Techniques for targeting cellular states

Abstract

The present disclosure provides, inter alia, techniques for targeting KAT2. In some embodiments, the present disclosure provides techniques for reducing KAT2 polypeptide levels in a variety of systems. In some embodiments, the present disclosure provides techniques for the treatment of a variety of diseases, disorders, or conditions, including those associated with KAT2 polypeptides, such as a variety of cancers.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Application No. 63 / 460,764, filed April 20, 2023; U.S. Application No. 63 / 561,294, filed March 4, 2024; U.S. Application No. 63 / 575,594, filed April 5, 2024; and International Application No. PCT / US2023 / 031835, filed September 1, 2023, the entire contents of which are hereby incorporated by reference. Background Technology

[0003] KAT2A (also known as general control non-depressible 5, GCN5) and KAT2B (also known as p300 / CBP-associated factor, PCAF) are both multidomain proteins containing an acetyltransferase domain and a bromo domain. KAT2A and KAT2B have been reported to function as epigenetic proteins because they are both reported to modify and recognize modified histones. They have been reported to participate in various cellular pathways, including cell proliferation and differentiation, metabolic regulation, and DNA damage repair. See, for example, Bassi, ZI, et al. ACS Chem. Biol., 2018, 13, 2862-67. Both KAT2A and KAT2B are associated with certain diseases, disorders, and conditions, such as cancer, neurodegenerative diseases, and inflammation. See, for example, Humphreys, PG, et al., J. Med. Chem., 2017, 60, 695-709. It has been reported that conditional knockout of KAT2A in mice carrying other mutations leading to acute myeloid leukemia delayed the onset of leukemia, depleted leukemia stem cells, and shifted the fate of leukemia cells from self-renewal to differentiation, resulting in a less aggressive disease. See, for example, Domingues AP, et al., eLife 9:e51754, 2020. Summary of the Invention

[0004] This disclosure specifically covers the understanding that various symptoms, disorders, or diseases are associated with certain cellular states. For example, while many types of normal cells typically undergo proliferative, plastic cellular states and subsequently terminally differentiate and commit to a specific cellular state and cease proliferation, many cancer cells are in plastic and proliferative states (which may be referred to as plastic states), for example, by blocking differentiation, dedifferentiation, and / or transdifferentiation. In some embodiments, the plastic state of cancer cells is associated with invasive tumors (e.g., invasive and / or metastatic tumors that may be resistant to reported treatments). In some embodiments, this disclosure provides techniques for preventing and / or treating symptoms, disorders, or diseases by targeting their associated cellular states. In some embodiments, this disclosure provides techniques for targeting the plastic state of cancer cells. In some embodiments, this disclosure identifies drivers associated with the plastic state of cancer cells. In some embodiments, drivers lock cancer cells into plastic and proliferative states. In some embodiments, drivers help maintain cancer cells in plastic and proliferative states. In some implementations, the provided technology restores cancer cells to a normal cellular state and / or inhibits their growth and proliferation.

[0005] In some embodiments, KAT2A and / or KAT2B are identified as drivers of plasticity in various cancer cells, such as small cell lung cancer, neuroendocrine prostate cancer, and acute myeloid leukemia. In some embodiments, this disclosure provides compounds that can be used to regulate KAT2 (KAT2A and / or KAT2B), such as compounds for reducing KAT2 activity (e.g., by degrading KAT2 (e.g., increasing its degradation)). In some embodiments, the provided techniques (e.g., compounds, compositions, or methods) can reduce the level of the KAT2 protein. In some embodiments, the provided techniques can reduce the level of KAT2A. In some embodiments, the provided techniques can reduce the level of KAT2B. In some embodiments, the provided techniques can reduce the levels of both KAT2A and KAT2B. In some embodiments, the provided techniques can selectively reduce the level of one of KAT2A and KAT2B relative to the other. In some embodiments, the provided techniques can selectively reduce the level of KAT2A relative to KAT2B. In some embodiments, the provided compounds are particularly useful for treating and / or preventing diseases, disorders, or conditions associated with KAT2 (e.g., KAT2A and / or KAT2B), such as diseases, disorders, or conditions related to the level and / or activity of KAT2 (e.g., KAT2A and / or KAT2B) proteins. In some embodiments, the provided technology provides techniques for preventing or treating conditions, disorders, or diseases associated with KAT2A and / or KAT2B. In some embodiments, the provided technology provides techniques for preventing or treating conditions, disorders, or diseases associated with KAT2A. In some embodiments, the provided technology provides techniques for preventing or treating conditions, disorders, or diseases associated with KAT2B.

[0006] In some embodiments, the provided compound comprises a protein-binding moiety capable of binding to KAT2 proteins (e.g., KAT2A and / or KAT2B) and an E3 ligase-binding moiety capable of binding to E3 ubiquitin ligases. In some embodiments, the protein-binding moiety binds to the bromo domain of KAT2A and / or KAT2B. In some embodiments, the provided compound recruits KAT2 proteins to E3 ubiquitin ligases, thereby promoting the degradation of KAT2 proteins (e.g., KAT2A and / or KAT2B) (or otherwise inhibiting KAT2 proteins). In some embodiments, the provided compound promotes the ubiquitination of KAT2A and / or KAT2B. In some embodiments, the provided compound promotes the degradation of KAT2A and KAT2B.

[0007] In some embodiments, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0008]

[0009] PBM, connector, and LBM are as defined herein. In some embodiments, the 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, the provided compound is a compound of formula IX, IXA, IXB, IXC, or IXD, or a salt thereof.

[0010] In some embodiments, the provided compound is a compound of formula III or a salt thereof. In some embodiments, the provided compound is a compound of formula IIIA or a salt thereof. In some embodiments, the provided compound is a compound of formula IIIB, IIIB-1, or IIIB-2, or a salt thereof. In some embodiments, the provided compound is a compound of formula IIIC or a salt thereof. In some embodiments, the provided compound is a compound of formula IIID or a salt thereof. In some embodiments, the provided compound is a compound of formula IV, IVA, or IVA-1, or a salt thereof. In some embodiments, the provided compound is a compound of formula V, VA, VA-1, VB, or VB-1, or a salt thereof. In some embodiments, the provided compound is a compound of formula VI, VIA, or VIA-1, or a salt thereof. In some embodiments, the provided compound is a compound of formula VII or VIIA, or a salt thereof. In some embodiments, the provided compound is a compound of formula VIII or VIIIA, or a salt thereof. In some embodiments, the provided compound is a compound of formula X, XA, XA-1, XA-2, or XB, or a salt thereof. In some embodiments, the provided compound is a compound of formula XI or XIA, or a salt thereof. In some embodiments, the provided compound is a compound of formula XII, XIIA, XIIB, or XIIB-1, or a salt thereof. In some embodiments, the provided compound is a compound of formula XIII or XIIIA, or a salt thereof. In some embodiments, the provided compound is a compound of formula XIV or a salt thereof. In some embodiments, the provided compound is a compound of formula XV or a salt thereof. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, such a compound can bind KAT2A and / or KAT2B as well as an E3 ligase. In some embodiments, such a compound promotes the ubiquitination of KAT2A and / or KAT2B. In some embodiments, such a compound promotes the degradation of KAT2A and / or KAT2B. In some embodiments, such a compound reduces the levels of KAT2A and / or KAT2B. In some embodiments, such a compound can be used to prevent and / or treat conditions, disorders, or diseases associated with KAT2A and / or KAT2B.

[0011] In some embodiments, this disclosure provides pharmaceutical compositions comprising the provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] In some embodiments, this disclosure provides techniques (e.g., compounds or methods) for preparing the provided compounds.

[0013] In some embodiments, this disclosure provides methods for preventing a condition, disorder, or disease, comprising administering or delivering an effective amount of the provided compound or a pharmaceutically acceptable salt thereof to a subject susceptible to said condition, disorder, or disease. In some embodiments, this disclosure provides methods for treating a condition, disorder, or disease, comprising administering or delivering an effective amount of the provided compound or a pharmaceutically acceptable salt thereof to a subject suffering from said condition, disorder, or disease. In some embodiments, a pharmaceutical composition is administered to administer or deliver the provided compound or a salt thereof. In some embodiments, the condition, disorder, or disease is associated with KAT2A and / or KAT2B. In some embodiments, the condition, disorder, or disease is cancer. In some embodiments, the condition, disorder, or disease is small cell lung cancer. In some embodiments, the condition, disorder, or disease is neuroendocrine prostate cancer. In some embodiments, the condition, disorder, or disease is acute myeloid leukemia. Attached Figure Description

[0014] Figure 1 The provided compounds exhibit a variety of activities, including inhibition of tumor growth in vivo. (A): The provided compounds inhibit tumor growth in vivo. Naked Balb / c mice were seeded with NCI-H1048 cells in matrix gel. Tumor growth was allowed to reach a maximum of approximately 200 mm. 3 Mice were then randomly divided into two groups. Mice were administered the load or 30 mg / kg compound 22 via intraperitoneal (ip) once weekly. Tumor size was measured every three to four days, and once the load-treated tumor reached 2000 mm², the tumor was counted. 3Mice were euthanized. Error bars are SEM images. Administration began on day 17 after tumor inoculation. (B): The provided technique reduces KAT2A and KAT2B levels as well as histone acetylation levels. This reduction was confirmed by Western blot data of small cell lung cancer NCI-H1048 cells treated with different concentrations of compound 22 for 24 hours, as shown. The loading agent was DMSO. (C): The provided technique inhibits cell growth. Cell count data after 8 days of treatment with compound 22 relative to the DMSO control are given as an example to confirm inhibition. GI50 = 6 nM. (D): The provided technique inhibits tumor growth in vivo. Naked balb / c mice inoculated with H1048 tumors were administered intraperitoneally once weekly (qw ip) with either the loading agent (HbCD) or compound 22. Mean tumor volume + / - SEM images from 6 mice are shown. A significant 70% inhibition of tumor growth was observed at 30 mg / kg, and the treatment was well tolerated. See also (A). (E): The provided technology was well tolerated. Certain body weights relative to the starting weight are given as examples to determine tolerability and safety. (F): The provided technology reduced KAT2A and KAT2B levels and histone acetylation levels in tumors in vivo. Western blots of tumors 168 hours after the last administration showed significant reductions in KAT2A and KAT2B, as well as histone acetylation. (G): The provided technology modulates cell state and induces differentiation. Box plots of epithelial GSEA showed a significant upregulation in tumors treated with compound 22 compared to the load.

[0015] Figure 2 The provided compounds offer a variety of activities. (A): The provided technique reduces KAT2A and KAT2B levels, as well as histone acetylation levels. This reduction was confirmed by Western blot data of acute myeloid leukemia MOLM-13 cells treated with compound 22 for 48 hours, as shown. (B): The provided technique inhibits cell growth. Cell count data after 8 days of treatment with compound 22, relative to the DMSO control, are given as an example to confirm inhibition. GI 50 = 1.2 nM. (C): The provided technique can regulate cell state and induce differentiation. CD86 was analyzed by flow cytometry at 48 hours, and monocyte differentiation was observed. EC50 = 0.3 nM.

[0016] Figure 3The provided compounds offer a variety of activities. (A): The provided technique reduces KAT2A and KAT2B levels, as well as histone acetylation levels. This reduction was confirmed by Western blot analysis of neuroendocrine prostate cancer LASCPC-01 cells treated with compound 22 for 24 hours, as shown. (B): The provided technique inhibits cell growth. Cell viability (Cell Titer Glo) data after 7 days of treatment with compound 22 relative to the DMSO control are given as an example to confirm the inhibition. 50 =5 nM. (C): The provided technique modulates cell state and induces differentiation. Box plots of epithelial GSEA show a significant upregulation in cells treated with compound 22 compared to DMSO. (D): The provided technique reduces KAT2A and KAT2B levels, as well as histone acetylation levels, including in organoids from primary neuroendocrine prostate cancer patients. As shown, this reduction was confirmed by Western blot analysis of NEPC primary patient organoids treated with compound 22 for 72 hours. The concentration is nM. (E): The provided technique inhibits cell growth. Cell viability data after 21 days of treatment with compound 22 relative to the DMSO control are given as an example to confirm inhibition. GI 50 = 3 nM. (F): The provided technology modulates cell state and induces differentiation. Box plots of microglia GSEA showed significant upregulation (both epithelial and neural components). Detailed Implementation

[0017] Some of the techniques (e.g., compounds, compositions, methods) provided in this disclosure include those generally described above, and are further illustrated by the categories, subclasses and types disclosed herein.

[0018] definition

[0019] As used herein, unless otherwise stated, the following definitions shall apply. For the purposes of this disclosure, chemical elements are determined according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th edition, Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0020] Unless otherwise stated, the structures described herein are intended to represent all stereoisomers (e.g., enantiomers or diastereomers) of the structure, as well as all geometric or conformational isomers of the structure. For example, in the presence of a stereocenter, in some embodiments, the R and / or S configurations of such a stereocenter are considered part of this disclosure. Thus, in some embodiments, single stereochemical isomers and / or enantiomers, diastereomers, and / or geometric (or conformational) mixtures of the provided compounds are within the scope of this disclosure. For example, in some cases, Tables 1 and 2 show one or more stereoisomers of the compound, and unless otherwise stated, they represent each stereoisomer individually and / or each stereoisomer as a mixture. Unless otherwise stated, tautomer forms of the provided compounds are within the scope of this disclosure.

[0021] Unless otherwise stated, the structures described herein are intended to include compounds distinguished only by the presence of one or more isotopically enriched atoms. For example, this includes replacing hydrogen with deuterium or tritium, or replacing carbon with isotopically enriched atoms. 13 C or 14 Compounds of carbon C that have the structure of this invention are all within the scope of this disclosure.

[0022] Aliphatic: The term "aliphatic" refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is non-aromatic (also referred to herein as "carbocyclic" or "alicyclic"). Unless otherwise stated, an aliphatic group contains 1 to 12 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 6 aliphatic carbon atoms (e.g., C16, C26, C36, C46, ​​C56, C66, C66, C66, C7 ... 1-6 In some embodiments, the aliphatic group comprises 1 to 5 aliphatic carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-5 In other embodiments, the aliphatic group comprises 1 to 4 aliphatic carbon atoms (e.g., C14, C24, C34, C44, C54, C64, C7 ... 1-4 In other embodiments, the aliphatic group comprises 1 to 3 aliphatic carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-3 In other embodiments, the aliphatic group comprises one to two aliphatic carbon atoms (e.g., C14-C24). 1-2 Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof. In some embodiments, “aliphatic” refers to a fully saturated or branched, optionally substituted, straight-chain (i.e., unbranched) or branched hydrocarbon chain containing one or more unsaturated units.

[0023] Alkyl: The term "alkyl" as used alone or as part of a larger part means having (unless otherwise specified) 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms (e.g., C12, C23, C14, C23, C2 ... 1-12 C 1-10 C 1-8 C 1-6 C 1-4 C 1-3 Or C 1-2 A saturated, optionally substituted, straight-chain or branched hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0024] Carbocyclic group: As used herein, the terms “carbocyclic group,” “carbocycle,” and “carbocyclic ring” refer to a cyclic aliphatic monocyclic, bicyclic, or polycyclic ring system having 3 to 14 members, saturated or partially unsaturated as described herein, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclic group” (or “alicyclic”) refers to a fully saturated or optionally substituted monocyclic C3-C8 hydrocarbon or optionally substituted C5-C4 hydrocarbon containing one or more unsaturated units. 10 (e.g., C7-C) 10 Or C8-C 10 Cycloalkyl refers to a bicyclic hydrocarbon, but it is non-aromatic. The term "cycloalkyl" refers to an optionally substituted saturated ring system with about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl has 3 to 6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic 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.

[0025] Alkenyl: The term "alkenyl" used alone or as part of a larger part refers to having at least one double bond and having (unless otherwise specified) 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C4, C5, C6, C7, C8, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 ( ) is an optional substituted straight-chain or branched hydrocarbon chain. Exemplary alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0026] Alkynyl: The term "alkynyl" used alone or as part of a larger part refers to having at least one triple bond and having (unless otherwise specified) 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C4, C5, C6, C7, C8, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 The alkynyl group may be an optionally substituted straight-chain or branched hydrocarbon group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, penynyl, hexynyl, and heptynyl.

[0027] Aryl: The term "aryl" refers to a group having a total of six to fourteen ring members (e.g., C14, C24, C34, C44, C54, C64, C7 ... 6-14 A monocyclic and bicyclic system, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, "aryl" refers to an aromatic ring system, including but not limited to phenyl, naphthyl, etc., which may have one or more substituents. Unless otherwise stated, "aryl" is a hydrocarbon.

[0028] Heteroaliphatic: As used herein, the term "heteroaliphatic" is given in its common sense in the art and refers to an aliphatic group as described herein in which one or more carbon atoms are independently replaced by one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). In some embodiments, one or more units selected from C, CH, CH2, and CH3 are independently replaced by one or more heteroatoms (including their oxidized and / or substituted forms). In some embodiments, the heteroaliphatic group is a heteroalkyl group. In some embodiments, the heteroaliphatic group is a heteroalkenyl group.

[0029] Heteroaryl: The term "heteroaryl" and its variations, used alone or as part of a larger portion (e.g., "heteroarylalkyl" or "heteroarylalkoxy"), refers to a monocyclic or bicyclic group having 5 to 10 ring atoms (e.g., a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl); said monocyclic or bicyclic group having 6, 10, or 14 π electrons in a cyclic array; and having one to five heteroatoms in addition to a carbon atom. Exemplary heteroaryls include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. azole group, iso azole group, Diazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridinoneyl, pyridazinyl, pyrazinyl, indoleyl, purine, naphridyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thieno[1,2-a]pyrimidinyl, triazol[1,2-a]pyrimidinyl, triazol[1,2-a]pyrimidinyl, and benzisocyanate Azolyl. The term "heteroaryl" as used herein, and its variations, also include groups in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings. Some non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzo[…]. Azolyl, quinolinyl, isoquinolinyl, cyclophosphinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolinyl, carbazoleyl, acridineyl, phenazinyl, phenthiazinyl, phen Azine, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4- Azine-3(4H)-one and benzene Azolium group. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaryl family," any of which includes an optionally substituted ring.

[0030] Heteroatoms: As used herein, the term “heteroatoms” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen.

[0031] Heterocycle: The terms “heterocycle,” “heterocyclic group,” and “heterocycle” as used herein are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, for example, one to four heteroatoms as defined above, in addition to a carbon atom. In some embodiments, it refers to a saturated or partially unsaturated 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that has one or more, for example, one to four heteroatoms as defined above, in addition to a carbon atom. When used to refer to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolidinyl), or NR. + (e.g., in N-substituted pyrrolidinyl groups). The heterocycle can be attached to its side group at any heteroatom or carbon atom that produces a stable structure, and any ring atom can be optionally substituted. Some examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, decahydroquinolinyl, etc. azolealkyl, piperazine, dioxanyl, dioxolanyl, diazapyridine diazepinyl, oxonium-nitrogen hybrid oxazepinyl, thiazepinyl The heterocyclic group can be thiazepinyl, morpholinyl, or thiazepinyl. The heterocyclic group can be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, and more preferably monocyclic or bicyclic. Bicyclic heterocycles also include groups in which the heterocycle is fused with one or more aryl, heteroaryl, or alicyclic rings. Exemplary bicyclic heterocyclic groups include indololinyl, isoindololinyl, benzodioxanepentenyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. Bicyclic heterocycles can also be spirocyclic systems (e.g., 7- to 11-membered spirocyclic fused heterocycles having one or more heteroatoms as defined above (e.g., one, two, three, or four heteroatoms) in addition to a carbon atom).

[0032] Partially unsaturated: As used herein, the term “partially unsaturated” when referring to a ring motif means a ring motif that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to cover rings having multiple unsaturated sites, but excludes aromatic (e.g., aryl or heteroaryl) motifs as defined herein.

