring is substituted (in addition to groups attached to the intervening atom(s)). In some embodiments, a formed ring is unsubstituted. In some embodiments, a formed ring is 3-membered. In some embodiments, a formed ring is 4-membered. In some embodiments, a formed ring is 5-membered. In some embodiments, a formed ring is 6-membered. In some embodiments, a formed ring is 7-membered. In some embodiments, a formed ring is 8-membered. In some embodiments, a formed ring is 9-membered. In some embodiments, a formed ring is 10-membered. In some embodiments, a formed ring is saturated. In some embodiments, a formed ring is partially unsaturated. In some embodiments, a formed ring is aromatic. In some embodiments, a formed ring is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered ring which is independently saturated, partially unsaturated or aromatic and has 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered ring which is independently saturated, partially unsaturated or aromatic and has 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, each monocyclic ring unit is independently 3-7 membered. In some embodiments, each monocyclic ring unit is independently 3-6 membered. In some embodiments, each monocyclic ring unit is independently 5-7 membered. In some embodiments, each monocyclic unit is independently saturated or partially unsaturated. In some embodiments, at least one monocyclic unit is saturated. In some embodiments, at least one monocyclic unit is partially unsaturated. In some embodiments, at least one monocyclic unit is aromatic. In some embodiments, a formed ring has, in addition to the intervening atom(s), 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, there are no additional heteroatoms. In some embodiments, there is one additional heteroatom. In some embodiments, there are 2 additional heteroatoms. In some embodiments, there are 3 additional heteroatoms. In some embodiments, there are 4 additional heteroatoms. In some embodiments, there are 5 additional heteroatoms. In some embodiments, there are 6 or more additional heteroatoms. In some embodiments, an additional heteroatom is nitrogen. In some embodiments, an additional heteroatom is oxygen. In some embodiments, an additional heteroatom is sulfur.

[0238] Various variables can be R as described herein. Various embodiments for R are extensively described herein, including in various sections for other variables that can be R (e.g., R1, R2, or R’).

[0239] In some embodiments^^5^LV^í+^^^,Q VRPH^HPERGLPHQWV^^5^LV^QRW^í+^

[0240] In some embodiments, R is optionally substituted C1-8(e.g., C1-7, C1-6, C1-5, C1-4, C1, C2, C3, C4, C5, C6, C7, or C8) aliphatic. In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-6alkyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted n-propyl. In some embodiments, R is optionally substituted isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is t-butyl. In some embodiments, R is pentyl. In some embodiments, R is hexyl.

[0241] In some embodiments, R is optionally substituted C1-8(e.g., C1-7, C1-6, C1-5, C1-4, C1, C2, C3, C4, C5, C6, C7, or C8) heteroaliphatic having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted C1-6heteroaliphatic having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, and S. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.

[0242] In some embodiments, R is optionally substituted C3-10(e.g., C4-10, C3-9, C3-7, or 3, 4, 5, 6, 7, 8, 9, or 10-membered) cycloaliphatic. In some embodiments, a cycloaliphatic group is a cycloalkyl group. In some embodiments, a cycloaliphatic group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., C4- 10, C3-9, C3-7, or 3, 4, 5, 6, 7, 8, 9, or 10) membered cycloaliphatic ring. In some embodiments, a cycloaliphatic group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is optionally substituted cycloheptyl. In some embodiments, R is cyclopropyl. In some embodiments, R is cyclobutyl. In some embodiments, R is cyclopentyl. In some embodiments, R is cyclohexyl. In some embodiments, R is cycloheptyl.

[0243] In some embodiments, R is optionally substituted 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10) membered heterocyclyl having 1-5 (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10) membered heterocyclyl having 1-4 (e.g., 1-2, 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, a heterocyclyl group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-8, 3-6, 3-5, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9 or 10) membered heterocyclyl ring having 1-4 (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, a heterocyclyl group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, a heterocyclyl ring has one heteroatom. In some embodiments, a heterocyclyl ring has two or more heteroatoms. In some embodiments, a heterocyclyl ring has three or more heteroatoms. In some embodiments, a heterocyclyl ring has four or more heteroatoms. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.

[0244] In some embodiments, R is optionally substituted C6-10(e.g., C6or C10) aryl. In some embodiments, R is optionally substituted C6aryl. In some embodiments, R is optionally substituted C10aryl. In some embodiments, an aryl ring is monocyclic. In some embodiments, an aryl ring is bicyclic. In some embodiments, an aryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 6-membered aromatic ring. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted 10-membered aryl. In some embodiments, R is optionally substituted naphthyl. In some embodiments, R is naphthyl.

[0245] In some embodiments, R is optionally substituted 5-10 (e.g., 5-9, 5-6, 5, 6, 7, 8, 9, or 10) membered heteroaryl having 1-5 (e.g., 1-5, 1-4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, R is 5-10 (e.g., 5-9, or 5, 6, 9, or 10) membered heteroaryl having 1-4 (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, a heteroaryl ring is monocyclic. In some embodiments, a heteroaryl ring is bicyclic. In some embodiments, a heteroaryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 5- or 6-membered aromatic ring having 0-4 heteroatoms, e.g., independently selected from N, O, and S, wherein at least one monocyclic unit contains 1-4 heteroatoms. In some embodiments, R is optionally substituted 5-membered monocyclic heteroaryl having 1- 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, a heteroaryl ring has one heteroatom. In some embodiments, a heteroaryl ring has two or more heteroatoms. In some embodiments, a heteroaryl ring has three or more heteroatoms. In some embodiments, a heteroaryl ring has four or more heteroatoms. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur.

[0246] In some embodiments of any Formulae described herein, each R is independently hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, R is C1-6 alkyl. In some embodiments, R is optionally substituted C1-2 alkyl. In some embodiments, R is C1-2 alkyl (e.g., methyl). In some embodiments, each R is C1-2 alkyl (e.g., methyl). In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted C3-7 cycloaliphatic. In some embodiments, R is optionally substituted C3-7 cycloalkyl (e.g., cyclopropyl). In some embodiments, R is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0247] As described herein, various groups may be optionally substituted. Substituents are routinely utilized in chemistry including in development of various therapeutics. Many substituents can be utilized inaccordance with the present disclosure. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. In some embodiments, substituents are those that result in the formation of compounds for a desired property, activity, use, etc., as described herein. In some embodiments, compounds are stable for therapeutic use as described herein. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a substituent is a hydrocarbon group. In some embodiments, a substituent comprises a heteroatom. In some embodiments, a substituent comprises multiple heteroatoms. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus and silicon. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in a substituent is about or no more than about 1; in some embodiments, it is about or no more than about 2; in some embodiments, it is about or no more than about 3; in some embodiments, it is about or no more than about 4; in some embodiments, it is about or no more than about 5; in some embodiments, it is about or no more than about 6; in some embodiments, it is about or no more than about 7; in some embodiments, it is about or no more than about 8; in some embodiments, it is about or no more than about 9; in some embodiments, it is about or no more than about 10; in some embodiments, it is about or no more than about 11; in some embodiments, it is about or no more than about 12; in some embodiments, it is about or no more than about 13; in some embodiments, it is about or no more than about 14; in some embodiments, it is about or no more than about 15; in some embodiments, it is about or no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 15. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 10. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 6. Substituents of various sizes are described herein including exemplified in various compounds. In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, Ring B, R, etc.) is independently halogen, C1-4DON\O^^í2+^^í&1^^í122, C1-4KDORDON\O^^H^J^^^í&)3^^^í25SB^^í^ N(RSB)2^^í&^2^25SB^^í&^2^1^5SB)2^^RU^í6^2^2N(RSB)2wherein each RSBLV^LQGHSHQGHQWO\^í+^^&1-4alkyl or C1-4haloalkyl. In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, Ring B, R, etc.) is independently halogen, C1-4alkyl, C1-4haloalkyl, or –OH. In some embodiments, each optional substituent on a substitutable group (e.g., Ring A, Ring B, R, etc.) is independently halogen or C1-4alkyl. As examples, many substituents are exemplified in compounds described herein, e.g., in Table 1.

