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WO2024220843A1 - Technologies ciblant des états de cellule - Google Patents

Technologies ciblant des états de cellule Download PDF

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Publication number
WO2024220843A1
WO2024220843A1 PCT/US2024/025468 US2024025468W WO2024220843A1 WO 2024220843 A1 WO2024220843 A1 WO 2024220843A1 US 2024025468 W US2024025468 W US 2024025468W WO 2024220843 A1 WO2024220843 A1 WO 2024220843A1
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WIPO (PCT)
Prior art keywords
optionally substituted
ring
compound
membered
independently selected
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PCT/US2024/025468
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English (en)
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WO2024220843A8 (fr
Inventor
James Anthony NEEF
David Simon Millan
Andrew John MCRINER
Jake Charles AXFORD
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Auron Therapeutics Inc
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Auron Therapeutics Inc
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Priority claimed from PCT/US2023/031835 external-priority patent/WO2024050078A1/fr
Application filed by Auron Therapeutics Inc filed Critical Auron Therapeutics Inc
Priority to AU2024256729A priority Critical patent/AU2024256729A1/en
Priority to CN202480026286.2A priority patent/CN120957715A/zh
Publication of WO2024220843A1 publication Critical patent/WO2024220843A1/fr
Publication of WO2024220843A8 publication Critical patent/WO2024220843A8/fr
Priority to IL324013A priority patent/IL324013A/en
Priority to MX2025012361A priority patent/MX2025012361A/es
Anticipated expiration legal-status Critical
Priority to CONC2025/0015654A priority patent/CO2025015654A2/es
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • KAT2A also referred to as general control non-depressible 5 (GCN5)
  • KAT2B also referred to as p300/CBP-associated factor (PCAF)
  • GCN5 general control non-depressible 5
  • PCAF p300/CBP-associated factor
  • 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.
  • 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.
  • the present disclosure encompasses the recognition that various conditions, disorders or diseases are associated with certain cell states.
  • a plastic state which may be referred to as a plastic state
  • plastic states of cancer cells are associated with aggressive tumors, e.g., aggressive and/or metastatic tumors which can be resistant to reported therapies.
  • 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 growth and proliferation.
  • 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.
  • 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).
  • KAT2A and/or KAT2B KAT2A and/or KAT2B
  • KAT2A and/or KAT2B KAT2A and/or KAT2B
  • provided technologies e.g., compounds, compositions or methods
  • provided technologies can reduce level of a KAT2 protein.
  • provided technologies can reduce level of KAT2A.
  • 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.
  • 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.
  • 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.
  • a protein binding moiety binds to a bromodomain of KAT2A and/or KAT2B.
  • 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).
  • provided compounds promote ubiquitination of KAT2A and/or KAT2B.
  • provided compounds promote degradation of KAT2A and KAT2B.
  • the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein PBM, linker, and LBM are as defined herein.
  • 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. [00007] 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.
  • a provided compound is a compound of formula IIIC or a salt thereof. In some embodiments, a provided 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.
  • 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.
  • 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.
  • such a compound is useful for preventing and/or treating a condition, disorder or disease associated with KAT2A and/or KAT2B.
  • the present disclosure provides a pharmaceutical composition comprising a provided compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present disclosure provides technologies (e.g., compounds or methods) for manufacturing provided compounds.
  • 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.
  • 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.
  • a pharmaceutical composition is administered to administer or deliver a provided compound or a salt thereof.
  • a condition, disorder or disease is associated with KAT2A and/or KAT2B.
  • a condition, disorder or disease is cancer.
  • a condition, disorder or disease is small-cell lung cancer.
  • a condition, disorder or disease is neuroendocrine prostate cancer.
  • a condition, disorder or disease is acute myeloid leukemia.
  • FIG. 1 Provided compounds can provide various activities including inhibiting tumor growth in vivo.
  • (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.
  • (B): Provided technologies can inhibit cell growth. Cell count data after 8 days of treatment with compound 22 relative to DMSO control are presented as examples to confirm inhibition. GI 50 1.2 nM.
  • (C): Provided technologies can modulate cell states and induce differentiation. CD86 was analyzed by flow cytometry at 48 hours and monocytic differentiation was observed. EC50 0.3nM. [00013] Figure 3. Provided compounds can provide various activities.
  • (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. GI 50 5 nM.
  • (E): Provided technologies can inhibit cell growth. Cell viability data relative to DMSO control after 21 days of treatment with compound 22 are presented as examples to confirm inhibition. GI 50 3 nM.
  • 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.
  • stereoisomeric e.g., enantiomeric or diastereomeric
  • 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.
  • 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. [00017] 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 by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • 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”).
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C 1-6 ).
  • aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5 ). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4 ). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C 1-3 ), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 ). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.
  • 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.
  • 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., C 1-12 , C 1- 10 ,C 1-8 ,C 1-6 ,C 1-4 ,C 1- 3 , or C 1- 2 ).
  • 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.
  • “carbocyclyl” refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C 5 -C 10 (e.g., C7-C 10 or C 8 - C 10 ) 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.
  • 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.
  • Alkenyl 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., C 2-12, C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • Alkynyl 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., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Aryl refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C 6-14 ), 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”.
  • “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, naphthyl, and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.
  • 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, CH 2 , and CH 3 are 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.
  • 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 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • 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,
  • 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.
  • 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
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • 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.
  • nitrogen When used in reference to a ring atom of a heterocycle, the term "nitrogen” includes a substituted nitrogen.
  • the nitrogen 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 any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • 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)).
  • 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)).
  • Partially Unsaturated when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms.
  • 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.
  • a patient or subject displays one or more symptoms of a disorder or condition.
  • a patient or subject has been diagnosed with one or more disorders or conditions.
  • a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • 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.
  • 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.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (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 R 1 NH 1 N R 1 R 1 NH R R 1 and refers to at least , , NH , or ).
  • 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.
  • stable 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.
  • Suitable monovalent substituents on Rq are independently halogen, –(CH2)0–2R z , –(haloR z ), –(CH2)0–2OH, –(CH 2 ) 0–2 OR z , –(CH 2 ) 0–2 CH(OR z ) 2 , -O(haloR z ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R z , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0– 2 C(O)OR z , –(CH 2 ) 0–2 SR z , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , –(CH 2 ) 0–2 NHR z
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic 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.
  • Suitable substituents on the aliphatic group of R * include halogen, –R z , -(haloR z ), -OH, –OR z , – O(haloR z ), –CN, –C(O)OH, –C(O)OR z , –NH 2 , –NHR z , –NR z 2 , or –NO 2 , wherein each R z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, – CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • 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(
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R z , -(haloR z ), –OH, –OR z , –O(haloR z ), –CN, –C(O)OH, –C(O)OR z , –NH2, –NHR z , –NR z 2, or -NO2, wherein each R z is 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.
  • treat 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.
  • 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.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
  • the term “a” or “an” may be understood to mean “at least one”;
  • the term “or” may be understood to mean “and/or”;
  • the terms “comprise”, “comprising”, “include” and “including” 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;
  • the term “another” may be understood to mean at least an additional/second one or more;
  • 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.
  • the present disclosure provides compounds useful for preventing or treating various conditions, disorders or diseases including cancer.
  • the present disclosure provides compounds useful for inhibiting cell proliferation, e.g., cancer cell proliferation.
  • the present disclosure provides compounds useful for reducing tumor growth.
  • the present disclosure provides compounds useful for reducing level of KAT2A and/or level of KAT2B.
  • the present disclosure provides compounds useful for inhibiting one or more functions of KAT2A and/or KAT2B.
  • 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.
  • the present disclosure provides KAT2 degrader compounds, comprising a KAT2 protein binding moiety, a linker, and an E3 ubiquitin ligase binding moiety.
  • 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.
  • PBM is or , and , , s v .
  • a compound comprises a moiety, e.g., PBM, that can bind a KAT2 protein or a fragment (e.g., bromodomain) thereof.
  • PBM-H or a salt thereof can bind a KAT2 protein or a fragment (e.g., bromodomain) thereof.
  • PBM-H or a salt thereof binds KAT2A or a fragment (e.g., bromodomain) thereof.
  • 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.
  • 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.
  • E3 ligase e.g., CRBN, VHL, IAP, or MDM2
  • H-linker-LBM or a salt thereof can bind an E3 ligase (e.g., CRBN, VHL, IAP, or MDM2).
  • E3 ligase e.g., CRBN, VHL, IAP, or MDM2.
  • H- linker-LBM or a salt thereof bind CRBN.
  • H- linker- LBM or a salt thereof bind VHL.
  • 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; L 1 is a covalent bond or a bivalent C1-3 straight or branched hydrocarbon chain; each R 1 is independently optionally substituted C1-6 aliphatic or optionally substituted C3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 5 is hydrogen, hal
  • 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; L 1 is a covalent bond or a bivalent C1-3 straight or branched hydrocarbon chain; each R 1 is independently optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 5 is hydrogen, halogen,
  • the present disclosure provides a compound of Formula IIA: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 1 , R 1 , R 9 , n, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIA-1, IIA-2, IIA- 3, or IIA-4: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , X, Z, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIA-1, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIA-2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIA-3, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIA-4, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIA-1: IIA-1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is optionally substituted C 1-6 aliphatic; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen or halogen; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 9 is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(
  • the present disclosure provides a compound of Formula IIA-1: IIA-1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 1-6 alkyl; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl; each R 3 is independently hydrogen or halogen; R 4 is C 1-6 alkyl; R 9 is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon 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 hetero
  • the present disclosure provides a compound of Formula IIA-5: linker LBM IIA-5 or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIA-6: IIA-6 or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C 1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR
  • 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; L 1 is a covalent bond or a bivalent C 1-3 straight or branched hydrocarbon chain; each R 1 is independently optionally substituted C 1-6 aliphatic or optionally substituted -6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted 6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 5
  • the present disclosure provides a compound of Formula IIIA: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each R b is hydrogen, or two R b groups, 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 R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the present disclosure provides a compound of Formula IIIB: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R b , R c , m, and linker are as defined above for Formula IIIA and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIIB-1 or IIIB-2: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIIB-1, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIIB-2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIIC: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , L 2 , R 1 , R 9 , 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 R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the present disclosure provides a compound of Formula IIID: or a pharmaceutically acceptable salt thereof, wherein Ring A, B, L 2 , R 1 , R 9 , R c , Y, m, and linker are as defined above for Formula IIIC and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIID: or a pharmaceutically acceptable salt, wherein: Ring A is ; R 1 is optionally substituted C 1-6 aliphatic; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen or halogen; R 4 is optionally substituted C1-6 aliphatic; R 9 is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 hydrocarbon 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
  • the present disclosure provides a compound of Formula IIID: IIID or a pharmaceutically acceptable salt, wherein: Ring A is ; R 1 is C1-6 alkyl; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl; each R 3 is independently hydrogen or halogen; R 4 is C1-6 alkyl; R 9 is hydrogen; linker ; L 6 and L 7 are both a covalent bond; Cy is is selected from: , , , , , , , , ; the moiety L 2 is 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 R c is independently selected from halogen, -O(C1-6 alkyl), and C1-6 alkyl; and m is 0, 1, 2, or 3.
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C 1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C 1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR
  • 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 independently selected from N, O, and S; L 1 is a covalent bond or an optionally substituted bivalent C 1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7 ;
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7 ;
  • the present disclosure provides a compound of Formula IIIM: IIIM 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7
  • the present disclosure provides a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , 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 R d , R e , R f , or R g ; each R d that is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C 1-6 aliphatic, or two R d , 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 R e that is not the point
  • the present disclosure provides a compound of Formula IVA: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , R d , R e , R f , R g , R h , p, n, and linker are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IVA-1: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R d , R e , R f , R g , R h , p, and linker are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C 1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR
  • 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.
  • the present disclosure provides a compound of Formula V: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , 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 R i or the ring formed when two R i groups are taken together; each R i that 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 R i groups, together with the atoms to which they are attached, combine to form an optionally substituted pheny
  • the present disclosure provides a compound of Formula VA: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , R i , R j , R k , n, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VA-1: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R i , R j , R k , q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VB: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R, R 1 , R 9 , R i , R j , R k , n, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VB-1: VB-1 or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R, R 1 , R 9 , R j , R k , n, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7
  • 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, C 1 -C 8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C 6-10 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure provides a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and R m is optionally substituted C1-6 aliphatic; each R n is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; and s is 0, 1, 2, 3, 4, or 5.
  • the present disclosure provides a compound of Formula VIA: s or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , R m , R n , n, s, and linker are as defined above for Formula VI and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VIA-1: s VIA-1 or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R m , R n , s, and linker are as defined above for Formula VI and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VI-1: s VI-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; L 1 is a covalent bond or an optionally substituted bivalent C 1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR
  • 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.
  • the present disclosure provides a compound of Formula VII: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each R p is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; each R q is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; each R r is independently hydrogen or optionally substituted C 1-6 aliphatic; each R s is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • the present disclosure provides a compound of Formula VIIA: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R p , R q , R r , R s , u, t, and linker are as defined above for Formula VII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VII-1: or a pharmaceu tically 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or
  • the present disclosure provides a compound of Formula VIIB: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R p , R q , R r , R s , u, t, and linker are as defined above for Formula VII-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VIII: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each R t is independently hydrogen or optionally substituted C1-6 aliphatic, or both R t groups, 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 R u is independently hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic; each R v is independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic, or one instance of R u and R v , together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membere
  • the present disclosure provides a compound of Formula VIIIA: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R t , R u , R v , R w , v, and linker are as defined above for Formula VIII and described in classes and subclasses herein, both singly and in combination.
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7
  • the present disclosure provides a compound of Formula VIIIB: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring F, R 1 , R 9 , R t , R u , R v , R w , v, and linker are as defined above for Formula VIII-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IX: or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: ; L 3 , L 4 , and L 5 are each independently a covalent bond or an optionally substituted bivalent C1-6 straight or branched hydrocarbon chain; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 5 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic, or R 2 and R 5 , together with the atoms to which they are attached, combine to
  • the present disclosure provides a compound of Formula IX, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: ; L 3 , L 4 , and L 5 are each independently a covalent bond or an optionally substituted bivalent C1-6 straight or branched hydrocarbon chain; Z is N or CR 3 ; R 2 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 5 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic, or R 2 and R 5 , together with the atoms to which they are attached, combine to form an optional
  • the present disclosure provides a compound of Formula IXA, IXB, IXC, or IXD: or a pharmaceutically acceptable salt thereof, wherein L 3 , L 4 , L 5 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , X, Z, linker, and LBM are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IXA, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IXB, or a pharmaceutically acceptable salt thereof.
  • 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. [00102] 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 CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7 ; R 7 is -R’, or R 4 and R 7 , together with
  • the present disclosure provides a compound of Formula X: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , 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 R a is independently hydrogen or an optionally substituted C1-6 aliphatic, or two R a groups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a straight or branched C1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-
  • the present disclosure provides a compound of Formula XA: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each R b is hydrogen, or two R b groups, 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 R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the present disclosure provides a compound of Formula XA-1 or XA-2: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XA-1, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula XA-2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula XB: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 2 , L 3 , L 4 , L 5 , R 8 , R 9 , 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 R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • 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.
  • the present disclosure provides a compound of Formula XA’: or a pharmaceutically acceptable salt thereof, wherein each R c is 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.
  • Ring A is selected from: ; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 is halogen ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR 7 ; R 7 is -R’, or R 4 and R 7 , 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; R 9 is -R’; L 3 , L 4 , and L 5 are each independently a covalent bond or an optionally substituted bivalent C 1-6 hydrocarbon chain; each R 8 is
  • 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.
  • Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula X-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XA-1’, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula XA-2’, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula XB’: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring F, L 2 , L 3 , L 4 , L 5 , R 8 , R 9 , 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 R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the present disclosure provides a compound of Formula XI: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , 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 R d , R e , R f , or R g ; each R d that is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C 1-6 aliphatic, or two R d , 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 R e
  • the present disclosure provides a compound of Formula XIA: XIA or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , R d , R e , R f , R g , R h , p, and linker are as defined above for Formula XI and described in classes and subclasses herein, both singly and in combination.
  • 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.
  • 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.
  • the present disclosure provides a compound of Formula XII: XII or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , 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 R i or the ring formed when two R i groups are taken together; each R i that is not the point of attachment of the linker is independently halogen, optionally substituted C 1-6 aliphatic, -C(O)N(R) 2 , or -N(R)C(O)R, or two R i groups, 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; R j is an optionally substituted group selected from C1-6
  • the present disclosure provides a compound of Formula XIIA: XIIA or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , R i , R j , R k , q, r, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XIIB: XIIB or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R, R 8 , R 9 , R i , R j , R k , q, r, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XIIB-1: XIIB-1 or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R, R 8 , R 9 , R j , R k , and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure provides a compound of Formula XIII: s XIII or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and R m is optionally substituted C1-6 aliphatic; each R n is independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic; and s is 0, 1, 2, 3, 4, or 5.
  • the present disclosure provides a compound of Formula XIIIA: s XIIIA or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , R m , R n , s, and linker are as defined above for Formula XIII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XIII-1: s XIII-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.
  • the present disclosure provides a compound of Formula XIIIB: s XIIIB or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring F, L 3 , L 4 , L 5 , R 8 , R 9 , R m , R n , s, and linker are as defined above for Formula XIII-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XIV: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each R p is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; each R q is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; each R r is independently hydrogen or optionally substituted C 1-6 aliphatic; each R s is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5.
  • 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.
  • the present disclosure provides a compound of Formula XV: XV or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each R t is independently hydrogen or optionally substituted C 1-6 aliphatic, or both R t groups, 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 R u is independently hydrogen, halogen, -CN, or optionally substituted C 1-6 aliphatic; each R v is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic, or one instance of R u and R v , together with the atoms to which they are attached combine to form
  • 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 is a KAT2 protein binding moiety, i.e., is a moiety that is capable of binding a KAT2 protein.
  • a PBM is a KAT2A protein binding moiety, i.e., is a moiety that is capable of binding a KAT2A protein.
  • a PBM is a KAT2B protein binding moiety, i.e., is a moiety that is capable of binding a KAT2B protein.
  • 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.
  • 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).
  • a PBM shares significant structural identity with a reference compound or moiety thereof that is capable of binding a KAT2 protein.
  • a PBM comprises the same or similar structure as a reference compound, except that a PBM comprises a point of attachment to a linker.
  • a reference compound is characterized by a K d of less than 1 ⁇ M in a biophysical assay, such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC).
  • a reference compound is characterized by a IC 50 of less than 1 ⁇ M in a competition or functional assay, such as time-resolved fluorescence resonance energy transfer (TR-FRET).
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • a reference compound is characterized by an DC 50 of less than 30 nM in the Western Blot assay of Example B1.
  • a reference compound binds to a KAT2 protein but does not cause KAT2 degradation when assessed, e.g., as described in Example B1.
  • a reference compound has the structure of PBM-H or a salt thereof.
  • 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 by reference.
  • 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.
  • a reference compound can be incorporated as a PBM (see, e.g., GSK4027 incorporated into various compounds as PBM).
  • a PBM is as described in WO 2024/003533, US20230391745, WO2017/197046, or Bassi, Z., et al., ACS Chem. Biol. 2018, 13, ⁇ the entirety of each of which is incorporated herein by reference.
  • technologies for identifying or assessing PBM are described in one or more of such references.
  • 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).
  • 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).
  • a reference compound is GSK4027: . In some embodiments, a reference compound is: .
  • a PBM has the structure , wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination.
  • 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.
  • 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 some embodiments, 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.
  • 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.
  • Ring F is an optionally substituted monocyclic ring (e.g., 3-10, 5-8, 3, 4, 5, 6, 7, 8, 9 or 10 membered).
  • Ring F is an optionally substituted bicyclic ring (e.g., 6-10, 6, 7, 8, 9 or 10 membered).
  • Ring F is polycyclic. [00135]
  • PBM is , wherein each variable are as defined and described in classes and subclasses herein, both singly and in combination.
  • a PBM has the following structure: , wherein Ring A, Ring B, L 1 , R 1 , R 9 , and n are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.
  • a PBM has the following structure: , wherein Ring A, L 1 , R 1 , R 9 , and n are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.
  • a PBM has the following structure: , wherein Ring A, R 1 , and R 9 are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.
  • a PBM has the following structure: , wherein Ring A, R 1 , and R 9 are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination. [00139] In some embodiments, a PBM has the following structure: , wherein Ring A, R 1 , and R 9 are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.
  • a PBM is selected from: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , X, and Z are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.
  • a PBM has the following structure: , wherein Ring A, L 3 , L 4 , L 5 , R 8 , and R 9 are as defined herein for Formula IX and described in classes and subclasses herein, both singly and in combination.
  • a PBM is selected from:
  • a PBM is selected from:
  • a PBM is selected from: .
  • Ring A is .
  • Ring A is .
  • 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 is . In some embodiments, Ring A is . In some embodiments, Ring A is .
  • Ring A is In some embodiments, Ring A is selected from: , , and N . In some embodiments, Ring A is selected from: O [00146] In some embodiments of any Formula described herein, Ring A is . In some embodiments, Ring . In some such embodiments, R 2 and R 5 , 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 [00147] In some embodiments of any Formula described herein, Ring . In some 5 embodiments, Ring . In some embodiments, Ring .
  • R 2 and R 5 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.
  • R 4 and R 7 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.
  • a formed ring is aromatic.
  • Ring A is selected from: .
  • Ring A is selected from: .
  • Z is N or CH.
  • Z is N. In some embodiments, Z is CR 3 (e.g., CH). In some embodiments, Z is optionally substituted CH.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. [00151] 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 C 1 -C 6 alkyl groups. In some embodiments, Ring F is optionally substituted with an optionally substituted -O(C 1 -C 6 alkyl) group.
  • Ring F is some 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 . [00152] In some embodiments, R 2 is -R as described herein. In some embodiments, R 2 is -R but not hydrogen. In some embodiments of any Formula described herein, R 2 is hydrogen, halogen, -CN, or optionally substituted C 1-6 aliphatic. In some embodiments, R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, or C 6-10 aryl. In some embodiments, R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S.
  • R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 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.
  • R 2 is hydrogen, halogen, or optionally substituted C 1-6 aliphatic.
  • R 2 is halogen or C 1-6 alkyl.
  • R 2 is chloro, bromo, or methyl.
  • R 2 is hydrogen.
  • R 2 is halogen.
  • R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo. In some embodiments, R 2 is –CN. In some embodiments, R 2 is optionally substituted C1-6 aliphatic. In some embodiments, R 2 is optionally substituted C1-6 alkyl. In some embodiments, R 2 is C1-2 alkyl (e.g., methyl or ethyl). In some embodiments, R 2 is optionally substituted C3-6 cycloaliphatic. In some embodiments, R 2 is optionally substituted C3-6 cycloalkyl. In some embodiments, R 2 is C3-4 cycloalkyl (e.g., cyclopropyl).
  • R 2 is C6-10 aryl. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is naphthyl. In some embodiments, R 2 is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 is 3- to 10-membered monocyclic heterocyclyl having 1- 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • R 3 is -R as described herein. In some embodiments, R 3 is -R but not H. In some embodiments of any Formula described herein, each R 3 is independently hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, each R 3 is independently hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, each R 3 is independently hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl.
  • each R 3 is 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.
  • each R 3 is 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.
  • each R 3 is hydrogen.
  • R 3 is hydrogen.