[0033] Patient or Subject: As used herein, the terms "patient" or "subject" refer to any organism to which the provided composition is applied or can be applied, for example, for experimental, diagnostic, preventative, 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, the patient is a human. In some embodiments, the patient or subject suffers from or is susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits symptoms of one or more disorders or conditions. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is receiving or has received some form of treatment to diagnose and / or treat a disease, disorder, or condition.

[0034] Specific binding: As used herein, the term "specific binding" refers to the ability to distinguish possible binding partners in the context in which binding occurs. When other potential targets are present, a binder that interacts with a particular target is referred to as "specifically bound" to that target. In some embodiments, specific binding is assessed by detecting or determining the degree and / or rate of association between the binder and its partner; in some embodiments, specific binding is assessed by detecting or determining the degree and / or rate of dissociation of the binder-partner complex; in some embodiments, specific binding is assessed by detecting or determining the ability of the binder to compete for alternative interactions between its partner and another entity. In some embodiments, specific binding is assessed by performing such detection or determination within a concentration range.

[0035] Substituted or optionally substituted: As described herein, compounds of this disclosure may contain an “optionally substituted” portion. Generally, the term “substituted,” whether or not preceded by the term “optionally,” means that one or more hydrogens of the specified portion are replaced by suitable substituents (i.e., as described below for optionally substituted groups). “Substituted” applies to one or more hydrogens explicitly or implicitly present in the structure (e.g., It means at least ;and It means at least , , or Unless otherwise stated, an "optionally substituted" group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from a particular group. The combinations of substituents contemplated in this invention are preferably those that result in the formation of stable or chemically viable compounds. The term "stable" as used herein means that a compound remains substantially unchanged when subjected to conditions permissible for its generation, detection, and, in some embodiments, its recovery, purification, and use for one or more purposes provided herein. A group described as "substituted" preferably has 1 to 4 substituents, more preferably 1 or 2 substituents. As mentioned above, a group described as "optionally substituted" may be unsubstituted or "substituted".

[0036] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0- 4R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°,-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4CH(OR°)2;-(CH2) 0-4 SR°; can be R o Substituted -(CH2) 0-4 Ph; -(CH2) that can be substituted by R° 0-4 O(CH2) 0-1 Ph; can be R o The substituent -CH=CHPh; can be R o Substituted -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° can be substituted as defined below, and is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5 to 6-membered heteroaryl ring), or a 3 to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above, two independently occurring R° together with intercalation atoms to form a 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as follows.

[0037] The suitable monovalent substituents on R° (or the ring formed by two independently occurring R° and their intercalation atoms) are independently halogens. Each of them It is unsubstituted, or, in the case of "halogenation" preceding it, substituted by only one or more halogens, and independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0038] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O ("oxo"), =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O-, or -S(C(R)* 2)) 2-3 S-, where R * Each time it appears independently, it is selected from hydrogen, and the C that is substituted can be limited as follows: 1-6 Aliphatic, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the ortho-substituted carbon of the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where R * Each time it appears independently, it is selected from hydrogen, and the C that can be substituted can be specified as follows: 1-6 Aliphatic, or having 0 to 4 unsubstituted 5 to 6 saturated, partially unsaturated or aryl rings independently selected from nitrogen, oxygen or sulfur.

[0039] R * Suitable substituents on aliphatic groups include halogens, Each of them It is either unsubstituted or, in the case of being preceded by "halogenated," substituted by only one or more halogens, and is independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0–1 Ph, or a 3 to 6 saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0040] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include ; each of them It is hydrogen independently, and the C atoms that can be substituted are defined as follows: 1-6 Aliphatic, or having 0 to 4 independently selected heteroatoms from nitrogen, oxygen, or sulfur, of an unsubstituted 3 to 6-membered saturated, partially unsaturated, or aryl ring, or, despite the above limitations, two independently occurring... Together with intercalated atoms, they form unsubstituted 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0041] Suitable substituents on the aliphatic group are independently halogens, Each of them It is either unsubstituted or, in the case of being preceded by "halogenated," substituted by only one or more halogens, and is independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3 to 6 saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0042] Treatment: As used herein, the term "treatment" and its variations refer to the application of any treatment that partially or completely reduces, improves, alleviates, inhibits, delays the onset of, reduces the severity of, and / or decreases the incidence of one or more symptoms, features and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be given to subjects who do not exhibit signs of the relevant disease, disorder, and / or condition, and / or who exhibit only early signs of said disease, disorder, and / or condition. Optionally or additionally, such treatment may be given to subjects who exhibit one or more definitive signs of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be given to subjects who have been diagnosed with the relevant disease, disorder, and / or condition.

[0043] Unless the context clearly indicates otherwise, as used in this disclosure, (i) nouns without quantifiers are to be understood as meaning "at least one / a"; (ii) the term "or" is to be understood as meaning "and / or"; (iii) the terms "comprising," "including," and "containing," and variations thereof (whether or not used with "not limited to") are to be understood as covering the listed components or steps, whether presented alone or with one or more additional components or steps; (iv) the term "another" is to be understood as meaning at least another / second or more; (v) the terms "about" and "approximately" are to be understood as allowing for variations in standards, as understood by one of ordinary skill in the art; and (vi) where a scope is provided, endpoints are included. Unless the context clearly indicates otherwise, isomers of the compound are included. As understood by one of ordinary skill in the art, the compound may be provided, administered, or delivered in various forms such as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, esters, prodrugs, tautomers, etc.

[0044] Some compounds

[0045] In some embodiments, this disclosure provides compounds that can be used to prevent or treat a variety of conditions, disorders, or diseases, including cancer. In some embodiments, this disclosure provides compounds that can be used to inhibit cell proliferation, such as cancer cell proliferation. In some embodiments, this disclosure provides compounds that can be used to reduce tumor growth. In some embodiments, this disclosure provides compounds that can be used to reduce KAT2A and / or KAT2B levels. In some embodiments, this disclosure provides compounds that can inhibit one or more functions of KAT2A and / or KAT2B. In some embodiments, this disclosure provides compounds that can bind to KAT2A and / or KAT2B and can bind to E3 ligases. Certain compounds are described below as examples.

[0046] In some embodiments, this disclosure provides a KAT2 degrading compound comprising a KAT2 protein-binding moiety, a linker, and an E3 ubiquitin ligase-binding moiety.

[0047] In some embodiments, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0048]

[0049] in:

[0050] PBM is the KAT2 protein binding site, or or ;

[0051] The connector is an optional connecting part, either a covalent bond or an optional substituted divalent C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;and

[0052] LBM is the E3 ubiquitin ligase-binding site, or , ;

[0053] in:

[0054] Ring A is selected from:

[0055] ;

[0056] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0057] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0058] Each R 1 Independently, it is -R;

[0059] n is 0, 1, 2, 3 or 4;

[0060] Z is N or CR 3 ;

[0061] R 2 It is a halogen, -CN, or -R;

[0062] Each R 3 It is halogen, -CN, or -R independently;

[0063] R 4 It is -R';

[0064] R 5 It is halogen, -CN or -R, or

[0065] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0066] R 6 It is -R';

[0067] X is O or NR 7 ;

[0068] R 7 It is -R', or

[0069] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0070] L 3 L 4 and L 5 Each is independently a covalent bond or an optional substituted divalent C. 1-6 hydrocarbon chain;

[0071] Each R 8 Independently, it is -R';

[0072] R 9 It is -R';

[0073] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0074] The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S;

[0075] Each R b It can be halogen, -CN, -R', or -OR independently;

[0076] t is 0, 1, 2, 3, or 4;

[0077] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0078] Ring E is Or, optionally, selected from the alternatives. and group;

[0079] Y is either N or CH;

[0080] Each R a It is independently a halogen, -CN, or -R';

[0081] Connector at R d R e R f Or R g One of the connections is with the bracketed part, or the connector is on an R. i In place or when two R i When groups are together, the ring formed is connected to the bracket portion;

[0082] R at each connection point that is not a connector d Independently, it is -R', or

[0083] Two Rs d Together with the atoms to which they are attached, they combine to form optionally substituted 5- to 6-membered rings having 1 to 3 heteroatoms independently selected from N, O, and S, and said rings are optionally fused with phenyl or 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from N, O, and S.

[0084] R at each connection point that is not a connector e Independently, it is -R;

[0085] When R f When it is not a connection point of a connector, it is -R;

[0086] R at each connection point that is not a connector g It can be halogen, -CN, R, or -OR independently;

[0087] p is 0, 1, 2, or 3;

[0088] R h It is a halogen or -R;

[0089] R at each connection point that is not a connector i It is independently a halogen, -R, -C(O)N(R')2 or -N(R)C(O)R, or

[0090] Two Rs i The groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl group or a 5- to 6-membered ring having 1 to 3 independent heteroatoms selected from N, O, and S;

[0091] R j It's -R, or

[0092] R j With an R i Examples and their intercalated atoms are combined together to form optional substituted 5- to 7-membered rings with 1 to 2 independent heteroatoms selected from N, O and S;

[0093] R k It is -R;

[0094] r is 1, 2, 3, 4 or 5;

[0095] q is 1 or 2;

[0096] R m It is -R;

[0097] R n R p R q R r R s and R u Each can be independently halogenated, -CN, -R, or -OR;

[0098] s is 0, 1, 2, 3, 4, or 5;

[0099] t is 0, 1, 2, 3, 4, or 5;

[0100] Each u is independently 0, 1, 2, 3, 4 or 5;

[0101] Each R t Independently, it is R, or

[0102] Two Rs t The groups, together with the atoms to which they are attached, combine to form optional substituted 3- to 7-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0103] Each R v It can be halogen, -CN, -R, or -OR independently, or

[0104] R v and R u One example combines with their intercalating atoms to form an optionally substituted 3- to 7-membered ring with 0 to 2 independent heteroatoms selected from N, O, and S;

[0105] Each R w It can be halogen, -CN, -R, or -OR independently, or

[0106] R w and R u One example combines with their intercalated atoms to form an optionally substituted 3- to 7-membered ring with 0 to 2 independent heteroatoms selected from N, O, and S;

[0107] Each v is independently 0, 1, 2, 3, 4 or 5;

[0108] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0109] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0110] In some embodiments, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0111]

[0112] in:

[0113] PBM is the KAT2 protein binding site;

[0114] The connector is an optional connection part; and

[0115] LBM is the E3 ubiquitin ligase binding site.

[0116] In some implementations, PBM is or And LBM is , In some implementations, PBM is And LBM is , In some implementations, PBM is And LBM is .

[0117] In some embodiments, the compound comprises a portion, such as PBM, capable of binding to the KAT2 protein or a fragment thereof (e.g., a bromo domain). In some embodiments, PBM-H or a salt thereof binds to the KAT2 protein or a fragment thereof (e.g., a bromo domain). In some embodiments, PBM-H or a salt thereof binds to KAT2A or a fragment thereof (e.g., a bromo domain). In some embodiments, PBM-H or a salt thereof binds to KAT2B or a fragment thereof (e.g., a bromo domain). In some embodiments, PBM-H or a salt thereof binds to both KAT2A or a fragment thereof (e.g., a bromo domain) and KAT2B or a fragment thereof (e.g., a bromo domain). In some embodiments, PBM-connector-H or a salt thereof binds to the KAT2 protein or a fragment thereof (e.g., a bromo domain). In some embodiments, PBM-connector-H or a salt thereof binds to KAT2A or a fragment thereof (e.g., a bromo domain). In some embodiments, PBM-connector-H or a salt thereof binds to KAT2B or a fragment thereof (e.g., a bromo domain). In some embodiments, PBM-linker-H or its salt binds to KAT2A or a fragment thereof (e.g., a bromo domain), and KAT2B or a fragment thereof (e.g., a bromo domain). In some embodiments, H-LBM or its salt may bind to an E3 ligase (e.g., CRBN, VHL, IAP, or MDM2). In some embodiments, H-LBM or its salt binds to CRBN. In some embodiments, H-LBM or its salt binds to VHL. In some embodiments, H-linker-LBM or its salt may bind to an E3 ligase (e.g., CRBN, VHL, IAP, or MDM2). In some embodiments, H-linker-LBM or its salt binds to CRBN. In some embodiments, H-linker-LBM or its salt binds to VHL.

[0118] In some embodiments, this disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof:

[0119]

[0120] in:

[0121] Ring A is selected from:

[0122] ;

[0123] Ring B is a 5- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S;

[0124] L 1 Is it a covalent bond or a divalent C? 1-3 Straight-chain or branched hydrocarbon chains;

[0125] Each R 1 Independently, it is the optional substituted C1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0126] n is 0, 1, 2, 3 or 4;

[0127] Z is N or CR 3 ;

[0128] R 2 It is hydrogen, halogen, -CN, or optionally substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0129] Each R 3 Independently hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0130] R 4 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0131] R 5 It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic, or

[0132] R 2 and R 5 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0133] R 6 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0134] X is O or NR 7 ;

[0135] R 7 It is hydrogen or optionally substituted C 1-6 aliphatic, or

[0136] R 4 and R 7 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0137] R 9 It is hydrogen or optionally substituted C 1-6 aliphatic;

[0138] The linker is a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0139] Each Cy is independently a substituted monocyclic or polycyclic 3- to 16-membered divalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0 to 6 heteroatoms independently selected from N, O, and S.

[0140] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic, phenyl, C 3-7 Alicyclic groups, comprising 5- to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, and 3- to 7-membered monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S; and

[0141] LBM is the E3 ubiquitin ligase binding site.

[0142] In some embodiments, this disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof, wherein:

[0143] Ring A is selected from:

[0144] ;

[0145] Ring B is a 5- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S;

[0146] L 1 Is it a covalent bond or a divalent C? 1-3 Straight-chain or branched hydrocarbon chains;

[0147] Each R 1 Independently, it is the optional substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0148] n is 0, 1, 2, 3 or 4;

[0149] Z is N or CR 3 ;

[0150] R 2 It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0151] Each R 3 Independently hydrogen, halogen, or optionally substituted C1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0152] R 4 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0153] R 5 It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic, or

[0154] R 2 and R 5 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0155] R 6 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0156] X is O or NR 7 ;

[0157] R 7 It is hydrogen or optionally substituted C 1-6 aliphatic, or

[0158] R 4 and R 7 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0159] R 9 It is hydrogen or optionally substituted C 1-6 aliphatic;

[0160] The linker is a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0161] Each Cy is independently a substituted monocyclic or polycyclic 3- to 16-membered divalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0 to 6 heteroatoms independently selected from N, O, and S.

[0162] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6Aliphatic, phenyl, C 3-7 Alicyclic groups, comprising 5- to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, and 3- to 7-membered monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S; and

[0163] LBM is the E3 ubiquitin ligase binding site.

[0164] In some embodiments, this disclosure provides compounds of formula IIA or pharmaceutically acceptable salts thereof:

[0165]

[0166] Among them, rings A and L 1 R 1 R 9 The terms n, connector, and LBM are defined above for Formula II and described in the categories and subcategories herein, both individually and in combination.

[0167] In some embodiments, this disclosure provides compounds of formula IIA-1, IIA-2, IIA-3, or IIA-4, or pharmaceutically acceptable salts thereof:

[0168]

[0169] Where R 1 R 2 R 3 R 4 R 5 R 6 R 9 X, Z, connector, and LBM are described above, individually and in combination, as defined for Formula II and in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IIA-1 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a compound of Formula IIA-2 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a compound of Formula IIA-3 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a compound of Formula IIA-4 or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, this disclosure provides a compound of formula IIA-1 or a pharmaceutically acceptable salt thereof:

[0171]

[0172] in:

[0173] R 1 It is an optional, substituted C 1-6 aliphatic;

[0174] Z is N or CR 3 ;

[0175] R 2 It is hydrogen, halogen, -CN, or optionally substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0176] Each R 3 It can be either hydrogen or halogen;

[0177] R 4 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0178] R 9 It is hydrogen;

[0179] The connector is an optional substituted divalent linear or branched chain, 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-;

[0180] Each Cy is independently a substituted group selected from the following: phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, a monocyclic 4- to 7-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O and S, and a bicyclic 6- to 11-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S;

[0181] Each R is independently hydrogen or optionally substituted C. 1-6 aliphatic;

[0182] LBM is ;

[0183] The ring C is optionally substituted with a group selected from the following: phenyl, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, and 9- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S;

[0184] Each R a It is hydrogen;

[0185] L 2 It is a covalent bond, -CH2-, -O-, or -N(R)-; and

[0186] Y is either N or CH.

[0187] In some embodiments, this disclosure provides a compound of formula IIA-1 or a pharmaceutically acceptable salt thereof:

[0188]

[0189] in:

[0190] R 1 It is C 1-6 alkyl;

[0191] Z is N or CR 3 ;

[0192] R 2 It is hydrogen, halogen, -CN, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0193] Each R 3 It can be either hydrogen or halogen;

[0194] R 4 It is C 1-6 alkyl;

[0195] R 9 It is hydrogen;

[0196] The connector is an optional substituted divalent linear or branched chain, 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-;

[0197] Each Cy is independently a substituted group selected from the following: phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, a monocyclic 4- to 7-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O and S, and a bicyclic 6- to 11-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S;

[0198] Each R is independently either hydrogen or C. 1-6 alkyl;

[0199] LBM is ;

[0200] The ring C is optionally substituted with a group selected from the following: phenyl, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, and 9- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S;

[0201] Each R a It is hydrogen;

[0202] L 2 It is a covalent bond, -CH2-, -O-, or -N(R)-; and

[0203] Y is either N or CH.

[0204] In some embodiments, this disclosure provides a compound of formula IIA-5 or a pharmaceutically acceptable salt thereof:

[0205]

[0206] Among them, rings A and R 1 R 9 The connector and LBM are described in both individual and combined cases as defined above for Formula II and in the categories and subcategories herein.

[0207] In some embodiments, this disclosure provides a compound of formula IIA-6 or a pharmaceutically acceptable salt thereof:

[0208]

[0209] Among them, rings A and R 1 R 9 The connector and LBM are described in both individual and combined cases as defined above for Formula II and in the categories and subcategories herein.

[0210] In some embodiments, this disclosure provides a compound of formula II-1 or a pharmaceutically acceptable salt thereof:

[0211]

[0212] in:

[0213] Ring A is selected from:

[0214] ;

[0215] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0216] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0217] Each R 1 Independently, it is -R;

[0218] n is 0, 1, 2, 3 or 4;

[0219] Z is N or CR 3 ;

[0220] R 2It is a halogen, -CN, or -R;

[0221] Each R 3 It is halogen, -CN, or -R independently;

[0222] R 4 It is -R';

[0223] R 5 It is halogen, -CN or -R, or

[0224] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0225] R 6 It is -R';

[0226] X is O or NR 7 ;

[0227] R 7 It is -R', or

[0228] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0229] R 9 It is -R';

[0230] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0231] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0232] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0233] LBM is the E3 ubiquitin ligase binding site;

[0234] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms bonded to them to form optionally substituted 3- to 16-membered rings with 1 to 5 independently selected heteroatoms from N, O, and S; and

[0235] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic compounds, C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S, C 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0236] In some embodiments, this disclosure provides a compound of formula III or a pharmaceutically acceptable salt thereof:

[0237]

[0238] in:

[0239] Ring A is selected from:

[0240] ;

[0241] Ring B is a 5- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S;

[0242] L 1 Is it a covalent bond or a divalent C? 1-3 Straight-chain or branched hydrocarbon chains;

[0243] Each R 1 Independently, it is the optional substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0244] n is 0, 1, 2, 3 or 4;

[0245] Z is N or CR 3 ;

[0246] R 2 It is hydrogen, halogen, -CN, or optionally substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0247] Each R 3 Independently hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0248] R 4 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0249] R 5It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic, or

[0250] R 2 and R 5 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0251] R 6 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0252] X is O or NR 7 ;

[0253] R 7 It is hydrogen or optionally substituted C 1-6 aliphatic, or

[0254] R 4 and R 7 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0255] R 9 It is hydrogen or optionally substituted C 1-6 aliphatic;

[0256] The linker is a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0257] Each Cy is independently a substituted monocyclic or polycyclic 3- to 16-membered divalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0 to 6 heteroatoms independently selected from N, O, and S.