[0248] In some embodiments of any Formulae described herein, linker is attached to the bracketed moietyat one of Rd, Re, Rf, or Rg, or linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together. In some embodiments, linker is attached to the bracketed moiety at one of Rd, Re, Rf, or Rg. In some embodiments, linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together. In some embodiments, linker is attached to a position having -H or a monovalent substituent, e.g., halogen, alkyl, etc. In some embodiments, linker is attached to a position having -H (e.g., for a compound of the structure of PBM-H or LBM-H, linker can replace -H to form a structure of PBM-linker or LBM-linker, respectively). LBM

[0249] In some embodiments, LBM is. In some embodiments, LBM isIn some embodiments, LBM is s. In some embodiments, LBM is . Ins ( ) some embodiments, LBM isIn some embodiments, LBM is . In some embodiments of any Formulae described herein, LBM is an E3 ubiquitinligase binding moiety, i.e., is a moiety that is capable of binding an E3 ubiquitin ligase. Typically, an LBM isconsidered to be capable of binding an E3 ubiquitin ligase if it specifically (i.e., preferentially) associates with the E3 ubiquitin ligase when contacted with the E3 ubiquitin ligase in the presence of at least one other protein. In some embodiments, an LBM is considered to be capable of binding an E3 ubiquitin ligase if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, an LBM is considered to be capable of binding an E3 ubiquitin ligase if a compound of LBM-H or a salt thereof, or LBM-linker-H or a salt thereof, has a KDtoward an E3 ubiquitin ligase of about or less than about 1 uM in an assay such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). In some embodiments, a compound of LBM-H or a salt thereof, or LBM-linker-H or a salt thereof, has an IC50 of about or less than about 1 uM in a competition or functional assay, such as time-resolved fluorescence resonance energy transfer (TR-FRET). An LBM may be capable of binding any suitable E3 ubiquitin ligase, including cereblon, Von Hippel-Lindau protein, Inhibitor of Apoptosis protein, MDM2, RNF114, DCAF16, DCAF15, KEAP1, FEM1B, Arylhydrocarbon Receptor, etc. Some moieties capable of binding an E3 ubiquitin ligase are known in the art – see, e.g., Sun, X., et al., Signal Transduction and Targeted Therapy, 2019, 4, 64; Ishida, T., et al., SLAS Discovery, 2021, 26(4), 484-502; Bricelj, A., et al., Frontiers in Chemistry, 2021, 9, Article 707317; Min, J., et al., Angew. Chem. Int. Ed., 2021, 60, 26663-70; and WO 2019 / 140387, the entire contents of each of which are hereby incorporated by reference. In some embodiments, technologies for identifying or assessing LBM are described in one or more of such references. Certain useful LBM and technologies are described in WO 2017 / 197036, WO 2017 / 197046, WO 2017 / 197051, WO 2017 / 197055, WO 2017 / 197056, WO 2018 / 220149, WO 2018 / 237026, WO 2019 / 023553, WO 2019 / 043208, WO 2019 / 043214, WO 2019 / 043217, WO 2019 / 060693, WO 2019 / 060742, WO 2019 / 099868, WO 2019 / 121562, WO 2019 / 133531, WO 2019 / 140380, WO 2019 / 140387, WO 2019 / 149922, WO 2019 / 191112, WO 2019 / 204354, WO 2019 / 236483, WO 2020 / 010177, WO 2020 / 010210, WO 2020 / 010227, WO 2020 / 051235, WO 2020 / 113233, WO 2020 / 132561, WO 2020 / 181232, WO 2020 / 206424, WO 2020 / 210630, WO 2020 / 251969, WO 2020 / 251971, WO 2020 / 251972, WO 2020 / 251974, WO 2020 / 264490, WO 2020 / 264499, WO 2021 / 011631, WO 2021 / 011634, WO 2021 / 011868, WO 2021 / 011871, WO 2021 / 083949, WO 2021 / 086785, WO 2021 / 119159, WO 2021 / 127190, WO 2021 / 127278, WO 2021 / 127283, WO 2021 / 127561, WO 2021 / 133917, WO 2021 / 133920, WO 2021 / 158634, WO 2021 / 178920, WO 2021 / 188696, WO 2021 / 188948, WO 2021 / 222366, WO 2021 / 231778, WO 2021 / 247897, WO 2021 / 247899, WO 2021 / 255212, WO 2021 / 255213, WO 2021 / 257914, WO 2022 / 027058, WO 2022 / 032026, WO 2022 / 032132, WO 2022 / 077010, WO 2022 / 081925, WO 2022 / 081927, WO 2022 / 081928, WO 2022 / 087216, WO 2022 / 125790, WO 2022 / 125800, WO 2022 / 125804, WO 2022 / 147465, WO 2022 / 174268, WO 2022 / 174269, WO 2022 / 178532, WO 2022 / 235945, WO 2022 / 236058, WO 2022 / 236339, WO 2022 / 251539, WO 2022 / 261250, WO 2023 / 039208, WO 2023 / 044046, WO 2023 / 049790, WO 2023 / 055952, WO 2023 / 076161, WO 2023 / 076556, WO 2023 / 107706, WO 2023 / 114933, WO 2023 / 137439, WO 2023 / 147594, WO 2023 / 154417, WO 2023 / 192578, WO 2023 / 192586, WO 2023 / 220425, WO 2023 / 239645, WO 2023 / 239697, WO 2023 / 239750, WO 2023 / 244764, WO 2023 / 250058, WO 2023 / 278402, WO 2023 / 278759, WO 2023 / 283372, WO 2023 / 283610, WO 2024 / 030628,