  • R 3 is halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is bromo. In some embodiments, R 3 is optionally substituted C 1-6 aliphatic. In some embodiments, R 3 is optionally substituted C 1-6 alkyl. In some embodiments, R 3 is C 1-2 alkyl (e.g., methyl). In some embodiments, R 3 is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R 3 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 3 is C 6-10 aryl. In some embodiments, R 3 is phenyl.
  • R 3 is naphthyl. In some embodiments, R 3 is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 3 is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 3 is 3- to 10- membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 3 is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00154] In some embodiments, R 4 is -R as described herein. In some embodiments, R 4 is -R but not hydrogen.
  • R 4 is hydrogen or optionally substituted C 1- 6 aliphatic. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is optionally substituted C1-6 aliphatic. In some embodiments, R 4 is optionally substituted C1-6 alkyl. In some embodiments, R 4 is C1-6 alkyl. In some embodiments, R 4 is optionally substituted C1-2 alkyl. In some embodiments, R 4 is C1-2 alkyl (e.g., methyl). In some embodiments, R 3 is methyl. In some embodiments, R 4 is optionally substituted C3-6 cycloaliphatic.
  • R 4 is optionally substituted C3-6 cycloalkyl. In some embodiments, R 4 is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 4 is -C(O)R. In some embodiments, R 4 is - C(O)(C1-6 alkyl). In some embodiments, R 4 is -S(O)2R. In some embodiments, R 4 is -S(O)2(C1-6 alkyl). [00155] In some embodiments, R 5 is -R as described herein. In some embodiments, R 5 is -R but is not hydrogen.
  • R 5 is hydrogen, halogen, or optionally substituted C1-6 aliphatic.
  • R 5 is hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl.
  • R 5 is hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl.
  • R 5 is 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.
  • R 5 is 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.
  • R 5 is hydrogen.
  • R 5 is halogen.
  • R 5 is fluoro.
  • R 5 is chloro.
  • R 5 is bromo.
  • R 5 is optionally substituted C1-6 aliphatic.
  • R 5 is optionally substituted C1-6 alkyl.
  • R 5 is C1-2 alkyl (e.g., methyl). In some embodiments, R 5 is optionally substituted C3-6 cycloaliphatic. In some embodiments, R 5 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 5 is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 5 is C 6-10 aryl. In some embodiments, R 5 is phenyl. In some embodiments, R 5 is naphthyl. In some embodiments, R 5 is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S.
  • R 5 is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 is 3- to 10-membered monocyclic heterocyclyl having 1- 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00156] In some embodiments, R 2 and R 5 , 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.
  • 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, R 2 and R 5 , 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.
  • R 2 and R 5 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 ⁇ .
  • R 2 and R 5 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.
  • R 2 and R 5 combine to form an optionally substituted pyrrole. In some embodiments, R 2 and R 5 , 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, R 2 and R 5 combine to form an optionally substituted phenyl or pyridine. In some embodiments, R 2 and R 5 combine to form an optionally substituted phenyl ring. In some embodiments, R 2 and R 5 combine to form an optionally substituted pyridine ring. In some embodiments, R 2 and R 5 combine to form optionally substituted .
  • R 6 is -R as described herein. In some embodiments, R 6 is -R but is not hydrogen. In some embodiments of any Formula described herein, R 6 is hydrogen or optionally substituted C1- 6 aliphatic. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is optionally substituted C1-6 aliphatic. In some embodiments, R 6 is optionally substituted C1-6 alkyl. In some embodiments, R 6 is C1-6 alkyl. In some embodiments, R 6 is optionally substituted C1-2 alkyl. In some embodiments, R 6 is C1-2 alkyl (e.g., methyl). In some embodiments, R 6 is methyl.
  • R 6 is optionally substituted C3-6 cycloaliphatic. In some embodiments, R 6 is optionally substituted C3-6 cycloalkyl. In some embodiments, R 6 is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 6 is -C(O)R. In some embodiments, R 6 is - C(O)(C 1-6 alkyl). In some embodiments, R 6 is -S(O) 2 R. In some embodiments, R 6 is -S(O) 2 (C 1-6 alkyl). [00158] In some embodiments of any Formula described herein, X is O. In some embodiments, X is NR 7 .
  • R 7 is -R as described herein. In some embodiments, R 7 is -R but is not hydrogen. In some embodiments of any Formula described herein, R 7 is hydrogen or optionally substituted C 1- 6 alkyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is optionally substituted C 1-6 aliphatic. In some embodiments, R 7 is optionally substituted C 1-6 alkyl.
  • R 7 is C 1-6 alkyl. In some embodiments, R 7 is optionally substituted C 1-2 alkyl. In some embodiments, R 7 is C 1-2 alkyl (e.g., methyl). In some embodiments, R 7 is optionally substituted C3-6 cycloaliphatic. In some embodiments, R 7 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 7 is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 7 is -C(O)R. In some embodiments, R 7 is -C(O)(C 1-6 alkyl). In some embodiments, R 7 is - S(O)2R.
  • R 7 is -S(O)2(C1-6 alkyl).
  • R 4 and R 7 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.
  • 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.
  • R 4 and R 7 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.
  • R 4 and R 7 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 ⁇ .
  • R 4 and R 7 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.
  • R 4 and R 7 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.
  • R 4 and R 7 combine to form an optionally substituted triazole.
  • R 4 and R 7 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.
  • a formed ring is optionally substituted . In some embodiments, a formed ring .
  • R 9 is -R as described herein. In some embodiments, R 9 is -R but is not hydrogen. In some embodiments of any Formula described herein, R 9 is hydrogen or optionally substituted C 1- 6 alkyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is optionally substituted C 1-6 aliphatic. In some embodiments, R 9 is optionally substituted C 1-6 alkyl. In some embodiments, R 9 is C 1-6 alkyl. In some embodiments, R 9 is optionally substituted C 1-2 alkyl.
  • R 9 is C 1-2 alkyl (e.g., methyl). In some embodiments, R 9 is methyl. In some embodiments, R 9 is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R 9 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 9 is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 9 is -C(O)R. In some embodiments, R 9 is -C(O)(C1-6 alkyl). In some embodiments, R 9 is -S(O) 2 R. In some embodiments, R 9 is -S(O) 2 (C 1-6 alkyl).
  • 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.
  • 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.
  • 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, [00163] In some embodiments of any Formulae described herein, L 1 is a covalent bond. In some embodiments, L 1 is an optionally substituted bivalent C 1-3 hydrocarbon chain.
  • L 1 is an optionally substituted bivalent saturated C 1-3 hydrocarbon chain. In some embodiments, L 1 is an optionally substituted bivalent partially unsaturated C 1-3 hydrocarbon chain. In some embodiments, L 1 is an optionally substituted bivalent linear C1-3 hydrocarbon chain. In some embodiments, L 1 is an optionally substituted bivalent branched C 1-3 hydrocarbon chain. In some embodiments, L 1 is a bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, L 1 is a bivalent C 1-3 straight hydrocarbon chain. In some embodiments, L 1 is a bivalent C1-2 straight hydrocarbon chain. In some embodiments, L 1 is optionally substituted In some embodiments, L 1 is –CH2-.
  • R 1 is -R as described herein. In some embodiments, R 1 is -R but not hydrogen. In some embodiments of any Formulae described herein, each R 1 is independently optionally substituted C1-6 alkyl or optionally substituted C3-6 cycloalkyl. In some embodiments, each R 1 is 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.
  • R 1 is optionally substituted C1-6 aliphatic. In some embodiments, R 1 is optionally substituted C1- 6 alkyl. In some embodiments, R 1 is C1-6 alkyl. In some embodiments, R 1 is optionally substituted C1-2 alkyl. In some embodiments, R 1 is C1-2 alkyl (e.g., methyl). In some embodiments, R 1 is methyl. In some embodiments, R 1 is optionally substituted C3-6 cycloaliphatic. In some embodiments, R 1 is optionally substituted C3-6 cycloalkyl. In some embodiments, R 1 is C3-4 cycloalkyl (e.g., cyclopropyl).
  • R 1 is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • n is 0, 1, 2, 3, or 4.
  • n is 0 or 1.
  • n is 1, 2, or 3.
  • n is 0.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • L 3 is an optionally substituted bivalent straight C 1-6 (e.g., C 1-3 , C 1 , C 2 , C 3 , C 4 , C 5 or C 6 ) hydrocarbon chain.
  • L 3 is an optionally substituted bivalent branched C 1-6 (e.g., C 1-3 , C 1 , C 2 , C 3 , C 4 , C 5 or C 6 ) hydrocarbon chain.
  • L 3 is a covalent bond or an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain.
  • L 3 is a covalent bond.
  • L 3 is a bivalent C 1-6 straight or branched hydrocarbon chain.
  • L 3 is an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain.
  • L 3 is a bivalent C 1-3 straight or branched hydrocarbon chain.
  • L 3 is optionally substituted -CH 2 -. In some embodiments, L 3 is selected from -CH 2 - and – CH(CH 3 )-. In some embodiments, a chain is saturated. In some embodiments, it is partially unsaturated. In some embodiments, L 3 is -CH 2 -. [00167] In some embodiments, L 4 is an optionally substituted bivalent straight C1-6 (e.g., C1-3, C1, C2, C3, C 4 , C 5 or C 6 ) hydrocarbon chain.
  • C1-6 e.g., C1-3, C1, C2, C3, C 4 , C 5 or C 6
  • L 4 is an optionally substituted bivalent branched C 1-6 (e.g., C 1-3 , C 1 , C 2 , C 3 , C 4 , C 5 or C 6 ) hydrocarbon chain.
  • L 4 is a covalent bond or an optionally substituted bivalent C1-3 straight or branched hydrocarbon chain.
  • L 4 is a covalent bond.
  • L 4 is an optionally substituted bivalent C1-6 straight or branched hydrocarbon chain.
  • L 4 is a bivalent C1-6 straight or branched hydrocarbon chain.
  • L 4 is an optionally substituted bivalent C1-3 straight or branched hydrocarbon chain.
  • L 4 is a bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L 4 is optionally substituted -CH2-. In some embodiments, L 4 is selected from –CH2- and – CH(CH3)-. In some embodiments, L 4 is -CH2-. [00168] In some embodiments, L 5 is an optionally substituted bivalent straight C1-6 (e.g., C1-3, C1, C2, C3, C4, C5 or C6) hydrocarbon chain. In some embodiments, L 5 is an optionally substituted bivalent branched C1-6 (e.g., C1-3, C1, C2, C3, C4, C5 or C6) hydrocarbon chain.
  • L 5 is a covalent bond or an optionally substituted bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L 5 is a covalent bond. In some embodiments, L 5 is an optionally substituted bivalent C1-6 straight or branched hydrocarbon chain. In some embodiments, L 5 is a bivalent C1-6 straight or branched hydrocarbon chain. In some embodiments, L 5 is an optionally substituted bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L 5 is a bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L 5 is optionally substituted -CH2-. In some embodiments, L 5 is selected from -CH2- and – CH(CH3)-.
  • L 5 is -CH2-.
  • R 8 is -R as described herein. In some embodiments, R 8 is -R but is not hydrogen. In some embodiments of any Formulae described herein, each R 8 is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is optionally substituted C 1-6 aliphatic. In some embodiments, R 8 is optionally substituted C 1-6 alkyl. In some embodiments, R 8 is C 1-6 alkyl. In some embodiments, R 8 is optionally substituted C 1-2 alkyl. In some embodiments, R 8 is C 1- 2 alkyl (e.g., methyl).
  • R 8 is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R 8 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 8 is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 8 is -C(O)R. In some embodiments, R 8 is -C(O)(C 1-6 alkyl). In some embodiments, R 8 is -S(O) 2 R. In some embodiments, R 8 is -S(O) 2 (C 1-6 alkyl). In some embodiments, the two R 8 groups are the same. In some embodiments, they are different.
  • two R 8 together 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.
  • a formed ring is 3-10 membered.
  • a formed ring is 3-6 membered.
  • a formed ring is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered.
  • linker is a linking moiety (i.e., any suitable bivalent moiety that connects a PBM to a LBM).
  • linker is a covalent bond.
  • linker is an optionally substituted bivalent C1-C20 (e.g., C1-C15, C1-C 10 , C 1 -C 6 , C1-C4, C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , 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
  • 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): . [00172] In some embodiments, a linker is 2-16 atoms in length. In some embodiments, a linker is 2-13 atoms in length.
  • 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 is 4-10 atoms in length.
  • 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.
  • 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.
  • 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.
  • linker is a covalent bond.
  • 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-.
  • 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-.
  • 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-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 (e.g., C1-C8, C 1 -C 6 , C1-C5, C1-C4, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 ) 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-.
  • C1-C 10 saturated or unsaturated C1-C 10
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 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-.
  • 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 sp 3 atoms 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 sp 3 atoms in the shortest path chain, with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring sp 3 atoms in the shortest path chain, with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring consecutive sp 3 atoms in the shortest path chain, with about or no more than about 0, 1, 2, 3, 4 or 5 non-ring consecutive sp 3 atoms in the
  • the number of non-ring consecutive sp 3 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 consecutive sp 3 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 consecutive sp 3 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 consecutive sp 3 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 sp 3 atoms in the shortest path chain of a linker is about or no more than about 5.
  • the number of non-ring sp 3 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 sp 3 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 sp 3 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 sp 3 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 sp 3 atoms in the shortest path chain of a linker is 0.
  • the number of non-ring sp 3 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 sp 3 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 sp 3 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 sp 3 C, O, and S atoms in the shortest path chain of a linker is about or no more than about 2.
  • the number of non-ring sp 3 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 sp 3 C, 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.
  • 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.
  • 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 no more 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.
  • 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.
  • -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.
  • -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.
  • -Cy- is 10-12 membered and is bicyclic.
  • -Cy- is 10-12 membered and is spiro-bicyclic.
  • -Cy- is 11-membered and is bicyclic.
  • -Cy- is 11-membered and is spiro-bicyclic.
  • 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.
  • 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).
  • 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.
  • linkers e.g., in -Cy- (e.g., in piperidine and/or piperazine rings) can provide improved solubility, improved dissolution rate, and/or longer T 1/2 , e.g., when assessed in rodent PK assays.
  • Various embodiments of linkers are described herein as examples, e.g., below or in various compounds.
  • 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)-, -C(NR)NR-,
  • 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-.
  • C1-C3 e.g., C1-C2, C1, C2, or C3 alkylene chain
  • 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-.
  • 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-.
  • 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).
  • 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.
  • 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.
  • about or no more than about 5 methylene units are independently replaced as described herein.
  • about or no more than about 4 methylene units are independently replaced as described herein.
  • about or no more than about 3 methylene units are independently replaced as described herein.
  • about or no more than about 2 methylene units are independently replaced as described herein.
  • about or no more than about 1 methylene unit is replaced as described herein.
  • linker comprises an ether moiety (e.g., -O-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -O-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -O-.
  • linker comprises an amine moiety (e.g., -N(R)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)- (e.g., -NH- or –N(C 1-6 alkyl)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)- (e.g., -NH- or –N(C1-6alkyl)-).
  • a methylene unit is replaced by -NH-.
  • linker comprises a carbonyl moiety.
  • 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)-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-.
  • linker comprises an ester moiety.
  • 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-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-.
  • linker comprises an amide moiety.
  • 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)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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)-).
  • 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(C 1-6 alkyl)C(O)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)C(O)- (e.g., -N(H)C(O)- or -N(C 1-6 alkyl)C(O)-).
  • linker comprises a bivalent ring moiety (e.g., -Cy-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-.
  • Cy is not phenyl.
  • linker comprises a triple bond.
  • 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-.
  • linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C 10 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-.
  • 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: M 1 and M 2 are each independently absent, -CH 2 -, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; and L 6 and L 7 are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 5 (e.g., C 1- C 4 , C 1- C 3 , C 1- C 2 , C 2- C 4 , C 1 , C 2 , C 3 , C 4 , or C 5 ) hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-,
  • linker is selected from: , [00192] In some embodiments of any Formulae described herein, linker is or L 6 Cy L 7 O . [00193] In some embodiments of any Formulae described herein, linker is selected from: ,
  • linker is selected from: .
  • M 1 is –CH2-, –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • M 1 is absent.
  • M 1 is optionally substituted -CH2-.
  • M 1 is –CH2-.
  • M 1 is -O-. In some embodiments, M 1 is -N(R)- (e.g., -N(H)- or –N(CH3)-). In some embodiments, M 1 is -C(O)-. In some embodiments, M 1 is -OC(O)-. In some embodiments, M 1 is -C(O)O-. In some embodiments, M 1 is -C(O)N(R)- (e.g., -C(O)N(H)- or –C(O)N(CH3)-).
  • M 1 is -N(R)C(O)- (e.g., -N(H)C(O)- or – N(CH3)C(O)-).
  • a variable is a covalent bond, and as those of ordinary skill in the art appreciate, it can be properly considered as absent.
  • M 1 is bonded to PBM.
  • M 2 is –CH2-, –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • M 2 is absent. In some embodiments, M 2 is –CH 2 -. In some embodiments, M 2 is –O-. In some embodiments, M 2 is -N(R)- (e.g., -N(H)- or –N(CH 3 )- ). In some embodiments, M 2 is -C(O)-. In some embodiments, M 2 is -OC(O)-. In some embodiments, M 2 is - C(O)O-. In some embodiments, M 2 is -C(O)N(R)- (e.g., -C(O)N(H)- or –C(O)N(CH 3 )-.
  • M 2 is -N(R)C(O)- (e.g., -N(H)C(O)- or –N(CH 3 )C(O)-). In some embodiments, M 2 is bonded to LBM. [00201] In some embodiments of any Formulae described herein, L 6 is a covalent bond.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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)-, or -N(R)C(O)-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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)-, or - N(R)C(O)-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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)-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by –O-. [00206] In some embodiments, L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain. In some embodiments, L 6 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 10 hydrocarbon chain.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain. In some embodiments, L 6 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 6 hydrocarbon chain. [00207] In some embodiments, L 6 is optionally substituted -CH 2 -. In some embodiments, L 6 is -CH 2 -. In some embodiments, L 6 is -C(O)-. In some embodiments, L 6 is bonded to PBM. [00208] In some embodiments of any Formulae described herein, L 7 is a covalent bond.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 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-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 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-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 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)-, or -N(R)C(O)-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 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)-, or - N(R)C(O)-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 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)-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by – . [00213] In some embodiments, L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C 10 hydrocarbon chain. In some embodiments, L 7 is an optionally substituted, bivalent, straight or branched, saturated C1-C 10 hydrocarbon chain.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain. In some embodiments, L 7 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 6 hydrocarbon chain. [00214] In some embodiments, L 7 is bonded to LBM. [00215] In some embodiments of any Formulae described herein, both L 6 and L 7 are a covalent bond. [00216] In some embodiments of any Formulae described herein, L 8 is a covalent bond.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 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-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 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-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 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-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 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)-, or -N(R)C(O)-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 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)-, or - N(R)C(O)-.
  • L 8 is 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)-.
  • L 8 is 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-.
  • L 8 is 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, L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain, wherein at least two methylene units are replaced by –O-. [00221] In some embodiments, L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15 hydrocarbon chain. In some embodiments, L 8 is an optionally substituted, bivalent, straight or branched, saturated C1-C15 hydrocarbon chain.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain. In some embodiments, L 8 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 6 hydrocarbon chain.
  • linker is selected from: , , [00223]
  • 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 sp 3 C, 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.
  • the number of bonds between two non-ring sp 3 atom 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 in in some embodiments, it is 1 (e.g., as in .
  • linkers can provide increased conformational rigidity, and/or can provide various benefits and advantages.
  • rings are monocyclic or bicyclic, in many cases spiro-bicyclic, and each monocyclic ring unit is independently about 3-, 4-, 5- or 6-membered.
  • rings independently contain 1, 2, or 3 heteroatoms.
  • one or more heteroatoms are nitrogen.
  • each heteroatom is nitrogen.
  • linker comprises one or more basic nitrogen atoms, e.g., in its shortest path chain.
  • linker is In some embodiments, linker is . In some embodiments, linker is . In some embodiments, linker is . In some embodiments, linker is . In some embodiments, linker is . In some embodiments, linker is O .
  • linker is . In some embodiments, linker is . In some embodiments, linker is . In some embodiments, linker is O . In some embodiments, linker is . In some embodiments, 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. [00224] In some embodiments of any Formulae described herein, linker is not: .
  • 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.
  • 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.
  • 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.
  • Cy is optionally substituted phenyl.
  • Cy is phenyl.
  • Cy is not phenyl.
  • Cy is optionally substituted C 9-10 bicyclic aryl.
  • Cy is optionally substituted C 13-16 polycyclic aryl.
  • Cy is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted triazole.
  • Cy is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted pyridine, pyridazine, or pyrimidine.
  • 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. [00230] In some embodiments, Cy is an optionally substituted monocyclic C3-7 cycloaliphatic. In some embodiments, Cy is an optionally substituted monocyclic C3-7 cycloalkyl.
  • Cy is an optionally substituted monocyclic C4-6 cycloalkyl (e.g., cyclobutane, cyclopentane, or cyclohexane).
  • Cy is an optionally substituted 5- to 10-membered bicyclic cycloaliphatic.
  • Cy is an optionally substituted 6- to 10-membered bicyclic cycloaliphatic.
  • Cy is an optionally substituted bicyclic 6- to 10-membered bridged, fused, or spirocyclic cycloaliphatic.
  • 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.
  • 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. [00233] 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.
  • 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.
  • Cy is an optionally substituted bicyclic 8-membered spirocyclic heterocyclyl having 1-3 heteroatoms 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.
  • Cy is an optionally substituted group selected from , , , , , , some embodiments, Cy is selected e embodiments, Cy is an optionally substituted bicyclic 10- to 16-membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S.
  • -Cy- is spiro-bicyclic.
  • -Cy- is optionally substituted spiro-bicyclic diamine.
  • -Cy- is optionally substituted spiro-bicyclic diamine boned to the rest of a compound at the two amino groups.
  • 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-. [00235] Rings are utilized in many formulae and compounds of the present disclosure.
  • each monocyclic ring unit in a ring 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.
  • each monocyclic ring unit is independently 3-8 membered.
  • each monocyclic ring unit is independently 3-6 membered.
  • each monocyclic ring unit is independently 5-6 membered.
  • 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.
  • 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.
  • R’ is hydrogen.
  • R’ is -R as described herein.
  • R’ is ⁇ C(O)R wherein 5 ⁇ LV ⁇ DV ⁇ GHVFULEHG ⁇ KHUHLQ ⁇ ,Q ⁇ VRPH ⁇ HPERGLPHQWV ⁇ 5 ⁇ LV ⁇ & ⁇ 2 ⁇ 25 ⁇ ZKHUHLQ ⁇ 5 ⁇ LV ⁇ DV ⁇ GHVFULEHG ⁇ KHUHLQ ⁇ ,Q ⁇ VRPH ⁇ HPERGLPHQWV ⁇ 5 ⁇ LV ⁇ 6 ⁇ 2 ⁇ 2 R wherein R is as described herein.
  • 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.
  • 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.
  • 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 addition to the atom, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms.
  • a formed ring is substituted (in addition to groups attached to the intervening atom(s)).
  • a formed ring is unsubstituted.
  • a formed ring is 3-membered.
  • a formed ring is 4-membered.
  • 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.
  • 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.
  • 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.
  • each monocyclic ring unit is independently 3-7 membered.
  • 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.