[0258] The ring C is a substituted monocyclic or polycyclic 3- to 16-membered divalent ring system, wherein the ring system is fully saturated, partially saturated or aromatic, and the ring system contains 0 to 6 heteroatoms independently selected from N, O and S.

[0259] L 2 Is it a covalent bond, a straight chain, or a branched chain? 1-3 The hydrocarbon chain, wherein one methylene group is optionally replaced by: -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)- or -N(R)C(O)-;

[0260] Y is either N or CH;

[0261] Each R a Independently hydrogen or optionally substituted C 1-6 Aliphatic, or two Rs a Groups, together with the atoms they are attached to, combine to form 3 to 6-membered saturated or partially unsaturated rings;

[0262] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic, phenyl, C 3-7 Alicyclic groups, comprising 5- to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, and 3- to 7-membered monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S; and

[0263] Ring A, Ring B, L 1 R 1 R 9 The terms n and connectors, both individually and in combination, are defined above for Equation II and are described in the categories and subcategories herein.

[0264] In some embodiments, this disclosure provides a compound of formula IIIA or a pharmaceutically acceptable salt thereof:

[0265]

[0266] Among them, rings A, B, and L 1 R 1 R 9 , n and the connector, both individually and in combination, are as defined above for Equation II and are described in the categories and subcategories herein; and

[0267] Each R b It is hydrogen, or two Rs on the same carbon atom. b Groups together form oxo groups or combine to form 3 to 6-membered saturated or partially unsaturated rings;

[0268] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[0269] m can be 0, 1, 2, or 3.

[0270] In some embodiments, this disclosure provides compounds of formula IIIB or pharmaceutically acceptable salts thereof:

[0271]

[0272] Among them, rings A and R1 R 9 R b R c The terms m and connector, both individually and in combination, are defined above for Formula IIIA and are described in the categories and subcategories herein.

[0273] In some embodiments, this disclosure provides compounds of formula IIIB-1 or IIIB-2 or their pharmaceutically acceptable salts:

[0274]

[0275] Among them, rings A and R 1 R 9 The connectors, both individually and in combination, are as defined above for Formula II and described in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of Formula IIIB-1 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a compound of Formula IIIB-2 or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, this disclosure provides a compound of formula IIIC or a pharmaceutically acceptable salt thereof:

[0277]

[0278] Among them, rings A, B, and L 1 L 2 R 1 R 9 Y, n, and the connector, both individually and in combination, are as defined above for Equation III and are described in the categories and subcategories herein; and

[0279] Each B is independently selected from N, C, and CH, provided that no more than two Bs are N;

[0280] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[0281] m can be 0, 1, 2, or 3.

[0282] In some embodiments, this disclosure provides a compound of formula IIID or a pharmaceutically acceptable salt thereof:

[0283]

[0284] Among them, rings A, B, and L 2 R 1 R 9 R cY, m, and connectors, individually and in combination, are defined above for Formula IIIC and described in the categories and subcategories herein.

[0285] In some embodiments, this disclosure provides a compound of formula IIID or a pharmaceutically acceptable salt thereof:

[0286]

[0287] in:

[0288] Ring A is ;

[0289] R 1 It is an optional, substituted C 1-6 aliphatic;

[0290] Z is N or CR 3 ;

[0291] R 2 It is hydrogen, halogen, -CN, or optionally substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0292] Each R 3 It can be either hydrogen or halogen;

[0293] R 4 It is an optional, substituted C 1-6 aliphatic;

[0294] R 9 It is hydrogen;

[0295] The connector is an optional substituted divalent linear or branched chain, 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-;

[0296] Each Cy is independently a substituted group selected from the following: phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, a monocyclic 4- to 7-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O and S, and a bicyclic 6- to 11-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S;

[0297] Each R is independently hydrogen or optionally substituted C. 1-6 aliphatic;

[0298] L 2 It is a covalent bond, -CH2-, -O-, or -N(R)-;

[0299] Y is either N or CH;

[0300] Each B is independently selected from N, C, and CH, provided that no more than two Bs are N;

[0301] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[0302] m can be 0, 1, 2, or 3.

[0303] In some embodiments, this disclosure provides a compound of formula IIID or a pharmaceutically acceptable salt thereof:

[0304]

[0305] in:

[0306] Ring A is ;

[0307] R 1 It is C 1-6 alkyl;

[0308] Z is N or CR 3 ;

[0309] R 2 It is hydrogen, halogen, -CN, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0310] Each R 3 It can be either hydrogen or halogen;

[0311] R 4 It is C 1-6 alkyl;

[0312] R 9 It is hydrogen;

[0313] The connector is ;

[0314] L 6 and L 7 Both are covalent bonds;

[0315] Cy is selected from:

[0316] ;

[0317] part yes ;

[0318] L 2 It is a covalent bond;

[0319] Y is CH;

[0320] Each B is independently selected from N, C, and CH, provided that no more than two Bs are N;

[0321] Each R c Independently selected from halogens, -O(C 1-6 alkyl) and C 1-6 Alkyl; and

[0322] m can be 0, 1, 2, or 3.

[0323] In some embodiments, this disclosure provides a compound of formula III-1 or a pharmaceutically acceptable salt thereof:

[0324]

[0325] in:

[0326] Ring A is selected from:

[0327] ;

[0328] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0329] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0330] Each R 1 Independently, it is -R;

[0331] n is 0, 1, 2, 3 or 4;

[0332] Z is N or CR 3 ;

[0333] R 2 It is a halogen, -CN, or -R;

[0334] Each R 3 It is halogen, -CN, or -R independently;

[0335] R 4 It is -R';

[0336] R 5 It is halogen, -CN or -R, or

[0337] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0338] R 6 It is -R';

[0339] X is O or NR 7 ;

[0340] R 7 It is -R', or

[0341] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0342] R 9 It is -R';

[0343] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0344] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0345] The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S;

[0346] Each R b It can be halogen, -CN, -R', or -OR independently;

[0347] t is 0, 1, 2, 3, or 4;

[0348] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0349] Ring E is Or, optionally, selected from the alternatives. and Groups;

[0350] Y is either N or CH;

[0351] Each R a It is independently a halogen, -CN, or -R';

[0352] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0353] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0354] In some embodiments, this disclosure provides compounds of formula IIIE or pharmaceutically acceptable salts thereof:

[0355]

[0356] in:

[0357] Ring A is selected from:

[0358] ;

[0359] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0360] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0361] Each R 1 Independently, it is -R;

[0362] n is 0, 1, 2, 3 or 4;

[0363] Z is N or CR 3 ;

[0364] R 2 It is a halogen, -CN, or -R;

[0365] Each R 3 It is halogen, -CN, or -R independently;

[0366] R 4 It is -R';

[0367] R 5 It is halogen, -CN or -R, or

[0368] R 2 and R5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0369] R 6 It is -R';

[0370] X is O or NR 7 ;

[0371] R 7 It is -R', or

[0372] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0373] R 9 It is -R';

[0374] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0375] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0376] The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S;

[0377] Each R b It can be halogen, -CN, -R', or -OR independently;

[0378] t is 0, 1, 2, 3, or 4;

[0379] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0380] Y is either N or CH;

[0381] Each R a It is independently a halogen, -CN, or -R';

[0382] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0383] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0384] In some embodiments, this disclosure provides compounds of formula IIIF or pharmaceutically acceptable salts thereof:

[0385]

[0386] in:

[0387] Ring A is selected from:

[0388] ;

[0389] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0390] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0391] Each R 1 Independently, it is -R;

[0392] n is 0, 1, 2, 3 or 4;

[0393] Z is N or CR 3 ;

[0394] R 2 It is a halogen, -CN, or -R;

[0395] Each R 3 It is halogen, -CN, or -R independently;

[0396] R 4 It is -R';

[0397] R 5 It is halogen, -CN or -R, or

[0398] R 2 and R5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0399] R 6 It is -R';

[0400] X is O or NR 7 ;

[0401] R 7 It is -R', or

[0402] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0403] R 9 It is -R';

[0404] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0405] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0406] The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S;

[0407] Each R b It can be halogen, -CN, -R', or -OR independently;

[0408] t is 0, 1, 2, 3, or 4;

[0409] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0410] Y is either N or CH;

[0411] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0412] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0413] In some embodiments, this disclosure provides compounds of formula IIIG or pharmaceutically acceptable salts thereof:

[0414]

[0415] in:

[0416] Ring A is selected from:

[0417] ;

[0418] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0419] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0420] Each R 1 Independently, it is -R;

[0421] n is 0, 1, 2, 3 or 4;

[0422] Z is N or CR 3 ;

[0423] R 2 It is a halogen, -CN, or -R;

[0424] Each R 3 It is halogen, -CN, or -R independently;

[0425] R 4 It is -R';

[0426] R 5 It is halogen, -CN or -R, or

[0427] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0428] R6 It is -R';

[0429] X is O or NR 7 ;

[0430] R 7 It is -R', or

[0431] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0432] R 9 It is -R';

[0433] L 6 It is a covalent bond, -C(O)- or optionally substituted -CH2-;

[0434] Cy is a 3- to 16-membered divalent ring system with 0 to 6 independently selected heteroatoms from N, O, and S, which are optionally substituted.

[0435] The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S;

[0436] Each R b It can be halogen, -CN, -R', or -OR independently;

[0437] t is 0, 1, 2, 3, or 4;

[0438] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0439] Ring E is Or, optionally, selected from the alternatives. and group;

[0440] Y is either N or CH;

[0441] Each R a It is independently a halogen, -CN, or -R';

[0442] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0443] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0444] In some embodiments, this disclosure provides compounds of formula IIIH or pharmaceutically acceptable salts thereof:

[0445]

[0446] in:

[0447] Ring A is selected from:

[0448] ;

[0449] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0450] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0451] Each R 1 Independently, it is -R;

[0452] n is 0, 1, 2, 3 or 4;

[0453] Z is N or CR 3 ;

[0454] R 2 It is a halogen, -CN, or -R;

[0455] Each R 3 It is halogen, -CN, or -R independently;

[0456] R 4 It is -R';

[0457] R 5 It is halogen, -CN or -R, or

[0458] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0459] R 6 It is -R';

[0460] X is O or NR 7 ;

[0461] R 7 It is -R', or

[0462] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0463] R 9 It is -R';

[0464] L 6 It is a covalent bond, -C(O)- or optionally substituted -CH2-;

[0465] Cy is a 3- to 16-membered divalent ring system with 0 to 6 independently selected heteroatoms from N, O, and S, which are optionally substituted.

[0466] The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S;

[0467] Each R b It can be halogen, -CN, -R', or -OR independently;

[0468] t is 0, 1, 2, 3, or 4;

[0469] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0470] Y is either N or CH;

[0471] Each R a It is independently a halogen, -CN, or -R';

[0472] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0473] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0474] In some embodiments, this disclosure provides compounds of formula IIIJ or pharmaceutically acceptable salts thereof:

[0475]

[0476] in:

[0477] Ring A is selected from:

[0478] ;

[0479] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0480] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0481] Each R 1 Independently, it is -R;

[0482] n is 0, 1, 2, 3 or 4;

[0483] Z is N or CR 3 ;

[0484] R 2 It is a halogen, -CN, or -R;

[0485] Each R 3 It is halogen, -CN, or -R independently;

[0486] R 4 It is -R';

[0487] R 5 It is halogen, -CN or -R, or

[0488] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0489] R 6 It is -R';

[0490] X is O or NR 7 ;

[0491] R 7 It is -R', or

[0492] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0493] R 9 It is -R';

[0494] L 6 It is a covalent bond, -C(O)- or optionally substituted -CH2-;

[0495] Cy is a 3- to 16-membered divalent ring system with 0 to 6 independently selected heteroatoms from N, O, and S, which are optionally substituted.

[0496] The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S;

[0497] Each R b It can be halogen, -CN, -R', or -OR independently;

[0498] t is 0, 1, 2, 3, or 4;

[0499] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0500] Y is either N or CH;

[0501] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0502] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0503] In some embodiments, this disclosure provides compounds of formula IIIK or pharmaceutically acceptable salts thereof:

[0504]

[0505] in:

[0506] Ring A is selected from:

[0507] ;

[0508] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0509] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0510] Each R 1 Independently, it is -R;

[0511] n is 0, 1, 2, 3 or 4;

[0512] Z is N or CR 3 ;

[0513] R 2 It is a halogen, -CN, or -R;

[0514] Each R 3 It is halogen, -CN, or -R independently;

[0515] R 4 It is -R';

[0516] R 5 It is halogen, -CN or -R, or

[0517] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0518] R 6 It is -R';

[0519] X is O or NR 7 ;

[0520] R 7 It is -R', or

[0521] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0522] R 9 It is -R';

[0523] L 6It is a covalent bond, -C(O)- or optionally substituted -CH2-;

[0524] Cy is a 3- to 16-membered divalent ring system with 0 to 6 independently selected heteroatoms from N, O, and S, which are optionally substituted.

[0525] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0526] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0527] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0528] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0529] In some embodiments, this disclosure provides compounds of formula IIIL or pharmaceutically acceptable salts thereof:

[0530]

[0531] in:

[0532] Ring A is selected from:

[0533] ;

[0534] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0535] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0536] Each R 1 Independently, it is -R;

[0537] n is 0, 1, 2, 3 or 4;

[0538] Z is N or CR 3 ;

[0539] R 2 It is a halogen, -CN, or -R;

[0540] Each R 3 It is halogen, -CN, or -R independently;

[0541] R 4 It is -R';

[0542] R 5 It is halogen, -CN or -R, or

[0543] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0544] R 6 It is -R';

[0545] X is O or NR 7 ;

[0546] R 7 It is -R', or

[0547] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0548] R 9 It is -R';

[0549] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0550] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0551] The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S;

[0552] Each R b and R b1It can be halogen, -CN, -R', or -OR independently;

[0553] t' is 0, 1, 2, or 3;

[0554] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0555] Ring E is Or, optionally, selected from the alternatives. and Groups;

[0556] Y is either N or CH;

[0557] Each R a It is independently a halogen, -CN, or -R';

[0558] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0559] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0560] In some embodiments, this disclosure provides compounds of formula IIIM or pharmaceutically acceptable salts thereof:

[0561]

[0562] in:

[0563] Ring A is selected from:

[0564] ;

[0565] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0566] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0567] Each R 1 Independently, it is -R;

[0568] n is 0, 1, 2, 3 or 4;

[0569] Z is N or CR 3 ;

[0570] R 2 It is a halogen, -CN, or -R;

[0571] Each R 3 It is halogen, -CN, or -R independently;

[0572] R 4 It is -R';

[0573] R 5 It is halogen, -CN or -R, or

[0574] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0575] R 6 It is -R';

[0576] X is O or NR 7 ;

[0577] R 7 It is -R', or

[0578] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0579] R 9 It is -R';

[0580] L 6 It is a covalent bond, -C(O)- or optionally substituted -CH2-;

[0581] Cy is a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O and S;

[0582] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0583] Each R b and R b1 It can be halogen, -CN, -R', or -OR independently;

[0584] t' is 0, 1, 2, or 3;

[0585] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0586] Ring E is Or, optionally, selected from the alternatives. and Groups;

[0587] Y is either N or CH;

[0588] Each R a It is independently a halogen, -CN, or -R';

[0589] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0590] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0591] In some embodiments, this disclosure provides compounds of formula IIIN or pharmaceutically acceptable salts thereof:

[0592]

[0593] in:

[0594] Ring A is selected from:

[0595] ;

[0596] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0597] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0598] Each R 1 Independently, it is -R;

[0599] n is 0, 1, 2, 3 or 4;

[0600] Z is N or CR 3 ;

[0601] R 2 It is a halogen, -CN, or -R;

[0602] Each R 3 It is halogen, -CN, or -R independently;

[0603] R 4 It is -R';

[0604] R 5 It is halogen, -CN or -R, or

[0605] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0606] R 6 It is -R';

[0607] X is O or NR 7 ;

[0608] R 7 It is -R', or

[0609] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0610] R 9 It is -R';

[0611] L 6 It is a covalent bond, -C(O)- or optionally substituted -CH2-;

[0612] Cy is a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O and S;

[0613] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0614] Each R b and R b1 It can be halogen, -CN, -R', or -OR independently;

[0615] t' is 0, 1, 2, or 3;

[0616] L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0617] Y is either N or CH;

[0618] Each R a It is independently a halogen, -CN, or -R';

[0619] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0620] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0621] In some embodiments, this disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof:

[0622]

[0623] Among them, rings A, B, and L 1 R 1 R 9 , n and the connector, both individually and in combination, are as defined above for Equation II and are described in the categories and subcategories herein; and

[0624] Connector at R d R e R f or R g One of them connects to the part in parentheses;

[0625] R that is not a connector connection point d It is independently hydrogen, -C(O)R, or optionally substituted C 1-6 aliphatic, or

[0626] Two Rsd Together with the atoms to which they are attached, they combine to form optionally substituted 5- to 6-membered rings having 1 to 3 heteroatoms independently selected from N, O, and S, and said rings are optionally fused with phenyl or 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from N, O, and S.

[0627] R that is not a connector connection point e Independently hydrogen or optionally substituted C 1-6 aliphatic;

[0628] When R f When it is not a junction connection point, it is hydrogen or optionally substituted C. 1-6 aliphatic;

[0629] R that is not a connector connection point g It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[0630] R h It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic; and

[0631] p is 0, 1, 2 or 3.

[0632] In some embodiments, this disclosure provides a compound of formula IVA or a pharmaceutically acceptable salt thereof:

[0633]

[0634] Among them, rings A, B, and L 1 R 1 R 9 R d R e R f R g R h p, n, and connectors, both individually and in combination, are defined above for Formula IV and described in the categories and subcategories herein.

[0635] In some embodiments, this disclosure provides a compound of formula IVA-1 or a pharmaceutically acceptable salt thereof:

[0636]

[0637] Among them, rings A and R 1 R 9 R d R e R f R g R hThe , p and connector, in both individual and combined cases, are as defined above for Formula IV and are described in the categories and subcategories herein.

[0638] In some embodiments, this disclosure provides a compound of formula IV-1 or a pharmaceutically acceptable salt thereof:

[0639]

[0640] in:

[0641] Ring A is selected from:

[0642] ;

[0643] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0644] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0645] Each R 1 Independently, it is -R;

[0646] n is 0, 1, 2, 3 or 4;

[0647] Z is N or CR 3 ;

[0648] R 2 It is a halogen, -CN, or -R;

[0649] Each R 3 It is halogen, -CN, or -R independently;

[0650] R 4 It is -R';

[0651] R 5 It is halogen, -CN or -R, or

[0652] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0653] R 6 It is -R';

[0654] X is O or NR 7 ;

[0655] R 7 It is -R', or

[0656] R 4 and R7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0657] R 9 It is -R';

[0658] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0659] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0660] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0661] Connector at R d R e R f Or R g One of them connects to the part in parentheses;

[0662] R that is not a connector connection point d Independently, it is -R', or

[0663] Two Rs d Together with the atoms to which they are attached, they combine to form optionally substituted 5- to 6-membered rings having 1 to 3 heteroatoms independently selected from N, O, and S, and said rings are optionally fused with phenyl or 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from N, O, and S.

[0664] R that is not a connector connection point e Independently, it is -R;

[0665] When R f When it is not a connector connection point, it is -R;

[0666] R that is not a connector connection point g It can be halogen, -CN, R, or -OR independently;

[0667] p is 0, 1, 2, or 3;

[0668] R h It is a halogen or -R;

[0669] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0670] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0671] In some embodiments, the compound of formula IV-1 is a compound of formula IVD:

[0672]

[0673] The variables, both individually and in combination, are defined as above for IVB and described in the categories and subclasses in this paper.