[0250] In some embodiments, LBM is wherein the variables are as defined anddescribed in classes and subclasses herein, both singly and in combination. In some embodiments, certain LBM types and species can provide improved properties and / or activities, e.g., improved stability, improved selectivity (e.g., for KAT2A over KAT2B), improved bioavailability, improved potency, and / or improved half- life. In some embodiments, LBM has the following structure, wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, LBM has the following structure, wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, LBM has the following structure, wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, LBM has the following structurewherein the variables are as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, LBM has the following structure, wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, LBM has the following structure of, wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination. In some embodiments, Ring C is an optionally substituted phenyl ring. In some embodiments, Ring C is an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatomsindependently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted naphthyl ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted bicyclic 9-membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted bicyclic 10-membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, L2is a covalent bond. In some embodiments, L2is -NH-. In some embodiments, L2is -O-. In some embodiments, L2is –C(O)-NH- wherein -C(O)- is bonded to Ring C. In some embodiments, L2is –C(O)-NH- wherein -NH- is bonded to Ring C. In some embodiments, L2is bonded to an atom next to the atom to which linker is bonded. In some embodiments, in the shortest path from the atom to with L2is bonded to the atom to which linker is bonded, there is one atom between the atom to with L2is bonded and the atom to which linker is bonded. In some embodiments, in the shortest path from the atom to with L2is bonded to the atom to which linker is bonded, there are two atoms between the atom to with L2is bonded and the atom to which linker is bonded. In some embodiments, in the shortest path from the atom to with L2is bonded to the atom to which linker is bonded, there are three atoms between the atom to with L2is bonded and the atom to which linker is bonded. In some embodiments, in the shortest path from the atom to with L2is bonded to the atom to which linker is bonded, there four two atoms between the atom to with L2is bonded and the atom to which linker is bonded. For example, in some embodiments, LBM is optionally substituted , , is ,, , ,

[0251] In some embodiments of any Formulae described herein, a LBM is a cereblon (CRBN) binding moiety, i.e., is a moiety that is capable of binding cereblon.

[0252] In some embodiments of any Formulae described herein, a LBM has the following structure:wherein Rb, Rc, and m are as defined herein for Formula IIIA and described in classes and subclasses herein, both singly and in combination; and each A is independently N, C, or CH, provided that no more than two A groups are N. It will be appreciated that A is C when it is the point of attachment to the rest of the molecule.

[0253] In some embodiments of any Formulae described herein, a LBM has the following structure:wherein Rb, Rc, and m are as defined herein for Formula IIIA and described in classes and subclasses herein, both singly and in combination.

[0254] In some embodiments of any Formulae described herein, a LBM is selected from:.

[0255] In some embodiments of any Formulae described herein, a LBM has the following structure:wherein B, L2, Rc, Y, and m are as defined herein for Formula IIIC and described in classes and subclassesherein, both singly and in combination. It will be appreciated that B is C when it is the point of attachment to the rest of the molecule.

[0256] In some embodiments of any Formulae described herein, a LBM has the following structure:wherein B, L2, Rc, Y, and m are as defined herein for Formula IIIC and described in classes and subclasses herein, both singly and in combination.

[0257] In some embodiments of any Formulae described herein, a LBM has the following structure:wherein B, L2, Rc, Y, and m are as defined herein for Formula IIIC and described in classes and subclasses herein, both singly and in combination.

[0258] In some embodiments of any Formulae described herein, a LBM is selected from:wherein B, L2, Rc, and m are as defined herein for Formula IIIC and described in classes and subclasses herein, both singly and in combination.

[0259] In some embodiments of any Formulae described herein, a LBM is selected from:,,,, , , d .

[0260] In some embodiments of any Formulae described herein, a LBM is selected from: O

[0261] In some embodiments, Rais halogen (e.g., -F, -Cl or -Br). In some embodiments, Rais -CN. In some embodiments, Rais -R’ as described herein. In some embodiments, Rais -R as described herein. In some embodiments, Rais -R but is not hydrogen. In some embodiments of any Formulae described herein, each Rais independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, each Rais independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rais independently hydrogen, halogen, -CN, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, each Rais independently is hydrogen, halogen, -CN, C1-6alkyl, C3-6cycloalkyl, or C6-10aryl. In some embodiments, each Rais independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Rais independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Rais hydrogen. In some embodiments, Rais hydrogen. In some embodiments, Rais optionally substituted C1-6 aliphatic. In some embodiments, Rais optionally substituted C1-6 alkyl. In some embodiments, Rais C1-6 alkyl. In some embodiments, Rais optionally substituted C1-2 alkyl. In some embodiments, Rais C1-2 alkyl (e.g., methyl). In some embodiments, Rais optionally substituted C3-6 cycloaliphatic. In some embodiments, Rais optionally substituted C3-6 cycloalkyl. In some embodiments, Rais C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, Rais C6-10 aryl. In some embodiments, Rais phenyl. In some embodiments, Rais naphthyl. In some embodiments, Rais 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rais 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Rais 3- to 10-membered monocyclic heterocyclyl having 1- 5 heteroatoms independently selected from N, O, and S. In some embodiments, Rais 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0262] In some embodiments, two Ragroups are each -R’ which are taken together with the atom to which they are attached to form an optionally substituted ring as described herein. In some embodiments, two Ragroups, together with the atom to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two Ragroups, together with the atom to which they are attached, combine to form a 3- to 6-membered saturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two Ragroups, together with the atom to which they are attached, combine to form a 3- to 4-membered saturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S).

[0263] In some embodiments of any Formulae described herein, Y is N. In some embodiments, Y is CH.

[0264] In some embodiments, L2is a covalent bond. In some embodiments, L2is an optionally substituted C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by - O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)- , -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L2is an optionally substituted straight C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)- , -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2- , -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments of any Formulae described herein, L2is a covalent bond or an optionally substituted straight or branched C1-3 hydrocarbon chain. In some embodiments, L2is a covalent bond or a straight or branched C1-3 hydrocarbon chain. In some embodiments, L2is a covalent bond or a straight or branched C1-3 hydrocarbon chain wherein one methylene is replaced with –O-, -S-, -N(R)-, - SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a covalent bond. In some embodiments, L2is a straight or branched C1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, - N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a C1 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a straight or branched C2 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a straight or branched C3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a covalent bond, -CH2-, –O-, or -N(R)-. In some embodiments, L2is –CH2-. In some embodiments, L2is –CH2-, -O-, or –N(R)-. In some embodiments, L2is –CH2-, -O-, or – N(H)-. In some embodiments, L2is –O- or –S-. In some embodiments, L2is –O-. In some embodiments, L2is -S-. In some embodiments, L2is –N(R)-. In some embodiments, L2is –N(H)-. In some embodiments, L2is – SO2-. In some embodiments, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is –C(O)N(R)-. In some embodiments, L2is –N(R)C(O)-. In some embodiments, L2is -C(O)NH-. In some embodiments, L2is - NHC(O)-. In some embodiments, L2is -S(O)-. In some embodiments, L2is -S(O)N(R)-. In some embodiments, L2is -N(R)S(O)-. In some embodiments, L2is -S(O)NH-. In some embodiments, L2is -NHS(O)-. In some embodiments, L2is -S(O)2-. In some embodiments, L2is -N(R)S(O)2-. In some embodiments, L2is -S(O)2N(R)- . In some embodiments, L2is -NHS(O)2-. In some embodiments, L2is -S(O)2NH-. In some embodiments, L2is -Cy- as described herein. In some embodiments, L2is -Cy- wherein -Cy- is aromatic.