  • an additional heteroatom is nitrogen.
  • an additional heteroatom is oxygen.
  • an additional heteroatom is sulfur.
  • R is optionally substituted C 1-8 (e.g., C 1-7 , C 1-6 , C 1-5 , C 1-4 , C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 ) aliphatic.
  • R is optionally substituted C 1-6 aliphatic.
  • R is optionally substituted C 1-6 alkyl.
  • R is optionally substituted methyl.
  • R is optionally substituted ethyl.
  • 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.
  • R is optionally substituted C 1-8 (e.g., C 1-7 , C 1-6 , C 1-5 , C 1-4 , C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 ) heteroaliphatic having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, and S.
  • R is optionally substituted C 1-6 heteroaliphatic having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, and S.
  • a heteroatom is nitrogen.
  • a heteroatom is oxygen.
  • a heteroatom is sulfur.
  • R is optionally substituted C 3-10 (e.g., C 4-10 , C 3-9 , C 3-7 , or 3, 4, 5, 6, 7, 8, 9, or 10-membered) cycloaliphatic.
  • a cycloaliphatic group is a cycloalkyl group.
  • 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.
  • a cycloaliphatic group is saturated. In some embodiments, it is partially unsaturated.
  • 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.
  • R is cycloheptyl.
  • 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.
  • 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.
  • 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.
  • 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. [00244] In some embodiments, R is optionally substituted C 6-10 (e.g., C 6 or C 10 ) aryl. In some embodiments, R is optionally substituted C 6 aryl. In some embodiments, R is optionally substituted C 10 aryl. In some embodiments, an aryl ring is monocyclic. In some embodiments, an aryl ring is bicyclic.
  • 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.
  • 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.
  • 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.
  • a heteroaryl ring is monocyclic.
  • a heteroaryl ring is bicyclic.
  • a heteroaryl ring is polycyclic.
  • 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.
  • R is optionally substituted 5-membered monocyclic heteroaryl having 1- 4 heteroatoms independently selected from N, O, and S.
  • R is optionally substituted 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • R is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • R is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • a heteroaryl ring has one heteroatom.
  • a heteroaryl ring has two or more heteroatoms.
  • a heteroaryl ring has three or more heteroatoms.
  • a heteroaryl ring has four or more heteroatoms.
  • a heteroatom is nitrogen.
  • a heteroatom is oxygen.
  • a heteroatom is sulfur.
  • 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).
  • each R is C1-2 alkyl (e.g., methyl).
  • R is optionally substituted phenyl.
  • R is optionally substituted C3-7 cycloaliphatic.
  • R is optionally substituted C3-7 cycloalkyl (e.g., cyclopropyl).
  • R is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • R is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • 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. [00247] 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 in accordance with the present disclosure. In some embodiments, an optionally substituted group is unsubstituted.
  • an optionally substituted group is substituted.
  • substituents are those that result in the formation of compounds for a desired property, activity, use, etc., as described herein.
  • compounds are stable for therapeutic use as described herein.
  • stable 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.
  • a substituent is a hydrocarbon group.
  • a substituent comprises a heteroatom.
  • a substituent comprises multiple heteroatoms.
  • 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.
  • 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
  • each optional substituent on a substitutable group is independently halogen, C 1-4 DON ⁇ O ⁇ 2+ ⁇ &1 ⁇ 12 2 , C 1-4 KDORDON ⁇ O ⁇ H ⁇ J ⁇ &) 3 ⁇ 25 SB ⁇ N(R SB ) 2 ⁇ & ⁇ 2 ⁇ 25 SB ⁇ & ⁇ 2 ⁇ 1 ⁇ 5 SB ) 2 ⁇ RU ⁇ 6 ⁇ 2 ⁇ 2 N(R SB ) 2 wherein each R SB LV ⁇ LQGHSHQGHQWO ⁇ + ⁇ & 1-4 alkyl or C 1- 4 haloalkyl.
  • each optional substituent on a substitutable group is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, or –OH.
  • each optional substituent on a substitutable group is independently halogen or C 1-4 alkyl.
  • many substituents are exemplified in compounds described herein, e.g., in Table 1.
  • linker is attached to the bracketed moiety at one of R d , R e , R f , or R g , or linker is attached to the bracketed moiety at one R i or the ring formed when two R i groups are taken together. In some embodiments, linker is attached to the bracketed moiety at one of R d , R e , R f , or R g . In some embodiments, linker is attached to the bracketed moiety at one R i or the ring formed when two R i groups are taken together.
  • 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 [00249] In some embodiments, LBM is . In some embodiments, LBM is s . In some embodiments, LBM is . In s ( ) some embodiments, LBM is In some embodiments, LBM is .
  • LBM is an E3 ubiquitin ligase binding moiety, i.e., is a moiety that is capable of binding an E3 ubiquitin ligase.
  • an LBM is considered 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.
  • 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).
  • 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 K D toward 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).
  • 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.
  • E3 ubiquitin ligase including cereblon, Von Hippel-Lindau protein, Inhibitor of Apoptosis protein, MDM2, RNF114, DCAF16, DCAF15, KEAP1, FEM1B, Arylhydrocarbon Receptor, etc.
  • 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,
  • 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.
  • LBM has the following structure , wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination.
  • LBM has the following structure , wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination.
  • LBM has the following structure , wherein the variables are as defined and described in classes and subclasses herein, both singly and in combination.
  • 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 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 heteroatoms independently selected from N, O, and S.
  • 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, L 2 is a covalent bond. In some embodiments, L 2 is -NH-.
  • L 2 is -O-. In some embodiments, L 2 is –C(O)-NH- wherein -C(O)- is bonded to Ring C. In some embodiments, L 2 is –C(O)-NH- wherein -NH- is bonded to Ring C. In some embodiments, L 2 is 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 L 2 is bonded to the atom to which linker is bonded, there is one atom between the atom to with L 2 is bonded and the atom to which linker is bonded.
  • LBM is optionally substituted , , is , , , , ,
  • a LBM is a cereblon (CRBN) binding moiety, i.e., is a moiety that is capable of binding cereblon.
  • a LBM has the following structure: wherein R b , R c , 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.
  • a LBM has the following structure: wherein R b , R c , and m are as defined herein for Formula IIIA and described in classes and subclasses herein, both singly and in combination. [00254] In some embodiments of any Formulae described herein, a LBM is selected from: . [00255] In some embodiments of any Formulae described herein, a LBM has the following structure: wherein B, L 2 , R c , Y, and m are as defined herein for Formula IIIC and described in classes and subclasses herein, 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.
  • a LBM has the following structure: wherein B, L 2 , R c , Y, and m are as defined herein for Formula IIIC and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: wherein B, L 2 , R c , Y, and m are as defined herein for Formula IIIC and described in classes and subclasses herein, both singly and in combination.
  • a LBM is selected from: wherein B, L 2 , R c , and m are as defined herein for Formula IIIC and described in classes and subclasses herein, both singly and in combination. [00259] In some embodiments of any Formulae described herein, a LBM is selected from: , ,
  • a LBM is selected from: O [00261]
  • R a is halogen (e.g., -F, -Cl or -Br).
  • R a is -CN.
  • R a is -R’ as described herein.
  • R a is -R as described herein.
  • R a is -R but is not hydrogen.
  • each R a is independently hydrogen or optionally substituted C 1-6 aliphatic.
  • each R a is independently hydrogen or optionally substituted C1-6 alkyl.
  • each R a is independently hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl. In some embodiments, each R a is independently is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, or C 6-10 aryl. In some embodiments, each R a is 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.
  • each R a is 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.
  • each R a is hydrogen.
  • R a is hydrogen.
  • R a is optionally substituted C1-6 aliphatic.
  • R a is optionally substituted C1-6 alkyl.
  • R a is C1-6 alkyl.
  • R a is optionally substituted C1-2 alkyl. In some embodiments, R a is C1-2 alkyl (e.g., methyl). In some embodiments, R a is optionally substituted C3-6 cycloaliphatic. In some embodiments, R a is optionally substituted C3-6 cycloalkyl. In some embodiments, R a is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R a is C6-10 aryl. In some embodiments, R a is phenyl. In some embodiments, R a is naphthyl.
  • R a is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R a is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R a is 3- to 10-membered monocyclic heterocyclyl having 1- 5 heteroatoms independently selected from N, O, and S. In some embodiments, R a is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00262] In some embodiments, two R a groups are each -R’ which are taken together with the atom to which they are attached to form an optionally substituted ring as described herein.
  • two R a groups, 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).
  • two R a groups, 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).
  • two R a groups 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).
  • Y is N.
  • Y is CH.
  • L 2 is a covalent bond.
  • L 2 is a covalent bond or an optionally substituted straight or branched C1-3 hydrocarbon chain. In some embodiments, L 2 is a covalent bond or a straight or branched C1-3 hydrocarbon chain. In some embodiments, L 2 is 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, L 2 is a covalent bond.
  • L 2 is 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)-.
  • L 2 is 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)-.
  • L 2 is 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)-.
  • L 2 is 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)-.
  • L 2 is a covalent bond, -CH2-, –O-, or -N(R)-.
  • L 2 is –CH2-. In some embodiments, L 2 is –CH2-, -O-, or –N(R)-. In some embodiments, L 2 is –CH2-, -O-, or – N(H)-. In some embodiments, L 2 is –O- or –S-. In some embodiments, L 2 is –O-. In some embodiments, L 2 is -S-. In some embodiments, L 2 is –N(R)-. In some embodiments, L 2 is –N(H)-. In some embodiments, L 2 is – SO2-. In some embodiments, -C(O)N(R)-, or -N(R)C(O)-.
  • L 2 is –C(O)N(R)-. In some embodiments, L 2 is –N(R)C(O)-. In some embodiments, L 2 is -C(O)NH-. In some embodiments, L 2 is - NHC(O)-. In some embodiments, L 2 is -S(O)-. In some embodiments, L 2 is -S(O)N(R)-. In some embodiments, L 2 is -N(R)S(O)-. In some embodiments, L 2 is -S(O)NH-. In some embodiments, L 2 is -NHS(O)-. In some embodiments, L 2 is -S(O)2-.
  • L 2 is -N(R)S(O)2-. In some embodiments, L 2 is -S(O)2N(R)- . In some embodiments, L 2 is -NHS(O)2-. In some embodiments, L 2 is -S(O)2NH-. In some embodiments, L 2 is -Cy- as described herein. In some embodiments, L 2 is -Cy- wherein -Cy- is aromatic. [00265] In some embodiments, Ring E is . In some embodiments, Ring E is . In some embodiments, Ring E is . [00266] In some embodiments, Ring E is optionally substituted . In some embodiments, Ring E is O .
  • Ring E is optionally substituted . In some embodiments, Ring E is . In some embodiments, Ring E is optionally substituted In 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 L 2 or Ring C.
  • stereochemical purity of a compound in a composition with respect to the carbon center at which Ring E is bonded to L 2 or 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%.
  • Ring E is optionally substituted . In some embodiments, Ring E is .
  • 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.
  • Ring C is an optionally substituted group selected from phenyl, C 5-6 cycloaliphatic, 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.
  • 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.
  • 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.
  • 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.
  • Ring C is optionally substituted phenyl ring.
  • Ring C is a phenyl ring.
  • Ring C is optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • 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. [00271] In some embodiments, Ring C is optionally substituted C3-C7 cycloaliphatic.
  • 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. [00272] 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.
  • 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. [00273] 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.
  • 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.
  • Ring C is optionally substituted phthalimide or isoindolin-1-one.
  • Ring C is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Ring C is optionally substituted some embodiments, the carbon atom is bonded to linker.
  • Ring C is optionally substituted some embodiments, Ring C is . In some embodiments, the carbon atom in the phenyl ring is bonded to linker. [00274] 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).
  • Ring wherein: each A is independently N, C, or CH, provided that no more than two A groups are N; each R b is hydrogen, or two R b groups, 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 R c is independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; m is 0, 1, 2, or 3. [00276] In some embodiments, Ring . [00277] .
  • Ring C wherein: each B is independently selected from N, C, and CH, provided that no more than two B are N; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • Ring C is optionally substituted . In some embodiments, Ring C is optionally substituted .
  • Ring C is . In some embodiments, Ring C is optionally substituted . In some embodiments, Ring C is . [00282] In some embodiments, Ring C has a substituent at a position next to the position (e.g., o for a phenyl ring) bonded to L 2 (as those skilled in the art appreciate, Ring E when L 2 is a covalent bond).
  • a substituent at a position next to the position bonded to L 2 e.g., R b , R b1 , or R c
  • R is -OR, -R or halogen. In some embodiments, it is -OR wherein R is as described herein.
  • it is -OR wherein R is optionally substituted C 1-4 aliphatic. In some embodiments, it is -OR wherein R is optionally substituted C 1-4 alkyl. In some embodiments, it is -OR wherein R is C 1-4 aliphatic. In some embodiments, it is -OR wherein R is C 1-4 alkyl. In some embodiments, it is -OR wherein R is C 1-4 haloalkyl. In some embodiments, it is -OCF 3 . 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.
  • it is optionally substituted C1-4 alkyl. In some embodiments, it is C 1-4 aliphatic. In some embodiments, it is C 1-4 alkyl. In some embodiments, it is C 1-4 haloalkyl. In some embodiments, it is methyl. In some embodiments, it is -CF 3 . 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 L 2 .
  • 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 L 2 (as those skilled in the art appreciate, Ring E when L 2 is a covalent bond).
  • Ring C is , wherein the carbon atom marked with * is bonded to L 2 .
  • R b1 is not hydrogen.
  • compounds comprising such Ring C can selectively degrade KAT2A over KAT2B (e.g., DC 50 for KAT2A is smaller than that for KAT2B when assessed, e.g., as in the Examples such as Example B1).
  • Ring C is selected from: , , , , , , , , , , , , , , , , , , ,
  • Ring C is selected from:
  • Ring F is an optionally substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S.
  • Ring F is an optionally substituted 4- to 10-membered bivalent ring system having 0-4 heteroatoms independently selected from N, O, and S.
  • Ring F is an optionally substituted 5- to 6- membered bivalent ring system having 0-3 heteroatoms independently selected from N, O, and S.
  • Ring F is an optionally substituted 6-membered bivalent ring system having 0-2 heteroatoms independently selected from N, O, and S.
  • Ring F is an optionally substituted phenyl.
  • each A is CH.
  • one A is N and the other A groups are CH.
  • two A groups are N, and the other A groups are CH.
  • R c as defined herein, such that the ring contains a –C(R c )- moiety.
  • A is C, when it is the point of attachment to the rest of the molecule.
  • R b is R’ as described herein.
  • R b is -R as described herein.
  • R b is -R but not hydrogen.
  • R b is -OR wherein R is as described herein. In some embodiments of any Formulae described herein, each R b is hydrogen. In some embodiments of any Formulae described herein, each R b is independently halogen, -CN, -R or -OR. In some embodiments, each R b is independently hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, each R b is independently hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, each R b is independently is hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl.
  • each R b is 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.
  • each R b is 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.
  • each R b is independently hydrogen.
  • R b is halogen. In some embodiments, R b is fluoro. In some embodiments, R b is chloro. In some embodiments, R b is bromo. In some embodiments, R b is optionally substituted C1-6 aliphatic. In some embodiments, R b is optionally substituted C1-6 alkyl. In some embodiments, R b is C1-2 alkyl (e.g., methyl). In some embodiments, R b is optionally substituted C3-6 cycloaliphatic. In some embodiments, R b is optionally substituted C3-6 cycloalkyl. In some embodiments, R b is C3-4 cycloalkyl (e.g., cyclopropyl).
  • R b is C6-10 aryl. In some embodiments, R b is phenyl. In some embodiments, R b is naphthyl. In some embodiments, R b is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R b is 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R b is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R b is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • two R b groups, on the same carbon are taken together to form an oxo.
  • two R b groups, on the same carbon combine to form a 3- to 6-membered saturated or partially unsaturated ring (e.g., a C 3-6 cycloaliphatic or 3- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S).
  • two R b groups, on the same carbon combine to form C 3-6 cycloalkyl (e.g., cyclopropyl).
  • R b1 is R b as described herein. In some embodiments, R b1 is not hydrogen. In some embodiments, it is -OR wherein R is as described herein. In some embodiments, it is -OR wherein R is optionally substituted C 1-4 aliphatic. In some embodiments, it is -OR wherein R is optionally substituted C 1- 4 alkyl. In some embodiments, it is -OR wherein R is C 1-4 aliphatic.
  • R is C 1-4 alkyl. In some embodiments, it is -OR wherein R is C 1-4 haloalkyl. In some embodiments, it is -OCF 3 . 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 C 1-4 aliphatic. In some embodiments, it is C 1-4 alkyl. In some embodiments, it is C 1-4 haloalkyl. In some embodiments, it is methyl. In some embodiments, it is -CF 3 .
  • each B is CH, C-R c , 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.
  • each R c is 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.
  • each R c is 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 R c is independently selected from halogen, -O(C1-6 alkyl), -O(C1-6 haloalkyl), C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R c is independently selected from halogen, -O(C1-6 alkyl), C1-6 alkyl, and C1-6 haloalkyl.
  • each R c is independently selected from halogen, -O(C1-6 alkyl), and C1-6 alkyl.
  • R c is halogen (e.g., fluoro or chloro).
  • R c is –OR (e.g., -OH, - O(C1-6 alkyl), or -O(C1-6 haloalkyl)).
  • R c is –OCH3 or –OCF3.
  • R c is -N(R)2 (e.g., -NH2, NH(C1-6 alkyl), or -N(C1-6 alkyl)2).
  • R c is –CN.
  • R c is optionally substituted C1-6 aliphatic. In some embodiments, R c is optionally substituted C1- 6 alkyl. In some embodiments, R c is C1-6 alkyl optionally substituted with one or more halogen. In some embodiments, R c is C 1-6 alkyl. In some embodiments, R c is optionally substituted C 1-2 alkyl. In some embodiments, R c is optionally substituted C 1-2 alkyl optionally substituted with one or more halogen. In some embodiments, R c is C 1-2 alkyl (e.g., methyl). In some embodiments, R c is C 1-6 haloalkyl.
  • R c is C 1-2 haloalkyl (e.g., -CF 3 ).
  • m is 0, 1, or 2.
  • m is 0 or 1.
  • m is 0.
  • m is 1.
  • m is 2.
  • m is 3.
  • 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.
  • VHL Von Hippel-Lindau protein
  • LBM has the following structure: , wherein R d , R e , R f , R g , R h , and p are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.
  • a LBM is selected from: .
  • R d , R e , R f , R g , R h , and p are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: .
  • R d , R e , R f , R g , R h , and p are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: .
  • R d , R e , R f , R g , R h , and p are as defined herein for Formula IV and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: .
  • a LBM moiety e.g., VHL binding moiety
  • a LBM moiety is attached to linker at a R d .
  • a LBM moiety e.g., VHL binding moiety
  • a LBM moiety is attached to linker at R f .
  • a LBM moiety e.g., VHL binding moiety
  • a R g ., VHL binding moiety is attached to linker at a R g .
  • R d is -R’ as described herein. In some embodiments, R d is -R as described herein. In some embodiments, R d is -R but is not hydrogen. In some embodiments of any Formulae described herein, each R d that is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6 aliphatic.
  • each R d is 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.
  • R d is hydrogen.
  • R d is –C(O)R.
  • R d is –C(O)(optionally substituted C1-6 alkyl).
  • R d is –C(O)(optionally substituted C3-6 cycloalkyl).
  • R d is optionally substituted C1-6 aliphatic. In some embodiments, R d is optionally substituted C1-6 alkyl. In some embodiments, R d is C1-6 alkyl. In some embodiments, R d is optionally substituted C1-2 alkyl. In some embodiments, R d is C1-2 alkyl (e.g., methyl). In some embodiments, each R d is optionally substituted C3-6 cycloaliphatic. In some embodiments, each R d is optionally substituted C3-6 cycloalkyl. In some embodiments, each R d is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, each R d is -C(O)R.
  • each R d is -C(O)(C1-6 alkyl). In some embodiments, each R d is -S(O)2R. In some embodiments, each R d is -S(O)2(C1-6 alkyl). In some embodiments, each R d is 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. [00302] In some embodiments, two R d are each R’ and the two R’ are taken together with the nitrogen to which they are bonded to form a ring as described herein.
  • two R d 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.
  • two R d 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.
  • two R d 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.
  • R e is -R as described herein. In some embodiments, R e is -R but is not hydrogen. In some embodiments of any Formulae described herein, each R e that is not the point of attachment for the linker is independently hydrogen or optionally substituted C 1-6 alkyl.
  • each R e is optionally substituted C 1-6 aliphatic. In some embodiments, each R e is optionally substituted C 1-6 alkyl (e.g., methyl). In some embodiments, R e is hydrogen. In some embodiments, R e is optionally substituted C 1-6 aliphatic. In some embodiments, R e is optionally substituted C 1-6 alkyl. In some embodiments, R e is C 1-6 alkyl. In some embodiments, R e is optionally substituted C 1-2 alkyl. In some embodiments, R e is C 1-2 alkyl (e.g., methyl).
  • each R e that is not the point of attachment for the linker is independently -R.
  • each R e is independently hydrogen, halogen, or optionally substituted C 1-6 aliphatic.
  • each R e is independently hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • each R e is independently is hydrogen, halogen, -CN, C 1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl.
  • each R e is 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.
  • each R e is 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.
  • R e is halogen.
  • R e is fluoro. In some embodiments, R e is chloro. In some embodiments, R e is bromo. In some embodiments, R e is optionally substituted C1-6 alkyl. In some embodiments, R e is C1-2 alkyl (e.g., methyl). In some embodiments, R e is optionally substituted C3-6 cycloaliphatic. In some embodiments, R e is optionally substituted C3-6 cycloalkyl. In some embodiments, R e is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R e is C6-10 aryl. In some embodiments, R e is phenyl.
  • R e is naphthyl. In some embodiments, R e is 5- to 10- membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R e is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R e is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R e is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00304] In some embodiments, R f is -R as described herein.
  • R f is -R but is not hydrogen. In some embodiments of any Formulae described herein, R f , when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6 alkyl. In some embodiments, R f is hydrogen. In some embodiments, R f is optionally substituted C1-6 aliphatic. In some embodiments, R f is optionally substituted C1- 6 alkyl. In some embodiments, R f is C 1-6 alkyl. In some embodiments, R f is optionally substituted C 1-2 alkyl. In some embodiments, R f is C 1-2 alkyl (e.g., methyl).
  • R f when it is not the point of attachment for the linker, is -R.
  • each R f is independently hydrogen, halogen, or optionally substituted C 1-6 aliphatic.
  • each R f is independently hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • each R f is independently is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, or C 6-10 aryl.
  • each R f is independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S.
  • each R f is independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 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.
  • R f is halogen.
  • R f is fluoro. In some embodiments, R f is chloro. In some embodiments, R f is bromo. In some embodiments, R f is optionally substituted C 1-6 aliphatic. In some embodiments, R f is C 1-2 alkyl (e.g., methyl). In some embodiments, R f is optionally substituted C3-6 cycloaliphatic. In some embodiments, R f is optionally substituted C 3-6 cycloalkyl. In some embodiments, R f is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R f is C 6-10 aryl. In some embodiments, R f is phenyl.
  • R f is naphthyl. In some embodiments, R f is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R f is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R f is 3- to 10-membered monocyclic heterocyclyl having 1- 5 heteroatoms independently selected from N, O, and S. In some embodiments, R f is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00305] In some embodiments, R g is -R as described herein.