[0674] In some embodiments, this disclosure provides a compound of formula V or a pharmaceutically acceptable salt thereof:

[0675]

[0676] Among them, rings A, B, and L 1 R 1 R 9 , n, and connectors, both individually and in combination, are as defined above for Equation II and described in the categories and subcategories herein; and

[0677] Connector in an R i In place or when two R i When groups are together, the ring formed is connected to the bracket portion;

[0678] R that is not a connector connection point i Independently halogenated, optionally substituted C 1-6 Aliphatic, -C(O)N(R)2 or -N(R)C(O)R, or

[0679] Two Rs i The groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or a 5- to 6-membered heteroaryl ring having 1 to 3 independent heteroatoms selected from N, O, and S;

[0680] R j It is an optional, substituted selection from C1-6 aliphatic and C 3-7 Alicyclic groups, or

[0681] R j With an R i Examples and the atoms to which they are attached are combined to form optional substituted 5- to 7-membered heterocycles with 1 to 2 independent heteroatoms selected from N, O and S;

[0682] R k It is an optional substituted C 1-6 aliphatic;

[0683] r is 1, 2, 3, 4, or 5; and

[0684] q is 1 or 2.

[0685] In some embodiments, this disclosure provides a compound of formula VA or a pharmaceutically acceptable salt thereof:

[0686]

[0687] Among them, rings A, B, and L 1 R 1 R 9 R i R j R k , n, q, r and connectors, individually and in combination, are defined above for formula V and described in the categories and subclasses herein.

[0688] In some embodiments, this disclosure provides a compound of formula VA-1 or a pharmaceutically acceptable salt thereof:

[0689]

[0690] Among them, rings A and R 1 R 9 R i R j R k , q, r and connector, in both individual and combined cases, are defined above for formula V and described in the categories and subclasses herein.

[0691] In some embodiments, this disclosure provides a compound of formula VB or a pharmaceutically acceptable salt thereof:

[0692]

[0693] Among them, rings A, B, and L 1 , R, R 1 R 9 R i R j Rk The terms n, q, r, and connectors, individually and in combination, are defined above for formula V and described in the categories and subclasses herein.

[0694] In some embodiments, this disclosure provides a compound of formula VB-1 or a pharmaceutically acceptable salt thereof:

[0695]

[0696] VB-1

[0697] Among them, rings A, B, and L 1 , R, R 1 R 9 R j R k The terms n and connectors, both individually and in combination, are defined above for formula V and described in the categories and subclasses herein.

[0698] In some embodiments, this disclosure provides a compound of formula V-1 or a pharmaceutically acceptable salt thereof:

[0699]

[0700] in:

[0701] Ring A is selected from:

[0702] ;

[0703] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0704] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0705] Each R 1 Independently, it is -R;

[0706] n is 0, 1, 2, 3 or 4;

[0707] Z is N or CR 3 ;

[0708] R 2 It is a halogen, -CN, or -R;

[0709] Each R 3 It is halogen, -CN, or -R independently;

[0710] R 4 It is -R';

[0711] R 5It is halogen, -CN or -R, or

[0712] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0713] R 6 It is -R';

[0714] X is O or NR 7 ;

[0715] R 7 It is -R', or

[0716] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0717] R 9 It is -R';

[0718] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0719] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0720] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0721] Connector in an R i In place or when two R i When groups are together, the ring formed is connected to the bracket portion;

[0722] R that is not a connector connection point i It is independently a halogen, -R, -C(O)N(R')2 or -N(R)C(O)R, or

[0723] Two Rs i The groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl group or a 5- to 6-membered ring having 1 to 3 independent heteroatoms selected from N, O, and S;

[0724] R j It's -R, or

[0725] R jWith an R i Examples and the atoms they are attached to are combined together to form optional substituted 5- to 7-membered rings with 1 to 2 independent heteroatoms selected from N, O and S;

[0726] R k It is -R;

[0727] r is 1, 2, 3, 4 or 5;

[0728] q is 1 or 2.

[0729] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0730] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0731] In some embodiments, the compound of formula V-1 is the compound of formula VC:

[0732]

[0733] The variables, both individually and in combination, are defined above for Equation V-1 and described in the categories and subclasses of this paper.

[0734] In some embodiments, the compound of formula V-1 is the compound of formula VD:

[0735]

[0736] The variables, both individually and in combination, are defined above for Equation V-1 and described in the categories and subclasses of this paper.

[0737] In some embodiments, the compound of formula V-1 is a compound of formula VE:

[0738]

[0739] The variables, both individually and in combination, are defined above for Equation V-1 and described in the categories and subclasses of this paper.

[0740] In some embodiments, this disclosure provides a compound of formula VI or a pharmaceutically acceptable salt thereof:

[0741]

[0742] Among them, rings A, B, and L 1 R 1 R 9 , n and the connector, both individually and in combination, are as defined above for Equation II and are described in the categories and subcategories herein; and

[0743] R m It is an optional substituted C 1-6 aliphatic;

[0744] Each R n It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 Aliphatic; and

[0745] s can be 0, 1, 2, 3, 4 or 5.

[0746] In some embodiments, this disclosure provides a compound of formula VIA or a pharmaceutically acceptable salt thereof:

[0747]

[0748] Among them, rings A, B, and L 1 R 1 R 9 R m R n , n, s and connectors, both individually and in combination, are defined as above for type VI and described in the categories and subcategories herein.

[0749] In some embodiments, this disclosure provides a compound of formula VIA-1 or a pharmaceutically acceptable salt thereof:

[0750]

[0751] Among them, rings A and R 1 R 9 R m R n , s and connectors, both individually and in combination, are defined as defined above for type VI and described in the categories and subcategories herein.

[0752] In some embodiments, this disclosure provides a compound of formula VI-1 or a pharmaceutically acceptable salt thereof:

[0753]

[0754] in:

[0755] Ring A is selected from:

[0756] ;

[0757] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0758] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0759] Each R 1 Independently, it is -R;

[0760] n is 0, 1, 2, 3 or 4;

[0761] Z is N or CR 3 ;

[0762] R 2 It is a halogen, -CN, or -R;

[0763] Each R 3 It is halogen, -CN, or -R independently;

[0764] R 4 It is -R';

[0765] R 5 It is halogen, -CN or -R, or

[0766] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0767] R 6 It is -R';

[0768] X is O or NR 7 ;

[0769] R 7 It is -R', or

[0770] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0771] R 9 It is -R';

[0772] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0773] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0774] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0775] R m It is R;

[0776] Each R n It can be halogen, -CN, -R, or -OR independently;

[0777] s is 0, 1, 2, 3, 4, or 5;

[0778] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0779] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0780] In some embodiments, this disclosure provides a compound of formula VIB or a pharmaceutically acceptable salt thereof:

[0781]

[0782] The variables, both individually and in combination, are defined as above for Equation VI-1 and described in the categories and subcategories of this paper.

[0783] In some embodiments, this disclosure provides compounds of formula VII or pharmaceutically acceptable salts thereof:

[0784]

[0785] Among them, rings A, B, and L 1 R 1 R 9, n, and connectors, both individually and in combination, are as defined above for Equation II and described in the categories and subcategories herein; and

[0786] Each R p It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[0787] Each R q It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[0788] Each R r Independently hydrogen or optionally substituted C 1-6 aliphatic;

[0789] Each R s It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[0790] t is 0, 1, 2, 3, 4, or 5; and

[0791] Each u is independently 0, 1, 2, 3, 4, or 5.

[0792] In some embodiments, this disclosure provides compounds of formula VIIA or pharmaceutically acceptable salts thereof:

[0793]

[0794] Among them, rings A and R 1 R 9 R p R q R r R s The terms u, t, and connector, both individually and in combination, are defined above for Equation VII and are described in the categories and subcategories herein.

[0795] In some embodiments, this disclosure provides compounds of formula VII-1 or pharmaceutically acceptable salts thereof:

[0796]

[0797] Ring A is selected from:

[0798] ;

[0799] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0800] L 1 It is a covalent bond or an optionally substituted divalent C.1-3 hydrocarbon chain;

[0801] Each R 1 Independently, it is -R;

[0802] n is 0, 1, 2, 3 or 4;

[0803] Z is N or CR 3 ;

[0804] R 2 It is a halogen, -CN, or -R;

[0805] Each R 3 It is halogen, -CN, or -R independently;

[0806] R 4 It is -R';

[0807] R 5 It is halogen, -CN or -R, or

[0808] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0809] R 6 It is -R';

[0810] X is O or NR 7 ;

[0811] R 7 It is -R', or

[0812] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0813] R 9 It is -R';

[0814] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0815] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0816] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0817] Each R' is independently -R, -C(O)R or -S(O)2R, or two R's connected to the same atom can be combined with the atom to which they are connected to form an optionally substituted 3 to 16-membered ring with 1 to 5 heteroatoms independently selected from N, O and S.

[0818] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S;

[0819] Each R p It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[0820] Each R q It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[0821] Each R r Independently hydrogen or optionally substituted C 1-6 aliphatic;

[0822] Each R s It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[0823] t is 0, 1, 2, 3, 4, or 5; and

[0824] Each u is independently 0, 1, 2, 3, 4, or 5.

[0825] In some embodiments, this disclosure provides compounds of formula VIIB or pharmaceutically acceptable salts thereof:

[0826]

[0827] Among them, rings A and R 1 R 9 R p R q R r R s The terms u, t, and connector, both individually and in combination, are defined above for formula VII-1 and described in the categories and subclasses herein.

[0828] In some embodiments, this disclosure provides a compound of formula VIII or a pharmaceutically acceptable salt thereof:

[0829]

[0830] Among them, rings A, B, and L 1 R 1 R 9 , n and the connector, both individually and in combination, are as defined above for Equation II and are described in the categories and subcategories herein; and

[0831] Each R t Independently hydrogen or optionally substituted C 1-6 aliphatic, or

[0832] Two Rs t Groups, together with the atoms to which they are attached, combine to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O, and S;

[0833] Each R u It is independently hydrogen, halogen, -CN, or optionally substituted C. 1-6 aliphatic;

[0834] Each R v It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic, or

[0835] R v and R u One example is that they combine with the atoms to which they are attached to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O and S;

[0836] Each R w It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic, or

[0837] R w and R u One example is the combination of these atoms with the atoms to which they are attached to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O, and S; and

[0838] Each v is independently 0, 1, 2, 3, 4, or 5.

[0839] In some embodiments, this disclosure provides compounds of formula VIIIA or pharmaceutically acceptable salts thereof:

[0840]

[0841] Among them, rings A and R 1 R 9 R t R u R v R w The , v and the connector, in both individual and combined cases, are defined above for formula VIII and described in the categories and subclasses herein.

[0842] In some embodiments, this disclosure provides a compound of formula VIII-1 or a pharmaceutically acceptable salt thereof:

[0843]

[0844] Ring A is selected from:

[0845] ;

[0846] Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S;

[0847] L 1 It is a covalent bond or an optionally substituted divalent C. 1-3 hydrocarbon chain;

[0848] Each R 1 Independently, it is -R;

[0849] n is 0, 1, 2, 3 or 4;

[0850] Z is N or CR 3 ;

[0851] R 2 It is a halogen, -CN, or -R;

[0852] Each R 3 It is halogen, -CN, or -R independently;

[0853] R 4 It is -R';

[0854] R 5 It is halogen, -CN or -R, or

[0855] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0856] R 6 It is -R';

[0857] X is O or NR 7 ;

[0858] R 7 It is -R', or

[0859] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0860] R 9 It is -R';

[0861] The connector is a covalent bond or an optional substituted divalent C1-C bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;

[0862] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0863] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0864] Each R' is independently -R, -C(O)R or -S(O)2R, or two R's connected to the same atom can be combined with the atom to which they are connected to form an optionally substituted 3 to 16-membered ring with 1 to 5 heteroatoms independently selected from N, O and S.

[0865] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S;

[0866] Each R t Independently hydrogen or optionally substituted C 1-6 aliphatic, or

[0867] Two Rs t Groups, together with the atoms to which they are attached, combine to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O, and S;

[0868] Each R u It is independently hydrogen, halogen, -CN, or optionally substituted C.1-6 aliphatic;

[0869] Each R v It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic, or

[0870] R v and R u One example is that they combine with the atoms to which they are attached to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O and S;

[0871] Each R w It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic, or

[0872] R w and R u One example is the combination of these atoms with the atoms to which they are attached to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O, and S; and

[0873] Each v is independently 0, 1, 2, 3, 4, or 5.

[0874] In some embodiments, this disclosure provides compounds of formula VIIIB or pharmaceutically acceptable salts thereof:

[0875]

[0876] Among them, rings A, F, and R 1 R 9 R t R u R v R w The , v and the connector, in both individual and combined cases, are defined above for formula VIII-1 and described in the categories and subclasses herein.

[0877] In some embodiments, this disclosure provides compounds of formula IX or pharmaceutically acceptable salts thereof:

[0878]

[0879] in:

[0880] Ring A is selected from:

[0881] ;

[0882] L 3 L 4 and L 5Each is independently a covalent bond or an optional substituted divalent C. 1-6 Straight-chain or branched hydrocarbon chains;

[0883] Z is N or CR 3 ;

[0884] R 2 It is hydrogen, halogen, -CN, or optionally substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0885] Each R 3 Independently hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0886] R 4 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0887] R 5 It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group, or

[0888] R 2 and R 5 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0889] R 6 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0890] X is O or NR 7 ;

[0891] R 7 It is hydrogen or optionally substituted C 1-6 aliphatic, or

[0892] R 4 and R 7 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0893] Each R 8 Independently hydrogen or optionally substituted C 1-6 aliphatic;

[0894] R 9It is hydrogen or optionally substituted C 1-6 aliphatic;

[0895] The linker is a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0896] Each Cy is independently a substituted monocyclic or polycyclic 3- to 16-membered divalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0 to 6 heteroatoms independently selected from N, O, and S.

[0897] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic, phenyl, C 3-7 Alicyclic groups, comprising 5- to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, and 3- to 7-membered monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S; and

[0898] LBM is the E3 ubiquitin ligase binding site.

[0899] In some embodiments, this disclosure provides a compound of formula IX or a pharmaceutically acceptable salt thereof, wherein:

[0900] Ring A is selected from:

[0901] ;

[0902] L 3 L 4 and L 5 Each is independently a covalent bond or an optional substituted divalent C. 1-6 Straight-chain or branched hydrocarbon chains;

[0903] Z is N or CR 3 ;

[0904] R 2 It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0905] Each R 3 Independently hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0906] R 4 It is hydrogen, with optional substituted C. 1-6Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0907] R 5 It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group, or

[0908] R 2 and R 5 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0909] R 6 It is hydrogen, with optional substituted C. 1-6 Aliphatic or optionally substituted C 3-6 Alicyclic group;

[0910] X is O or NR 7 ;

[0911] R 7 It is hydrogen or optionally substituted C 1-6 aliphatic, or

[0912] R 4 and R 7 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0913] Each R 8 Independently hydrogen or optionally substituted C 1-6 aliphatic;

[0914] R 9 It is hydrogen or optionally substituted C 1-6 aliphatic;

[0915] The linker is a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0916] Each Cy is independently a substituted monocyclic or polycyclic 3- to 16-membered divalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0 to 6 heteroatoms independently selected from N, O, and S.

[0917] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic, phenyl, C 3-7Alicyclic groups, comprising 5- to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, and 3- to 7-membered monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S; and

[0918] LBM is the E3 ubiquitin ligase binding site.

[0919] In some embodiments, this disclosure provides compounds of formula IXA, IXB, IXC, or IXD, or their pharmaceutically acceptable salts:

[0920]

[0921] Where L 3 L 4 L 5 R 2 R 3 R 4 R 5 R 6 R 8 R 9 X, Z, connector, and LBM are described above, individually and in combination, as defined for formula IX and in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula IXA or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a compound of formula IXB or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a compound of formula IXC or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a compound of formula IXD or a pharmaceutically acceptable salt thereof.

[0922] In some embodiments, this disclosure provides a compound of formula IX-1 or a pharmaceutically acceptable salt thereof:

[0923]

[0924] in:

[0925] Ring A is selected from:

[0926] ;

[0927] Z is N or CR 3 ;

[0928] R 2 It is a halogen, -CN, or -R;

[0929] Each R 3 It is halogen, -CN, or -R independently;

[0930] R 4 It is -R';

[0931] R5 It is halogen, -CN or -R, or

[0932] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0933] R 6 It is -R';

[0934] X is O or NR 7 ;

[0935] R 7 It is -R', or

[0936] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0937] R 9 It is -R';

[0938] L 3 L 4 and L 5 Each is independently a covalent bond or an optional substituted divalent C. 1-6 hydrocarbon chain;

[0939] Each R 8 Independently, it is -R';

[0940] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0941] The linker is a covalent bond or an optionally substituted divalent straight or branched chain, saturated; or the linker is a covalent bond or an optionally substituted divalent C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0942] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0943] LBM is the E3 ubiquitin ligase binding site;

[0944] Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and

[0945] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

[0946] In some embodiments, this disclosure provides a compound of formula X or a pharmaceutically acceptable salt thereof:

[0947]

[0948] Among them, rings A and L 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for Formula IX and described in the categories and subclasses herein; and

[0949] The ring C is a 3- to 16-membered divalent ring system of optional substituted monocyclic or polycyclic rings, wherein the ring system is fully saturated, partially saturated or aromatic, and the ring system contains 0 to 6 heteroatoms independently selected from N, O and S.

[0950] Each R a Independently hydrogen or optionally substituted C 1-6 Aliphatic, or two Rs a Groups, together with the atoms they are attached to, combine to form 3 to 6-membered saturated or partially unsaturated rings;

[0951] L 2 Is it a covalent bond, a straight chain, or a branched chain? 1-3 The hydrocarbon chain, wherein one methylene group is optionally replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; and

[0952] Y is either N or CH.

[0953] In some embodiments, this disclosure provides a compound of formula XA or a pharmaceutically acceptable salt thereof:

[0954]

[0955] Among them, rings A and L 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for Formula IX and described in the categories and subclasses herein; and

[0956] Each R b It is hydrogen, or two Rs on the same carbon atom. b Groups together form oxo groups or combine to form 3 to 6-membered saturated or partially unsaturated rings;

[0957] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[0958] m can be 0, 1, 2, or 3.

[0959] In some embodiments, this disclosure provides compounds of formula XA-1 or XA-2, or pharmaceutically acceptable salts thereof:

[0960]

[0961] Among them, rings A and L 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for formula IX and described in the categories and subcategories herein. In some embodiments, this disclosure provides a compound of formula XA-1 or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a compound of formula XA-2 or a pharmaceutically acceptable salt thereof.

[0962] In some embodiments, this disclosure provides a compound of formula XB or a pharmaceutically acceptable salt thereof:

[0963]

[0964] Among them, rings A and L 2 L 3 L 4 L 5 R 8 R 9 Y and the connector, both individually and in combination, are as defined above for formula X and described in the categories and subclasses herein; and

[0965] Each B is independently selected from N, C, and CH, provided that no more than two Bs are N;

[0966] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[0967] m can be 0, 1, 2, or 3.

[0968] In some embodiments, this disclosure provides compounds of formula X-1, X-2, or X-2, or pharmaceutically acceptable salts thereof:

[0969]

[0970] The variables are defined individually and in combination as in Equation I or IIIL and are described in the categories and subclasses in this paper.