[0265] In some embodiments, Ring E is. In some embodiments, Ring E is . In some embodiments, Ring E is.

[0266] In some embodiments, Ring E is optionally substituted. In some embodiments, Ring E isO . In some embodiments, Ring E is optionally substituted. In some embodiments, Ring E is. In some embodiments, Ring E is optionally substitutedIn some embodiments, Ring E is. In some embodiments, one stereoisomeric form binds an E3 ubiquitin ligase stronger than the other. In some embodiments, an stereoisomeric form can convert into the other, e.g., during storage, upon administration, after administration, etc. In some embodiments, a compound can be provided or administered either as a stereochemically pure form or as a mixture of two stereoisomers with respect to the carbon at which Ring E is bonded to L2or Ring C. In some embodiments, stereochemical purity of a compound in a composition with respect to the carbon center at which Ring E is bonded to L2or Ring C is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95%. In some embodiments, stereochemical purity of a compound in a composition with respect to any other chiral center is about or at least about 90% or 95%.

[0267] In some embodiments, Ring E is optionally substituted. In some embodiments, Ring E is.

[0268] In some embodiments of any Formulae described herein, Ring C is an optionally substituted, mono- or bicyclic, 3- to 10-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted group selected from phenyl, C5-6cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C isan optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted C3-C7 cycloaliphatic or optionally substituted 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0269] In some embodiments, Ring C is an optionally substituted 3-16 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 3-15, 3-10, 5-10, 3-8, 3-7, or 5-6) membered ring having 0-6 (e.g., 0, 1-6, 1-4, 1, 2, 3, 4, 5, or 6) heteroatoms independently selected from N, O, and S.

[0270] In some embodiments, Ring C is optionally substituted phenyl ring. In some embodiments, Ring C is a phenyl ring. In some embodiments, Ring C is optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted 5- to 6-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted 5-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is a pyrrole. In some embodiments, Ring C is optionally substituted 6-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is a pyridine, pyridone, or pyrimidine.

[0271] In some embodiments, Ring C is optionally substituted C3-C7 cycloaliphatic. In some embodiments, Ring C is optionally substituted C3-C7 cycloalkyl. In some embodiments, Ring C is optionally substituted C5-C6 cycloaliphatic. In some embodiments, Ring C is optionally substituted C5-C6 cycloalkyl. In some embodiments, Ring C is a cyclohexane.

[0272] In some embodiments, Ring C is optionally substituted 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is a 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is a piperidine or piperazine.

[0273] In some embodiments, Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted phthalimide, isoindolin-1-one, indazole, benzo[d][1,2,3]triazole, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-benzo[d]imidazole-2-one, or isoquinoline. In some embodiments, Ring C is optionally substituted phthalimide or isoindolin-1-one. In some embodiments, Ring C is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. For example, in some embodiments, Ring C is optionally substitutedsome embodiments, the carbon atom is bonded to linker. In some embodiments, Ring C is optionally substitutedsome embodiments, Ring C is. In some embodiments, the carbon atom in the phenyl ring is bonded to linker.

[0274] In some embodiments, Ring C is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted 11-membered tricyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (e.g., 6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione).

[0275] In some embodiments, Ring, wherein: each A is independently N, C, or CH, provided that no more than two A groups are N; each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; m is 0, 1, 2, or 3.

[0276] In some embodiments, Ring.

[0277] .

[0278] In some embodiments, Ring C, wherein: each B is independently selected from N, C, and CH, provided that no more than two B are N;each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0279] In some embodiments, Ring, wherein:each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; and m is 0, 1, 2, or 3. . ,

[0281] In some embodiments, Ring C is optionally substituted. In some embodiments, Ring C is optionally substituted . In some embodiments, Ring C is . In some embodiments, Ring C is optionally substituted . In some embodiments, Ring C is.

[0282] In some embodiments, Ring C has a substituent at a position next to the position (e.g., o for a phenyl ring) bonded to L2(as those skilled in the art appreciate, Ring E when L2is a covalent bond). For example, in some embodiments, a substituent at a position next to the position bonded to L2(e.g., Rb, Rb1, or Rc) is -OR, -R or halogen. In some embodiments, it is -OR wherein R is as described herein. In some embodiments, it is -OR wherein R is optionally substituted C1-4aliphatic. In some embodiments, it is -OR wherein R is optionally substituted C1-4alkyl. In some embodiments, it is -OR wherein R is C1-4aliphatic. In some embodiments, it is -OR wherein R is C1-4alkyl. In some embodiments, it is -OR wherein R is C1-4haloalkyl. In some embodiments, it is -OCF3. In some embodiments, it is -OMe. In some embodiments, it is -R as described herein. In some embodiments, it is optionally substituted C1-4 aliphatic. In some embodiments, it is optionally substituted C1-4alkyl. In some embodiments, it is C1-4aliphatic. In some embodiments, it is C1-4alkyl. In some embodiments, it is C1-4haloalkyl. In some embodiments, it is methyl. In some embodiments, it is -CF3. In some embodiments, it is halogen. In some embodiments, it is -F. In some embodiments, it is -Cl. In some embodiments, it is -Br. e For example, in some embodiments, Ring C is, , , , or, wherein the carbon atom marked with * is bonded to L2. In some embodiments, Ring C is a bicyclic or polycyclic ring, and Ring C has two ring atoms bonded to a position next to the position bonded to L2(as those skilled in the art appreciate, Ring E when L2is a covalent bond). For examples, in some embodiments, Ring C is, wherein the carbon atom marked with * is bonded to L2. In some embodiments,wherein Rb1is not hydrogen. In some embodiments, compounds comprising such Ring C can selectively degrade KAT2A over KAT2B (e.g., DC50for KAT2A is smaller than that for KAT2B when assessed, e.g., as in the Examples such as Example B1).

[0283] In some embodiments, Ring C is selected from: , , ,, , , , , ,

[0284] In some embodiments, Ring C is selected from:

[0285] In some embodiments of any Formulae described herein, Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 4- to 10-membered bivalent ring system having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 5- to 6- membered bivalent ring system having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted 6-membered bivalent ring system having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring F is an optionally substituted phenyl.

[0286] In some embodiments of any Formulae described herein, each A is CH. In some embodiments,one A is N and the other A groups are CH. In some embodiments, two A groups are N, and the other A groups are CH. It will be appreciated that when A is CH, it may be substituted with Rc, as defined herein, such that the ring contains a –C(Rc)- moiety. It will also be appreciated that A is C, when it is the point of attachment to the rest of the molecule.