  • R g is -R but is not hydrogen. In some embodiments, R g is -OR wherein R is as described herein. In some embodiments of any Formulae described herein, each R g that is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6 alkyl. In some embodiments, R g is halogen (e.g., fluoro or chloro). In some embodiments, R g is –OR (e.g., -OH or –O(C1-6 alkyl)). In some embodiments, R g is –CN. In some embodiments, R g is optionally substituted C1-6 aliphatic.
  • R g is optionally substituted C1- 6 alkyl. In some embodiments, R g is C1-6 alkyl. In some embodiments, R g is optionally substituted C1-2 alkyl. In some embodiments, R g is C1-2 alkyl (e.g., methyl).
  • each R g that is not the point of attachment for the linker is independently halogen, -CN, R or -OR. In some embodiments, each R g is independently hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, each R g is independently hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl.
  • each R g is independently is hydrogen, halogen, -CN, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, each R g is 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.
  • each R g is 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.
  • each R g is independently hydrogen.
  • R g is halogen.
  • R g is fluoro.
  • R g is chloro.
  • R g is bromo.
  • R g is -CN.
  • R g is optionally substituted C 1-6 aliphatic. In some embodiments, R g is optionally substituted C 1-6 alkyl. In some embodiments, R g is C 1-2 alkyl (e.g., methyl). In some embodiments, R g is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R g is optionally substituted C 3-6 cycloalkyl. In some embodiments, R g is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R g is C 6-10 aryl. In some embodiments, R g is phenyl. In some embodiments, R g is naphthyl.
  • R g is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R g is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R g is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R g is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00306] In some embodiments, R h is -R as described herein. In some embodiments, R h is -R but is not hydrogen.
  • R h is hydrogen, halogen, or optionally substituted C1-6 alkyl. In some embodiments, R h is hydrogen. In some embodiments, R h is halogen (e.g., fluoro or chloro). In some embodiments, R h is optionally substituted C1-6 aliphatic. In some embodiments, R h is optionally substituted C1-6 alkyl. In some embodiments, R h is C1-6 alkyl. In some embodiments, R h is optionally substituted C1-2 alkyl. In some embodiments, R h is C1-2 alkyl (e.g., methyl). In some embodiments of any Formulae described herein, R h is hydrogen, halogen, or -R.
  • each R h is independently hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, each R h is independently hydrogen, halogen, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, each R h is independently is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, each R h is 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.
  • each R h is independently hydrogen, halogen, 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.
  • R h is halogen.
  • R h is fluoro.
  • R h is chloro.
  • R h is bromo.
  • R h is optionally substituted C1-6 aliphatic.
  • R h is optionally substituted C3-6 cycloaliphatic.
  • R h is optionally substituted C3-6 cycloalkyl. In some embodiments, R h is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R h is C6-10 aryl. In some embodiments, R h is phenyl. In some embodiments, R h is naphthyl. In some embodiments, R h is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R h is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S.
  • R h is 3- to 10- membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R h is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00307] In some embodiments of any Formulae described herein, p is 0, 1, or 2. In some embodiments of any Formulae described herein, p is 0, 1, 2, or 3. In some embodiments, p is 0 or 1. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.
  • a LBM is an Inhibitor of Apoptosis protein (IAP) binding moiety, i.e., is a moiety that is capable of binding Inhibitor of Apoptosis protein.
  • IAP Apoptosis protein
  • a LBM has the following structure: , wherein R i , R j , R k , r, and q are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination.
  • a LBM is selected from: , wherein R i , R j , R k , r, and q are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Ring D is the ring formed when two R i groups, together with the atoms to which they are attached, combine.
  • a LBM has the following structure: , wherein R i , R j , R k , r, and q are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination.
  • a LBM is selected from: , wherein R i , R j , R k , r, and q are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Ring D is the ring formed when two R i groups, together with the atoms to which they are attached, combine.
  • a LBM has the following structure: , wherein R, R i , R j , R k , r, and q are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: , wherein R, R j , and R k are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination. [00315] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein R m , R n , and s are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: , wherein R m , R n , and s are as defined herein for Formula VI and described in classes and subclasses herein, both singly and in combination.
  • a LBM moiety e.g., IAP binding moiety
  • a LBM moiety is attached to linker at a R i .
  • a LBM moiety e.g., IAP binding moiety
  • R i is -R as described herein. In some embodiments, R i is -R but is not hydrogen. In some embodiments of any Formulae described herein, each R i that is not the point of attachment of the linker is independently halogen, optionally substituted C 1-6 aliphatic, -C(O)N(R) 2 , or -N(R)C(O)R. In some embodiments, each R i is -R. In some embodiments, R i is halogen (e.g., fluoro or chloro). In some embodiments, R i is optionally substituted C 1-6 aliphatic. In some embodiments, R i is optionally substituted C 1- 6 alkyl.
  • R i is C 1-6 alkyl. In some embodiments, R i is optionally substituted C 1-2 alkyl. In some embodiments, R i is C 1-2 alkyl (e.g., methyl). In some embodiments, R i is -C(O)N(R) 2 . In some embodiments, at least one R i is -C(O)N(R) 2 . In some embodiments, R i is -N(R)C(O)R. In some embodiments, two R i groups, 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.
  • two R i groups, together with the atoms to which they are attached combine to form an optionally substituted phenyl. In some embodiments, two R i groups, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. [00319]
  • R j is -R as described herein. In some embodiments, R j is -R but is not hydrogen. In some embodiments of any Formulae described herein, R j is an optionally substituted group selected from C 1-6 aliphatic and C 3-7 cycloaliphatic.
  • R j is optionally substituted C 1-6 aliphatic. In some embodiments, R j is optionally substituted C 1-6 alkyl. In some embodiments, R j is C 1-6 alkyl (e.g., tert-butyl or isopropyl). In some embodiments, R j is optionally substituted C1-2 alkyl. In some embodiments, R j is C1-2 alkyl (e.g., methyl). In some embodiments, R j is optionally substituted C3-7 cycloaliphatic. In some embodiments, R j is optionally substituted C3-7 cycloalkyl.
  • R j is C3-7 cycloalkyl (e.g., cyclohexyl). In some embodiments, R j combines with one instance of R i , 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. In some embodiments of any Formulae described herein, R j is -R. In some embodiments, R j is hydrogen, or optionally substituted C1-6 aliphatic. In some embodiments, R j is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl.
  • R j is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, R j is hydrogen, 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, R j is hydrogen, 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, R j is hydrogen.
  • R j is optionally substituted C1-6 aliphatic. In some embodiments, R j is optionally substituted C1- 6 alkyl. In some embodiments, R j is C1-2 alkyl (e.g., methyl). In some embodiments, R j is optionally substituted C3-6 cycloaliphatic. In some embodiments, R j is optionally substituted C3-6 cycloalkyl. In some embodiments, R j is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R j is C6-10 aryl. In some embodiments, R j is phenyl. In some embodiments, R j is naphthyl.
  • R j is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R j is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R j is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R j is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00320] In some embodiments, R k is -R as described herein. In some embodiments, R k is -R but is not hydrogen.
  • R k is an optionally substituted C 1-6 alkyl. In some embodiments, R k is C 1-6 alkyl. In some embodiments, R k is optionally substituted C 1-2 alkyl. In some embodiments, R k is C 1-2 alkyl (e.g., methyl). In some embodiments of any Formulae described herein, R k is - R. In some embodiments, R k is hydrogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R k is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • R k is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 6-10 aryl. In some embodiments, R k is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R k is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 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.
  • R k is hydrogen. In some embodiments, R k is optionally substituted C 1-6 aliphatic. In some embodiments, R k is optionally substituted C 1- 6 alkyl. In some embodiments, R k is C 1-2 alkyl (e.g., methyl). In some embodiments, R k is optionally substituted C3-6 cycloaliphatic. In some embodiments, R k is optionally substituted C3-6 cycloalkyl. In some embodiments, R k is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R k is C6-10 aryl. In some embodiments, R k is phenyl.
  • R k is naphthyl. In some embodiments, R k is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R k is 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R k is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R k is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00321] In some embodiments of any Formulae described herein, r is 1, 2, or 3.
  • r is 1 or 2. In some embodiments, r is 1, 2, 3, 4, or 5. In some embodiments, r is 0 or 1. In some embodiments, r is 1, 2, or 3. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. [00322] In some embodiments of any Formulae described herein, q is 1. In some embodiments, q is 2. [00323] In some embodiments, R m is -R as described herein. In some embodiments, R m is -R but is not hydrogen.
  • R m is optionally substituted C1-6 alkyl. In some embodiments, R m is C1-6 alkyl (e.g., isobutyl). In some embodiments, R m is optionally substituted C1-2 alkyl. In some embodiments, R m is C1-2 alkyl (e.g., methyl). In some embodiments of any Formulae described herein, R m is -R. In some embodiments, R m is hydrogen, or optionally substituted C1-6 aliphatic. In some embodiments, R m is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl.
  • R m is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C6-10 aryl. In some embodiments, R m is hydrogen, 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, R m is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 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.
  • R m is hydrogen. In some embodiments, R m is optionally substituted C 1-6 aliphatic. In some embodiments, R m is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R m is optionally substituted C 3-6 cycloalkyl. In some embodiments, R m is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R m is C 6-10 aryl. In some embodiments, R m is phenyl. In some embodiments, R m is naphthyl. In some embodiments, R m is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S.
  • R m is 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R m is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R m is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00324] In some embodiments, R n is -R as described herein. In some embodiments, R n is -R but is not hydrogen. In some embodiments, R n is -OR wherein R is as described herein.
  • each R n is independently halogen, -OR, -CN, or optionally substituted C 1-6 alkyl.
  • R n is –OR (e.g., -OH or –O(C1-6 alkyl)).
  • R n is halogen (e.g., fluoro or chloro).
  • R n is –OR.
  • R n is –CN.
  • R n is optionally substituted C1-6 aliphatic.
  • R n is optionally substituted C1-6 alkyl.
  • R n is C1-6 alkyl.
  • R n is optionally substituted C1-2 alkyl. In some embodiments, R n is C1-2 alkyl (e.g., methyl). [00325] In some embodiments of any Formulae described herein, each of R n , R p , R q , R r , R s , and R u is independently halogen, -CN, -R or -OR. In some embodiments, R n is -CN. In some embodiments, R n is -R. In some embodiments, R n is -OR. In some embodiments, R p is -CN. In some embodiments, R p is -R. In some embodiments, R p is -OR.
  • R q is -CN. In some embodiments, R q is -R. In some embodiments, R q is -OR. In some embodiments, R r is -CN. In some embodiments, R r is -R. In some embodiments, R r is -OR. In some embodiments, R s is -CN. In some embodiments, R s is -R. In some embodiments, R s is -OR. In some embodiments, R u is -CN. In some embodiments, R u is -R. In some embodiments, R u is -OR. [00326] In some embodiments of any Formulae described herein, s is 0, 1, or 2. In some embodiments, s is 1, 2, or 3.
  • s is 0, 1, 2, 3, 4, or 5. In some embodiments, s is 0 or 1. In some embodiments, s is 1, 2, or 3. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5. [00327] In some embodiments of any Formulae described herein, a LBM is a MDM2 binding moiety, i.e., is a moiety that is capable of binding MDM2.
  • a LBM has the following structure: , wherein R p , R q , R r , R s , u and t are as defined herein for Formula VII and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: , wherein R t , R u , R v , R w , and v are as defined herein for Formula VIII and described in classes and subclasses herein, both singly and in combination.
  • R p is -R as described herein.
  • R p is hydrogen. In some embodiments, R p is -R but is not hydrogen. In some embodiments, R p is -OR wherein R is as described herein. In some embodiments of any Formulae described herein, each R p is independently halogen, -OR, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R p is –OR (e.g., -OH or –O(C 1-6 alkyl)). In some embodiments, each R p is halogen (e.g., chloro). In some embodiments, R p is halogen (e.g., chloro or fluoro). In some embodiments, R p is –OR.
  • R p is –CN. In some embodiments, R p is optionally substituted C 1-6 aliphatic. In some embodiments, R p is optionally substituted C 1-6 alkyl. In some embodiments, R p is C1-6 alkyl. In some embodiments, R p is optionally substituted C1-2 alkyl. In some embodiments, R p is C1- 2 alkyl (e.g., methyl). [00331] In some embodiments, R q is -R as described herein. In some embodiments, R q is hydrogen. In some embodiments, R q is -R but is not hydrogen. In some embodiments, R q is -OR wherein R is as described herein.
  • each R q is independently halogen, -OR, -CN, or optionally substituted C1-6 alkyl.
  • each R q is –OR (e.g., -OH or –O(C1-6 alkyl)).
  • each R q is halogen (e.g., chloro).
  • R q is halogen (e.g., chloro or fluoro).
  • R q is –OR.
  • R q is –CN.
  • R q is optionally substituted C1-6 aliphatic.
  • R q is optionally substituted C1-6 alkyl.
  • R q is C1-6 alkyl. In some embodiments, R q is optionally substituted C1-2 alkyl. In some embodiments, R q is C1-2 alkyl (e.g., methyl). [00332] In some embodiments, R r is -R as described herein. In some embodiments, R r is -R but is not hydrogen. In some embodiments, R r is -OR wherein R is as described herein. In some embodiments, R r is halogen (e.g., -F, -Cl or -Br). In some embodiments, R r is -CN. In some embodiments of any Formulae described herein, each R r is independently hydrogen or optionally substituted C1-6 alkyl.
  • R r is hydrogen. In some embodiments, R r is optionally substituted C1-6 aliphatic. In some embodiments, R r is optionally substituted C1-6 alkyl. In some embodiments, R r is C1-6 alkyl. In some embodiments, R r is optionally substituted C1-2 alkyl. In some embodiments, R r is C1-2 alkyl (e.g., methyl). In some embodiments, each R r is methyl. [00333] In some embodiments, R s is -R as described herein. In some embodiments, R s is hydrogen. In some embodiments, R s is -R but is not hydrogen. In some embodiments, R s is -OR wherein R is as described herein.
  • R s is halogen (e.g., -F, -Cl or -Br). In some embodiments of any Formulae described herein, each R s is independently halogen, -OR, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, each R s is halogen (e.g., chloro). In some embodiments, R s is halogen (e.g., chloro or fluoro). In some embodiments, R s is –OR (e.g., -OH or –O(C1-6 alkyl)). In some embodiments, R s is –OR (e.g., -O(C1- 6 alkyl)).
  • R s is –CN. In some embodiments, R s is optionally substituted C 1-6 aliphatic. In some embodiments, R s is optionally substituted C 1-6 alkyl. In some embodiments, R s is C 1-6 alkyl (e.g., tert- butyl). In some embodiments, R s is optionally substituted C1-2 alkyl. In some embodiments, R s is C1-2 alkyl (e.g., methyl). [00334] In some embodiments of any Formulae described herein, t is 0, 1, or 2. In some embodiments, t is 0, 1, 2, 3, 4, or 5. In some embodiments, t is 0, 1, 2, 3, or 4. In some embodiments, t is 0 or 1.
  • t is 1, 2, or 3. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. [00335] In some embodiments of any Formulae described herein, each u is independently 0, 1, or 2. In some embodiments, each u is independently 1, 2, or 3. In some embodiments, each u is independently 0 or 1. In some embodiments, each u is independently 0, 1, 2, 3, 4, or 5. In some embodiments, u is 0 or 1. In some embodiments, u is 1, 2, or 3. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3.
  • R t is -R as described herein. In some embodiments, R t is -R but not hydrogen. In some embodiments of any Formulae described herein, each R t is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, R t is hydrogen. In some embodiments, R t is optionally substituted C1-6 aliphatic. In some embodiments, R t is optionally substituted C1-6 alkyl. In some embodiments, R t is C1-6 alkyl (e.g., tert-butyl or isobutyl). In some embodiments, R t is optionally substituted C1-2 alkyl.
  • R t is C1-2 alkyl (e.g., methyl). In some embodiments, at least one R t is optionally substituted C1-6 aliphatic. In some embodiments of any Formulae described herein, each R t is independently -R. In some embodiments, R t is hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, R t is hydrogen, halogen, -CN, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, R t is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, or C 6-10 aryl.
  • R t is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S.
  • R t is hydrogen, halogen, -CN, C 1-6 alkyl, C 3- 6 cycloalkyl, C 6-10 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.
  • R t is hydrogen.
  • R t is halogen.
  • R t is fluoro. In some embodiments, R t is chloro. In some embodiments, R t is bromo. In some embodiments, R t is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R t is optionally substituted C 3-6 cycloalkyl. In some embodiments, R t is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R t is C 6-10 aryl. In some embodiments, R t is phenyl. In some embodiments, R t is naphthyl.
  • R t is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R t is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R t is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R t is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • both R t groups, 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.
  • both R t groups, 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.
  • both R t groups, together with the atom to which they are attached combine to form an optionally substituted C3-7 cycloaliphatic (e.g., C3-7 cycloalkyl, such as cyclohexyl).
  • both R t groups together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S.
  • R u is -R as described herein.
  • R u is -R but not hydrogen.
  • R u is -OR wherein R is as described herein.
  • each R u is independently hydrogen, halogen, -CN, or optionally substituted C1-6 alkyl.
  • R u is hydrogen.
  • at least one R u is hydrogen.
  • R u is halogen (e.g., fluoro or chloro). In some embodiments, R u is –CN. In some embodiments, R u is optionally substituted C1-6 aliphatic. In some embodiments, R u is optionally substituted C1-6 alkyl. In some embodiments, R u is C1-6 alkyl. In some embodiments, R u is optionally substituted C1-2 alkyl. In some embodiments, R t is C1-2 alkyl (e.g., methyl). [00339] In some embodiments, R v is -R as described herein. In some embodiments, R v is -R but not hydrogen.
  • R v is -OR wherein R is as described herein. In some embodiments of any Formulae described herein, each R v is independently halogen, -OR, -CN, or optionally substituted C1-6 alkyl. In some embodiments, each R v is halogen (e.g., chloro). In some embodiments, R v is halogen (e.g., chloro or fluoro). In some embodiments, R v is –OR (e.g., -OH or –O(C 1-6 alkyl)). In some embodiments, R v is –OR (e.g., -O(C 1-6 alkyl)). In some embodiments, R v is –CN.
  • R v is optionally substituted C 1-6 aliphatic. In some embodiments, R v is optionally substituted C 1-6 alkyl. In some embodiments, R v is C 1-6 alkyl (e.g., tert-butyl). In some embodiments, R v is optionally substituted C 1-2 alkyl. In some embodiments, R v is C 1- 2 alkyl (e.g., methyl). In some embodiments of any Formulae described herein, each R v is independently halogen, -CN, -R or -OR. In some embodiments, R v is -OR. In some embodiments, R v is hydrogen, halogen, or optionally substituted C 1-6 aliphatic.
  • R v is hydrogen, halogen, -CN, C 1-6 alkyl, or C 3- 6 cycloalkyl. In some embodiments, R v is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, or C 6-10 aryl. In some embodiments, R v is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S.
  • R v is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 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.
  • R v is hydrogen.
  • R v is halogen.
  • R v is fluoro.
  • R v is chloro.
  • R v is bromo.
  • R v is optionally substituted C 3-6 cycloaliphatic.
  • R v is optionally substituted C 3-6 cycloalkyl. In some embodiments, R v is C 3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R v is C6-10 aryl. In some embodiments, R v is phenyl. In some embodiments, R v is naphthyl. In some embodiments, R v is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R v is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S.
  • R v is 3- to 10- membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R v is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. [00340] In some embodiments, one instance of R u and R w , together with the atoms 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.
  • one instance of R u and R v 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.
  • one instance of R u and R v together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic.
  • one instance of R u and R v , together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S.
  • R w is -R as described herein. In some embodiments, R w is -R but not hydrogen. In some embodiments, R w is -OR wherein R is as described herein. In some embodiments of any Formulae described herein, each R w is independently halogen, -OR, -CN, or optionally substituted C1-6 alkyl. In some embodiments, each R w is halogen (e.g., chloro). In some embodiments, R w is halogen (e.g., chloro or fluoro). In some embodiments, R w is –OR (e.g., -O(C 1-6 alkyl)). In some embodiments, R w is –CN.
  • R w is optionally substituted C 1-6 aliphatic. In some embodiments, R w is optionally substituted C 1- 6 alkyl. In some embodiments, R w is C 1-6 alkyl (e.g., tert-butyl). In some embodiments, R w is optionally substituted C 1-2 alkyl. In some embodiments, R w is C 1-2 alkyl (e.g., methyl). In some embodiments of any Formulae described herein, each R w is independently halogen, -CN, -R or -OR. In some embodiments, R w is - OR. In some embodiments, R w is hydrogen, halogen, or optionally substituted C 1-6 aliphatic.
  • R w is hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl. In some embodiments, R w is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, or C 6-10 aryl. In some embodiments, R w is hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S.
  • R w is hydrogen, halogen, -CN, C 1-6 alkyl, C 3- 6 cycloalkyl, C 6-10 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.
  • R w is hydrogen.
  • R w is halogen.
  • R w is fluoro.
  • R w is chloro.
  • R w is bromo.
  • R w is optionally substituted C 1-6 aliphatic.
  • R w is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R w is optionally substituted C 3-6 cycloalkyl. In some embodiments, R w is C3-4 cycloalkyl (e.g., cyclopropyl). In some embodiments, R w is C6-10 aryl. In some embodiments, R w is phenyl. In some embodiments, R w is naphthyl. In some embodiments, R w is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R w is 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S.
  • R w is 3- to 10-membered monocyclic heterocyclyl having 1-5 heteroatoms independently selected from N, O, and S.
  • R v is 4- to 6-membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • one instance of R u and R w together with the atoms 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.
  • one instance of R u and R w 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.
  • one instance of R u and R w together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic.
  • one instance of R u and R w , together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S.
  • each v is independently 0, 1, or 2. In some embodiments, each v is independently 1, 2, or 3. In some embodiments, each v is independently 0, 1, 2, 3, 4, or 5. In some embodiments, v is 0 or 1. In some embodiments, v is 1, 2, or 3. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 5.
  • each R’ is independently -R, -C(O)R, or -S(O) 2 R, 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 -R.
  • each R’ is independently -C(O)R.
  • each R’ is independently -S(O) 2 R,.
  • each R’ is independently 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.
  • each R is independently hydrogen or an optionally substituted group selected from C 1-8 aliphatic, C 3-10 cycloaliphatic, C 1 -C 8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C 6-10 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 R is independently hydrogen. In some embodiments, R is C1-8 aliphatic. In some embodiments, R is C6-10 aryl. In some embodiments, R is phenyl. In some embodiments, R is naphthyl. In some embodiments, R is C 3-10 cycloaliphatic. In some embodiments, R is 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R is 3- to 10-membered monocyclic heterocyclyl having 1-5 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.
  • the compound is not: .
  • the present disclosure provides compounds selected from Table 1, or a pharmaceutically acceptable salt thereof. Table 1
  • the present disclosure provides compounds selected from Table 2, or a pharmaceutically acceptable salt thereof. Table 2.
  • the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds (such as GSK983, GSK699, and/or GSK702, described in Bassi, Z.I., et al. ACS Chem. Biol., 2018, 13, 2862-67).
  • provided compounds are more potent than certain known compounds in one or more assays described herein, e.g., the Western Blot assay of Example B1.