[0971] In some embodiments, this disclosure provides compounds of formula XA' or pharmaceutically acceptable salts thereof:

[0972]

[0973] Each R c The variables are independently selected from halogens, -OR, -N(R)2, -CN, and -R; m is 0, 1, 2, or 3; and other variables are defined individually and in combination as in Equation I and described in the categories and subcategories herein. In some embodiments, ring A is selected from:

[0974] ;

[0975] Z is N or CR 3 ;

[0976] R 2 It is a halogen, -CN, or -R;

[0977] Each R 3 It is halogen, -CN, or -R independently;

[0978] R 4 It is -R';

[0979] R 5 It is halogen, -CN or -R, or

[0980] R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S;

[0981] R 6 It is -R';

[0982] X is O or NR 7 ;

[0983] R 7 It is -R', or

[0984] R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S;

[0985] R 9 It is -R';

[0986] L 3 L 4 and L 5 Each is independently a covalent bond or an optional substituted divalent C. 1-6 hydrocarbon chain;

[0987] Each R 8 Independently, it is -R';

[0988] Ring F is an optional substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S;

[0989] The linker is a covalent bond or an optionally substituted divalent straight or branched chain, saturated; or the linker is a covalent bond or an optionally substituted divalent C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: ;

[0990] Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S;

[0991] Each R' is independently -R, -C(O)R or -S(O)2R, or two R's connected to the same atom can be combined with the atom to which they are connected to form an optionally substituted 3 to 16-membered ring with 1 to 5 heteroatoms independently selected from N, O and S.

[0992] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S;

[0993] Each R b It is hydrogen, or two Rs on the same carbon atom. b Groups together form oxo groups or combine to form 3 to 6-membered saturated or partially unsaturated rings;

[0994] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[0995] m can be 0, 1, 2, or 3.

[0996] In some embodiments, this disclosure provides compounds of formula XA-1' or XA-2' or their pharmaceutically acceptable salts:

[0997]

[0998] The variables, both individually and in combination, are defined as in Equation I and described in the categories and subcategories herein. In some implementations, rings A and L... 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for formula X-1 and described in the categories and subcategories herein. In some embodiments, this disclosure provides compounds of formula XA-1' or pharmaceutically acceptable salts thereof. In some embodiments, this disclosure provides compounds of formula XA-2' or pharmaceutically acceptable salts thereof.

[0999] In some embodiments, this disclosure provides compounds of formula XB' or pharmaceutically acceptable salts thereof:

[1000]

[1001] Among them, rings A, F, and L 2 L 3 L 4 L 5 R 8 R 9 Y and the connector, both individually and in combination, are as defined above for formula X-1 and described in the categories and subclasses herein; and

[1002] Each B is independently selected from N, C, and CH, provided that no more than two Bs are N;

[1003] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[1004] m can be 0, 1, 2, or 3.

[1005] In some embodiments, this disclosure provides a compound of formula XI or a pharmaceutically acceptable salt thereof:

[1006]

[1007] Among them, rings A and L 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for Formula IX and described in the categories and subclasses herein; and

[1008] Connector at R d R e R f Or R g One of them connects to the part in parentheses;

[1009] R that is not a connector connection point d It is independently hydrogen, -C(O)R, or optionally substituted C 1-6 aliphatic, or

[1010] Two Rs d Together with the atoms to which they are attached, they combine to form optionally substituted 5- to 6-membered rings having 1 to 3 heteroatoms independently selected from N, O, and S, and said rings are optionally fused with phenyl or 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from N, O, and S.

[1011] R that is not a connector connection point e Independently hydrogen or optionally substituted C 1-6 aliphatic;

[1012] When R f When it is not a junction connection point, it is hydrogen or optionally substituted C. 1-6 aliphatic;

[1013] R that is not a connector connection point g It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[1014] R h It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic; and

[1015] p is 0, 1, 2 or 3.

[1016] In some embodiments, this disclosure provides compounds of formula XIA or pharmaceutically acceptable salts thereof:

[1017]

[1018] Among them, rings A and L 3 L 4 L 5 R 8 R 9 R d R e R f R g R h p and connector, both individually and in combination, are defined above for formula XI and described in the categories and subclasses herein.

[1019] In some embodiments, this disclosure provides a compound of formula XI-1 or a pharmaceutically acceptable salt thereof:

[1020]

[1021] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1022] In some embodiments, this disclosure provides compounds of formula XIB or pharmaceutically acceptable salts thereof:

[1023]

[1024] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1025] In some embodiments, this disclosure provides a compound of formula XII or a pharmaceutically acceptable salt thereof:

[1026]

[1027] Among them, rings A and L 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for Formula IX and described in the categories and subclasses herein; and

[1028] Connector in an R i In place or when two R i When groups are together, the ring formed is connected to the bracket portion;

[1029] R that is not a connector connection point i Independently halogenated, optionally substituted C 1-6Aliphatic, -C(O)N(R)2 or -N(R)C(O)R, or

[1030] Two Rs i The groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or a 5- to 6-membered heteroaryl ring having 1 to 3 independent heteroatoms selected from N, O, and S;

[1031] R j It is an optional, substituted selection from C 1-6 aliphatic and C 3-7 Alicyclic groups, or

[1032] R j With an R i Examples and the atoms to which they are attached are combined to form optional substituted 5- to 7-membered heterocycles with 1 to 2 independent heteroatoms selected from N, O and S;

[1033] R k It is an optional substituted C 1-6 aliphatic;

[1034] r is 1, 2, 3, 4, or 5; and

[1035] q is 1 or 2.

[1036] In some embodiments, this disclosure provides a compound of formula XIIA or a pharmaceutically acceptable salt thereof:

[1037]

[1038] Among them, rings A and L 3 L 4 L 5 R 8 R 9 R i R j R k , q, r and connector, in both individual and combined cases, are defined above for Formula XII and described in the categories and subclasses herein.

[1039] In some embodiments, this disclosure provides compounds of formula XIB or pharmaceutically acceptable salts thereof:

[1040]

[1041] Among them, rings A and L 3 L 4 L 5 , R, R 8 R 9 R i R j Rk , q, r and connector, in both individual and combined cases, are defined above for Formula XII and described in the categories and subclasses herein.

[1042] In some embodiments, this disclosure provides a compound of formula XIIB-1 or a pharmaceutically acceptable salt thereof:

[1043]

[1044] Among them, rings A and L 3 L 4 L 5 , R, R 8 R 9 R j R k The connectors, both individually and in combination, are as defined above for Formula XII and are described in the categories and subcategories herein.

[1045] In some embodiments, this disclosure provides a compound of formula XII-1 or a pharmaceutically acceptable salt thereof:

[1046]

[1047] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1048] In some embodiments, this disclosure provides compounds of formula XIIA' or pharmaceutically acceptable salts thereof:

[1049]

[1050] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1051] In some embodiments, this disclosure provides compounds of formula XIIB' or pharmaceutically acceptable salts thereof:

[1052]

[1053] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1054] In some embodiments, this disclosure provides a compound of formula XIIB-1' or a pharmaceutically acceptable salt thereof:

[1055]

[1056] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1057] In some embodiments, this disclosure provides a compound of formula XIII or a pharmaceutically acceptable salt thereof:

[1058]

[1059] Among them, rings A and L 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for Formula IX and described in the categories and subclasses herein; and

[1060] R m It is an optional substituted C 1-6 aliphatic;

[1061] Each R n It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 Aliphatic; and

[1062] s can be 0, 1, 2, 3, 4 or 5.

[1063] In some embodiments, this disclosure provides a compound of formula XIIIA or a pharmaceutically acceptable salt thereof:

[1064]

[1065] XIIIA

[1066] Among them, rings A and L 3 L 4 L 5 R 8 R 9 R m R n , s and connectors, both individually and in combination, are defined above for formula XIII and described in the categories and subclasses herein.

[1067] In some embodiments, this disclosure provides a compound of formula XIII-1 or a pharmaceutically acceptable salt thereof:

[1068]

[1069] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1070] In some embodiments, this disclosure provides a compound of formula XIIIB or a pharmaceutically acceptable salt thereof:

[1071]

[1072] Among them, rings A, F, and L 3 L 4 L 5 R 8 R 9 R m R n , s and connectors, both individually and in combination, are defined above for formula XIII-1 and described in the categories and subclasses herein.

[1073] In some embodiments, this disclosure provides a compound of formula XIV or a pharmaceutically acceptable salt thereof:

[1074]

[1075] Among them, rings A and L 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for Formula IX and described in the categories and subclasses herein; and

[1076] Each R p It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[1077] Each R q It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[1078] Each R r Independently hydrogen or optionally substituted C 1-6 aliphatic;

[1079] Each R s It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic;

[1080] t is 0, 1, 2, 3, 4, or 5; and

[1081] Each u is independently 0, 1, 2, 3, 4, or 5.

[1082] In some embodiments, this disclosure provides a compound of formula XIV-1 or a pharmaceutically acceptable salt thereof:

[1083]

[1084] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1085] In some embodiments, this disclosure provides compounds of formula XV or pharmaceutically acceptable salts thereof:

[1086]

[1087] Among them, rings A and L 3 L 4 L 5 R 8 R 9 The connectors, both individually and in combination, are as defined above for Formula IX and described in the categories and subclasses herein; and

[1088] Each R t Independently hydrogen or optionally substituted C 1-6 aliphatic, or

[1089] Two Rs t Groups, together with the atoms to which they are attached, combine to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O, and S;

[1090] Each R u It is independently hydrogen, halogen, -CN, or optionally substituted C. 1-6 aliphatic;

[1091] Each R v It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic, or

[1092] R v and R u One example is that they combine with the atoms to which they are attached to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O and S;

[1093] Each R w It is independently a halogen, -OR, -CN, or optionally substituted C. 1-6 aliphatic, or

[1094] R w and R u One example is that they combine with the atoms to which they are attached to form optionally substituted 3- to 7-membered alicyclic compounds or heterocycles having 1 to 2 independent heteroatoms selected from N, O and S;

[1095] Each v is independently 0, 1, 2, 3, 4, or 5.

[1096] In some embodiments, this disclosure provides a compound of formula XV-1 or a pharmaceutically acceptable salt thereof:

[1097]

[1098] The variables are defined in both individual and combined cases as in Equation I and are described in the categories and subclasses in this paper.

[1099] PBM

[1100] In some embodiments described herein, the PBM is a KAT2 protein-binding portion, i.e., the PBM is a portion capable of binding to the KAT2 protein. In some embodiments, the PBM is a KAT2A protein-binding portion, i.e., the PBM is a portion capable of binding to the KAT2A protein. In some embodiments, the PBM is a KAT2B protein-binding portion, i.e., the PBM is a portion capable of binding to the KAT2 protein. Generally, a PBM is considered capable of binding to a KAT2 protein (e.g., KAT2A and / or KAT2B) if it specifically (i.e., preferentially) associates with the KAT2 protein when in contact with it in the presence of at least one other protein. In some embodiments, a PBM is considered capable of binding to the KAT2 protein if it specifically associates with the KAT2 protein intracellularly (e.g., in vitro or in vivo).

[1101] In some embodiments, the PBM shares significant structural identity with a reference compound or a portion thereof capable of binding the KAT2 protein. For example, in some embodiments, the PBM contains the same or similar structure as the reference compound, except that it includes a connection site with the linker. In some embodiments, the reference compound is characterized by K... d Less than 1 μM. In some embodiments, the reference compound is characterized by an IC50 value in competitive or functional assays (e.g., time-resolved fluorescence resonance energy transfer, TR-FRET). 50 Less than 1 μM. In some embodiments, the reference compound is characterized by DC in the Western blot assay of Example B1. 50Less than 30 nM. In some embodiments, the reference compound binds to the KAT2 protein but does not cause KAT2 degradation during evaluation, for example as described in Example B1. In some embodiments, the reference compound has the structure of PBM-H or a salt thereof. In some embodiments, the reference compound is the compound described in the following: WO 2016 / 036954; WO 2016 / 036873; WO 2016 / 112298; Chaikudad, A., et al., J. Med. Chem., 2016, 59, 1648-53; Humphreys, PG, 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 which are incorporated herein by reference. Reference compounds can be used to evaluate the binding properties of the PBM of this disclosure, for example, by comparing the binding data of the PBM of this disclosure with the binding data of the reference compound. In some embodiments, the reference compound may be incorporated as a PBM (see, for example, GSK4027 incorporated as a PBM into a variety of compounds). In some embodiments, the PBM is as described in: WO 2024 / 003533, US20230391745, WO2017 / 197046, or Bassi, Z., et al., ACS Chem. Biol. 2018, 13, 2862-2867, the entire contents of which are incorporated herein by reference. In some embodiments, techniques for identifying or evaluating PBMs are described in one or more of these references. In some embodiments, if the PBM-H compound or its salt, or the PBM-connector-H compound or its salt, is used to determine the K+ of the KAT2A protein in a assay (e.g., surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC)), the PBM is considered to be effective. D A concentration of approximately or less than approximately 1 μM indicates that PBM is considered capable of binding the KAT2A protein. In some embodiments, during competitive or functional assays (e.g., time-resolved fluorescence resonance energy transfer (TR-FRET)), the IC50 of the PBM-H compound or a salt thereof, or the PBM-connector-H compound or a salt thereof, is considered to be... 50 It is approximately or less than approximately 1 μM.

[1102] In some implementations, the reference compound is GSK4027:

[1103] .

[1104] In some implementations, the reference compound is:

[1105] .

[1106] In some implementations, the PBM has a structure The variables are defined and described individually and in combination, as in the categories and subcategories herein. In some embodiments, ring F is an optionally substituted 3- to 10-membered ring having 0 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 5- to 10-membered ring (e.g., 5 to 8, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10) having 0 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 5-membered ring having 0 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 6-membered ring having 0 to 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 benzene ring. In some embodiments, ring F is a optionally substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a optionally substituted 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 5- to 6-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted monocyclic ring (e.g., 3 to 10, 5 to 8, 3, 4, 5, 6, 7, 8, 9, or 10-membered). In some embodiments, ring F is an optionally substituted bicyclic ring (e.g., 6 to 10, 6, 7, 8, 9, or 10-membered). In some embodiments, ring F is polycyclic.

[1107] In some implementations, PBM is Each variable is defined and described both individually and in combination, as in the categories and subcategories described herein. In some implementations, the PBM has the following structure:

[1108] ,

[1109] Among them, rings A, B, and L 1 R 1 R 9 And n, both individually and in combination, are defined in this paper as for Equation II and described in the categories and subclasses herein.

[1110] In some implementations, the PBM has the following structure:

[1111] ,

[1112] Among them, rings A and L 1 R 1 R 9 And n, both individually and in combination, are defined in this paper as for Equation II and described in the categories and subclasses herein.

[1113] In some implementations, the PBM has the following structure:

[1114] ,

[1115] Among them, rings A and R 1 and R 9 Both individually and in combination, as defined herein with respect to Equation II and described in the categories and subclasses herein.

[1116] In some implementations, the PBM has the following structure:

[1117] ,

[1118] Among them, rings A and R 1 and R 9 Both individually and in combination, as defined herein with respect to Equation II and described in the categories and subclasses herein.

[1119] In some implementations, the PBM has the following structure:

[1120] ,

[1121] Among them, rings A and R 1 and R 9 Both individually and in combination, as defined herein with respect to Equation II and described in the categories and subclasses herein.

[1122] In some implementations, the PBM is selected from:

[1123] ,

[1124] Where R 1 R 2 R 3 R 4 R 5 R 6 R 9 X and Z, individually and in combination, are defined in this paper as for Equation II and are described in the categories and subclasses herein.

[1125] In some implementations, the PBM has the following structure:

[1126] ,

[1127] Among them, rings A and L 3 L 4 L 5 R 8 and R 9 Both individually and in combination, as defined herein for Formula IX and described in the categories and subclasses herein.

[1128] In some implementations, the PBM is selected from:

[1129] ,

[1130] Where L 3 L 4 L 5 R 2 R 3 R 4 R 5 R 6 R 8 R 9 X and Z are defined individually and in combination as described herein for formula IX and in the categories and subclasses described herein.

[1131] In some implementations, the PBM is selected from:

[1132] .

[1133] In some implementations, the PBM is selected from:

[1134] .

[1135] In some embodiments of any formula described herein (unless otherwise explicitly stated, the embodiments described (e.g., for variables or parts) shall apply to all suitable formulas, structures, etc., such as all those containing such variables or parts, whether or not "any formula described herein" or similar language is used), ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is selected from: In some implementations, ring A is selected from: .

[1136] In some embodiments of any of the forms described herein, ring A is In some implementations, ring A is In some such implementations, R 2 and R 5 Together with the atoms they are attached to, they combine to form optionally substituted 5- to 6-membered rings having 0 to 2 independent heteroatoms selected from N, O, and S. In some embodiments, the formed ring is aromatic. In some embodiments, ring A is... .

[1137] In some embodiments of any of the forms described herein, ring A is In some implementations, ring A is In some implementations, ring A is In some such implementations, R 2 and R 5 Together with the atoms they are attached to, they combine to form optionally substituted 5- to 6-membered aromatic rings having 0 to 2 independent heteroatoms selected from N, O, and S. In some such embodiments, R 4 and R 7 Together with the atoms they are attached to, they combine to form optionally substituted 5- to 6-membered rings having 2 to 3 independently selected heteroatoms chosen from N, O, and S. In some embodiments, the formed ring is aromatic. In some embodiments, ring A is selected from: , .

[1138] In some embodiments of any of the forms described herein, ring A is In some implementations, ring A is .

[1139] In some embodiments of any of the forms described herein, Z is N or CH. In some embodiments, Z is N. In some embodiments, Z is CR. 3 (e.g., CH). In some implementations, Z is optionally substituted CH.

[1140] In some embodiments, ring F is an optionally substituted 3- to 16-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 3 to 15, 3 to 10, 5 to 10, 3 to 8, 3 to 7, 5 to 6-membered) ring having 0 to 6 (e.g., 0, 1 to 6, 1 to 4, 1, 2, 3, 4, 5, or 6) heteroatoms independently selected from N, O, and S. In some embodiments, ring F is 3 to 10-membered. In some embodiments, it is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7-membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is aromatic. In some embodiments, it has 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1, 2, 3, or 4 heteroatoms. In some embodiments, it has no heteroatoms. In some embodiments, it is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, at least one monocyclic ring unit is saturated. In some embodiments, at least one monocyclic ring unit is partially unsaturated. In some embodiments, at least one monocyclic ring unit is aromatic. In some embodiments, at least one monocyclic ring unit has heteroatoms. In some embodiments, at least one monocyclic ring unit has no heteroatoms. In some embodiments, ring F is optionally substituted, a 5- to 6-membered ring having 0 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is optionally substituted, a benzene ring. In some embodiments, ring F is optionally substituted, a pyridine ring. In some embodiments, ring F is optionally substituted, a 5-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 6-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is 3 to 10-membered. In some embodiments, it is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7-membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated.In some embodiments, it is aromatic. In some embodiments, it has 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1, 2, 3, or 4 heteroatoms. In some embodiments, it has no heteroatoms. In some embodiments, it is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, at least one monocyclic ring unit is saturated. In some embodiments, at least one monocyclic ring unit is partially unsaturated. In some embodiments, at least one monocyclic ring unit is aromatic. In some embodiments, at least one monocyclic ring unit has heteroatoms. In some embodiments, at least one monocyclic ring unit has no heteroatoms.

[1141] In some embodiments, ring F is optionally substituted with one or more halogens. In some embodiments, ring F is optionally substituted with one or more C1-C6 alkyl groups. In some embodiments, ring F is optionally substituted with an optionally substituted -O (C1-C6 alkyl) group. In some embodiments, ring F is... In 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 implementations, ring F is .

[1142] In some implementation schemes, R 2 It is -R as described in this document. In some implementations, R 2 It is -R, but not hydrogen. In some embodiments of any of the forms described herein, R 2 It is hydrogen, halogen, -CN, or optionally substituted C. 1-6 Aliphatic. In some implementations, R 2 It is hydrogen, halogen, -CN, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 2 It is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl or C 6-10 Aryl. In some implementations, R 2 It is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 It is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10Aryl, 5- to 10-membered heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic. In some implementations, R 2 Is it halogen or C? 1-6 Alkyl group. In some embodiments, R 2 It is chlorine, bromine, or methyl. In some implementations, R 2 It is hydrogen. In some implementations, R 2 It is a halogen. In some implementations, R 2 It is fluorine. In some implementations, R 2 It is chlorine. In some implementations, R 2 It is bromine. In some implementations, R 2 Yes -CN. In some implementations, R 2 It is an optional, substituted C 1-6 Aliphatic. In some implementations, R 2 It is an optional, substituted C 1-6 Alkyl group. In some embodiments, R 2 It is C 1-2 Alkyl (e.g., methyl or ethyl). In some embodiments, R 2 It is an optional, substituted C 3-6 Alicyclic group. In some implementations, R 2 It is an optional, substituted C 3-6 Cycloalkyl. In some embodiments, R 2 It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R 2 It is C 6-10 Aryl. In some implementations, R 2 It is phenyl. In some embodiments, R 2 It is naphthyl. In some embodiments, R 2 It is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 It is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 It is a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S.