[0287] In some embodiments, Rbis R’ as described herein. In some embodiments, Rbis -R as described herein. In some embodiments, Rbis -R but not hydrogen. In some embodiments, Rbis -OR wherein R is as described herein. In some embodiments of any Formulae described herein, each Rbis hydrogen. In some embodiments of any Formulae described herein, each Rbis independently halogen, -CN, -R or -OR. In some embodiments, each Rbis independently hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, each Rbis independently hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, each Rbis independently is hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, each Rbis independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Rbis independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10- membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Rbis independently hydrogen. In some embodiments, Rbis halogen. In some embodiments, Rbis fluoro. In some embodiments, Rbis chloro. In some embodiments, Rbis bromo. In some embodiments, Rbis optionally substituted C1-6 aliphatic. In some embodiments, Rbis optionally substituted C1-6 alkyl. In some embodiments, Rbis C1-2 alkyl (e.g., methyl). In some embodiments, Rbis optionally substituted C3-6 cycloaliphatic. In some embodiments, Rbis optionally substituted C3-6 cycloalkyl. In some embodiments, Rbis C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, Rbis C6-10 aryl. In some embodiments, Rbis phenyl. In some embodiments, Rbis naphthyl. In some embodiments, Rbis 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rbis 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Rbis 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rbis 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0288] In some embodiments, two Rbgroups, on the same carbon, are taken together to form an oxo. In some embodiments, two Rbgroups, on the same carbon, combine to form a 3- to 6-membered saturated or partially unsaturated ring (e.g., a C3-6cycloaliphatic or 3- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two Rbgroups, on the same carbon, combine to form C3-6cycloalkyl (e.g., cyclopropyl). In some embodiments, two Rbgroups, on the same carbon, combine to form a 3- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0289] In some embodiments, Rb1is Rbas described herein. In some embodiments, Rb1is not hydrogen. In some embodiments, it is -OR wherein R is as described herein. In some embodiments, it is -OR wherein Ris optionally substituted C1-4aliphatic. In some embodiments, it is -OR wherein R is optionally substituted C1-4alkyl. In some embodiments, it is -OR wherein R is C1-4aliphatic. In some embodiments, it is -OR wherein R is C1-4alkyl. In some embodiments, it is -OR wherein R is C1-4haloalkyl. In some embodiments, it is -OCF3. In some embodiments, it is -OMe. In some embodiments, it is -R as described herein. In some embodiments, it is optionally substituted C1-4 aliphatic. In some embodiments, it is optionally substituted C1-4 alkyl. In some embodiments, it is C1-4aliphatic. In some embodiments, it is C1-4alkyl. In some embodiments, it is C1-4haloalkyl. In some embodiments, it is methyl. In some embodiments, it is -CF3. In some embodiments, it is halogen. In some embodiments, it is -F. In some embodiments, it is -Cl. In some embodiments, it is -Br.

[0290] In some embodiments, t’ is 0. In some embodiments, t’ is 1. In some embodiments, t’ is 2. In some embodiments, t’ is 3.

[0291] In some embodiments of any Formulae described herein, each B is CH, C-Rc, or C. In some embodiments, one B is N and the other B groups are CH or C. In some embodiments, two B groups are N and the other B groups are CH or C. In some embodiments, B is N. In some embodiments, B is CH. In some embodiments, B is C-Rc. In some embodiments, B is C. It will be appreciated that B is C, when it is the point of attachment to the rest of the molecule.

[0292] In some embodiments of any Formulae described herein, each Rcis independently selected from halogen, -OH, -O(C1-6 alkyl), -O(C1-6 haloalkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -CN, and optionally substituted C1-6 alkyl. In some embodiments, each Rcis independently selected from halogen, -OH, -O(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -CN, and optionally substituted C1-6 alkyl. In some embodiments, each Rcis independently selected from halogen, -O(C1-6 alkyl), -O(C1-6 haloalkyl), C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each Rcis independently selected from halogen, -O(C1-6 alkyl), C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each Rcis independently selected from halogen, -O(C1-6 alkyl), and C1-6 alkyl. In some embodiments, Rcis halogen (e.g., fluoro or chloro). In some embodiments, Rcis –OR (e.g., -OH, - O(C1-6 alkyl), or -O(C1-6 haloalkyl)). In some embodiments, Rcis –OCH3 or –OCF3. In some embodiments, Rcis -N(R)2 (e.g., -NH2, NH(C1-6 alkyl), or -N(C1-6 alkyl)2). In some embodiments, Rcis –CN. In some embodiments, Rcis optionally substituted C1-6 aliphatic. In some embodiments, Rcis optionally substituted C1- 6 alkyl. In some embodiments, Rcis C1-6 alkyl optionally substituted with one or more halogen. In some embodiments, Rcis C1-6alkyl. In some embodiments, Rcis optionally substituted C1-2alkyl. In some embodiments, Rcis optionally substituted C1-2alkyl optionally substituted with one or more halogen. In some embodiments, Rcis C1-2alkyl (e.g., methyl). In some embodiments, Rcis C1-6haloalkyl. In some embodiments, Rcis C1-2haloalkyl (e.g., -CF3).

[0293] In some embodiments of any Formulae described herein, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0294] In some embodiments of any Formulae described herein, a LBM is a Von Hippel-Lindau protein (VHL) binding moiety, i.e., is a moiety that is capable of binding Von Hippel-Lindau protein.

[0295] In some embodiments,. In some embodiments of any Formulae described herein, LBM has the following structure:, wherein Rd, Re, Rf, Rg, Rh, and p are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0296] In some embodiments of any Formulae described herein, a LBM is selected from:. In some embodiments, Rd, Re, Rf, Rg, Rh, and p are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0297] In some embodiments of any Formulae described herein, a LBM has the following structure:. In some embodiments, Rd, Re, Rf, Rg, Rh, and p are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0298] In some embodiments of any Formulae described herein, a LBM has the following structure:. In some embodiments, Rd, Re, Rf, Rg, Rh, and p are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0299] In some embodiments of any Formulae described herein, a LBM has the following structure:.

[0300] In some embodiments of any Formulae described herein, a LBM moiety (e.g., VHL binding moiety) is attached to linker at a Rd. In some embodiments, a LBM moiety (e.g., VHL binding moiety) is attached to linker at a Re. In some embodiments, a LBM moiety (e.g., VHL binding moiety) is attached to linker at Rf. In some embodiments, a LBM moiety (e.g., VHL binding moiety) is attached to linker at a Rg.

[0301] In some embodiments, Rdis -R’ as described herein. In some embodiments, Rdis -R as described herein. In some embodiments, Rdis -R but is not hydrogen. In some embodiments of any Formulae described herein, each Rdthat is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6 aliphatic. In some embodiments, each Rdis hydrogen, optionally substituted C1-6 aliphatic, -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rdis hydrogen. In some embodiments, Rdis –C(O)R. In some embodiments, Rdis –C(O)(optionally substituted C1-6 alkyl). In some embodiments, Rdis –C(O)(optionally substituted C3-6 cycloalkyl). In some embodiments, Rdis optionally substituted C1-6 aliphatic. In some embodiments, Rdis optionally substituted C1-6 alkyl. In some embodiments, Rdis C1-6 alkyl. In some embodiments, Rdis optionally substituted C1-2 alkyl. In some embodiments, Rdis C1-2 alkyl (e.g., methyl). In some embodiments, each Rdis optionally substituted C3-6 cycloaliphatic. In some embodiments, each Rdis optionally substituted C3-6 cycloalkyl. In some embodiments, each Rdis C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, each Rdis -C(O)R. In some embodiments, each Rdis -C(O)(C1-6 alkyl). In some embodiments, each Rdis -S(O)2R. In some embodiments, each Rdis -S(O)2(C1-6 alkyl). In some embodiments, each Rdis two R’ attached to the same atom, together with the atom to which they are attached, combined to form an optionally substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S.