  • provided compounds are more soluble than certain known compounds, as measured by, e.g., kinetic and/or thermodynamic solubility assays.
  • provided compounds have improved metabolic stability than certain known compounds, as measured by, e.g., intrinsic clearance using an in vitro liver microsomal stability assay and/or an in vivo pharmacokinetic analysis.
  • provided compounds have improved permeability, as measured by, e.g., a MDCK and/or Caco2 permeability assays.
  • pharmacokinetic properties such as AUC, T1/2, MRT, or CL.
  • the present disclosure encompasses the recognition that provided compounds are capable of degrading KAT2A, KAT2B, or both KAT2A and KAT2B.
  • compounds capable of degrading both KAT2A and KAT2B provide benefits over compounds that only degrade one of KAT2A or KAT2B.
  • compounds that selectively degrade KAT2A over KAT2B may be desirable.
  • compounds that selectively degrade KAT2B over KAT2A may be desirable.
  • provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form).
  • references to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.
  • Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977).
  • a compound of Formula I is intended to also include Formulae II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5, IIA- 6, III, IIIA, IIIB, IIIB-1, IIIB-2, IIIC, IIID, IV, IVA, IVA-1, V, VA, VA-1, VB, VB-1, VI, VIA, VIA-1, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, IXC, IXD, X, XA, XA-1, XA-2, XB, XI, XIA, XII, XIIA, XIIB, XIIB-1, XIII, XIIIA, XIV, and XV, and compound species of such formulas disclosed herein.
  • provided compounds may generally be made by the processes described in the ensuing schemes and examples.
  • provided compounds e.g., compounds with a linker comprising an amide
  • PBM, linker, LBM, and R are as defined in Formulae herein.
  • compound A is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 in the presence of a suitable coupling agent (e.g., N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate), optionally in the presence of a suitable base (e.g., N-methylimidazole).
  • a suitable coupling agent e.g., N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate
  • a suitable base e.g., N-methylimidazole
  • intermediate A.1 has the following structure: .
  • intermediate A.1 has the following structure: .
  • provided compounds e.g., compounds with a linker comprising an amide
  • PBM, linker, LBM, and Cy are as defined in Formulae herein.
  • compound B is prepared by a process comprising contacting intermediate A.1 with intermediate B.1 in the presence of a suitable coupling agent (e.g., N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate), optionally in the presence of a suitable base (e.g., N-methylimidazole).
  • a suitable coupling agent e.g., N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate
  • a suitable base e.g., N-methylimidazole
  • intermediate A.1 has the following structure: .
  • intermediate A.1 has the following structure: .
  • provided compounds are prepared according to the following Scheme: wherein PBM, linker, and LBM are as defined in Formulae herein.
  • compound C is prepared by a process comprising contacting intermediate A.1 with intermediate C.1 in the presence of a suitable coupling agent (e.g., N,N'-diisopropylcarbodiimide), optionally in the presence of a suitable base (e.g., 4-dimethylaminopyridine).
  • a suitable coupling agent e.g., N,N'-diisopropylcarbodiimide
  • a suitable base e.g., 4-dimethylaminopyridine
  • intermediate A.1 has the following structure: . In some embodiments, intermediate A.1 has the following structure: . [00356] In some embodiments, provided compounds are prepared according to the following Scheme: reducing agent, wherein PBM, linker, LBM, and Cy are as defined in Formulae herein. Accordingly, in some embodiments, compound D is prepared by a process comprising contacting intermediate D.1 with intermediate B.1 in the presence of a suitable reducing agent (e.g., NaCNBH3), optionally in the presence of a suitable acid (e.g., AcOH). In some embodiments, intermediate D.1 has the following structure: . In some embodiments, intermediate D.1 has the following structure: .
  • a suitable reducing agent e.g., NaCNBH3
  • a suitable acid e.g., AcOH
  • intermediate D.1 has the following structure: . In some embodiments, intermediate D.1 has the following structure: .
  • provided compounds are prepared according to one of the following Schemes: wherein PBM, linker, LBM, and Cy are as defined in Formulae herein.
  • compound D is prepared by a process comprising contacting intermediate E.1 with intermediate B.1, optionally in the presence of a suitable base (e.g., Cs2CO3).
  • compound E is prepared by a process comprising contacting intermediate E.1 with intermediate C.1, optionally in the presence of a suitable base (e.g., Cs2CO3).
  • intermediate E.1 has the following structure: l .
  • intermediate E.1 has the following structure: l .
  • provided compounds are prepared according to the following Scheme: wherein PBM, linker, and LBM are as defined in Formulae herein.
  • compound F is prepared by a process comprising contacting intermediate F.1 with intermediate F.2, optionally in the presence of a suitable catalyst (e.g., a copper catalyst).
  • a suitable catalyst e.g., a copper catalyst.
  • intermediate F.1 has the following structure: .
  • intermediate F.1 has the following structure: .
  • the present disclosure provides compounds of high purity.
  • purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, or 95%. In some embodiments, purity of a compound is or greater than about 80%. In some embodiments, purity of a compound is or greater than about 85%. In some embodiments, purity of a compound is or greater than about 90%. In some embodiments, purity of a compound is or greater than about 95%. In some embodiments, a percentage is wt%.
  • a percentage is peak area%, e.g., from a separation technology (e.g., HPLC, UPLC, or GC) which can separate a compound from impurities using a suitable detection technology (e.g., UV at one or more lengths (e.g., 220 nm or 254 nm), MS, or MS n ).
  • a suitable detection technology e.g., UV at one or more lengths (e.g., 220 nm or 254 nm), MS, or MS n ).
  • purity is assessed using quantitative NMR (qNMR).
  • a qNMR technology utilizes an internal standard.
  • an internal standard is of suitable purity, e.g., at least about 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.99%, etc.
  • a composition of a compound when assessed using a LC technology has a peak area purity of about or at least about 95%, e.g., when using UV detection at a suitable wavelength (e.g., 220 nm or 254 nm).
  • a composition of a compound when assessed using a qNMR technology has a purity (e.g., wt%) of about or at least about 95%, and/or about or no more than about 105%.
  • the present disclosure provides compounds of high stereochemical purity.
  • stereochemical purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, or 95%.
  • stereochemical purity of a compound is or greater than about 80%.
  • stereochemical purity of a compound is or greater than about 85%.
  • stereochemical purity of a compound is or greater than about 90%. In some embodiments, stereochemical purity of a compound is or greater than about 95%. In some embodiments, stereochemical purity is the percentage of the peak area of one stereoisomer over the total peak areas of all stereoisomers, e.g., when detected using UV (e.g., at certain wavelength such as 220 nm or 254 nm). In some embodiments, stereochemical purity of a stereoisomer is assessed by NMR. In some embodiments, stereochemical purity is performed on a sample having high purity (e.g., as assessed using technologies described herein (e.g., in some embodiments, LC-UV and/or qNMR).
  • the present disclosure provides compounds of high enantiomeric purity.
  • enantiomeric purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, or 95%.
  • enantiomeric purity of a compound is or greater than about 80%.
  • enantiomeric purity of a compound is or greater than about 85%.
  • enantiomeric purity of a compound is or greater than about 90%.
  • enantiomeric purity of a compound is or greater than about 95%.
  • the present disclosure provides compounds of high diastereomeric purity.
  • diastereomeric purity of a compound is or greater than about 85%, 90%, 91%, 92%, 93%, 94%, or 95%. In some embodiments, diastereomeric purity of a compound is or greater than about 80%. In some embodiments, diastereomeric purity of a compound is or greater than about 85%. In some embodiments, diastereomeric purity of a compound is or greater than about 90%. In some embodiments, diastereomeric purity of a compound is or greater than about 95%. [00364] Stereochemically pure, e.g., enantiomerically pure or diastereomerically pure, compounds and compositions can be prepared utilizing various technologies in accordance with the present disclosure.
  • enantiomeric purity is the percentage of the peak area of one enantiomer over the total peak areas of both enantiomers, e.g., when detected using UV (e.g., at certain wavelength such as 220 nm, 254 nm, etc.).
  • enantiomeric purity of an enantiomer is assessed by NMR (e.g., in a chiral solvent, in the present of a chiral agent that interact with an enantiomer).
  • enantiomeric purity is performed on a sample having high purity (e.g., as assessed using technologies described herein (e.g., in some embodiments, LC-UV and/or qNMR).
  • diastereomeric purity is the percentage of the peak area of one diastereomer over the total peak areas of all diastereomers, e.g., when detected using UV (e.g., at certain wavelength such as 220 nm or 254 nm).
  • diastereomeric purity of a diastereomer is assessed by NMR (e.g., in a chiral solvent, in the present of a chiral agent that interact with an diastereomer).
  • compositions that comprise or deliver a compound as provided herein.
  • compositions comprising a compound provided herein with one or more other components.
  • pharmaceutical composition refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers.
  • a pharmaceutical composition may be specially formulated for administration in a particular form (e.g., in a solid form or a liquid form), and/or may be specifically adapted for, for example: oral administration (for example, as a drenche [aqueous or non-aqueous solutions or suspensions], tablet, capsule, bolus, powder, granule, paste, etc., which may be formulated specifically for example for buccal, sublingual, or systemic absorption); parenteral administration (for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation, etc.); topical application (for example, as a cream, ointment, patch or spray applied for example to skin, lungs, or oral cavity); intravaginal or intrarect
  • compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.
  • a compound is in a pharmaceutically acceptable salt form.
  • pharmaceutically acceptable salt refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J.
  • pharmaceutically acceptable salt include nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, peroxine sodium
  • a salt is citrate salt.
  • a provided compound comprises one or more acidic groups, e.g., an oligonucleotide, and a pharmaceutically acceptable salt is an alkali, alkaline earth metal, or ammonium (e.g., an ammonium salt of N(R) 3 , wherein each R is independently defined and described in the present disclosure) salt.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • a pharmaceutically acceptable salt is a sodium salt.
  • a pharmaceutically acceptable salt is a potassium salt.
  • a pharmaceutically acceptable salt is a calcium salt.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • a provided compound comprises more than one acid groups, for example, an oligonucleotide may comprise two or more acidic groups (e.g., in natural phosphate linkages and/or modified internucleotidic linkages).
  • a pharmaceutically acceptable salt, or generally a salt, of such a compound comprises two or more cations, which can be the same or different.
  • pharmaceutically acceptable carrier means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • a pharmaceutically acceptable carrier is a buffer.
  • a pharmaceutical composition comprises a buffer.
  • a pharmaceutical composition comprises the solid components a buffer.
  • a pharmaceutical composition is re-constituted by addition of solvent, e.g., water.
  • a pharmaceutically acceptable carrier is an acidic buffer.
  • its pH is about 2-6.5, 2-6, 3-6, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 or 6.5.
  • a pharmaceutically acceptable carrier is a citrate buffer, e.g., pH about 3.5.
  • a provided compound can be formulated without using compounds such as cyclodextrins (e.g., HPBCD) to improve apparent solubility and/or dissolution rate.
  • provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae I, II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5, IIA-6, II-1, III, IIIA, IIIB, IIIB-1, IIIB-2, IIIC, IIID, III-1, IIIE, IIIF, IIIG, IIIH, IIIJ, IIIK, IIIL, IIIM, IIIM, IV, IVA, IVA-1, IV-1, IVD, V, VA, VA-1, VB, VB-1, V-1, VC, VD, VE, VI, VIA, VIA-1, VI-1, VIB, VII, VIIA, VII-1, VIIB, VIII, VIIIA, VIII-1, VIIIB, IX, IX-1, IX-1, IX-1, IX-1, I
  • a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I, II, IIA, IIA-1, IIA-2, IIA-3, IIA- 4, IIA-5, IIA-6, II-1, III, IIIA, IIIB, IIIB-1, IIIB-2, IIIC, IIID, III-1, IIIE, IIIF, IIIG, IIIH, IIIJ, IIIK, IIIL, IIIM, IIIM, IV, IVA, IVA-1, IV-1, IVD, V, VA, VA-1, VB, VB-1, V-1, VC, VD, VE, VI, VIA, VIA-1, VI-1, VIB, VII, VIIA, VII-1, VIIB, VIII, VIIIA, VIII-1, VIIIB, IX, IX-1, IXA, IXB, IXC, IXD, X, XA, XA-1, XA-2, XB, X-1, X
  • a composition e.g., a pharmaceutical composition, comprises a compound and one or more of its stereoisomers.
  • stereochemical purity of the compound is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, it is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% with respect to a specific chiral center (e.g., a Ring E chiral carbon atom at which Ring E is bonded to Ring C).
  • stereochemical purity is about 10%-80%, 20%-80%, 30%-70%, 40%-70%, 40%-60%, 40%, 45%, 50%, 55% or 60%. In some embodiments, it is about or at least about 85%. In some embodiments, it is about or at least about 90%. In some embodiments, it is about or at least about 95%.
  • compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects.
  • an active agent e.g., a compound described herein
  • provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti-statics, etc.
  • Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and/or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.
  • provided pharmaceutical compositions can be prepared with any appropriate available technologies.
  • provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage.
  • the expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent.
  • a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect.
  • a unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
  • a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents
  • a solid pharmaceutical composition e.g., a tablet, a capsule, or the like
  • sustained release formulation containing a predetermined quantity of one or more active agents
  • a drug delivery device containing a predetermined amount of one or more active agents
  • compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and/or decreasing incidence and/or intensity of) a disease or disorder, for example as described herein.
  • a dosing regimen i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration
  • a dosing regimen i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration
  • a dosing regimen i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration
  • the present disclosure also provides methods of preparing pharmaceutical compositions provided herein.
  • provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt
  • present disclosure provides uses for compounds and compositions described herein.
  • provided compounds and compositions are useful in medicine (e.g., as therapy).
  • provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
  • a provided compound or a salt thereof is formulated, utilized, provided or administered in a pharmaceutical composition as described herein.
  • the present disclosure encompasses the recognition and KAT2 polypeptides, e.g., KAT2A are associated with various dysregulated cell states of various diseases, disorders, or conditions including cancer.
  • the present disclosure provides technologies targeting such cell states and associated diseases, disorders, or conditions.
  • provided compounds are useful as KAT2 degraders and/or inhibitors. In some embodiments, provided compounds promote degradation of KAT2A. In some embodiments, provided compounds promote degradation of KAT2B. [00379] In some embodiments, a compound binds to KAT2A and an E3 ubiquitin ligase. In some embodiments, a compound binds to KAT2B and an E3 ubiquitin ligase. In some embodiments, a compound binds to KAT2A, KAT2B and an E3 ubiquitin ligase. Various technologies can be utilized for assessing binding.
  • K D of a compound binding to a target is about or less than about 1 uM in an assay such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC).
  • the present disclosure provides methods of degrading and/or inhibiting KAT2 (e.g., KAT2A and/or KAT2B), comprising contacting a provided compound with KAT2.
  • contacting occurs in a cell.
  • contacting occurs in a subject (e.g., a human subject).
  • the present disclosure provides methods for reducing level of KAT2A in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides methods for reducing level of KAT2B in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides methods for reducing level of KAT2A and KAT2B in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides methods for modulating epigenetic state of a system, comprising administering or delivering to the system an effective amount of a provided compound.
  • the present disclosure provides methods for reducing histone acetylation in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, H3K9 acetylation is reduced. In some embodiments, the present disclosure provides methods for inducing or promoting cell differentiation in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides methods for reducing or blocking de-differentiation in a system, comprising administering or delivering to the system an effective amount of a provided compound. In some embodiments, the present disclosure provides methods for reducing or blocking trans-differentiation in a system, comprising administering or delivering to the system an effective amount of a provided compound.
  • a system comprises or expresses KAT2A. In some embodiments, a system comprises or expresses KAT2B. In some embodiments, a system comprises or expresses KAT2A and KAT2B. In some embodiments, a system is or comprises a cell. In some embodiments, a system is or comprises a cell expressing KAT2A and/or KAT2B. In some embodiments, a cell is a cell of a disease, disorder, or condition. In some embodiments, a cell is a cancer cell. In some embodiments, a cell is an acute myeloid leukemia cell. In some embodiments, a cell is a small cell lung cancer cell.
  • a cell is a neuroendocrine prostate cancer cell.
  • a system is or comprises a tissue.
  • a system is or comprises an organ.
  • a system is or comprises a sample.
  • a system is or comprises an organism.
  • a system is or comprises a subject.
  • a system is or comprises an animal.
  • a system is or comprises a human.
  • the present disclosure provides 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 provided compound.
  • a dysregulated cell state is associated with a disease, disorder, or condition, e.g., cancer. In some embodiments, after modulation a cell state is not or less associated with a disease, disorder, or condition.
  • a dysregulated cell state is associated with or of a cancer as described herein.
  • a dysregulated cell state is associated with or of acute myeloid leukemia.
  • a dysregulated cell state is associated with or of small cell lung cancer.
  • a dysregulated cell state is associated with or of neuroendocrine prostate cancer.
  • a dysregulated cell state is or comprises a dedifferentiated neuroendocrine cell state.
  • a dysregulated cell state is or comprises blocked or reduced differentiation. In some embodiments, dysregulated cell state is or comprises de-differentiation. In some embodiments, dysregulated cell state is or comprises trans-differentiation. In some embodiments, a dysregulated cell state is or comprises a dedifferentiated neuroendocrine cell state. In some embodiments, a provided technology induces or promotes conversion of a dysregulated cell state into another cell state. In some embodiments, a dysregulated cell state is more associated with a condition, disease or disorder, e.g., a cancer as described herein, than another cell state. In some embodiments, a dysregulated cell state is more proliferative than another cell state.
  • a dysregulated cell state is less differentiated than another cell state.
  • another cell state is or comprises a more differentiated epithelial cell state.
  • another cell state comprises more differentiation.
  • another cell state comprises more terminal differentiation.
  • another cell state comprises more myeloid differentiation.
  • another cell state comprises more monocytic differentiation.
  • another cell state comprises increased level of a marker associated with a cell state.
  • another cell state comprises increased level of a marker associated with differentiation.
  • another cell state comprises increased level of CD11b expression.
  • another cell state comprises increased levels of CD14 expression.
  • another cell state comprises increased levels of CD15 expression.
  • another cell state comprises increased levels of CD86 expression. In some embodiments, another cell state comprises decreased stemness, translation, and/or replication. In some embodiments, another cell state comprises decreased stemness. In some embodiments, another cell state comprises decreased translation. In some embodiments, another cell state comprises decreased replication. In some embodiments, another cell state comprises decreased stemness, translation, and/or replication GESA signatures. In some embodiments, another cell state comprises decreased stem GSEA signatures. In some embodiments, another cell state comprises decreased translation GSEA signatures. In some embodiments, another cell state comprises decreased replication GSEA signatures. In some embodiments, another cell state comprises increased myeloid differentiation. In some embodiments, another cell state comprises increased myeloid differentiation GSEA signatures.
  • another cell state comprises increased monocytic differentiation. In some embodiments, another cell state comprises increased monocytic differentiation GSEA signatures. In some embodiments, another cell state comprises increased epithelial differentiation. In some embodiments, another cell state comprises increased epithelial differentiation GSEA signatures. In some embodiments, another cell state comprises epithelial cell state. In some embodiments, another cell state comprises increased neural differentiation. In some embodiments, another cell state comprises neural cell state. In some embodiments, another cell state comprises increased epithelial neural GSEA signatures. In some embodiments, a provided method increases myeloid differentiation. In some embodiments, a provided method decreases stemness. In some embodiments, a provided method decreases translation. In some embodiments, a provided method decreases replication.
  • a provided method decreases stem, translation and/or replication GSEA signatures.
  • a method increases epithelial differentiation.
  • a method increases epithelial GESA signatures.
  • a method increases neural differentiation.
  • a method increases neural GESA signatures.
  • a provided method increases myeloid differentiation.
  • a provided method increases myeloid GSEA signatures.
  • a provided method increases monocytic differentiation.
  • a provided method increases monocytic GSEA signatures.
  • a method increases level of CD11b + cells. In some embodiments, a method increases level of CD14 + cells.
  • a method increases level of CD15 + cells. In some embodiments, a method increases level of CD86 + cells.
  • a compound promote degradation of one target more than the other.
  • certain compounds have selectivity for KAT2A over KAT2B. In some embodiments, certain compounds have selectivity for KAT2B over KAT2A.
  • DC50 for KAT2B e.g., when assessed in certain cells as in Example B1, is about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 fold more than DC50 for KAT2A.
  • DC50 for KAT2A is about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 fold more than DC50 for KAT2B.
  • certain compounds have DC50 at about 1 nM or lower for both KAT2A and KAT2B.
  • certain compounds have DC50 at about 1 nM or lower for both KAT2A and KAT2B, and have selectivity for KAT2A over KAT2B.
  • certain compounds have DC50 at about 1 nM or lower for both KAT2A and KAT2B, and have selectivity for KAT2B over KAT2A.
  • certain compounds have DC50 at about 1 nM or lower for KAT2A but DC50 higher than about 1nM for KAT2B. In some embodiments, certain compounds have DC 50 at about 1 nM or lower for KAT2B but DC 50 higher than about 1nM for KAT2A. Certain examples are presented in Table 3 in the Examples. [00384] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with KAT2 (e.g., KAT2A and/or KAT2B).
  • KAT2A and/or KAT2B e.g., KAT2A and/or KAT2B
  • a condition, disorder or disease is associated with KAT2A. In some embodiments, a condition, disorder or disease is associated with level of KAT2A. In some embodiments, a condition, disorder or disease is associated with activity of KAT2A. In some embodiments, a condition, disorder or disease is associated with KAT2B. In some embodiments, a condition, disorder or disease is associated with level of KAT2B. In some embodiments, a condition, disorder or disease is associated with activity of KAT2B. In some embodiments, a condition, disorder or disease is associated with KAT2A and KAT2B. In some embodiments, a condition, disorder or disease is associated with level of KAT2A and KAT2B.
  • a condition, disorder or disease is associated with combined level of KAT2A and KAT2B. In some embodiments, a condition, disorder or disease is associated with activity of KAT2A and KAT2B. [00385] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with KAT2 (e.g., KAT2A and/or KAT2B), comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with KAT2 (e.g., KAT2A and/or KAT2B), comprising administering or delivering a provided compound or composition to a subject in need thereof.
  • KAT2 e.g., KAT2A and/or KAT2B
  • the present disclosure provides methods of treating a disease, disorder, or condition, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, comprising delivering a provided compound or composition to a subject in need thereof. In some embodiments, provided methods are for treating cancer.
  • a cancer is characterized by a solid tumor. In some embodiments, a cancer is characterized by a neuroendocrine tumor. In some embodiments, a cancer is characterized by a hematologic tumor.
  • a cancer is selected from hematopoietic cancers, including leukemias, lymphomas (e.g., Hodgkin’s and non-Hodgkin’s), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, carcinomas of solid tissue, squamous cell carcinomas of the mouth, throat, larynx, and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine, and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastro-intestinal cancers and nervous system cancers, benign lesions such as papillomas, and the like.
  • leukemias e.g., lymphomas (e.g., Hodgkin’s and non
  • provided methods are for treating a leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.)
  • a disease, disorder, or condition selected from acute myeloid leukemia (AML), neuroblastoma, non-small cell lung cancer (NCSLC), small cell lung cancer (SCLC), colorectal cancer, melanoma, and prostate cancer.
  • AML acute myeloid leukemia
  • NCSLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • colorectal cancer colorectal cancer
  • melanoma melanoma
  • prostate cancer a disease, disorder, or condition
  • a disease, disorder, or condition is acute myeloid leukemias (AML).