[1143] In some implementation schemes, R 3It is -R as described in this document. In some implementations, R 3 It is -R, but not H. In some implementations of any of the forms described herein, each R 3 Independently hydrogen, halogen, or optionally substituted C 1-6 Aliphatic. In some implementations, each R 3 Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, each R 3 Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl or C 6-10 Aryl. In some implementations, each R 3 Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, or 5- to 10-membered heteroaryl groups having 1 to 5 independent heteroatoms selected from N, O, and S. In some embodiments, each R 3 Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 The aryl group is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S, or a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, each R 3 It is hydrogen. In some implementations, R 3 It is hydrogen. In some implementations, R 3 It is a halogen. In some implementations, R 3 It is fluorine. In some implementations, R 3 It is chlorine. In some implementations, R 3 It is bromine. In some implementations, R 3 It is an optional substituted C 1-6 Aliphatic. In some implementations, R 3 It is an optional substituted C 1-6 Alkyl group. In some embodiments, R 3 It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R 3 It is an optional substituted C 3-6 Alicyclic group. In some implementations, R 3 It is an optional substituted C 3-6 Cycloalkyl. In some embodiments, R 3 It is C 6-10 Aryl. In some implementations, R3 It is phenyl. In some embodiments, R 3 It is naphthyl. In some embodiments, R 3 It is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 3 It is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 3 It is a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 3 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S.

[1144] In some implementation schemes, R 4 It is -R as described in this document. In some implementations, R 4 It is -R, but not hydrogen. In some embodiments of any of the forms described herein, R 4 It is hydrogen or optionally substituted C 1-6 Aliphatic. In some implementations, R 4 It is hydrogen. In some implementations, R 4 It is an optional substituted C 1-6 Aliphatic. In some implementations, R 4 It is hydrogen. In some implementations, R 4 It is an optional substituted C 1-6 Aliphatic. In some implementations, R 4 It is an optional substituted C 1-6 Alkyl group. In some embodiments, R 4 It is C 1-6 Alkyl group. In some embodiments, R 4 It is an optional substituted C 1-2 Alkyl group. In some embodiments, R 4 It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R 3 It is methyl. In some embodiments, R 4 It is an optional substituted C 3-6 Alicyclic group. In some implementations, R 4 It is an optional substituted C 3-6 Cycloalkyl. In some embodiments, R 4 It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R 4 It is -C(O)R. In some implementations, R 4 It is -C(O)(C 1-6 Alkyl group). In some embodiments, R4 It is -S(O)2R. In some implementations, R 4 It is -S(O)2(C 1-6 alkyl).

[1145] In some implementation schemes, R 5 It is -R as described in this document. In some implementations, R 5 It is -R, but not hydrogen. In some embodiments of any of the forms described herein, R 5 It is hydrogen, halogen, or optionally substituted C 1-6 Aliphatic. In some implementations, R 5 It is hydrogen, halogen, -CN, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 5 It is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl or C 6-10 Aryl. In some implementations, R 5 It is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, or a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 It is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 The aryl group is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S, or a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 It is hydrogen. In some implementations, R 5 It is a halogen. In some implementations, R 5 It is fluorine. In some implementations, R 5 It is chlorine. In some implementations, R 5 It is bromine. In some implementations, R 5 It is an optional, substituted C 1-6 Aliphatic. In some implementations, R 5 It is an optional, substituted C 1-6 Alkyl group. In some embodiments, R 5 It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R 5 It is an optional, substituted C 3-6 Alicyclic group. In some implementations, R 5 It is an optional, substituted C 3-6Cycloalkyl. In some embodiments, R 5 It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R 5 It is C 6-10 Aryl. In some implementations, R 5 It is phenyl. In some embodiments, R 5 It is naphthyl. In some embodiments, R 5 It is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 It is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 It is a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S.

[1146] In some implementation schemes, R 2 and R 5 Together with the atoms they are attached to, they combine to form optionally substituted 5- to 6-membered rings having 0 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, the formed ring is monocyclic. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it has 1 to 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 to 2 heteroatoms independently selected from N, O, and S. In some embodiments of any of the formulas described herein, R 2 and R 5 Together with the atoms they are attached to, they combine to form optionally substituted 5- to 6-membered aromatic rings having 0 to 2 independent heteroatoms selected from N, O, and S. In some embodiments, R 2 and R 5 Together with the atoms they are attached to, they form a 5- to 6-membered aromatic ring having 0 to 2 independent heteroatoms selected from N, O, and S, and optionally, one or more halogens, -R°, -OR°, -N(R°)2, and -CN are substituted on the substituted carbon atoms, and one or more halogens are substituted on the substituted nitrogen atoms. Replacement. In some implementations, R 2 and R 5Together with the atoms they are attached to, they combine to form optionally substituted 5-membered aromatic rings having one or two independent heteroatoms selected from N, O, and S. In some embodiments, R 2 and R 5 Combining to form optionally substituted pyrroles. In some embodiments, R 2 and R 5 Together with the atoms they are attached to, they combine to form optionally substituted six-membered aromatic rings having 0 to 2 independent heteroatoms selected from N, O, and S. In some embodiments, R 2 and R 5 Combining to form optionally substituted phenyl or pyridine. In some embodiments, R 2 and R 5 Combining to form an optionally substituted benzene ring. In some embodiments, R 2 and R 5 Combining to form an optionally substituted pyridine ring. In some embodiments, R 2 and R 5 Combining to form optional substituted .

[1147] In some implementation schemes, R 6 It is -R as described in this document. In some implementations, R 6 It is -R, but not hydrogen. In some embodiments of any of the forms described herein, R 6 It is hydrogen or optionally substituted C 1-6 Aliphatic. In some implementations, R 6 It is hydrogen. In some implementations, R 6 It is an optional substituted C 1-6 Aliphatic. In some implementations, R 6 It is an optional substituted C 1-6 Alkyl group. In some embodiments, R 6 It is C 1-6 Alkyl group. In some embodiments, R 6 It is an optional substituted C 1-2 Alkyl group. In some embodiments, R 6 It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R 6 It is methyl. In some embodiments, R 6 It is an optional substituted C 3-6 Alicyclic group. In some implementations, R 6 It is an optional substituted C 3-6 Cycloalkyl. In some embodiments, R 6 It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R6 It is -C(O)R. In some implementations, R 6 It is -C(O)(C 1-6 Alkyl group). In some embodiments, R 6 It is -S(O)2R. In some implementations, R 6 It is -S(O)2(C 1-6 alkyl).

[1148] In some embodiments of any of the forms described herein, X is 0. In some embodiments, X is NR. 7 In some implementations, when X is NR 7 When, then R 4 and R 7 Together with the atoms to which they are attached, they combine to form optional substituted 5- to 6-membered aromatic rings with 2 to 3 independent heteroatoms selected from N, O, and S.

[1149] In some implementation schemes, R 7 It is -R as described in this document. In some implementations, R 7 It is -R, but not hydrogen. In some embodiments of any of the forms described herein, R 7 It is hydrogen or optionally substituted C 1-6 Alkyl group. In some embodiments, R 7 It is hydrogen. In some implementations, R 7 It is an optional substituted C 1-6 Aliphatic. In some implementations, R 7 It is an optional substituted C 1-6 Alkyl group. In some embodiments, R 7 It is C 1-6 Alkyl group. In some embodiments, R 7 It is an optional substituted C 1-2 Alkyl group. In some embodiments, R 7 It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R 7 It is an optional substituted C 3-6 Alicyclic group. In some implementations, R 7 It is an optional substituted C 3-6 Cycloalkyl. In some embodiments, R 7 It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R 7 It is -C(O)R. In some implementations, R 7 It is -C(O)(C 1-6 Alkyl group). In some embodiments, R 7It is -S(O)2R. In some implementations, R 7 It is -S(O)2(C 1-6 alkyl).

[1150] In some implementation schemes, R 4 and R 7 Together with the atoms they are attached to, they combine to form optionally substituted 5- to 6-membered rings having 2 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, the formed ring is monocyclic. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it has 2 heteroatoms. In some embodiments, it has 3 heteroatoms. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is aromatic. In some embodiments of any of the formulas described herein, R 4 and R 7 Together with the atoms they are attached to, they combine to form optionally substituted 5- to 6-membered aromatic rings having 2 to 3 independently selected heteroatoms chosen from N, O, and S. In some embodiments, R 4 and R 7 Together with the atoms they are attached to, they form a 5- to 6-membered aromatic ring having 2 to 3 independent heteroatoms selected from N, O, and S, and optionally substituted for one or more halogens, -R°, -OR°, -N(R°)2, and -CN on the substituted carbon atom, and substituted for one or more nitrogen atoms. Replacement. In some implementations, R 4 and R 7 Together with the atoms they are attached to, they form a 5- to 6-membered aromatic ring having 2 to 3 independent heteroatoms selected from N, O, and S, and optionally bounded by one or more C atoms. 1-6 Alkyl substitution. In some embodiments, R 4 and R 7 Together with the atoms they are attached to, they combine to form a 5-membered aromatic ring having 2 to 3 independent heteroatoms selected from N, O, and S. In some embodiments, R 4 and R 7 Combining to form optionally substituted triazoles. In some embodiments, R 4 and R 7 Together with the atoms they are attached to, they form a six-membered aromatic ring having two to three independent heteroatoms selected from N, O, and S. In some embodiments, the formed ring is optionally substituted. In some implementations, the formed ring is .

[1151] In some implementation schemes, R9 It is -R as described in this document. In some implementations, R 9 It is -R, but not hydrogen. In some embodiments of any of the forms described herein, R 9 It is hydrogen or optionally substituted C 1-6 Alkyl group. In some embodiments, R 9 It is hydrogen. In some implementations, R 9 It is an optional substituted C 1-6 Aliphatic. In some implementations, R 9 It is an optional substituted C 1-6 Alkyl group. In some embodiments, R 9 It is C 1-6 Alkyl group. In some embodiments, R 9 It is an optional substituted C 1-2 Alkyl group. In some embodiments, R 9 It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R 9 It is methyl. In some embodiments, R 9 It is an optional substituted C 3-6 Alicyclic group. In some implementations, R 9 It is an optional substituted C 3-6 Cycloalkyl. In some embodiments, R 9 It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R 9 It is -C(O)R. In some implementations, R 9 It is -C(O)(C 1-6 Alkyl group). In some embodiments, R 9 It is -S(O)2R. In some implementations, R 9 It is -S(O)2(C 1-6 alkyl).

[1152] In some embodiments, ring B is an optionally substituted 5-membered heterocyclic group having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is an optionally substituted 5-membered saturated heterocyclic group having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is an optionally substituted 5-membered partially unsaturated heterocyclic group having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is an optionally substituted 6-membered heterocyclic group having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is an optionally substituted 9-membered saturated heterocyclic group having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is an optionally substituted 5-membered partially unsaturated heterocyclic group having one or two 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 implementations, ring B is optionally substituted. In some implementations, ring B is... In some embodiments of any of the forms described herein, ring B is a 5- to 6-membered heterocyclic group having one heteroatom independently selected from N, O, and S. In some embodiments, ring B is a 5- to 6-membered heterocyclic group having one to two heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N. In some embodiments, ring B is a 5-membered heterocyclic group having one to two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a 6-membered heterocyclic group having one to two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is piperidine. In some embodiments, yes In some implementation schemes, yes .

[1153] In some embodiments of any of the forms described herein, L 1 It is a covalent bond. In some implementations, L 1 It is an optional substituted divalent C 1-3 Hydrocarbon chain. In some implementations, L 1 It is an optional substituted divalent saturated C 1-3 Hydrocarbon chain. In some implementations, L 1 It is an optional substituted divalent unsaturated C 1-3 Hydrocarbon chain. In some implementations, L 1 It is an optional substituted divalent linear C 1-3 Hydrocarbon chain. In some implementations, L 1 It is an arbitrarily substituted divalent branch C 1-3 Hydrocarbon chain. In some implementations, L 1 It is divalent C1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 1 It is divalent C 1-3 Straight-chain hydrocarbon chain. In some implementations, L 1 It is divalent C 1-2 Straight-chain hydrocarbon chain. In some implementations, L 1 It is optional and can be replaced. In some implementations, L 1 It is -CH2-.

[1154] In some implementation schemes, R 1 It is -R as described in this document. In some implementations, R 1 It is -R, but not hydrogen. In some embodiments of any of the formulations described herein, each R 1 Independently, it is the optional substituted C 1-6 Alkyl or optionally substituted C 3-6 Cycloalkyl. In some embodiments, each R 1 Independently hydrogen or optionally substituted groups selected from the following: C 1-8 aliphatic, C 6-10 Aryl, C 3-10 Alicyclic groups, comprising 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 It is an optional, substituted C 1-6 Aliphatic. In some implementations, R 1 It is an optional, substituted C 1-6 Alkyl group. In some embodiments, R 1 It is C 1-6 Alkyl group. In some embodiments, R 1 It is an optional, substituted C 1-2 Alkyl group. In some embodiments, R 1 It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is an optional, substituted C 3-6 Alicyclic group. In some implementations, R 1 It is an optional, substituted C 3-6 Cycloalkyl. In some embodiments, R 1 It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R 1 It is -CH2-C 3-6 Alicyclic group. In some implementations, R 1 It is -CH2-cyclopropyl. In some embodiments, R1 It is C 6-10 Aryl. In some implementations, R 1 It is phenyl. In some embodiments, R 1 It is naphthyl. In some embodiments, R 1 It is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 It is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 It is a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S.

[1155] In some embodiments of any of the forms described herein, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[1156] In some implementations, L 3 It is an optional substituted divalent linear C 1-6 (For example, C) 1-3 Hydrocarbon chains of C1, C2, C3, C4, C5, or C6. In some embodiments, L... 3 It is an arbitrarily substituted divalent branch C 1-6 (For example, C) 1-3 A hydrocarbon chain consisting of C1, C2, C3, C4, C5, or C6. In some embodiments of any of the forms described herein, L... 3 It is a covalent bond or an optional substituted divalent C. 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 3 It is a covalent bond. In some implementations, L 3 It is divalent C 1-6 Straight-chain or branched hydrocarbon chains. In some embodiments, L 3 It is an optional substituted divalent C 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 3 It is divalent C 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 3 It is an optional substituted -CH2-. In some implementations, L 3Selected from -CH2- and -CH(CH3)-. In some embodiments, the chain is saturated. In some embodiments, it is partially unsaturated. In some embodiments, L 3 It is -CH2-.

[1157] In some implementations, L 4 It is an optional substituted divalent linear C 1-6 (For example, C) 1-3 Hydrocarbon chains of C1, C2, C3, C4, C5, or C6. In some embodiments, L... 4 It is an arbitrarily substituted divalent branch C 1-6 (For example, C) 1-3 A hydrocarbon chain consisting of C1, C2, C3, C4, C5, or C6. In some embodiments of any of the forms described herein, L... 4 It is a covalent bond or an optional substituted divalent C. 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 4 It is a covalent bond. In some implementations, L 4 It is an optional substituted divalent C 1-6 Straight-chain or branched hydrocarbon chains. In some embodiments, L 4 It is divalent C 1-6 Straight-chain or branched hydrocarbon chains. In some embodiments, L 4 It is an optional substituted divalent C 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 4 It is divalent C 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 4 It is an optional substituted -CH2-. In some implementations, L 4 Selected from -CH2- and -CH(CH3)-. In some implementations, L 4 It is -CH2-.

[1158] In some implementations, L 5 It is an optional substituted divalent linear C 1-6 (For example, C) 1-3 Hydrocarbon chains of C1, C2, C3, C4, C5, or C6. In some embodiments, L... 5 It is an arbitrarily substituted divalent branch C 1-6 (For example, C) 1-3 A hydrocarbon chain consisting of C1, C2, C3, C4, C5, or C6. In some embodiments of any of the forms described herein, L... 5 It is a covalent bond or an optional substituted divalent C. 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 5 It is a covalent bond. In some implementations, L5 It is an optional substituted divalent C 1-6 Straight-chain or branched hydrocarbon chains. In some embodiments, L 5 It is divalent C 1-6 Straight-chain or branched hydrocarbon chains. In some embodiments, L 5 It is an optional substituted divalent C 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 5 It is divalent C 1-3 Straight-chain or branched hydrocarbon chains. In some embodiments, L 5 It is an optional substituted -CH2-. In some implementations, L 5 Selected from -CH2- and -CH(CH3)-. In some implementations, L 5 It is -CH2-.

[1159] In some implementation schemes, R 8 It is -R as described in this document. In some implementations, R 8 It is -R, but not hydrogen. In some embodiments of any of the formulations described herein, each R 8 Independently hydrogen or optionally substituted C 1-6 Alkyl group. In some embodiments, R 8 It is hydrogen. In some implementations, R 8 It is an optional substituted C 1-6 Aliphatic. In some implementations, R 8 It is an optional substituted C 1-6 Alkyl group. In some embodiments, R 8 It is C 1-6 Alkyl group. In some embodiments, R 8 It is an optional substituted C 1-2 Alkyl group. In some embodiments, R 8 It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R 8 It is an optional substituted C 3-6 Alicyclic group. In some implementations, R 8 It is an optional substituted C 3-6 Cycloalkyl. In some embodiments, R 8 It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R 8 It is -C(O)R. In some implementations, R 8 It is -C(O)(C 1-6 Alkyl group). In some embodiments, R 8 It is -S(O)2R. In some implementations, R 8 It is -S(O)2(C1-6 Alkyl group). In some embodiments, the two R groups... 8 The groups are the same. In some embodiments, they are different. In some embodiments, the two R groups are... 8 Together with the nitrogen atoms to which they are attached, they combine to form optionally substituted 3 to 16 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 3 to 15, 3 to 10, 5 to 10, 3 to 8, 3 to 7, or 5 to 6) member rings having 1 to 5 (e.g., 1 to 2, 1 to 3, 1 to 4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, the formed rings are 3 to 10 members. In some embodiments, the formed rings are 3 to 6 members. In some embodiments, the formed rings are 3 members. In some embodiments, they are 4 members. In some embodiments, they are 5 members. In some embodiments, they are 6 members. In some embodiments, they are monocyclic. In some embodiments, they are bicyclic. In some embodiments, they are polycyclic. In some embodiments, it is saturated or at least one monocyclic unit is saturated. In some embodiments, it is partially unsaturated or at least one monocyclic unit is partially unsaturated. In some embodiments, it is aromatic or at least one monocyclic unit is aromatic. In some embodiments, it is heteroaromatic or at least one monocyclic unit is heteroaromatic.

[1160] connector

[1161] In some embodiments described herein, the connector is a connecting portion (i.e., any suitable divalent portion connecting the PBM to the LBM). In some embodiments, the connector is a covalent bond. In some embodiments, the connector is an optionally substituted divalent C1-C bond. 20 (For example, C) 1- C 15 C 1- C 10 C 1- C6, C 1- C4, C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 Or C 20The hydrocarbon chain (which may be straight or branched, and saturated or partially unsaturated, and may contain one or more (e.g., 1 to 2, 1 to 3, 1 to 4, 1, 2, 3, 4 or 5) hydrocarbon rings), one or more (e.g., 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 3, 1 to 2, 2 to 10, 2 to 5, 2 to 3, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) methylene units are optionally and independently replaced by the following: In some embodiments, the various connectors described herein can provide superior properties, such as improved efficacy, improved half-life, improved stability, and / or reduced toxicity.