[0302] In some embodiments, two Rdare each R’ and the two R’ are taken together with the nitrogen to which they are bonded to form a ring as described herein. In some embodiments, two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6- membered ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6- membered ring having 1-3 heteroatoms independently selected from N, O, and S that is fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S.

[0303] In some embodiments, Reis -R as described herein. In some embodiments, Reis -R but is not hydrogen. In some embodiments of any Formulae described herein, each Rethat is not the point of attachment for the linker is independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, each Reis optionally substituted C1-6aliphatic. In some embodiments, each Reis optionally substituted C1-6alkyl (e.g.,methyl). In some embodiments, Reis hydrogen. In some embodiments, Reis optionally substituted C1-6aliphatic. In some embodiments, Reis optionally substituted C1-6alkyl. In some embodiments, Reis C1-6alkyl. In some embodiments, Reis optionally substituted C1-2alkyl. In some embodiments, Reis C1-2alkyl (e.g., methyl). In some embodiments of any Formulae described herein, each Rethat is not the point of attachment for the linker is independently -R. In some embodiments, each Reis independently hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, each Reis independently hydrogen, halogen, -CN, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, each Reis independently is hydrogen, halogen, -CN, C1-6alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, each Reis independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Reis independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Reis halogen. In some embodiments, Reis fluoro. In some embodiments, Reis chloro. In some embodiments, Reis bromo. In some embodiments, Reis optionally substituted C1-6 alkyl. In some embodiments, Reis C1-2 alkyl (e.g., methyl). In some embodiments, Reis optionally substituted C3-6 cycloaliphatic. In some embodiments, Reis optionally substituted C3-6 cycloalkyl. In some embodiments, Reis C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, Reis C6-10 aryl. In some embodiments, Reis phenyl. In some embodiments, Reis naphthyl. In some embodiments, Reis 5- to 10- membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Reis 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Reis 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Reis 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0304] In some embodiments, Rfis -R as described herein. In some embodiments, Rfis -R but is not hydrogen. In some embodiments of any Formulae described herein, Rf, when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6 alkyl. In some embodiments, Rfis hydrogen. In some embodiments, Rfis optionally substituted C1-6 aliphatic. In some embodiments, Rfis optionally substituted C1-6alkyl. In some embodiments, Rfis C1-6alkyl. In some embodiments, Rfis optionally substituted C1-2alkyl. In some embodiments, Rfis C1-2alkyl (e.g., methyl). In some embodiments of any Formulae described herein, Rf, when it is not the point of attachment for the linker, is -R. In some embodiments, each Rfis independently hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, each Rfis independently hydrogen, halogen, -CN, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, each Rfis independently is hydrogen, halogen, -CN, C1-6alkyl, C3-6cycloalkyl, or C6-10aryl. In some embodiments, each Rfis independently hydrogen, halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Rfis independently hydrogen, halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, 5- to 10-membered heteroarylhaving 1-5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rfis halogen. In some embodiments, Rfis fluoro. In some embodiments, Rfis chloro. In some embodiments, Rfis bromo. In some embodiments, Rfis optionally substituted C1-6aliphatic. In some embodiments, Rfis C1-2alkyl (e.g., methyl). In some embodiments, Rfis optionally substituted C3-6 cycloaliphatic. In some embodiments, Rfis optionally substituted C3-6cycloalkyl. In some embodiments, Rfis C3-4cycloalkyl (e.g., cyclopropyl). In some embodiments, Rfis C6-10aryl. In some embodiments, Rfis phenyl. In some embodiments, Rfis naphthyl. In some embodiments, Rfis 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rfis 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Rfis 3- to 10-membered monocyclic heterocyclyl having 1- 5 heteroatoms independently selected from N, O, and S. In some embodiments, Rfis 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0305] In some embodiments, Rgis -R as described herein. In some embodiments, Rgis -R but is not hydrogen. In some embodiments, Rgis -OR wherein R is as described herein. In some embodiments of any Formulae described herein, each Rgthat is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6 alkyl. In some embodiments, Rgis halogen (e.g., fluoro or chloro). In some embodiments, Rgis –OR (e.g., -OH or –O(C1-6 alkyl)). In some embodiments, Rgis –CN. In some embodiments, Rgis optionally substituted C1-6 aliphatic. In some embodiments, Rgis optionally substituted C1- 6 alkyl. In some embodiments, Rgis C1-6 alkyl. In some embodiments, Rgis optionally substituted C1-2 alkyl. In some embodiments, Rgis C1-2 alkyl (e.g., methyl). In some embodiments of any Formulae described herein, each Rgthat is not the point of attachment for the linker is independently halogen, -CN, R or -OR. In some embodiments, each Rgis independently hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, each Rgis independently hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, each Rgis independently is hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, each Rgis independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Rgis independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10- membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Rgis independently hydrogen. In some embodiments, Rgis halogen. In some embodiments, Rgis fluoro. In some embodiments, Rgis chloro. In some embodiments, Rgis bromo. In some embodiments, Rgis -CN. In some embodiments, Rgis optionally substituted C1-6aliphatic. In some embodiments, Rgis optionally substituted C1-6alkyl. In some embodiments, Rgis C1-2alkyl (e.g., methyl). In some embodiments, Rgis optionally substituted C3-6cycloaliphatic. In some embodiments, Rgis optionally substituted C3-6cycloalkyl. In some embodiments, Rgis C3-4cycloalkyl (e.g., cyclopropyl). In some embodiments, Rgis C6-10aryl. In some embodiments, Rgis phenyl. In some embodiments, Rgis naphthyl. In some embodiments, Rgis5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rgis 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Rgis 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, Rgis 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0306] In some embodiments, Rhis -R as described herein. In some embodiments, Rhis -R but is not hydrogen. In some embodiments of any Formulae described herein, Rhis hydrogen, halogen, or optionally substituted C1-6 alkyl. In some embodiments, Rhis hydrogen. In some embodiments, Rhis halogen (e.g., fluoro or chloro). In some embodiments, Rhis optionally substituted C1-6 aliphatic. In some embodiments, Rhis optionally substituted C1-6 alkyl. In some embodiments, Rhis C1-6 alkyl. In some embodiments, Rhis optionally substituted C1-2 alkyl. In some embodiments, Rhis C1-2 alkyl (e.g., methyl). In some embodiments of any Formulae described herein, Rhis hydrogen, halogen, or -R. In some embodiments, each Rhis independently hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, each Rhis independently hydrogen, halogen, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, each Rhis independently is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, each Rhis independently hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each Rhis independe...

Claims

CLAIMS 1. A compound selected from: , , ,,, , , , ,,, , ,,, ,,,, , ,,, , ,,or a pharmaceutically acceptable salt thereof.