  • SCLC small cell lung cancer
  • a disease, disorder, or condition is neuroendocrine prostate cancer (NEPC).
  • NEPC neuroendocrine prostate cancer
  • a disease, disorder, or condition is high-grade neuroendocrine carcinomas, e.g., those in the GI tract and pancreas.
  • a disease, disorder, or condition is castration resistant prostate cancer (CRPC).
  • CRPC castration resistant prostate cancer
  • Applicant Using its AI/ML platform AURIGIN, Applicant created a high-resolution atlas and identified histone acetyltransferase KAT2A as a key driver of tumor cell plasticity in various cancers such as certain acute myeloid leukemias (AML), small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC).
  • AML acute myeloid leukemias
  • SCLC small cell lung cancer
  • NEPC neuroendocrine prostate cancer
  • provided compounds are useful for treating such cancers.
  • compounds of the present disclosure were assessed across representative models of AML, SCLC and NEPC.
  • compounds of the present disclosure inhibited proliferation and promoted profound cell state changes in, e.g., MOLM-13 (AML) cells; in NCI-H1048 (SCLC), LASPC-01 (NEPC) cell lines as well as a primary NEPC organoid model, compounds of the present disclosure demonstrated potent antiproliferative effects; in vivo, compounds of the present disclosure significantly inhibited tumor growth in an NCI-H1048 xenograft model.
  • the present disclosure genetically and pharmacologically validated KAT2A and KAT2B as key drivers of cell state plasticity in tumors such as SCLC, NEPC and AML tumors and confirmed their utility as novel targets in these aggressive, metastatic and drug resistant cancers.
  • a provided compound or composition is administered as part of a combination therapy.
  • the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.
  • a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).
  • provided technologies can provide various benefits and/or advantages.
  • provided technologies are more potent, e.g., when assessed for KAT2A and/or KAT2B degradation, cell state modulation, cell growth inhibition, tumor size reduction, and/or treatment of various conditions, diseases or disorders.
  • provided technologies provide improved bioavailability (e.g., oral bioavailability), flexibility in administration routes and/or regimens, reduced clearance (e.g., unbound clearance), increased exposure, increased low solubility, improved exposure levels, lower doses, etc.
  • properties, activities, parameters, etc., for assessment are cLogD, tPSA, molecular weight, kinetic solubility (e.g., at pH like about 7.4), dose (mg/kg, e.g., for achieving an effect or a result), CL (e.g., CL, u), T1/2 (e.g., in plasma, a system, etc.), Vdss, AUC (e.g., 0-last), mPPB (%), bioavailability, DC 50 (e.g., for KAT2A, KAT2B, etc.), DC 90 , GI 50 , GI 90 , etc.
  • DC 50 e.g., for KAT2A, KAT2B, etc.
  • DC 90 e.g., GI 50 , GI 90 , etc.
  • assessment is performed with cells, e.g., MOLM-13, NCI-H1048, LASCPC-01, etc. In some embodiments, assessment is performed with human primary cells (e.g., from a patent sample). In some embodiments, assessment is performed with a sample. In some embodiments, assessment is performed with a tissue. In some embodiments, assessment is performed with a organ. In some embodiments, assessment is performed with a organoid. In some embodiments, assessment is performed with an animal, e.g., an animal model. [00390] In some embodiments, a reference technology for comparison is or comprises a reference compound or a salt thereof. In some embodiments, a reference compound is (Compound Ref-1) or a pharmaceutically acceptable salt thereof.
  • a reference compound pharmaceutically acceptable salt thereof in some embodiments, a reference compound pharmaceutically acceptable salt thereof.
  • the present disclosure incorporates various information, including patent application publications, patents and non-patent references, by reference; in the case of any conflict, the present disclosure will control.
  • the present disclosure provides the following Embodiments as examples: 1.
  • a compound of Formula I PBM – linker – LBM I wherein: PBM is a KAT2 protein binding moiety; linker is an optional linking moiety; and LBM is an E3 ubiquitin ligase binding moiety. 2.
  • 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; L 1 is a covalent bond or an optionally substituted bivalent C 1-3 hydrocarbon chain; each R 1 is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is halogen, -CN, or -R; each R 3 is independently halogen, -CN, or -R; R 4 is -R’; R 5 LV ⁇ KDORJHQ ⁇ &1 ⁇ RU ⁇ -R, or R 2 and R 5 , 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; R 6 is -R’; X is O or NR
  • Ring F is an optionally substituted 3- to 10- membered ring having 0-4 heteroatoms independently selected from N, O, and S.
  • Ring F is an optionally substituted 5-6 membered ring having 0-4 heteroatoms independently selected from N, O, and S.
  • Ring F is an optionally substituted 6- membered ring.
  • Ring F is optionally substituted 1,4- phenylene.
  • Ring F is 1,4-phenylene.
  • 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; L 1 is a covalent bond or a bivalent C 1-3 straight or branched hydrocarbon chain; each R 1 is independently optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or
  • the compound of any one of the preceding Embodiments, wherein the shortest-path length of linker is about or no more than 10 atoms.
  • the compound of any one of the preceding Embodiments, wherein the number of bonds between two non-ring sp 3 atoms in the shortest path chain of linker is about or no more than 5, 4, 3, 2 or 1. 74. The compound of any one of the preceding Embodiments, wherein the number of bonds between two non-ring sp 3 atoms in the shortest path chain of linker is about or no more than 1. 75. The compound of any one of the preceding Embodiments, wherein the number of non-ring sp 3 C, O, and S atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1. 76.
  • the compound of any one of the preceding Embodiments, wherein the number of non-ring sp 3 C, O, and S atoms in the shortest path chain of linker is about or no more than about 1. 77. The compound of any one of the preceding Embodiments, wherein the number of non-ring sp 3 atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1. 78. The compound of any one of the preceding Embodiments, wherein the number of non-ring sp 3 atoms in the shortest path chain of linker is about or no more than about 1. 79.
  • the compound of any one of the preceding Embodiments, 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. 80. The compound of any one of the preceding Embodiments, wherein the number of non-ring atoms in the shortest path chain of linker is about or no more than about 1. 81.
  • 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-. 84.
  • 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-.
  • 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-.
  • a methylene unit is replaced by - C(O)-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. 91.
  • 102. The compound of any one of Embodiments 100-101, wherein -Cy- is 6-16 membered.
  • the compound of any one of Embodiments 100-111, wherein -Cy- is saturated.
  • Ring C is an optionally substituted 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from N, O, and S. 177.
  • Ring C is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. 178.
  • Ring C is an optionally substituted 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. 179.
  • 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 R a is independently hydrogen or an optionally substituted C1-6 aliphatic, or two R a groups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring;
  • L 2 is a covalent bond or a straight or branched C 1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO 2 -, -C(O)N(R)-,
  • each B is independently selected from N, C, and CH, provided that no more than two B are N; each R c is independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; and m is 0, 1, 2, or 3. 192.
  • each A is independently N, C, or CH, provided that no more than two A groups are N; each R b is hydrogen, or two R b groups, 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 R c is independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; and m is 0, 1, 2, or 3. 198.
  • each R’ is independently -R, -C(O)R, or -S(O) 2 R, 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, C 1 -C 8 heteroaliphatic having 1-3 heteroatoms independently selected from N, O, and S, C 6-10 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 R p is independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic
  • each R q is independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic
  • each R r is independently hydrogen or optionally substituted C1-6 aliphatic
  • each R s is independently halogen, -OR, -CN, or optionally substituted C1-6 aliphatic
  • t is 0, 1, 2, 3, 4, or 5
  • each u is independently 0, 1, 2, 3, 4, or 5.
  • each R p is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • each R q is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • each R r is independently hydrogen or optionally substituted C 1-6 aliphatic
  • each R s is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • t is 0, 1, 2, 3, 4, or 5
  • each u is independently 0, 1, 2, 3, 4, or 5.
  • Embodiment 240 wherein the compound is of Formula VIIA: VIIA or a pharmaceutically acceptable salt thereof.
  • v 242 The compound of any one of Embodiments 1-148, wherein . 243.
  • Ring A is selected from: ; L 3 , L 4 , and L 5 are each independently a covalent bond or an optionally substituted bivalent C 1-6 straight or branched hydrocarbon chain; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 5 is hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic, or R 2 and R 5 , together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having
  • the compound of Embodiment 275, wherein X is O. 277.
  • the compound of Embodiment 275, wherein X is NR 7 . 278.
  • the compound of any one of Embodiments 246-300, wherein the number of non-ring consecutive sp 3 atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1. 307.
  • the compound of any one of Embodiments 246-300, wherein the number of non-ring consecutive sp 3 atoms in the shortest path chain of linker is about or no more than about 2. 308.
  • the compound of any one of Embodiments 246-300, wherein the number of bonds between two non- ring sp 3 atoms in the shortest path chain of linker is about or no more than 5, 4, 3, 2 or 1. 309.
  • the compound of any one of Embodiments 246-300, wherein the number of bonds between two non- ring sp 3 atoms in the shortest path chain of linker is about or no more than 1. 310.
  • the compound of any one of Embodiments 246-300, wherein the number of non-ring sp 3 C, O, and S atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1. 311.
  • the compound of any one of Embodiments 246-300, wherein the number of non-ring sp 3 C, O, and S atoms in the shortest path chain of linker is about or no more than about 1. 312.
  • the compound of any one of Embodiments 246-300, wherein the number of non-ring sp 3 atoms in the shortest path chain of linker is about or no more than about 5, 4, 3, 2 or 1. 313.
  • the compound of any one of Embodiments 246-300, wherein the number of non-ring sp 3 atoms in the shortest path chain of linker is about or no more than about 1. 314.
  • the compound of any one of Embodiments 246-300, 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. 315.
  • the compound of any one of Embodiments 246-300, wherein the number of non-ring atoms in the shortest path chain of linker is about or no more than about 1. 316.
  • 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-. 319.
  • 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-.
  • 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-.
  • 320 The compound of any one of Embodiments 246-300, wherein a methylene unit
  • 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 –Cy-. 326.
  • the compound of any one of Embodiments 335-346, wherein -Cy- is saturated. 348.
  • linker comprises one or more basic nitrogen. 351.
  • Ring C is an optionally substituted phenyl ring. 404.
  • Ring C is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. 410.
  • Ring C is an optionally substituted 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from N, O, and S. 411.
  • the compound of any one of Embodiments 246-410, wherein Ring E is . 412.
  • the compound of any one of Embodiments 246-410, wherein Ring E is an optionally substituted . 413.
  • 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 R a is independently hydrogen or an optionally substituted C 1-6 aliphatic, or two R a groups, together with the atom to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is 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)-; and Y is N or CH.
  • Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated
  • each B is independently selected from N, C, and CH, provided that no more than two B are N; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3. 424.
  • Ring C is optionally substituted C3-C7 cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 427.
  • Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 428.
  • each A is independently N, C, or CH, provided that no more than two A groups are N; each R b is hydrogen, or two R b groups, 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 R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3. 429.
  • each R b is hydrogen, or two R b groups, 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 R c is independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; and m is 0, 1, 2, or 3. 445.
  • the compound of Embodiment 444 wherein the compound is of Formula XA-1 or XA-2: XA-2 or a pharmaceutically acceptable salt thereof. 446.
  • each R d that is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C 1-6 aliphatic, or two R d , 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 R e that is not the point of attachment for the linker is independently hydrogen or optionally substituted C 1-6 aliphatic; R f , when it is not the point of attachment for the linker
  • the compound of Embodiment 452-454 wherein two R i groups, 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. 457.
  • the compound of Embodiment 452-456 wherein the compound is a compound of Formula XIIA: XIIA or a pharmaceutically acceptable salt thereof. 458.
  • Embodiment 452-454 wherein the compound is a compound of Formula XIIB-1: XIIB-1 or a pharmaceutically acceptable salt thereof.
  • 460 The compound of any one of Embodiments 246-380, wherein LBM is . 461.
  • 461. The compound of any one of Embodiments 246-380, wherein the compound is a compound of Formula XIII-1: s XIII-1 or a pharmaceutically acceptable salt thereof. 462.
  • each R p is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • each R q is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • each R r is independently hydrogen or optionally substituted C 1-6 aliphatic
  • each R s is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • t is 0, 1, 2, 3, 4, or 5
  • each u is independently 0, 1, 2, 3, 4, or 5.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 480.
  • a compound, wherein the compound is: H or a pharmaceutically acceptable salt thereof. 481.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof.
  • 482. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof.
  • 483. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof.
  • 484. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 485.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 486.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 487.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 488.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 489. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 490. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 491. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 492. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 493. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 494. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 495. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 496. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 497.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 498. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 499. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 500. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 501. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 502. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 503. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 504. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 505. A compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 506.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 507.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 508.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 509.
  • a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof. 510.
  • the compound of any one of the preceding Embodiments, wherein the compound is in a pharmaceutically acceptable salt form. 511.
  • the compound of any one of the preceding Embodiments, wherein the stereochemical purity of each chiral center in PBM is at least about 90%.
  • 512. The compound of any one of the preceding Embodiments, wherein the stereochemical purity of each chiral center is at least about 90%. 513.
  • a pharmaceutical composition comprising a compound of any one of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 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%. 516.
  • composition of Embodiment 514 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 20%-80%.
  • the composition of any one of Embodiments 514-516, wherein the salt is a citrate salt.
  • the composition of any one of Embodiments 514-516, wherein the composition comprises a buffer or components thereof. 519.
  • the composition of Embodiment 518, wherein the buffer is a citrate buffer.
  • 520. The composition of any one of Embodiments 518-519, wherein the pH of the buffer is about 2-6.5. 521.
  • composition of any one of Embodiments 514-520, wherein the composition comprises a cyclodextrin. 522.
  • the composition of any one of Embodiments 514-520, wherein the composition is substantially free of cyclodextrin. 524.
  • a method of preparing a pharmaceutical composition of any one of Embodiments 514-523 comprising: providing the compound of any one of Embodiments 1-514, or a pharmaceutically acceptable salt thereof; and formulating the compound with suitable excipients to give the pharmaceutical composition. 525.
  • a method for reducing KAT2A in a system comprising administering or delivering to the system an effective amount of a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding Embodiments. 526.
  • a method for reducing KAT2B in a system comprising administering or delivering to the system an effective amount of a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding Embodiments. 527.
  • a method for reducing KAT2A and KAT2B in a system comprising administering or delivering to the system an effective amount of a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding Embodiments. 528.
  • 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 Embodiments, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding Embodiments. 529.
  • 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 Embodiments, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding Embodiments. 531.
  • 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 Embodiments, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding Embodiments. 532.
  • 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 Embodiments, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding Embodiments. 533.
  • a system is or comprises an acute myeloid leukemia cell. 537.
  • the method of any one of Embodiments 525-533, wherein a system is or comprises a small cell lung cancer cell. 538.
  • the method of any one of Embodiments 525-533, wherein a system is or comprises a neuroendocrine prostate cancer cell. 539.
  • the method of any one of Embodiments 525-533, wherein a system is or comprises a tissue.
  • 540 The method of any one of Embodiments 525-533, wherein a system is or comprises an organ. 541.
  • the method of any one of Embodiments 525-533, wherein a system is or comprises a sample.
  • 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 Embodiments, or a pharmaceutically acceptable salt thereof, or a composition of any one of the preceding Embodiments. 546.
  • the method of Embodiment 545, wherein the dysregulated cell state is of cancer.
  • the method of Embodiment 546, wherein the dysregulated call state is of small cell lung cancer. 548. The method of Embodiment 546, wherein the dysregulated call state is of neuroendocrine prostate cancer. 549. The method of Embodiment 545, wherein the dysregulated call state is of acute myeloid leukemia. 550. The method of any one of Embodiments 545-549, wherein the method induces or promotes conversion of the dysregulated cell state into another cell state. 551. The method of any one of Embodiments 545-550, wherein the dysregulated cell state is more proliferative than the another cell state. 552.
  • the method of any one of Embodiments 545-556, wherein the another cell state is or comprises a more differentiated epithelial cell state.
  • the method of any one of Embodiments 545-557, wherein the another cell state comprises increased levels of CD11b expression.
  • the method of any one of Embodiments 545-558, wherein the another cell state comprises increased levels of CD14 expression.
  • the method of any one of Embodiments 545-559, wherein the another cell state comprises increased levels of CD15 expression.
  • the method of any one of Embodiments 545-560, wherein the another cell state comprises increased levels of CD86 expression. 562.
  • a method comprising administering a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the preceding Embodiments, to a subject in need thereof.
  • a method comprising delivering a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the preceding Embodiments, to a subject in need thereof.
  • a method of treating a cancer comprising administering a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the preceding Embodiments, to a subject in need thereof. 576.
  • a method of treating a cancer comprising delivering a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the preceding Embodiments, to a subject in need thereof.
  • the method of Embodiment 575 or 576, wherein the cancer is selected from acute myeloid leukemia, neuroblastoma, non-small cell lung cancer, small cell lung cancer, colorectal cancer, melanoma, and prostate cancer. 578.
  • a method of degrading KAT2 in a subject comprising administering a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the preceding Embodiments, to a subject in need thereof.
  • An in vitro method of degrading KAT2 comprising contacting a biological sample with a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the preceding Embodiments. 580.
  • a method for treating a disease, disorder, or condition comprising administering or delivering to a subject suffering from an effective amount of a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the preceding Embodiments. 581.
  • the method of Embodiment 580, wherein the disease, disorder, or condition is associated with KAT2A. 582.
  • the method of any one of Embodiments 580-581, wherein the disease, disorder, or condition is associated with KAT2B. 583.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is cancer. 584.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is acute myeloid leukemia. 585.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is neuroblastoma. 586.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is non- small cell lung cancer. 587.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is small cell lung cancer. 588.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is colorectal cancer, melanoma. 589.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is prostate cancer. 590. The method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is neuroendocrine prostate cancer. 591. The method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is castration resistant prostate cancer. 592. The method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is high- grade neuroendocrine carcinomas. 593. The method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is high- grade neuroendocrine carcinomas in GI tract. 594.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is high- grade neuroendocrine carcinomas in pancreas. 595.
  • the method of any one of Embodiments 580-582, wherein the disease, disorder, or condition is pancreatic cancer. 596.
  • 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; L 1 is a covalent bond or a bivalent C 1-3 straight or branched hydrocarbon chain; each R 1 is independently optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 5 is hydrogen, halogen, optionally substituted C1-6 aliphatic
  • 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-. 627.
  • 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-. 628.
  • 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)-. 629.
  • linker comprises at least one triple bond.
  • 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 –Cy-. 631.
  • 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. 638.
  • Cy is optionally substituted phenyl or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 639.
  • each R is independently hydrogen or optionally substituted C 1-6 alkyl. 644.
  • linker is selected from: -CH 2 -, , , , , , , ,
  • 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 R a is independently hydrogen or an optionally substituted C1-6 aliphatic, or two R a groups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a straight or branched C1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO 2 -, -C(O)N(R)-, or -N(R)C(O)-; and Y is N or CH.
  • Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring
  • Ring C is an optionally substituted group selected from phenyl, C 5-6 cycloaliphatic, 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. 655.
  • Ring C is optionally substituted phenyl or 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 656.
  • each B is independently selected from N, C, and CH, provided that no more than two B are N; each R c is independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; and m is 0, 1, 2, or 3. 657.
  • the compound of any one of Embodiments 653-657, w herein the compound is of Formula IIIC: IIIC or a pharmaceutically acceptable salt thereof. 659.
  • Ring C is optionally substituted C3-C7 cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 661.
  • Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 662.
  • each A is independently N, C, or CH, provided that no more than two A groups are N; each R b is hydrogen, or two R b groups, 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 R c is independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6 aliphatic; and m is 0, 1, 2, or 3. 663.
  • a compound of Formula IX IX or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: L 3 , L 4 , and L 5 are each independently a covalent bond or an optionally substituted bivalent C 1-6 straight or branched hydrocarbon chain; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic; R 5 is hydrogen, halogen, optionally substituted C1-6 aliphatic, or optionally substituted C3-6 cycloaliphatic, or R 2 and R 5 , together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic
  • the compound of any one of Embodiments 674-676, wherein the linker is less than 14 atoms in length. 678.
  • a pharmaceutical composition comprising a compound of any one of Embodiments 597-682, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 684.
  • a method of preparing the pharmaceutical composition of Embodiment 683 comprising: providing a compound of any one of Embodiments 597-682, or a pharmaceutically acceptable salt thereof; and formulating the compound with suitable excipients to give the pharmaceutical composition. 685.
  • a method comprising administering a compound of any one of Embodiments 597-682, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 685 to a subject in need thereof.
  • 686. A method of treating a cancer, comprising administering a compound of any one of Embodiments 597-682, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 683 to a subject in need thereof. 687.
  • Embodiment 686 wherein the cancer is selected from acute myeloid leukemia, neuroblastoma, non-small cell lung cancer, small cell lung cancer, colorectal cancer, melanoma, and prostate cancer.
  • a method of degrading KAT2 in a subject comprising administering a compound of any one of Embodiments 597-682, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 683 to a subject in need thereof.
  • An in vitro method of degrading KAT2 comprising contacting a biological sample with a compound of any one of Embodiments 597-682, or a pharmaceutically acceptable salt thereof.
  • Method A prep-HPLC: Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 0.1% TFA in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: 0.0 min 5% B, 0.2-3.0 min 5-5% B, 3-40 min 60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-5% B, 48-55 min 5-5% B.
  • Method B (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 10 mM Ammonium Bicarbonate in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: 0.0 min 5% B, 0.2-3.0 min 5-5% B, 3-40 min 60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-5% B, 48-55 min 5- 5% B.
  • Method C (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 0.1% TFA in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: 0.0 min 10% B, 0.2-3.0 min 10-10% B, 3- 40 min 10-60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-10% B, 48-55 min 10-10%B.
  • Method D (Combiflash®): Column: YMC, Dimension: 4 g (irregular silica, 40-63 ⁇ m, 60 ⁇ ), Eluents A: DCM, B: MeOH, Gradient: 0-5% MeOH/DCM for 30 min, Flow Rate: 20.0 mL/min.
  • Method E prep-HPLC: Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 10 mM Ammonium Bicarbonate in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: Linear gradient.
  • Method F (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 0.1% Formic Acid in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: 0.0 min 2% B, 0.2-3.0 min 2-2% B, 3-50 min 2-55% B, 50-51 min 55-95% B, 51-57 min 95-95% B, 57-58 min 95-2% B, 58-65 min 2-2% B.
  • Method G Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 0.1% Formic Acid in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: Linear gradient.
  • Method H Column: SYNERGY C18, (150 x 19 mm) 5 ⁇ m, Eluents A: 10 mM ammonium bicarbonate in H2O, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient (Time/%B): 0/10 ,10/30, 20/40, 30/50, 40/60, 50/70, 55/98.
  • reaction mixture was quenched with saturated NH 4 Cl solution.
  • the aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give crude compound.
  • reaction mixture was stirred at RT for 16 h. Progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated to give crude compound.
  • the crude compound was purified by column chromatography (5% methanol in DCM) to afford compound methyl 4-((cis)-5-((tert-butoxycarbonyl)amino)-1-methylpiperidin-3- yl)benzoate (1.70 g, 68%) as an off-white solid along with compound methyl 4-((trans)-5-((tert- butoxycarbonyl)amino)-1-methylpiperidin-3-yl)benzoate.