[1162] In some embodiments, the joint has a specific length (e.g., as measured by the number of atoms). It should be understood that when describing the length of the joint, the longest continuous chain of atoms is used. For example, in some embodiments, the joint has a structure with a length of 14 atoms (as counted in italics):

[1163] .

[1164] In some embodiments, the joint length is 2 to 16 atoms. In some embodiments, the joint length is 2 to 13 atoms. In some embodiments, the joint length is 2 to 10 atoms. In some embodiments, the joint length is 2 to 8 atoms. In some embodiments, the joint length is 2 to 7 atoms. In some embodiments, the joint length is 0 to 16 atoms. In some embodiments, the joint length is 0 to 13 atoms. In some embodiments, the joint length is 0 to 10 atoms. In some embodiments, the joint length is 0 to 7 atoms. In some embodiments, the joint length is 4 to 16 atoms. In some embodiments, the joint length is 4 to 13 atoms. In some embodiments, the joint length is 4 to 10 atoms. In some embodiments, the joint length is 4 to 8 atoms. In some embodiments, the joint length is 4 to 7 atoms. In some embodiments, the joint length is less than 14 atoms. In some embodiments, the joint length is less than 11 atoms. In some embodiments, the joint length is less than 9 atoms. In some embodiments, the joint length is less than 8 atoms.

[1165] As an alternative or supplement, in some embodiments, the shortest path length of the connector (the number of atoms in the chain along the shortest path from one end of the connector to the other (the shortest path chain)) is about 0 to 16 atoms (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 1 to 15, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 3 to 15, 3 to 10, 5 to 10, 3 to 8, 3 to 7, or 5 to 6). In some embodiments, it is 0. In some embodiments, it is about 1 to 16 atoms. In some embodiments, it is about 1 to 10 atoms. In some embodiments, it is 1 atom. In some embodiments, it is about or no more than about 2 atoms. In some embodiments, it is about or no more than about 2 atoms. In some embodiments, it is about or no more than about 3 atoms. In some embodiments, it comprises about or no more than about 4 atoms. In some embodiments, it comprises about or no more than about 5 atoms. In some embodiments, it comprises about or no more than about 6 atoms. In some embodiments, it comprises about or no more than about 7 atoms. In some embodiments, it comprises about or no more than about 8 atoms. In some embodiments, it comprises about or no more than about 9 atoms. In some embodiments, it comprises about or no more than about 10 atoms. In some embodiments, it comprises about or no more than about 11 atoms. In some embodiments, it comprises about or no more than about 12 atoms. In some embodiments, it comprises about or no more than about 13 atoms. In some embodiments, it comprises about or no more than about 14 atoms.

[1166] In some embodiments of any of the forms described herein, the joint is a covalent bond.

[1167] In some embodiments of any of the forms described herein, the connector is optionally a substituted divalent linear or branched chain, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: In some embodiments, the connector is optionally a substituted divalent linear or branched, saturated or unsaturated C1-C. 20 Hydrocarbon chain, wherein at least one methylene unit is replaced by the following: In some embodiments, the connector is optionally a substituted divalent linear or branched, saturated or unsaturated C1-C. 20 Hydrocarbon chain, wherein at least two methylene units are replaced by the following: .

[1168] In some embodiments, the linker is optionally a substituted divalent linear or branched chain, saturated or unsaturated C1-C. 10The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: In some embodiments, the connector is optionally a substituted divalent linear or branched, saturated or unsaturated C1-C. 10 Hydrocarbon chain, wherein at least one methylene unit is replaced by the following: In some embodiments, the connector is optionally a substituted divalent linear or branched, saturated or unsaturated C1-C. 10 Hydrocarbon chain, wherein at least two methylene units are replaced by the following: .

[1169] In some embodiments, the linker is optionally a substituted divalent linear or branched chain, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently substituted with -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein at least one methylene unit is substituted with one of the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 20 A hydrocarbon chain in which at least two methylene units are replaced by the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)- or -Cy-.

[1170] In some embodiments, the linker is optionally a substituted divalent linear or branched chain, saturated or unsaturated C1-C. 10 (For example, C) 1- C8, C 1- C6, C 1- C5, C 1- C4, C1, C2, C3, C4, C5, C6, C7, C8, C9 or C 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently substituted with -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C... 10The hydrocarbon chain, wherein at least one methylene unit is substituted with one of the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 10 A hydrocarbon chain in which at least two methylene units are replaced by the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)- or -Cy-.

[1171] As illustrated herein, in several embodiments, the joints in the provided compounds are short (e.g., their length and / or shortest path length is 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., having about or no more than about 0, 1, 2, 3, 4, or 5 noncyclic continuous sps in the shortest path chain). 3 Atoms; having approximately or no more than approximately 0, 1, 2, 3, 4, or 5 non-cyclic continuous atoms in the shortest path chain; having approximately or no more than approximately 0, 1, 2, 3, 4, or 5 non-cyclic sp atoms in the shortest path chain. 3 Atoms; having about or no more than about 0, 1, 2, 3, 4, or 5 non-cyclic atoms in the shortest path chain; having about or no more than about 0, 1, 2, 3, 4, or 5 consecutive non-cyclic sp atoms in the shortest path chain. 3 Atoms, wherein each atom is independently C, N, O, or S; having about or no more than about 0, 1, 2, 3, 4, or 5 non-cyclic continuous atoms in the shortest path chain, wherein each atom is independently C, N, O, or S; having about or no more than about 0, 1, 2, 3, 4, or 5 non-cyclic sp atoms in the shortest path chain. 3 C, N, O, or S atoms; or having about or no more than about 0, 1, 2, 3, 4, or 5 non-cyclic C, N, O, or S atoms in the shortest path chain. In some embodiments, the non-cyclic continuous sp in the shortest path chain of the connector 3 The number of atoms is about 5 or no more than about 5. In some embodiments, the non-cyclic continuous sp in the shortest path chain of the joint 3 The number of atoms is about 4 or no more than about 4. In some embodiments, the non-cyclic continuous sp in the shortest path chain of the joint 3 The number of atoms is about 3 or no more than about 3. In some embodiments, the non-cyclic continuous sp in the shortest path chain of the joint 3 The number of atoms is about 2 or no more than about 2. In some embodiments, the non-cyclic sp in the shortest path chain of the joint... 3The number of atoms is about 5 or no more than about 5. In some embodiments, the non-cyclic sp in the shortest path chain of the joint... 3 The number of atoms is about 4 or no more than about 4. In some embodiments, the non-cyclic sp in the shortest path chain of the joint 3 The number of atoms is about 3 or no more than about 3. In some embodiments, the non-cyclic sp in the shortest path chain of the joint 3 The number of atoms is about 2 or no more than about 2. In some embodiments, the non-cyclic sp in the shortest path chain of the joint... 3 The number of atoms is about 1 or no more than about 1. In some embodiments, the non-cyclic sp in the shortest path chain of the joint... 3 The number of atoms is 0. In some implementations, the non-cyclic sp in the shortest path chain of the connector... 3 The number of C, O, and S atoms is about 5 or no more than about 5. In some embodiments, the non-cyclic sp in the shortest path chain of the connector 3 The number of C, O, and S atoms is about 4 or no more than about 4. In some embodiments, the non-cyclic sp in the shortest path chain of the joint... 3 The number of C, O, and S atoms is about 3 or no more than about 3. In some embodiments, the non-cyclic sp in the shortest path chain of the joint... 3 The number of C, O, and S atoms is about 2 or no more than about 2. In some embodiments, the non-cyclic sp in the shortest path chain of the joint... 3 The number of C, O, and S atoms is about 1 or no more than about 1. In some embodiments, the non-cyclic sp in the shortest path chain of the connector 3The number of C, O, and S atoms is 0. In some embodiments, the number of non-cyclic C, O, and S atoms in the shortest path chain of the connector is about 5 or no more than about 5. In some embodiments, the number of non-cyclic C, O, and S atoms in the shortest path chain of the connector is about 4 or no more than about 4. In some embodiments, the number of non-cyclic C, O, and S atoms in the shortest path chain of the connector is about 3 or no more than about 3. In some embodiments, the number of non-cyclic C, O, and S atoms in the shortest path chain of the connector is about 2 or no more than about 2. In some embodiments, the number of non-cyclic C, O, and S atoms in the shortest path chain of the connector is about 1 or no more than about 1. In some embodiments, the number of non-cyclic atoms in the shortest path chain of the connector is 0. In some embodiments, the number of non-cyclic atoms in the shortest path chain of the connector is about 5 or no more than about 5. In some embodiments, the number of non-cyclic atoms in the shortest path chain of the connector is about 4 or no more than about 4. In some embodiments, the number of non-cyclic atoms in the shortest path chain of the connector is about 3 or no more than about 3. In some embodiments, the number of acyclic atoms in the shortest path chain of the connector is about 2 or no more than about 2. In some embodiments, the number of acyclic atoms in the shortest path chain of the connector is about 1 or no more than about 1. In some embodiments, the number of acyclic atoms in the shortest path chain of the connector is 0. As those skilled in the art will understand, the connector may have one or more shortest path chains. In some embodiments, the connector contains one or more (e.g., 1 to 2, 1 to 3, 1 to 4, 1, 2, 3, 4, or 5) -Cy-. In some embodiments, the connector contains one or more (e.g., 1 to 2, 1 to 3, 1 to 4, 1, 2, 3, 4, or 5) -Cy- in its shortest path chain. In some embodiments, each -Cy- is independently located in the shortest path chain of the connector. In some embodiments, -Cy- is monocyclic. In some embodiments, -Cy- is bicyclic. In some embodiments, -Cy- is spirocyclic-bicyclic. In some embodiments, -Cy- is polycyclic. In some embodiments, -Cy- is saturated. In some embodiments, -Cy- is partially unsaturated. In some embodiments, -Cy- is aromatic. In some embodiments, -Cy- is 3 to 10 (e.g., 3 to 8, 3 to 6, 3 to 5, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10) units and is monocyclic. In some embodiments, -Cy- is 6 to 16 (e.g., 6 to 15, 7 to 15, 10 to 15, 10 to 16, 11 to 16, 11 to 15, 10 to 11, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) units and is bicyclic.In some embodiments, -Cy- is 6 to 16 (e.g., 6 to 15, 7 to 15, 10 to 15, 10 to 16, 11 to 16, 11 to 15, 10 to 11, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) units and is helical-to-double ring. In some embodiments, -Cy- is 10 to 12 units and is double ring. In some embodiments, -Cy- is 10 to 12 units and is helical-to-double ring. In some embodiments, -Cy- is 11 units and is double ring. In some embodiments, -Cy- is 11 units and is helical-to-double ring. In some embodiments, each single ring unit in -Cy- is independently 3 to 10 (e.g., 3 to 8, 3 to 6, 3 to 5, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10) units. In some embodiments, each monocyclic ring unit in -Cy- is independently 3 to 8 (e.g., 3 to 6, 3 to 5, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10) cells. In some embodiments, each monocyclic ring unit in -Cy- is independently 3 to 6 (e.g., 3 to 5, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10) cells. In some embodiments, each monocyclic ring unit in -Cy- is independently 5 or 6 cells. In some embodiments, the monocyclic ring units in -Cy- are saturated. In some embodiments, the monocyclic ring units in -Cy- are partially unsaturated. In some embodiments, the monocyclic ring units in -Cy- are 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 of -Cy- is independently 0 to 4 (e.g., 0, 1 to 4, 1 to 2, 1, 2, 3, or 4). In some embodiments, the number of N, O, or S heteroatoms in each monocyclic ring unit of -Cy- is independently 0 to 2. In some embodiments, the number of N, O, or S heteroatoms in each monocyclic ring unit of -Cy- is independently 0 to 1. In some embodiments, -Cy- contains at least one nitrogen atom. In some embodiments, each heteroatom in -Cy- is nitrogen. In some embodiments, the spirocyclic ring in the linker is observed to provide a variety of benefits and advantages, including high potency. In some embodiments, the number of basic nitrogen atoms can be used to modulate compound properties and / or potency, such as pharmacokinetic properties. In some embodiments, the basic nitrogen atoms in the linker, such as basic nitrogen atoms in -Cy- (e.g., basic nitrogen atoms in piperidine and / or piperazine rings), are observed to provide improved solubility, improved dissolution rate, and / or longer T. 1 / 2For example, when evaluated in rodent PK assays. Multiple embodiments of the connector are described herein as examples, such as in the following or in various compounds.

[1172] In some implementations, the connector is optionally a substituted divalent C1-C5 (e.g., C 1- C4, C 1- C3, C 1- A C2, C1, C2, C3, C4, or C5 hydrocarbon chain (which may be straight or branched and saturated or partially unsaturated), wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by the following: In some embodiments, the connector is optionally a substituted divalent C1-C3 (e.g., C...). 1- A C2, C1, C2, or C3 hydrocarbon chain (which may be straight or branched and saturated or partially unsaturated) wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by the following: In some embodiments, the connector is optionally a substituted divalent linear C1-C3 (e.g., C1-C3). 1- A 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: In some embodiments, the linker is an optionally substituted divalent straight-chain C1-C3 (e.g., C1-C2, C1, C2, or C3) alkylene chain, wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(NR)-, or -Cy-. In some embodiments, the linker is an optionally substituted divalent straight-chain C1 or C2 alkylene chain, wherein one or more (e.g., 1, 2, 3, 4, or 5) methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(NR)-, or -Cy-. In some embodiments, the connector also has a finite number of acyclic atoms in its shortest path chain as described herein, for example, the number of acyclic atoms in its shortest path chain is about or no more than about 0, 1, 2, 3, 4 or 5 (as illustrated herein, in several embodiments, about 2 or no more than about 2, and in several embodiments, about 1 or no more than about 1). For example, in some embodiments, the connector is -C(O)-Cy-, wherein -C(O)- is bonded to PBM; in some embodiments, the connector is -CH2-Cy-, wherein -CH2- is bonded to PBM; in some embodiments, the connector is -CH2-O-, wherein -CH2- is bonded to PBM; in some embodiments, the connector is -Cy-O-, wherein -Cy- is bonded to PBM.

[1173] In some embodiments, about or no more than about 1 to 10 methylene units (e.g., 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 3, 1 to 2, 2 to 10, 2 to 5, 2 to 3, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) are independently substituted as described herein. In some embodiments, about 5 or no more than about 5 methylene units are independently substituted as described herein. In some embodiments, about 4 or no more than about 4 methylene units are independently substituted as described herein. In some embodiments, about 3 or no more than about 3 methylene units are independently substituted as described herein. In some embodiments, about 2 or no more than about 2 methylene units are independently substituted as described herein. In some embodiments, about 1 or no more than about 1 methylene unit is substituted as described herein.

[1174] In some embodiments, the linker comprises an ether moiety (e.g., -O-). In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 20 A hydrocarbon chain in which at least one methylene unit is substituted with -O-. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 10A hydrocarbon chain in which at least one methylene unit is replaced by -O-.

[1175] In some embodiments, the linker comprises an amine moiety (e.g., -N(R)-). In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 20 Hydrocarbon chain, wherein at least one methylene unit is -N(R)- (e.g., -NH- or -N(C)-). 1-6 Alkyl group substitution. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C group. 10 Hydrocarbon chain, wherein at least one methylene unit is -N(R)- (e.g., -NH- or -N(C)-). 1-6 Alkyl group is substituted. In some embodiments, the methylene unit is substituted with -NH-.

[1176] In some embodiments, the linker comprises a carbonyl moiety. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C group. 20 A hydrocarbon chain in which at least one methylene unit is replaced by -C(O)-. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 10 A hydrocarbon chain in which at least one methylene unit is replaced by -C(O)-.

[1177] In some embodiments, the linker comprises an ester moiety. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C moiety. 20 A hydrocarbon chain in which at least one methylene unit is replaced by -OC(O)- or -C(O)O-. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 10 A hydrocarbon chain in which at least one methylene unit is replaced by -OC(O)- or -C(O)O-.

[1178] In some embodiments, the linker comprises an amide moiety. In some embodiments, the linker is optionally a substituted divalent linear or branched, saturated or unsaturated C1-C moiety. 20 Hydrocarbon chain, wherein at least one methylene unit is -C(O)N(R)- (e.g., -C(O)NH- or -C(O)N(C 1-6 Alkyl group substitution. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C group. 10 Hydrocarbon chain, wherein at least one methylene unit is -C(O)N(R)- (e.g., -C(O)NH- or -C(O)N(C 1-6Alkyl group substitution. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C group. 20 Hydrocarbon chain, wherein at least one methylene unit is -N(R)C(O)- (e.g., -N(H)C(O)- or -N(C 1-6 Alkyl)C(O)-) substitution. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C 10 Hydrocarbon chain, wherein at least one methylene unit is -N(R)C(O)- (e.g., -N(H)C(O)- or -N(C 1-6 Alkyl)C(O)-) is substituted. In some embodiments, the methylene unit is substituted with -C(O)NH-.

[1179] In some embodiments, the connector comprises a divalent ring portion (e.g., -Cy-). In some embodiments, the connector is optionally a substituted divalent linear or branched, saturated or unsaturated C1-C. 20 A hydrocarbon chain in which at least one methylene unit is replaced by -Cy-. In some embodiments, the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 10 A hydrocarbon chain in which at least one methylene unit is replaced by -Cy-. In some such embodiments, Cy is not phenyl.

[1180] In some embodiments, the linker comprises a triple bond. In some embodiments, the linker is an optionally substituted divalent straight-chain or branched, partially unsaturated C1-C bond containing at least one triple bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: In some embodiments, the linker is an optionally substituted divalent linear or branched, partially unsaturated C1-C bond containing at least one triple bond. 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: In some embodiments, the linker is an optionally substituted divalent linear or branched, partially unsaturated C1-C bond containing at least one triple bond. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently substituted with -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, the linker is an optionally substituted divalent straight-chain or branched, partially unsaturated C1-C chain containing at least one triple bond. 10The hydrocarbon chain in which 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-.

[1181] In some embodiments of any of the types described herein, the connector has the following structure:

[1182] ,

[1183] Whereby Cy is defined both alone and in combination as per Equation II in this paper and described in the categories and subclasses herein; and:

[1184] M 1 and M 2 Each of these can be independently nonexistent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; and

[1185] L 6 and L 7 Each is independently a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C. 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: .

[1186] In some embodiments of any of the types described herein, the connector has the following structure:

[1187] ,

[1188] Whereby Cy is defined both alone and in combination as per Equation II in this paper and described in the categories and subclasses herein; and:

[1189] M 1 and M 2 Each of these can be independently nonexistent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; and

[1190] L 6 and L 7 Each is independently a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C5 (e.g., C1-C5). 1- C4, C 1- C3, C 1- C2, C 2-A C4, C1, C2, C3, C4, or C5 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: .

[1191] In some embodiments of any of the types described herein, the connector is selected from:

[1192] .

[1193] In some embodiments of any of the forms described herein, the connector is or .

[1194] In some embodiments of any of the types described herein, the connector is selected from:

[1195] .

[1196] In some embodiments of any of the types described herein, the connector has the following structure:

[1197] ,

[1198] in:

[1199] M 1 and M 2 Each of these can be independently nonexistent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; and

[1200] L 6 and L 7 Each is independently a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C. 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: .

[1201] In some embodiments of any of the types described herein, the connector is selected from:

[1202] .

[1203] In some embodiments of any of the types described herein, the connector has the following structure:

[1204] ,

[1205] in:

[1206] M 1 and M 2Each of these can be independently nonexistent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; and

[1207] L 8 It is a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: .

[1208] In some embodiments of any of the types described herein, the connector is selected from:

[1209] .