2. A compound of Formula I: PBM – linker – LBM I or a pharmaceutically acceptable salt thereof, wherein: PBM is a KAT2 protein binding moiety,; linker is an optional linking moiety, or is a covalent bond or an optionally substituted bivalent C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or -Cy-; and LBM is an E3 ubiquitin ligase binding moiety, or is,, ,; wherein: Ring A is selected from:; Ring B is an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L1is a covalent bond or an optionally substituted bivalent C1-3hydrocarbon chain; each R1is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is halogen, -CN, or -R; each R3is independently halogen, -CN, or -R; R4is -R’; R5is halogen, −CN, or -R, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 0-2 heteroatoms independently selected from N, O, and S; R6is -R’; X is O or NR7; R7is -R’, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 2-3 heteroatoms independently selected from N, O, and S; L3, L4, and L5are each independently a covalent bond or an optionally substituted bivalent C1-6 hydrocarbon chain; each R8is independently -R’; R9is -R’;each Cy is independently an optionally substituted, 3- to 16-membered bivalent ring having 0-6 heteroatoms independently selected from N, O, and S; each of Ring C and Ring F is independently an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ringoptionally substituted group selected from; Y is N or CH; each Rais independently halogen, -CN or -R’; linker is attached to the bracketed moiety at one of Rd, Re, Rf, or Rg, or linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together; each Rdthat is not the point of attachment for the linker is independently -R’, or two , together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each Rethat is not the point of attachment for the linker is independently -R; Rf, when it is not the point of attachment for the linker, is -R; each Rgthat is not the point of attachment for the linker is independently halogen, -CN, R or -OR; p is 0, 1, 2, or 3; Rhis halogen, or -R; each Rithat is not the point of attachment of the linker is independently halogen, -R, -C(O)N(R’)2, or - N(R)C(O)R, or two Rigroups, together with the atoms to which they are attached, combine to form an optionallysubstituted phenyl or 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S; Rjis -R, or Rjcombines with one instance of Ri, together with their intervening atoms, to form an optionally substituted 5- to 7-membered ring having 1-2 heteroatoms independently selected from N, O, and S; Rkis -R; r is 1, 2, 3, 4, or 5; q is 1 or 2; Rmis -R; each of Rn, Rp, Rq, Rr, Rs, and Ruis independently halogen, -CN, -R or -OR; s is 0, 1, 2, 3, 4, or 5; t is 0, 1, 2, 3, 4, or 5; each u is independently 0, 1, 2, 3, 4, or 5; each Rtis independently R, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered ring having 0-2 heteroatoms independently selected from N, O, and S; each Rvis independently halogen, -CN, -R or -OR, or one instance of Ruand Rv, together with their intervening atoms, combine to form an optionally substituted 3- to 7-membered ring having 0-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -CN, -R or -OR, or one instance of Ruand Rw, together with their intervening atoms, combine to form an optionally substituted 3- to 7-membered ring having 0-2 heteroatoms independently selected from N, O, and S; each v is independently 0, 1, 2, 3, 4, or 5; each R’ is independently -R, -C(O)R, or -S(O)2R, or two R’ attached to the same atom, together with the atom to which they are attached, combine to form an optionally substituted 3- to 16-membered ring having 1-5 heteroatoms independently selected from N, O, and S; and each R is independently hydrogen or an optionally substituted group selected from C1-8aliphatic, C3-10cycloaliphatic, C1-C8heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C6-10 aryl, 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.

3. The compound of any one of the preceding claims, wherein the PBM is a KAT2A protein binding moiety and / or a KAT2B protein binding moiety.

4. The compound of any one of claims 2-3, wherein.

5. The compound of any one of claims 2-4, wherein Ring F is an optionally substituted phenyl ring.

6. The compound of any one of claims 2-5, wherein R2is halogen.

7. The compound of any one of claims 2-5, wherein Ring.

8. The compound of claim 7, wherein Ring A is selected from, ,.

9. The compound of any one of claims 2-5, wherein Ringr.

10. The compound of claim 9, wherein R6is optionally substituted C1-6 aliphatic and / or wherein R4is optionally substituted C1-6 alkyl.

11. The compound of any one of claims 2-5, wherein Ring A is selected from,.

12. The compound of any one of claims 2-11, wherein Ring B is an optionally substituted 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

13. The compound of any one of claims 2-11, wherein Ring B is optionally substituted.

14. The compound of any one of claims 2-11, wherein.

15. The compound of any one of claims 2-14, wherein each R1is independently optionally substituted C1-6alkyl, preferably methyl.

16. The compound of any one of claims 2-15, wherein L1is a covalent bond.

17. The compound of any one of claims 2-16, whereinor,18. The compound of any one of the preceding claims, wherein the linker is less than 14 atoms in length, or wherein the linker is less than 11 atoms in length; and / or wherein the shortest-path length of linker is about or no more than 14 atoms, or wherein the shortest- path length of linker is about or no more than 10 atoms; and / or wherein the number of non-ring consecutivesp3atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1; and / or wherein the number of non-ring consecutive sp3atoms in the shortest path chain of linker is about or no more than about 2; and / or wherein the number of bonds between two non-ring sp3atoms in the shortest path chain of linker is about or no more than 5, 4, 3, 2 or 1; and / or wherein the number of bonds between two non-ring sp3atoms in the shortest path chain of linker is about or no more than 1; and / or wherein the number of non-ring sp3C, O, and S atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1; and / or wherein the number of non-ring sp3atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1; and / or wherein the number of non-ring sp3atoms in the shortest path chain of linker is about or no more than about 1; and / or wherein the number of non-ring atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1; and / or wherein the number of non-ring atoms in the shortest path chain of linker is about or no more than about 1.

19. The compound of any one of claims 2-17, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-, preferably: wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1- C20 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-; and wherein a methylene unit is replaced by -C(O)-, a methylene unit is replaced by -Cy-, preferably wherein -Cy- is in a shortest path chain, and / or a methylene unit is replaced by -C(O)N(R)-.

20. The compound of any one of claims 2-17, wherein linker is:, wherein: M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

21. The compound of any one of claims 2-17, wherein linker is selected from,.

22. The compound of any one of claims 2-17, wherein -Cy- is monocyclic and optionally 3-10 membered, or wherein -Cy- is bicyclic optionally wherein -Cy- is 6-, 7-, 8-, 9-, 10- or 11-membered.

23. The compound of any one of claims 2-22, wherein each monocyclic ring unit independently has 1-2 heteroatoms independently selected from N, O, and S.

24. The compound of any one of claims 2-23, wherein Cy is optionally substituted monocyclic 5- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

25. The compound of any one of claims 2-23, wherein Cy is optionally substituted bicyclic or spirocyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

26. The compound of any one of claims 2-20, wherein linker is selected from ,, ,,,27. The compound of any one of claims 2-26, wherein LBM is an E3 ubiquitin ligase binding moiety, or wherein LBM is a VHL binding moiety, an IAP binding moiety, or a MDM2 binding moiety.