  • Step-5 and 6 methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoate
  • DMSO DMSO
  • K2CO3 5.00 g, 36.29 mmol
  • 4,5-dibromo-2- methylpyridazin-3(2H)-one intermediate 2, 4.86 g, 18.14 mmol
  • This compound was purified by chiral SFC to afford methyl 4-((3S,5S)-5-((5-bromo-1-methyl-6-oxo-1,6- dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate and methyl 4-((3R,5R)-5-((5-bromo-1-methyl- 6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate (0.20 g, 24%).
  • the chiral SFC conditions were as follows: Phenomenex Cellulose-3 column (250 mm x 21.2 mm, 5 ⁇ m); mobile phase: methanol; flow rate: 18 mL/min; diluent: methanol; loading: 80 mg/injection. Isomer 1 at RT 10.5 min and Isomer 2 at 18 min. [00408] Isomer 1: methyl 4-((3S,5S)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- EtOH; A:B-40% B Isocratic ⁇ 57 ⁇ ⁇ PLQV ⁇ 100.00%.
  • Step-7 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)benzoic acid [00410] To a stirred solution of methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1-methylpiperidin-3-yl)benzoate (0.23 g, 0.52 mmol, from step 6) in ethanol (5 mL) and water (0.5 mL), lithium hydroxide (0.03 g, 0.63 mmol) was added and the reaction mixture was stirred at 70 °C for 2 h.
  • a pressure vial (100 mL) equipped with a magnetic stirring bar was charged with tert-butyl (3R)- 3-(pyridine-2-carbonylamino)piperidine-1-carboxylate (10.00 g, 32.8 mmol, from step 1), silver carbonate (9 g, 32.8 mmol), Pd(OAc)2 (0.74 g, 0.32 mmol), methyl 4-iodobenzoate (43 g, 164 mmol), 2,6-dimethylbenzoic acid (1.23 g, 8.2 mmol) and t-BuOH (100 mL).
  • the vessel was flushed with argon, sealed with a crimp cap and heated to 120 °C. After 24 h, the reaction vessel was removed from the oil bath and cooled to room temperature and DCM was added to the reaction mixture. The progress of the reaction was monitored by TLC. The mixture was thoroughly stirred for 10 min and the solids were removed by filtration which was additionally rinsed with DCM. The combined filtrates were concentrated under reduced pressure and the residue was purified by column chromatography to afford tert-butyl (3R,5R)-3-(4-methoxycarbonylphenyl)-5-(pyridine-2- carbonylamino)piperidine-1-carboxylate (8.00 g, 56%) as a white solid.
  • Step-6 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)benzoic acid
  • 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)benzoic acid was prepared from methyl 4-((3R,5R)-5-amino-1-methylpiperidin-3-yl)benzoate generally following the procedures in steps 5 and 7 of the Preparation of Intermediate 1 above.
  • Step 1 [00417] To a stirred solution of an aniline or a dihaloarene (13.00 mmol) in 1,4-dioxane (25 mL) was added 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15.00 mmol) followed by potassium carbonate (25.00 mmol) dissolved in water and the reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, Pd(118) (1.30 mmol) was added and the reaction mixture was again purged with argon for 20 min.
  • Step 2 To a stirred solution of intermediate from step 1 (4.80 mmol) in ACN (40 mL) was added isoamyl nitrite (29.00 mmol) at RT and was stirred for 10 min.
  • Step 3 To a stirred solution of intermediate from step 2 (2.30 mmol) in toluene (20 mL) was added tert- butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2.70 mmol) followed by sodium tert-butoxide (3.40 mmol) at RT. The reaction mixture was purged with argon for 30 min.
  • Step 4 To a stirred solution of intermediate from step 3 (0.69 mmol) in 1,4-dioxane (10 mL) was added 10% Pd/C at RT. The reaction mixture was stirred in a steel bomb under 50 psi H2 gas pressure at RT for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to afford the desired product.
  • Step 5 To a stirred solution of the intermediate from step 4 (0.49 mmol) in DCM (5 mL) was added TFA (2 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 5 min followed by at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford the desired product.
  • Step 6 To a stirred solution of the intermediate from step 5 (0.30 mmol) in DMF (4 mL) was added 1- methylimidazole (1.00 mmol) followed by a benzoic acid intermediate (0.30 mmol) and the reaction mixture was stirred at RT for 10 min.
  • Step 2 c To a stirred solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,6-dihydro-2H- pyridine-1-carboxylate (0.25 mmol, from step 2) in EtOAc (0.5 mL) and EtOH (0.5 mL), 10% Pd/C was added followed by triethyl silane (2.55 mmol) at RT. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to afford desired product.
  • Example 1 3-(5-(4-((1-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin2yl)piperidine-2,6-dione (Compound 22) [00428] To a stirred solution of 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.02 g, 0.04 mmol, intermediate 1) in
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.01 g, 0.06 mmol) was added and stirred at 80 °C for 5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • reaction mixture was purged with argon for 30 min.
  • Pd 2 (dba) 3 (0.24 g, 0.26 mmol) and xantphos-Pd (0.42 g, 0.74 mmol) was added and the reaction mixture was again purged with argon for 20 min.
  • the reaction mixture was stirred in a sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate.
  • Step-2 tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate [00430] To a stirred solution of tert-butyl 4-(3-bromophenyl)piperazine-1-carboxylate (2.00 g, 5.86 mmol, from step 1) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.00 g, 11.72 mmol) in 1,4-dioxane (20 mL), KOAc (1.70 g, 17.58 mmol) was added at RT and the reaction mixture was purged with argon for 30 min.
  • Step-3 tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperazine-1-carboxylate [00431] To a stirred solution of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]piperazine-1-carboxylate (1.30 g, 3.35 mmol, from step 2) and 2,6-dibenzyloxy-3-bromo-pyridine (1.48 g, 4.02 mmol) in 1,4-dioxane (13 mL), K3PO4 (2.11 g, 10.05 mmol) was added dissolved in H2O (3 mL) at RT.
  • reaction mixture was purged with argon for 30 min.
  • PdCl 2 (dppf) (0.32 g, 0.40 mmol) was added and the reaction mixture was again purged with argon for 20 min.
  • the reaction mixture was stirred in a sealed tube at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • reaction mixture was stirred at RT for 72 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (40% EtOAc/hexane) to afford tert-butyl 4-[3-(2,6-dioxo-3- piperidyl)phenyl]piperazine-1-carboxylate (0.10 g, 59%) as brown solid.
  • LC-MS m/z 374.45 [M+H] + .
  • Step-5 3-(3-piperazin-1-ylphenyl)piperidine-2,6-dione [00433] To stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)phenyl]piperazine-1-carboxylate (0.10 g, 0.26 mmol, from step 4) in DCM (2 mL) and TFA (0.92 g, 0.80 mmol) was added and the reaction mixture was stirred at 0 °C for 5 min followed by at RT for 2 h. The progress of the reaction was monitored by TLC.
  • reaction mixture was purged with argon for 30 min.
  • Pd 2 (dba) 3 (0.64 g, 0.70 mmol) and xantphos-Pd (0.80 g, 1.40 mmol) were added and the reaction mixture was again purged with argon for 20 min.
  • the reaction mixture was stirred in a sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC.
  • the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-2 tert-butyl 9-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate H [00436] To a stirred solution of tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 g, 2.45 mmol, from step 1) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.24 g, 3.71 mmol) in 1,4-dioxane (40 mL), Na2CO3 (0.52 g, 4.95 mmol) was added dissolved in H2O (10 mL) at RT.
  • reaction mixture was purged with argon for 30 min.
  • PdCl2(dppf) (0.20 g, 0.02 mmol) was added and the reaction mixture was again purged with argon for 20 min.
  • the reaction mixture was stirred in a sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC.
  • the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-3 tert-butyl 7-[4-(2,6-dioxo-3-piperidyl)phenyl]-2,7-diazaspiro[4.4]nonane-2 carboxylate [00437] To a stirred solution of tert-butyl 9-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (0.60 g, 0.96 mmol, from step 2) in EtOAc (6.6 mL) and EtOH (6.6 mL), Pd/C (0.49 g) and triethyl silane (1.20 g, 0.96 mmol) were added at RT.
  • Step-4 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2,6-dione [00438] A mixture of tert-butyl 9-[4-(2,6-dioxo-3-piperidyl)phenyl]-3,9-diazaspiro[5.5]undecane-3- carboxylate (0.40 g, 0.90 mmol, from step 3) in DCM (10 mL) and 30% TFA in DCM (0.6 mL) was stirred at 0 °C for 5 min followed by at RT for 2 h. The progress of the reaction was monitored by TLC.
  • Step-5 3-[4-[3-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-3,9-diazaspiro[5.5]undecan-9-yl]phenyl]piperidine-2,6-dione OH N [00439] To a stirred solution of 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2,6-dione (0.08 g, 0.23 mmol, from step 4) in DMF (1.5 mL), 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1- methyl-3-piperidyl]benzoic acid (0.09 g, 0.23 mmol, intermediate 1) was added followed
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.09 g, 0.35 mmol) was added and stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice cold water.
  • reaction mixture was purged with argon for 30 min.
  • Pd 2 (dba) 3 (0.32 g, 0.35 mmol) and xantphos-Pd (0.40 g, 0.70 mmol) were added at RT and the reaction mixture was again purged with argon for 20 min.
  • the reaction mixture was stirred in a sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate.
  • Step-2 tert-butyl 9-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate H [00444] To a stirred solution of tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.60 g, 1.47 mmol, from step 1) in 1,4-dioxane (20 mL) was added (2,6-dibenzyloxy-3-pyridyl)boronic acid (0.90 g, 2.17 mmol) followed by Na2CO3 (0.30 g, 2.94 mmol) at RT.
  • reaction mixture was purged with argon for 30 min.
  • PdCl2(dppf) (0.11 g, 0.14 mmol) was added at RT and the reaction mixture was again purged with argon for 20 min.
  • the reaction mixture was stirred in sealed tube at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate.
  • Step-3 tert-butyl 9-[4-(2,6-dioxo-3-piperidyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate [00445] To a stirred solution of tert-butyl 9-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (0.60 g, 0.96 mmol, from step 2) in EtOAc (1 mL) and EtOH (1 mL) were added triethyl silane (1.60 g, 14.40 mmol) and 10% Pd/C (0.39 g) at RT.
  • reaction mixture was stirred in a sealed tube at RT for 24 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% MeOH in DCM) to afford tert-butyl 9-[4-(2,6-dioxo-3-piperidyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.25 g, 62%) as a brown solid. LCMS: m/z 442.50 [M+H] + .
  • Step-4 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2,6-dione
  • reaction mixture was stirred at RT for 10 min. To this was added 3-[4-(3,9- diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2,6-dione (0.10 g, 0.29 mmol, from step 4) and the reaction mixture was stirred at 80 °C for 8 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate.
  • reaction mixture was stirred at RT for 10 min. To this was added 3-[4-(3,9-diazaspiro [5.5]undecan-3-yl)-2-fluoro-phenyl]piperidine-2,6-dione (0.08 g, 0.22 mmol) at RT. The reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate.
  • reaction mixture was diluted with sodium thiosulfate solution and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 6-bromo-3-iodo-1H-indazole (6.50 g, crude) as an off white solid, which was used as such for the next reaction.
  • LC-MS m/z 322.82 and 324.82 [M+H] + .
  • Step-2 6-bromo-3-iodo-1-methyl-indazole
  • acetone 100 mL
  • KOH 2.30 g, 41.00 mmol
  • reaction mixture was stirred at RT for 5 min.
  • iodomethane 7.20 g, 50.00 mmol
  • reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with cold water and extracted with DCM.
  • Step-3 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole [00451] To a stirred solution of 6-bromo-3-iodo-1-methyl-indazole (6.00 g, 17.80 mmol, from step 2) in THF (70 mL) and water (60 mL) was added 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (11.15 g, 26.72 mmol) followed by cesium carbonate (17.40 g, 53.40 mmol) and the reaction bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (1.63 g, 1.78 mmol) was added at RT.
  • reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by CombiFlash® column chromatography (15% EtOAc/heptane) to afford 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (3.80 g, 43%) as pale yellow solid.
  • LC-MS m/z 500.0 and 502.0 [M+H] + .
  • Step-4 tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3- carboxylate n [00452] To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (2.00 g, 3.99 mmol, from step 3) in 1,4-dioxane (40 mL) was added tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.11 g, 4.39 mmol) followed by cesium carbonate (2.65 g, 8.13 mmol) at RT.
  • reaction mixture was purged with argon for 10 min.
  • tris(dibenzylideneacetone)dipalladium(0) (0.36 g, 0.40 mmol)
  • 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.39 g, 0.80 mmol) were added and the reaction mixture was again purged with argon for 2 min.
  • the reaction mixture was stirred in a sealed tube at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate.
  • Step-5 tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3- carboxylate [00453] To a mixture of tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (1.00 g, 1.48 mmol, from step 4) in 2,2,2-trifluoroethanol (15 mL) was added 10% Pd/C (1.00 g) and reaction mixture was stirred at RT under 100 psi hydrogen gas pressure in autoclave for 8 h.
  • Step-6 3-[6-(3,9-diazasp -dione [00454] To a stirred solution of tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (0.50 g, 1.00 mmol, from step 5) in DCM (10 mL) was added TFA (1.16 g, 10.09 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC.
  • Step-7 3-[6-[3-[4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-3,9-diazaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione [00455] To a stirred solution of 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl- 3-piperidyl]benzoic acid (0.07 g, 0.18 mmol, intermediate 8) in DMF (2 mL) was added 1-methylimidazole (0.07 g, 0.92 mmol) followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0
  • the present disclosure provides technologies useful for, among other things, manufacturing various compounds described herein. Certain useful technologies are described herein as examples.
  • the present disclosure provides a compound having the structure salt thereof, wherein LG is a leaving group, R PG is a protecting group, and the other variables are as defined and described in classes and subclasses herein, both singly and in combination.
  • Various leaving groups are available and can be utilized in accordance with the present disclosure.
  • a leaving group utilized in the present disclosure is ⁇ Cl, ⁇ Br, ⁇ I, ⁇ OTs, or ⁇ OTf.
  • R PG is Bn.
  • Ring C is Ring Cy a , wherein Cy a is Cy a is optionally substituted mono- or bicyclic 6- to 10-membered aryl or optionally substituted mono- or bicyclic 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S.
  • the present disclosure provides a compound having the structure of , wherein LG is ⁇ Cl, ⁇ Br or ⁇ I, and Cy a is optionally substituted mono- or bicyclic 6- to 10-membered aryl or optionally substituted mono- or bicyclic 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S.
  • LG is ⁇ Cl, ⁇ Br or ⁇ I
  • Cy a is optionally substituted mono- or bicyclic 6- to 10-membered aryl or optionally substituted mono- or bicyclic 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S.
  • Step 1 & step 1b To a stirred solution of substituted halo-aniline or dihaloaryl (13.00 mmol) in 1,4-dioxane (2 mL per mmol) is added 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15.00 mmol) followed by potassium carbonate (25.00 mmol) dissolved in water and the reaction mixture is purged with argon for 30 min. To the resulting reaction mixture, Pd-118 (0.83 g, 1.30 mmol) is added and the reaction mixture is again purged with argon for 20 min.
  • reaction mixture is stirred in a sealed tube at 100 °C for 16 h.
  • the progress of the reaction is monitored by TLC.
  • the reaction mixture is filtered through celite.
  • the filtrate is diluted with cold water and extracted with ethyl acetate.
  • the combined organic layer is washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound is purified by silica gel column chromatography (50% EtOAc in heptane) to afford desired intermediate.
  • step 2 if aniline starting material used in step 1.
  • Step 2 To a stirred solution of intermediate from step 1 (4.80 mmol) in ACN (8 mL per mmol) is added isoamyl nitrite (29.00 mmol) at RT. Stir the reaction for 10 min then add copper (I) iodide (14.00 mmol) at RT. The reaction mixture is stirred at 60 °C for 1 h. The progress of reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is diluted with cold water and extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step 2 [00463] To a stirred solution of intermediate from step 1 (0.69 mmol) in 1,4-dioxane (14.5 mL per mmol) is added 10% Pd/C (0.30 g) at RT. The reaction mixture is stirred in a steel bomb under 50 psi H2 gas pressure at RT for 16 h. The progress of the reaction is monitored by TLC and LCMS. After completion of reaction, the reaction mixture is filtered through celite. The filtrate is concentrated under reduced pressure.
  • Step 3 To a stirred solution of intermediate from step 2 (0.49 mmol, from step 2) in DCM (10 mL) is added TFA (2 mL) at 0 °C and the reaction mixture is stirred at 0 °C for 5 min followed by at RT for 3 h. The progress of the reaction is monitored by TLC. After completion of reaction, the reaction mixture is concentrated under reduced pressure to afford the desired product.
  • Step 2 tert-butyl (3R,5R)-3-(4-methoxycarbonylphenyl)-5-(pyridine-2-carbonylamino)piperidine-1- carboxylate
  • a pressure vial (100 mL) equipped with a magnetic stirring bar is charged with tert-butyl (3R)-3- (pyridine-2-carbonylamino)piperidine-1-carboxylate (10.00 g, 32.8 mmol, from step 1), silver carbonate (9 g, 32.8 mmol), Pd(OAc) 2 (0.74 g, 0.32 mmol), methyl 4-iodobenzoate (43 g, 164 mmol), 2,6-dimethylbenzoic acid (1.23 g, 8.2 mmol) and t-BuOH (100 mL).
  • the vessel is flushed with argon, sealed with a crimp cap and is heated to 120 °C. After 24 h, the reaction vessel is removed from the oil bath and cooled to room temperature and DCM is added to the reaction mixture. The progress of the reaction is monitored by TLC. The mixture is thoroughly stirred for 10 min and the solids are removed by filtration which is additionally rinsed with DCM. The combined filtrates are concentrated under reduced pressure and the residue is purified by silica-gel column chromatography to afford tert-butyl (3R,5R)-3-(4-methoxycarbonylphenyl)-5-(pyridine-2- carbonylamino)piperidine-1-carboxylate (8.00 g, 56%) as a white solid.
  • Step 4 methyl 4-[(3R,5R)-1-methyl-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate [00468] To a stirred solution of methyl 4-[(3R,5R)-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate (7.0 g, 21 mmol, from step 3) and glacial acetic acid (1 mL) in methanol (70 mL) is added 37% w/v formaldehyde (2.9 mL) and stirred for 5 h. Then sodium triacetoxyborohydride (6.53g, 31mmol) is added over a period of 30 min at 0 °C.
  • Step-5 methyl 4-((3R,5R)-5-amino-1-methylpiperidin-3-yl)benzoate [00469] To a stirred suspension of methyl 4-[(3R,5R)-1-methyl-5-(pyridine-2-carbonylamino)-3- piperidyl]benzoate (1.00 g, 2.80 mmol, from step 4) in water (50 mL) is added 12 N HCl solution (5 mL) at 0 °C, followed by zinc powder (2.76 g, 42.00 mmol) and DCM (50 mL) and the reaction mixture is stirred at RT for 12 h in a round bottomed flask. The progress of the reaction is monitored by TLC.
  • Step 6 methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin- 3-yl)benzoate [00470] To a stirred solution of methyl 4-((cis)-5-amino-1-methylpiperidin-3-yl)benzoate (3.00 g, 12.09 mmol, from step 5) in DMSO (30 mL), K2CO3 (5.00 g, 36.29 mmol) is added, followed by 4,5-dibromo-2- methylpyridazin-3(2H)-one (general intermediate 29, 4.86 g, 18.14 mmol), and the reaction mixture is stirred at 100 °C for 16 h.
  • Step 7 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)benzoic acid [00471] To a stirred solution of methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1-methylpiperidin-3-yl)benzoate (0.23 g, 0.52 mmol, from step 6) in ethanol (5 mL) and water (0.5 mL), lithium hydroxide (0.03 g, 0.63 mmol) is added and the reaction mixture is stirred at 70 °C for 2 h.
  • reaction mixture is stirred at 100 °C for 16 h. The progress of the reaction is monitored by TLC. After completion of reaction, the reaction mixture is diluted with cold water and extracted with ethyl acetate. The combined organic layer is washed with water and brine, respectively, then dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford ethyl 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo- pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate (5.50 g, 29%) as an off white solid.
  • Step 2 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid [00473] To a stirred solution of ethyl 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1- methyl-3-piperidyl]benzoate (3.00 g, 7.40 mmol from step 1) in ethanol (10 mL), THF (10 mL) and H 2 O (10 mL) is added LiOH.H 2 O (0.35 g, 14.82 mmol) at RT.
  • reaction mixture is stirred at 50 °C for 2 h. After completion of reaction, the reaction mixture is concentrated, and washed with diethyl ether to obtain crude. The crude is diluted with water, acidified with 1N HCl (pH 3) to get solid, which is filtered and washed with diethyl ether to afford 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid (2.10 g, 75%) as an off white solid.
  • LC-MS m/z 377.20 [M+H] + .
  • reaction mixture is purged with argon for 30 min.
  • PdCl 2 (dppf).DCM (0.85 g, 1.11 mmol) is added and the reaction mixture is again purged with argon for 20 min.
  • the reaction mixture is stirred in a sealed tube at 90 °C for 16 h.
  • the progress of the reaction is monitored by TLC.
  • the reaction mixture is filtered through a pad of celite. The filtrate is diluted with cold water and extracted with ethyl acetate. The combined organic layer is washed with water and brine, respectively, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude.
  • Step 2 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid: [00475] To a stirred solution of ethyl 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl- 3-piperidyl]benzoate (2.50 g, 6.20 mmol) in ethanol (20 mL) and H2O (4 mL) is added LiOH.H2O (0.54 g, 22.54 mmol) at RT.
  • reaction mixture is stirred at 70 °C for 2 h.
  • the progress of the reaction is monitored by TLC.
  • the reaction mixture is concentrated, and the residue is washed with diethyl ether to obtain crude.
  • the crude is diluted with water and acidified with 1N aq. HCl (pH 3) to get solid, which is filtered and washed with diethyl ether to afford 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4- yl)amino]-1-methyl-3-piperidyl]benzoic acid (2.10 g, 90%) as brown solid.
  • Step 2 [00477] To a stirred solution of intermediate from step 1 (0.19 mmol, step 1 of intermediate 24) in DCM (10 mL), thionyl chloride (0.39 mmol) is added at 0 °C, and the reaction mixture is stirred at RT for 4 h. The progress of the reaction is monitored by TLC. After completion of reaction, the reaction mixture is concentrated under reduced pressure. The residue is diluted with water, and the aqueous layer is extracted with ethyl acetate. The combined organic layer is dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which is purified by silica-gel column chromatography (50% ethyl acetate in hexane) to afford the desired general intermediate.
  • Step-1 To a stirred solution of general intermediate 21 (0.45 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.54 mmol) in 1,4-dioxane (3 mL), is added Na2CO3 (0.67 mmol) dissolved in H2O (1.2 mL) at RT. The reaction mixture is purged with argon for 30 min.
  • reaction mixture is stirred at RT for 5 min.
  • intermediate 26-28 (0.31 mmol) at RT and the reaction mixture is stirred at 100 °C for 16 h.
  • the progress of the reaction is monitored by TLC.
  • the reaction mixture is diluted with water and extracted with DCM. The combined organic layer is dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • the crude compound is purified by prep HPLC to afford the desired product.
  • Step 2 To a stirred solution of intermediate from step 1 (3.00 mmol) in tetrahydrofuran (20 mL), methanol (20 mL) and water (10 mL) is added lithium hydroxide (0.15 g, 6.10 mmol). The reaction mixture is heated to 55°C for 16h.
  • Step 3 To a stirred solution of intermediate from step 2 (2.66 mmol) in DMF (20 mL) is added N,N- diisopropylethylamine (7.96 mmol) and 3-aminopiperidine-2,6-dione (2.90 mmol), respectively, and the reaction mixture is stirred at RT for 10 min.
  • Step 4 To a stirred solution of intermediate from step 3 (1.46 mmol) in dichloromethane (30 mL) is added TFA (5 mL) at 0 oC and the reaction mixture is stirred at RT for 2 h. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and then the residue is triturated with DCM and diethyl ether, respectively, to afford the desired intermediate. Step 5
  • Step 2 To the stirred solution of N,N-dibenzyl-4-bromo-2-fluoroaniline (5.29 mmol, from step 1) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (5.29 mmol) in toluene (20 mL) is added sodium tert- butoxide (15.88 mmol) and purged with argon gas for 15 min.
  • Step 3 To a stirred solution of tert-butyl 9-(4-(dibenzylamino)-3-fluorophenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (2.70 mmol, from step 2) in 1,4-dioxane (5 mL) is added 10% Pd/C (0.50 g) and the reaction mixture is stirred under hydrogen atmosphere (50 psi) at 80 oC for 12 h. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is passed through a celite pad, and the filtrate is concentrated under reduced pressure to obtain the crude product.
  • Step 4 To the stirred solution of tert-butyl 9-(4-amino-3-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (1.87 mmol, from step 3) in DMF (10 mL), is added N,N-diisopropylethylamine (9.33 mmol) and stirred for 2 min. Then 3-bromopiperidine-2,6-dione (2.80 mmol) is added to the reaction mixture and the reaction mixture is stirred at 100 oC for 12 h. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is filtered, and the filtrate is concentrated to obtain crude product.
  • Step 5 To a stirred solution of tert-butyl 9-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (0.35 g, 0.73 mmol, from step 4) in DCM (20 mL) is added TFA (1.5 mL) at 0 oC and the reaction mixture is stirred at RT for 2 h. The progress of the reaction is monitored by TLC.
  • Step 6 To a stirred solution of 3-((2-fluoro-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)-piperidine- 2,6-dione (0.44 mmol, from step 5) and general intermediate 23-25 (0.44 mmol) in DMF (5 mL) are added 1- methylimidazole (2.33 mmol) and TCFH (0.93 mmol), respectively. The reaction mixture is stirred at RT for 16 h. The progress of the reaction is monitored by TLC. After completion of reaction, the reaction mixture is diluted with ice-cold water and extracted with ethyl acetate.
  • Step 1 To a stirred solution of bromo chloro quinoline (16.49 mmol) in propionitrile (40 mL) are added sodium iodide (32.50 mmol) and chlorotrimethylsilane (2.3 mL), respectively, at 0 o C. The reaction mixture is stirred at 100 o C for 16 h. The progress of the reaction is monitored by TLC. After completion the reaction, the reaction mixture is basified using aq.
  • Step 2 To a stirred solution of intermediate from step 1 (5.98 mmol) and cesium carbonate (4.88 g, 14.90 mmol) in 1,4-dioxane (20 ml) were added MS 4 ⁇ (200 mg) and 3-(4-methoxybenzyl)dihydropyrimidine- 2,4(1H,3H)-dione (6.60 mmol, from step 6), and the reaction mixture is purged with argon for 20 min.
  • Step 3 To a stirred solution of intermediate from step 2 (4.12 mmol) and tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate (4.12 mmol) in DMSO (18 mL), is added potassium carbonate (12.40 mmol) at RT and the reaction mixture is purged with argon for 30 min. To the resulting reaction mixture, L- Proline (0.81 mmol) is added and purged with argon for 10 min and then copper (I) iodide (0.40 mmol) is added and the reaction mixture is again purged with argon for 5 min.
  • reaction mixture is stirred at 110 o C for 16 h.
  • the progress of the reaction is monitored by TLC.
  • the reaction mixture is filtered through a celite pad.
  • the filtrate is diluted with cold water and extracted with ethyl acetate.
  • Combined organic layer is washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain crude product.
  • the crude compound is purified by silica gel column chromatography to afford the desired intermediate.
  • Step 4 To a stirred cooled solution of intermediate from step 3 (0.65 mmol) in dichloromethane (8 mL), is added trifluoromethanesulfonic acid (4 mL) and TFA (4 mL) at 0 °C. The reaction mixture is then stirred at RT for 3 h. The progress of the reaction is monitored by TLC. After completion of reaction, the reaction mixture is concentrated under reduced pressure to afford the desired intermediate.
  • Step 5 To a stirred solution of intermediate from step 4 (0.30 mmol) in DMF (5 mL), is added 1- methylimidazole (1.00 mmol) and general intermediate 23-25 (0.25 mmol), respectively, and the reaction mixture is stirred at RT for 10 min.
  • Step 6 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione [00501] To a stirred solution of hexahydropyrimidine-2,4-dione (43.82 mmol) in DMF (60 mL) is added cesium carbonate (64.40 mmol) and 4-methoxybenzyl chloride (65.7 mmol) the reaction mixture is stirred at 30 o C for 12 h. The progress of the reaction is monitored by TLC. After completion of reaction, the reaction mixture is quenched with ice-cold water.
  • Step 1 tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate
  • tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (4.25 mmol) in dichloromethane (10 mL) is added triethylamine (13 mmol) and 4-dimethylaminopyridine (0.42 mmol) at 0 oC.
  • Trifluoromethanesulfonic anhydride (6.35 mmol) is added to the reaction mixture and reaction mixture is stirred at RT for 16 h. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is quenched with saturated aq. sodium bicarbonate solution, and then extracted with DCM. The organic layer is dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain crude product.
  • Step 2 To a stirred solution of general intermediate 1 (24.00 mmol) in 1,4-dioxane (35 mL) is added potassium acetate (23.00 mmol) and the reaction mixture is purged with argon for 10 min. To the resulting reaction mixture, [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.78 mmol) is added and the reaction mixture is again purged with argon for 10 min. The reaction mixture is stirred at 100 °C for 16 h in a sealed tube. The progress of the reaction is monitored by TLC.
  • reaction mixture is filtered through a celite pad, and the filtrate is concentrated under reduced pressure to obtain crude compound.
  • the crude is purified by flash chromatography (silica) where the product is eluted with 10% ethyl acetate in heptane to afford the desired intermediate.
  • Step 3 To a stirred solution of intermediate form step 2 (1.08 mmol) in 1,4-dioxane (10 mL) and water (2 mL), is added 2,6-dibenzyloxy-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-pyridine (1.29 mmol, from step 1) and sodium carbonate (2.72 mmol) and the reaction mixture is purged under nitrogen atmosphere for 10 min. 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.10 mmol) is added to the reaction mixture under nitrogen atmosphere.
  • reaction mixture is stirred at 100 °C for 16 h.
  • the progress of the reaction is monitored by TLC.
  • the reaction mixture is cooled to room temperature, diluted with water, and extracted with EtOAc.
  • the organic layer is washed with brine solution, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain crude product.
  • the crude is purified by flash chromatography (silica) where the product is eluted with 10% ethyl acetate in heptane to afford the desired intermediate.
  • Step 4 To a stirred solution of intermediate from step 3 (0.42 mmol) in ethyl acetate (2 mL) and tetrahydrofuran (2 mL) is added 10% Pd/C (0.2 g) at RT. The reaction mixture is stirred under hydrogen pressure (100 psi) at RT for 16 h. The progress of the reaction is monitored by TLC. The reaction mixture is filtered through a celite pad washing with 10% MeOH in DCM. The combined filtrate is concentrated under reduced pressure and the obtained crude compound is purified by flash chromatography (silica) where the product is eluted with 2% MeOH in DCM to afford the desired intermediate.
  • Step 5 To a stirred solution intermediate from step 4 (0.36 mmol) in dichloromethane (2 mL), is added TFA (0.5 mL) at 0 oC and the reaction mixture is stirred at RT for 2 h. The progress of the reaction is monitored by TLC. After the completion of the reaction, the reaction mixture is concentrated under reduced pressure and triturated with DCM and diethyl ether, respectively, to afford the desired intermediate as TFA salt.
  • Step 6 To a stirred solution of intermediate from step 5 (0.22 mmol) in N,N-dimethyl formamide (2 mL), is added sodium bicarbonate (1.11 mmol) followed by general intermediate 26-28 (0.22 mmol).
  • Reaction is stirred at 85 oC for 16 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, ice cold water is added to the reaction mixture and the precipitated solids were filtered, dried, and purified by preparative HPLC to afford the desired product.
  • Step 2 2-(2,6-dioxopiperidin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1,3-dione [00509] A stirred solution of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.96 mmol, from Step 1), bis(pinacolato)diboron (8.90 mmol) and potassium acetate (8.88 mmol) in 1,4-dioxane (20 mL) is purged with argon for 15 min.
  • Step 3 tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,3-difluoro-3,6-dihydropyridine- 1(2H)-carboxylate [00510] A stirred solution of tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1(2H)-carboxylate (1.36 mmol, from step of 1 general procedure 10), 2-(2,6-dioxopiperidin- 3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1,3-dione (1.36 mmol, from step 2) and potassium carbonate (4.08 mmol) in
  • reaction mixture PdCl 2 (dtbpf) (0.13 mmol) is added, and the reaction mixture is again purged with argon for 15 min. The reaction mixture is stirred at 100 °C for 16 h in sealed tube. The progress of the reaction is monitored by TLC. After completion of reaction, the reaction mixture is filtered through a celite pad.
  • Step 4 tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,3-difluoropiperidine-1- carboxylate [00511] To a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,3- difluoro-3,6-dihydropyridine-1(2H)-carboxylate (0.35 mmol, from step 3) in ethyl acetate (5 mL) is added 10% Pd/C (0.15 g) at RT.
  • reaction mixture is stirred at RT under H 2 atmosphere (100 psi) for 16 h.
  • the progress of the reaction is monitored by TLC and LCMS.
  • the reaction mixture is filtered through a celite pad, and the filtrate is concentrated under reduced pressure to obtain crude.
  • the crude compound is purified by silica-gel column chromatography using 5% MeOH in DCM as eluent to afford tert- butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,3-difluoropiperidine-1-carboxylate as a yellow liquid.
  • LCMS m/z 476.28 [M-H]-.
  • Step 5 5-(3,3-difluoropiperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [00512] To a cooled stirring solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)- 3,3-difluoropiperidine-1-carboxylate (0.20 mmol, from step 4) in dichloromethane (2 mL), is added TFA (0.1 mL) at 0 °C. The reaction mixture is warmed to RT and stirred for 3 h. The progress of the reaction is monitored by TLC.
  • Step 2 tert-butyl 4-(3-(aminomethyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(3-(aminomethyl)phenyl)piperazine-1-carboxylate [00515] To a stirred solution of tert-butyl tert-butyl 4-(3-cyanophenyl)piperazine-1-carboxylate (2.00 g, 5.62 mmol, from step 1) in methanol (15 mL) is added Raney nickel (34.07 mmol) followed by 7M ammonia in MeOH (5 mL) and the reaction mixture is stirred at 60 psi H 2 gas pressure at RT for 16 h.
  • reaction mixture is filtered through celite. The filtrate is concentrated under reduced pressure to afford tert-butyl 4-(3-(aminomethyl)phenyl)piperazine- 1-carboxylate which is used such as for the next reaction.
  • Step 3 tert-butyl 4-(3-(((2-cyanoethyl)amino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(3-(aminomethyl)phenyl)piperazine-1-carboxylate 3.10 mmol, from step 2) in ethanol (11 mL) is added acrylonitrile (2.43 mmol) at RT.
  • the reaction mixture is stirred at 90 °C for 3 h.
  • the progress of the reaction is monitored by TLC. After completion of reaction, the reaction mixture is cooled at RT.
  • Step 4 tert-butyl 4-(3-((N-(2-cyanoethyl)cyanamido)methyl)phenyl)piperazine-1-carboxylate [00517] To a stirred solution of tert-butyl 4-(3-(((2-cyanoethyl)amino)methyl)phenyl)piperazine-1- carboxylate (0.60 mmol, from step 3) in ethanol (3 mL) is added sodium acetate (0.60 mmol) followed by cyanogen bromide (0.60 mmol) at RT and the reaction mixture is stirred at RT for 16 h. The progress of the reaction is monitored by TLC.
  • reaction mixture is cooled to RT, diluted with water and extracted with ethyl acetate.
  • the combined organic layer is washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford tert-butyl 4-(3-((N-(2- cyanoethyl)cyanamido)methyl)phenyl)piperazine-1-carboxylate which is used as such for the next reaction.
  • Step 5 1-(3-(piperazin-1-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione [00518] To a stirred solution of tert-butyl 4-(3-((N-(2-cyanoethyl)cyanamido)methyl)phenyl)piperazine-1- carboxylate (0.22 mmol, from step 4) in THF (2 mL) is added 6N HCl (1 mL) and the reaction mixture is stirred at 100 °C for 2 h. The progress of the reaction is monitored by TLC.
  • Step 6 [00519] To a stirred solution of 1-(3-(piperazin-1-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione (0.22 mmol, from step 5) in N,N-dimethyl formamide (2 mL), is added sodium bicarbonate (1.11 mmol) followed by general intermediate 26-28 (0.22 mmol). The reaction is stirred at 85 oC for 16 h.
  • reaction mixture is concentrated under reduced pressure to obtain crude which is dissolved in acetic acid (30 mL).
  • urea 6.3 g, 100 mmol
  • reaction heated to 110 oC for 16 h The progress of the reaction is monitored by TLC.
  • the reaction mixture is concentrated under reduced pressure, basified with aq. sodium bicarbonate, the precipitated solids were filtered and dried under vacuum to afford 1-(4-bromo-2,6-dimethylphenyl)dihydropyrimidine-2,4(1H,3H)-dione as a yellow solid.
  • Step 2 Desired product is obtained by using 1-(4-bromo-2,6-dimethylphenyl)dihydropyrimidine- 2,4(1H,3H)-dione (from step 2) and following steps 3 to 5 in general procedure 9.
  • Step 2 tert-butyl 9-(3-((3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylat [00523] To a stirred solution of 1-[(3-bromophenyl)methyl]-3-[(4-methoxyphenyl)methyl]hexa- hydropyrimidine-2,4-dione (2.1 mmol, from step 1) in 1,4-dioxane (20 mL), caesium carbonate (11 mmol) is added at RT.
  • reaction mixture is purged with argon for 30 min.
  • the reaction mixture is stirred in a sealed tube at 110 °C for 16 h.
  • the progress of the reaction is monitored by TLC and LCMS.
  • the reaction mixture is filtered through a pad of celite and washed with ethyl acetate (100 mL). The filtrate is diluted with cold water and extracted with ethyl acetate.
  • Step 3 1-(3-(3,9-diazaspiro[5.5]undecan-3-yl)benzyl)-3-(4-methoxybenzyl)dihydropyri—midine-2,4(1H,3H)- dione [00524] A mixture of tert-butyl 9-(3-((3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)- yl)methyl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 mmol, from step 2) in formic acid (10 mL) is stirred at 0 °C for 5 min followed by at RT for 3 h.
  • Step 4 tert-butyl ((3R,5R)-5-(4-(9-(3-((3-(4-methoxybenzyl)-2,4-dioxotetrahydropyri-midin-1(2H)- yl)methyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)-1-methylpiper-idin-3-yl)carbamate [00525] To a stirred solution of tert-butyl ((3R,5R)-5-(4-bromophenyl)-1-methylpiperidin-3-yl)carbamate (1.76 mmol) and 1-(3-(3,9-diazaspiro[5.5]undecan-3-yl)benzyl)-3-(4-methoxybenzyl)dihydropyrimidine- 2,4(1H,3H)-dione (1.23 mmol, from step 3) in 1,
  • Step 5 1-(3-(9-(4-((3R,5R)-5-amino-1-methylpiperidin-3-yl)phenyl)-3,9-diazaspiro-[5.5]undecan-3- yl)benzyl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione [00526]
  • reaction mixture is stirred at 110 °C for 2 h in a microwave.
  • the progress of the reaction is monitored by TLC and LCMS.
  • the reaction mixture is filtered through a pad of celite. The filtrate is concentrated under reduced pressure to obtain crude, which is purified by silica-gel column chromatography using 15% MeOH in DCM as eluent to afford the desired intermediate.
  • the reaction mixture is stirred at RT for 2 h.
  • the progress of the reaction is monitored by TLC.
  • (2S,4R)-1- ((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (0.34 mmol) is added at 0 oC and then stirred at RT for 10 min.
  • BOP (0.25 g, 0.54 mmol) is added to the reaction mixture and stirred at RT for 2 h. Progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get crude product.
  • Step 2 To a stirred solution of intermediate from step 1 (0.17 mmol) in dichloromethane (5 mL) is added TFA (0.2 mL) and reaction mixture is stirred at 0 °C for 5 min and at RT for 2 h. The progress of the reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and then triturated with heptane and diethyl ether, respectively, to afford the desired intermediate as a TFA salt.
  • Step 3 To a stirred solution of general intermediate 23-25 (0.21 mmol) in DMF (5 mL) is added N,N- diisopropylethylamine 0.5 mmol) at RT and stirred at RT for 5 min. To the reaction mixture, intermediate from step 2 (0.17 mmol) and BOP (0.12 g, 0.26 mmol) is added. The reaction mixture is stirred at RT for 2 h. Progress of the reaction is monitored by TLC and LCMS. After completion the reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain crude product.
  • Step 2 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol [00534] To a stirred solution of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (3.0 g, 13.87 mmol, from step-1) in tetrahydrofuran (40 mL) was added LAH (1 M in THF, 4 mL, 4 mmol) at 0 °C and the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aq. sodium sulphate solution and extracted with ethyl acetate.
  • Step 3 tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate
  • 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (0.60 g, 2.72 mmol, from step 2) in DMF (6 mL) were added (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.93 g, 2.72 mmol) and N,N- diisopropylethylamine (2.36 mL), respectively, and the reaction mixture was stirred at RT for 10 min.
  • Step 4 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide
  • Step 5 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide
  • (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2- hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.10 g, 0.20 mmol, from step 4) in DMF (3 mL) were added 1-acetylimidazole (0.05 g, 0.43 mmol) and N,N-diisopropylethylamine (0.196 mL, 1.12 mmol), respectively, and the reaction mixture was stirred at RT for 16 h.
  • Step 6 tert-butyl (6-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)hexyl)-carbamate [00538] To a stirred solution of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(2- hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.08 g, 0.16 mmol, from step 5) in DMF (2 mL, 25.8 mmol) were added tert-butyl (6-bromohexyl)carbamate (0.09 g, 0.32 mmol) and N,N- diisopropylethylamine (0.14
  • Step 7 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((6-aminohexyl)oxy)-4-(4-methylthiazol- 5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide [00539] To a stirred solution of tert-butyl (6-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)- 4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)hexyl)carba-mate (0.07 g, 0.10 mmol, from step 6) in DCM was added hydrochloric acid (4 M in 1,4-dioxane, 1 mL) at 0 oC, and the reaction mixture was stirred at RT for 2 h.
  • Step 8 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((6-(4-((3R,5R)-5-((5-bromo-1-methyl- 6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzamido)hexyl)oxy)-4-(4- methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide [00540] To a stirred solution of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((6- aminohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide (0.09 g, 0.16 mmol, from step 7) in DMF

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Abstract

Entre autres, la présente divulgation propose des technologies ciblant KAT2. Dans certains modes de réalisation, la présente divulgation propose des technologies pour réduire les niveaux de polypeptides KAT2 dans divers systèmes. Dans certains modes de réalisation, la présente divulgation propose des technologies pour traiter divers troubles, maladies ou affections, notamment ceux associés à un polypeptide KAT2, tels que divers cancers.
PCT/US2024/025468 2023-04-20 2024-04-19 Technologies ciblant des états de cellule Pending WO2024220843A1 (fr)

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AU2024256729A AU2024256729A1 (en) 2023-04-20 2024-04-19 Technologies targeting cell states
CN202480026286.2A CN120957715A (zh) 2023-04-20 2024-04-19 靶向细胞状态的技术
IL324013A IL324013A (en) 2023-04-20 2025-10-16 Technologies targeting cell states
MX2025012361A MX2025012361A (es) 2023-04-20 2025-10-16 Tecnologias dirigidas a estados celulares
CONC2025/0015654A CO2025015654A2 (es) 2023-04-20 2025-11-11 Tecnologías dirigidas a estados celulares

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PCT/US2023/031835 WO2024050078A1 (fr) 2022-09-02 2023-09-01 Dérivés de pyridazinone utilisés comme agents de dégradation de kat2 pour le traitement de troubles prolifératifs
US202463561294P 2024-03-04 2024-03-04
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Citations (5)

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WO2017079267A1 (fr) * 2015-11-02 2017-05-11 Yale University Composés chimères de ciblage de protéolyse et procédés de préparation et d'utilisation de ceux-ci
WO2018144649A1 (fr) * 2017-01-31 2018-08-09 Arvinas, Inc. Ligands de céréblon et composés bifonctionnels les contenant
WO2020206137A1 (fr) * 2019-04-04 2020-10-08 Dana-Farber Cancer Institute, Inc. Agents de dégradation de cdk2/5 et utilisations associées
WO2021055756A1 (fr) * 2019-09-19 2021-03-25 The Regents Of The University Of Michigan Agents de dégradation de protéine de récepteur d'androgène spirocycliques
WO2021058017A1 (fr) * 2019-09-29 2021-04-01 Beigene, Ltd. Dégradation du récepteur des androgènes (ar) par conjugaison d'antagonistes ar avec un ligand de ligase e3 et procédés d'utilisation

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Publication number Priority date Publication date Assignee Title
WO2017079267A1 (fr) * 2015-11-02 2017-05-11 Yale University Composés chimères de ciblage de protéolyse et procédés de préparation et d'utilisation de ceux-ci
WO2018144649A1 (fr) * 2017-01-31 2018-08-09 Arvinas, Inc. Ligands de céréblon et composés bifonctionnels les contenant
WO2020206137A1 (fr) * 2019-04-04 2020-10-08 Dana-Farber Cancer Institute, Inc. Agents de dégradation de cdk2/5 et utilisations associées
WO2021055756A1 (fr) * 2019-09-19 2021-03-25 The Regents Of The University Of Michigan Agents de dégradation de protéine de récepteur d'androgène spirocycliques
WO2021058017A1 (fr) * 2019-09-29 2021-04-01 Beigene, Ltd. Dégradation du récepteur des androgènes (ar) par conjugaison d'antagonistes ar avec un ligand de ligase e3 et procédés d'utilisation

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LIANG YUQING; NANDAKUMAR KUTTY SELVA; CHENG KUI: "Design and pharmaceutical applications of proteolysis-targeting chimeric molecules", BIOCHEMICAL PHARMACOLOGY, ELSEVIER, US, vol. 182, 29 August 2020 (2020-08-29), US , XP086362245, ISSN: 0006-2952, DOI: 10.1016/j.bcp.2020.114211 *

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