28. The compound of any one of claims 2-27, wherein.

29. The compound of any one of claims 2-27, wherein the compound is of Formula III-1:III-1 or a pharmaceutically acceptable salt thereof, wherein: each Rbis independently halogen, -CN, -R’ or -OR; t is 0, 1, 2, 3, or 4; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ringn optionally substituted group selected; Y is N or CH; and each Rais independently halogen, -CN or -R’.

30. The compound of any one of claims 2-27, wherein.

31. The compound of any one of claims 2-27, wherein the compound is of Formula IIIL:IIIL or a pharmaceutically acceptable salt thereof, wherein: each Rband Rb1is independently halogen, -CN, -R’ or -OR; t’ is 0, 1, 2, or 3; L2is a covalent bond or an optionally substituted C1-3 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ringoptionally substituted group selected from; Y is N or CH; and each Rais independently halogen, -CN or -R’.

32. The compound of any one of claims 2-31, wherein Rb1is not -H, or wherein Rb1is optionally substituted C1-6 aliphatic or halogen, or wherein Rb1is -OR wherein R is optionally substituted C1-6 aliphatic.

33. The compound of any one of claims 2-31, wherein Ring C is an optionally substituted phenyl ring.

34. The compound of any one of claims 2-31, wherein Ring C is an optionally substituted 5- or 6- membered heteroaryl ring having 1-2 heteroatoms independently selected from N, O, and S, or Ring C is an optionally substituted 9- or 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S.

35. The compound of any one of claims 2-34, wherein Ringisoptionally substituted and selected from.

36. The compound of any one of claims 2-35, wherein Ring C is:each A is independently N, C, or CH, provided that no more than two A groups are N; each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

37. The compound of any one of claims 2-36, wherein L2is a covalent bond.

38. The compound of any one of claims 2-37, whereinmoiety is ,,.

39. The compound of any one of claims 2-35, wherein LBM is.

40. The compound of any one of claims 2-3, wherein PBM is.

41. The compound of any one of claims 2-3 or 40, wherein Ring F is an optionally substituted 3- to 10- membered ring having 0-4 heteroatoms independently selected from N, O, and S.

43. The compound of any one of claims 40-42, wherein.

44. The compound of any one of the preceding claims, wherein the compound is in a pharmaceutically acceptable salt form.

45. The compound of any one of the preceding claims, wherein the stereochemical purity of each chiral center in PBM is at least about 90%.

46. The compound of any one of the preceding claims, wherein the stereochemical purity of each chiral center is at least about 90%.

47. The compound of any one of the preceding claims, wherein purity of the compound by qNMR is at least about 90% (wt%).

48. A pharmaceutical composition comprising a compound of any one of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

49. The composition of claim 48, wherein the composition further comprises one or more stereoisomers of the compound, wherein the percentage of the compound, among the total of the compound and all its stereoisomers in the composition, is about or at least about 90%, or wherein the percentage of the compound, among the total of the compound and all its stereoisomers in the composition, is about or at least about 20%- 80%.

50. The composition of any one of claims 48-49, wherein the composition comprises a buffer or components thereof, preferably wherein the buffer is a citrate buffer and / or the pH of the buffer is about 2-6.

5.

51. The composition of any one of claims 48-50, wherein the composition comprises a cyclodextrin.

52. The composition of any one of claims 48-50, wherein the composition is substantially free of cyclodextrin.

53. A method of preparing a pharmaceutical composition of claim 48, comprising: providing the compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof; and formulating the compound with suitable excipients to give the pharmaceutical composition.

54. A method for reducing KAT2A and / or KAT2B in a system, comprising administering or delivering to the system an effective amount of a compound or composition of any one of the preceding claims; or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding claims.

55. A method for modulating a dysregulated cell state associated with KAT2A and / or KAT2B, comprising administering or delivering to the cell an effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding claims.

56. The method of claim 55, wherein the dysregulated cell state is of cancer, e.g., of acute myeloid leukemia, small cell lung cancer, or neuroendocrine prostate cancer.

57. The method of any one of claims 55-56, wherein the method induces or promotes conversion of the dysregulated cell state into another cell state; wherein the dysregulated cell state is more proliferative than the another cell state; wherein the dysregulated cell state is less differentiated than the another cell state; wherein the dysregulated cell state is or comprises blocked or reduced differentiation; wherein the dysregulated cell state is or comprises de-differentiation; wherein the dysregulated cell state is or comprises trans- differentiation; wherein the dysregulated cell state is or comprises a dedifferentiated neuroendocrine cell state; and / or wherein the another cell state is or comprises a more differentiated epithelial cell state.

58. The method of any one of claims 55-57, wherein the another cell state comprises increased levels of CD11b, CD14, CD15, and / or CD86 expression; wherein the method increases myeloid differentiation, and / or decreases stem, translation and replication; and / or wherein the method increases myeloid differentiation, and / or decreases stem, translation and / or replication GSEA signatures.

59. The method of any one of claims 55-58, wherein the method increases epithelial GSEA signatures; and / or wherein the method increases neural GSEA signatures; and / or wherein the method increases monocytic differentiation; and / or wherein the method increases neural differentiation; and / or wherein the method increases epithelial differentiation; and / or wherein the method increases level of CD11b+ cells; and / or wherein the method increases level of CD14+ cells; and / or wherein the method increases level of CD15+ cells; and / or wherein the method increases level of CD86+ cells.

60. A method for reducing histone acetylation in a system, comprising administering or delivering to the system an effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding claims.

61. The method of claim 60, wherein H3K9 acetylation is reduced.

62. A method of degrading KAT2 in a subject, comprising administering the compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of the preceding claims, to a subject in need thereof.

63. A method for inducing or promoting cell differentiation in a system, comprising administering or delivering to the system an effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding claims; or a method for reducing or blocking de-differentiation in a system, comprising administering or delivering to the system an effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding claims; or a method for reducing or blocking trans- differentiation in a system, comprising administering or delivering to the system an effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding claims.

64. The method of any one of claims 60-63, wherein the system comprises or expresses KAT2A and / or KAT2B.

65. The method of any one of claims 54-64, wherein a system is or comprises a cell.

66. The method of any one of claims 54-64, wherein a system is or comprises a cancer cell.

67. The method of any one of claims 54-64, wherein a system is or comprises an acute myeloid leukemia cell.

68. A method for treating a disease, disorder, or condition, comprising administering or delivering to a subject suffering therefrom an effective amount of a compound or composition of any one of the preceding claims.

69. The method of claim 68, wherein the disease, disorder, or condition is associated with KAT2A and / or KAT2B.

70. The method of any one of claims 68-69, wherein the disease, disorder, or condition is cancer, or wherein the disease, disorder, or condition is selected from acute myeloid leukemia, neuroblastoma, non- small cell lung cancer, small cell lung cancer, colorectal cancer, melanoma, prostate cancer, neuroendocrine prostate cancer, castration resistant prostate cancer, high-grade neuroendocrine carcinomas, high-grade neuroendocrine carcinomas in GI tract, high-grade neuroendocrine carcinomas in pancreas, and pancreatic cancer.

71. A compound, composition, or method of any one of Embodiments 1-689.

Images