[1210] In some implementations, the connector is -M 1 -L 6 -L 7 -M 2 -

[1211] In some embodiments of any of the forms described herein, M 1 It is -CH2-, -O-, -N(R)-, -C(O)-, -OC(O), -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, M 1 It does not exist. In some implementations, M 1 Optionally replaced by -CH2-. In some implementations, M 1 It is -CH2-. In some implementations, M 1 Yes -O-. In some implementations, M 1 It is -N(R)- (e.g., -N(H)- or -N(CH3)-). In some implementations, M 1 It is -C(O)-. In some implementations, M 1 It is -OC(O)-. In some implementations, M 1 It is -C(O)O-. In some implementations, M 1 It is -C(O)N(R)- (e.g., -C(O)N(H)- or -C(O)N(CH3)-). In some embodiments, M 1 It is -N(R)C(O)- (e.g., -N(H)C(O)- or -N(CH3)C(O)-). In some embodiments, the variable is a covalent bond, and as will be understood by those skilled in the art, it may be properly considered not to exist. In some embodiments, M 1 Bonded to PBM.

[1212] In some embodiments of any of the forms described herein, M 2 It is -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some implementations, M 2 It does not exist. In some implementations, M 2 It is -CH2-. In some implementations, M 2 Yes -O-. In some implementations, M 2 It is -N(R)- (e.g., -N(H)- or -N(CH3)-). In some implementations, M 2 It is -C(O)-. In some implementations, M 2 It is -OC(O)-. In some implementations, M 2 It is -C(O)O-. In some implementations, M 2 It is -C(O)N(R)- (e.g., -C(O)N(H)- or -C(O)N(CH3)-. In some embodiments, M 2 It is -N(R)C(O)- (e.g., -N(H)C(O)- or -N(CH3)C(O)-). In some embodiments, M 2 It bonds with LBM.

[1213] In some embodiments of any of the forms described herein, L 6 It is a covalent bond.

[1214] In some implementations, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: In some implementations, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 Hydrocarbon chain, wherein at least one methylene unit is replaced by the following: In some implementations, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 Hydrocarbon chain, wherein at least two methylene units are replaced by the following: .

[1215] In some implementations, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain, wherein at least one methylene unit is replaced by one of the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least two methylene units are replaced by the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)- or -Cy-.

[1216] In some implementations, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 The 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)-. In some embodiments, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain wherein at least one methylene unit is replaced by one of the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain in which 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)-.

[1217] In some implementations, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently substituted with -O-. In some embodiments, L 6 It is an optional substituted divalent straight or branched C, saturated or unsaturated. 1- C10 A hydrocarbon chain in which at least one methylene unit is replaced by -O-. In some embodiments, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least two methylene units are replaced by -O-.

[1218] In some implementations, L 6 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 Hydrocarbon chain. In some implementations, L 6 It is an optional substituted divalent straight or branched chain, saturated C1-C 10 Hydrocarbon chain. In some implementations, L 6 It is an optional substituted divalent straight-chain or branched, saturated or unsaturated C1-C6 hydrocarbon chain. In some embodiments, L 6 It is an optional substituted divalent straight-chain or branched, saturated C1-C6 hydrocarbon chain.

[1219] In some implementations, L 6 It is an optional substituted -CH2-. In some implementations, L 6 It is -CH2-. In some implementations, L 6 It is -C(O)-. In some implementations, L 6 Bonded to PBM.

[1220] In some embodiments of any of the forms described herein, L 7 It is a covalent bond.

[1221] In some implementations, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: In some implementations, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 Hydrocarbon chain, wherein at least one methylene unit is replaced by the following: In some implementations, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 Hydrocarbon chain, wherein at least two methylene units are replaced by the following: .

[1222] In some implementations, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain, wherein at least one methylene unit is replaced by one of the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least two methylene units are replaced by the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)- or -Cy-.

[1223] In some implementations, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 The 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)-. In some embodiments, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain wherein at least one methylene unit is replaced by one of the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain in which 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)-.

[1224] In some implementations, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently substituted with -O-. In some embodiments, L 7 It is an optional substituted divalent straight or branched C, saturated or unsaturated. 1- C10 A hydrocarbon chain in which at least one methylene unit is replaced by -O-. In some embodiments, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least two methylene units are replaced by -O-.

[1225] In some implementations, L 7 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 10 Hydrocarbon chain. In some implementations, L 7 It is an optional substituted divalent straight or branched chain, saturated C1-C 10 Hydrocarbon chain. In some implementations, L 7 It is an optional substituted divalent straight-chain or branched, saturated or unsaturated C1-C6 hydrocarbon chain. In some embodiments, L 7 It is an optional substituted divalent straight-chain or branched, saturated C1-C6 hydrocarbon chain.

[1226] In some implementations, L 7 It bonds with LBM.

[1227] In some embodiments of any of the forms described herein, L 6 and L 7 Both are covalent bonds.

[1228] In some embodiments of any of the forms described herein, L 8 It is a covalent bond.

[1229] In some implementations, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by the following: In some implementations, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 Hydrocarbon chain, wherein at least one methylene unit is replaced by the following: In some implementations, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 Hydrocarbon chain, wherein at least two methylene units are replaced by the following: .

[1230] In some implementations, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 A hydrocarbon chain, wherein at least one methylene unit is replaced by one of the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 A hydrocarbon chain in which at least two methylene units are replaced by the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)- or -Cy-.

[1231] In some implementations, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 The 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)-. In some embodiments, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 A hydrocarbon chain wherein at least one methylene unit is replaced by one of the following: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 A hydrocarbon chain in which 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)-.

[1232] In some implementations, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 The hydrocarbon chain, wherein one or more methylene units are optionally and independently substituted with -O-. In some embodiments, L 8 It is an optional substituted divalent straight or branched C, saturated or unsaturated. 1- C15 A hydrocarbon chain in which at least one methylene unit is replaced by -O-. In some embodiments, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 A hydrocarbon chain in which at least two methylene units are replaced by -O-.

[1233] In some implementations, L 8 It is an optional substituted divalent straight or branched chain, saturated or unsaturated C1-C 15 Hydrocarbon chain. In some implementations, L 8 It is an optional substituted divalent straight or branched chain, saturated C1-C 15 Hydrocarbon chain. In some implementations, L 8 It is an optional substituted divalent straight-chain or branched, saturated or unsaturated C1-C6 hydrocarbon chain. In some embodiments, L 8 It is an optional substituted divalent straight-chain or branched, saturated C1-C6 hydrocarbon chain.

[1234] In some embodiments of any of the types described herein, the connector is selected from:

[1235] .

[1236] As described herein and illustrated in various compounds, many linker lengths are short (e.g., the shortest path chain length is about or no more than about 8, 9, or 10 atoms) and / or contain very few conformationally flexible chain atoms, for example, they contain about or no more than about 1, 2, 3, 4, or 0 acyclic sp atoms in their shortest path chain. 3 C, N, O, or S atoms. In some embodiments, there are about or no more than about 1, 2, or 3 acyclic atoms in its shortest path chain. In some embodiments, there are about or no more than about 2 acyclic atoms in its shortest path chain. In some embodiments, there are about or no more than about 1 acyclic atom in its shortest path chain (e.g., as in...). (in the middle). In some implementations, the two non-cyclic sps in the shortest path chain of the joint. 3 The number of bonds between atoms is approximately or no more than 1 to 2, 1 to 3, 1 to 4, 1, 2, 3, 4, or 5; in some embodiments, it is 0 (e.g., as in...). In some implementations, it is one (e.g., as in...). (Middle). Such joints can provide, in particular, enhanced conformational stiffness and / or a variety of benefits and advantages. In some embodiments, the rings are monocyclic or bicyclic, and in many cases are spirocyclic-bicyclic, and each monocyclic ring unit is independently about 3, 4, 5, or 6-membered. In some embodiments, the rings independently contain 1, 2, or 3 heteroatoms. In some embodiments, one or more heteroatoms are nitrogen. In some embodiments, each heteroatom is nitrogen. In some embodiments, the joint contains one or more basic nitrogen atoms, for example, in its shortest path chain. For example, in some embodiments, the joint is... In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some implementations, the connector is In some embodiments, the -C(O)- in the connector is bonded to the PBM. In some embodiments, the connector is -CH2-O-. In some embodiments, the connector is... In some implementations, the connector is bonded to the LBM at point O.

[1237] In some embodiments of any of the forms described herein, the connector is not:

[1238] .

[1239] In some embodiments of any of the forms described herein, each Cy is independently a 3- to 11-membered divalent ring system of optionally substituted monocyclic or bicyclic rings, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently a group of optionally substituted groups selected from: phenyl, C 9-10 Bicyclic aryl groups, 5- to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, and 8- to 10-membered bicyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, monocyclic C 3-7Alicyclic, specifically 5- to 10-membered bicyclic alicyclic groups, comprising monocyclic 4- to 7-membered heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclic groups having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently a optionally substituted group selected from: phenyl, 5- to 6-membered monocyclic heterocyclic groups having 1 to 4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclic groups having 1 to 3 heteroatoms independently selected from N, O, and S.

[1240] In some embodiments, Cy is an optionally substituted phenyl group. In some embodiments, Cy is a phenyl group. In some embodiments, Cy is not a phenyl group.

[1241] In some implementations, Cy is an optional substituted C 9-10 Bicyclic aryl. In some embodiments, Cy is optionally substituted C. 13-16 Polycyclic aryl groups.

[1242] In some embodiments, Cy is an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted triazole. In some embodiments, Cy is an optionally substituted 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted pyridine, pyridazine, or pyrimidine.

[1243] In some embodiments, Cy is an 8- to 10-membered bicyclic heteroaryl group optionally substituted with 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a 10- to 16-membered polycyclic heteroaryl group optionally substituted with 1 to 4 heteroatoms independently selected from N, O, and S.

[1244] In some implementations, Cy is an optionally substituted monocyclic C 3-7 Alicyclic. In some embodiments, Cy is an optionally substituted monocyclic C. 3-7 Cycloalkyl. In some embodiments, Cy is an optionally substituted monocyclic C. 4-6 Cycloalkyl (e.g., cyclobutane, cyclopentane, or cyclohexane).

[1245] In some embodiments, Cy is an optionally substituted 5- to 10-membered bicyclic alicyclic compound. In some embodiments, Cy is an optionally substituted 6- to 10-membered bicyclic alicyclic compound. In some embodiments, Cy is an optionally substituted bicyclic 6- to 10-membered bridging, fused, or spirocyclic alicyclic compound.

[1246] In some embodiments, Cy is an optionally substituted monocyclic 4- to 7-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 5- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 4-membered heterocyclic group having 1 heteroatom independently selected from N, O, and S. In some embodiments, Cy is a nitrogen-containing heterocyclic butane. In some embodiments, Cy is an optionally substituted monocyclic 5-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is pyrrolidine. In some embodiments, Cy is an optionally substituted monocyclic 6-membered heterocyclic group having 1 to 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 heterocyclic group having one or two independently selected heteroatoms chosen from N, O, and S. In some embodiments, at least one heteroatom is N; in some embodiments, each is N.

[1247] In some embodiments, Cy is a optionally substituted bicyclic 6- to 11-membered heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a optionally substituted bicyclic 6- to 11-membered bridged, fused, or spirocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a optionally substituted bicyclic 7- to 11-membered spirocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a optionally substituted bicyclic 7-membered spirocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered bridged heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 8-membered spirocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 9-membered spirocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 10-membered spirocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 11-membered spirocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted group selected from the following:

[1248] .

[1249] In some implementations, Cy is selected from:

[1250] .

[1251] In some embodiments, Cy is an optionally substituted bicyclic 10- to 16-membered heterocyclic group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, -Cy- is spirocyclic-bicyclic. In some embodiments, -Cy- is an optionally substituted spirocyclic-bicyclic diamine. In some embodiments, -Cy- is an optionally substituted spirocyclic-bicyclic diamine bonded to the remainder of the compound at two amino groups.

[1252] In some embodiments, Cy is optionally substituted with a group selected from the following:

[1253] .

[1254] In some implementations, Cy is selected from:

[1255]

[1256] .

[1257] In some implementations, the connector includes -Cy-. In some implementations, the connector is -Cy-.

[1258] Rings are used in many formulas and compounds of this disclosure. In some embodiments, each monocyclic ring unit in the ring (e.g., -Cy-, certain R embodiments, ring B, ring C, or ring F) is independently 3 to 10-membered (e.g., 3 to 8, 3 to 6, 3 to 5, 4 to 6, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10-membered), independently saturated, partially unsaturated, or aromatic, and independently has 0 to 4 (e.g., 0, 1 to 4, 1 to 2, 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, each monocyclic ring unit is independently 3 to 8-membered. In some embodiments, each monocyclic ring unit is independently 3 to 6-membered. In some embodiments, each monocyclic ring unit is independently 5 to 6-membered. In some embodiments, the monocyclic ring unit is 3-membered. In some embodiments, the monocyclic ring unit is 4-membered. In some embodiments, the monocyclic ring unit is 5-membered. In some embodiments, the monocyclic ring unit is hexavalent. In some embodiments, the monocyclic ring unit is saturated. In some embodiments, each is saturated. In some embodiments, the monocyclic ring unit is partially unsaturated. In some embodiments, the monocyclic ring unit is aromatic. In some embodiments, the monocyclic ring unit is heteroaromatic. In some embodiments, the ring is saturated. In some embodiments, the ring is partially unsaturated. In some embodiments, the ring is aromatic. In some embodiments, the ring is heteroaromatic. In some embodiments, the monocyclic ring unit does not have heteroatoms. In some embodiments, the monocyclic ring unit has 1 to 4 (e.g., 1 to 3, 1 to 2, 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, each monocyclic ring unit independently has 1 to 4 (e.g., 1 to 3, 1 to 2, 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, the monocyclic ring unit has a nitrogen atom. In some implementations, each monocyclic ring unit independently has a nitrogen atom.

[1259] Multiple variables can be R' as described herein. In some implementations, R' is hydrogen.

[1260] In some embodiments, R' is -R as described herein. In some embodiments, R' is -C(O)R, where R is as described herein. In some embodiments, R' is -C(O)OR, where R is as described herein. In some embodiments, R' is -S(O)2R, where R is as described herein. In some embodiments, two R' groups on the same atom, or two groups that are R' or may be R', may be together with the atom to form an optionally substituted ring as described herein. In some embodiments, two R's bonded to the same atom are combined with the atoms to which they are bonded to form optionally substituted 3 to 16 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 3 to 15, 3 to 10, 5 to 10, 3 to 8, 3 to 7, or 5 to 6) member rings having 1 to 5 (e.g., 1 to 2, 1 to 3, 1 to 4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, two R' groups on the same atom are optionally and independently joined with that atom to form an optionally substituted 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 5 to 10, 3 to 8, 3 to 7, or 5 to 6) member ring, which has 0 to 4 (e.g., 0, 1, 2, 3, or 4) heteroatoms in addition to the atom. In some embodiments, the formed ring is substituted (except for the groups connected to intercalated atoms). In some embodiments, the formed ring is unsubstituted. In some embodiments, the formed ring is ternary. In some embodiments, the formed ring is quaternary. In some embodiments, the formed ring is quinary. In some embodiments, the formed ring is septate. In some embodiments, the formed ring is septate. In some embodiments, the formed ring is octate. In some embodiments, the formed ring is quinary. In some embodiments, the formed ring is decaternate. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring is aromatic. In some embodiments, the formed ring is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3 to 10 (e.g., 3 to 8, 3 to 6, 5 to 6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered ring, which is independently saturated, partially unsaturated, or aromatic, and has 0 to 4 (e.g., 0, 1, 2, 3, or 4) heteroatoms.In some embodiments, each monocyclic unit is independently a 3 to 10 (e.g., 3 to 10, 3 to 8, 3 to 6, 5 to 6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered ring, independently saturated, partially unsaturated, or aromatic, and has 0 to 4 (e.g., 0, 1, 2, 3, or 4) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic ring unit is independently 3 to 7 members. In some embodiments, each monocyclic ring unit is independently 3 to 6 members. In some embodiments, each monocyclic ring unit is independently 5 to 7 members. 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, in addition to the intercalated atoms, the formed ring has 0 to 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, one additional heteroatom is present. In some embodiments, two additional heteroatoms are present. In some embodiments, three additional heteroatoms are present. In some embodiments, four additional heteroatoms are present. In some embodiments, five additional heteroatoms are present. In some embodiments, six or more additional heteroatoms are present. In some embodiments, the additional heteroatom is nitrogen. In some embodiments, the additional heteroatom is oxygen. In some embodiments, the additional heteroatom is sulfur.

[1261] Multiple variables can be R as described in this paper. Several implementations of R are extensively described in this paper, including regarding other variables that can be R (e.g., R0). 1 R 2 In multiple sections of (or R').

[1262] In some implementations, R is -H. In other implementations, R is not -H.

[1263] In some implementations, R is an optional substituted C. 1-8 (For example, C) 1-7 C 1-6 C 1-5 C 1-4 (C1, C2, C3, C4, C5, C6, C7, or C8) aliphatic. In some embodiments, R is optionally a substituted C 1-6 Aliphatic. In some embodiments, R is optionally substituted C. 1-6Alkyl group. In some embodiments, R is an optionally substituted methyl group. In some embodiments, R is an optionally substituted ethyl group. In some embodiments, R is an optionally substituted n-propyl group. In some embodiments, R is an optionally substituted isopropyl group. In some embodiments, R is n-butyl group. In some embodiments, R is tert-butyl group. In some embodiments, R is pentyl group. In some embodiments, R is hexyl group.

[1264] In some embodiments, R is an optionally substituted C having one to three (e.g., one, two, or three) heteroatoms independently selected from N, O, and S. 1-8 (For example, C) 1-7 C 1-6 C 1-5 C 1-4 (C1, C2, C3, C4, C5, C6, C7, or C8) heteroaliphatic compounds. In some embodiments, R is an optionally substituted C having 1 to 3 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, and S. 1-6 Heteroatom. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[1265] In some implementations, R is an optional substituted C. 3-10 (For example, C) 4-10 C 3-9 C 3-7 Alicyclic groups (or 3, 4, 5, 6, 7, 8, 9, or 10 cyclic units). In some embodiments, the alicyclic group is a cycloalkyl group. In some embodiments, the alicyclic group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently 3 to 10 (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 4-10 C 3-9 C 3-7 (Or 3, 4, 5, 6, 7, 8, 9, or 10) alicyclic rings. In some embodiments, the alicyclic group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R is an optionally substituted cyclobutyl group. In some embodiments, R is an optionally substituted cyclopentyl group. In some embodiments, R is an optionally substituted cyclohexyl group. In some embodiments, R is an optionally substituted cycloheptyl group. In some embodiments, R is a cyclopropyl group. In some embodiments, R is a cyclobutyl group. In some embodiments, R is a cyclopentyl group. In some embodiments, R is a cyclohexyl group. In some embodiments, R is a cycloheptyl group.

[1266] In some embodiments, R is an optionally substituted 3 to 10 (e.g., 3 to 9, 3 to 6, 3 to 5, or 3, 4, 5, 6, 7, 8, 9, or 10) membered heterocyclic group having 1 to 5 (e.g., 1 to 2, 1 to 3, 1 to 4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 3 to 10 (e.g., 3 to 9, 3 to 6, 3 to 5, or 3, 4, 5, 6, 7, 8, 9, or 10) membered heterocyclic group having 1 to 4 (e.g., 1 to 2, 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclic 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 to 10 (e.g., 3 to 8, 3 to 6, 3 to 5, 4 to 6, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10)-membered heterocyclic base ring having 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclic base is saturated. In some embodiments, it is partially unsaturated. In some embodiments, the heterocyclic base ring has one heteroatom. In some embodiments, the heterocyclic base ring has two or more heteroatoms. In some embodiments, the heterocyclic base ring has three or more heteroatoms. In some embodiments, the heterocyclic base ring has four or more heteroatoms. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[1267] In some implementations, R is an optional substituted C. 6-10 (For example, C6 or C) 10 aryl. In some embodiments, R is an optionally substituted C6 aryl group. In some embodiments, R is an optionally substituted C6 aryl group. 10 Aryl group. In some embodiments, the aryl ring is monocyclic. In some embodiments, the aryl ring is bicyclic. In some embodiments, the aryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 6-membered aromatic ring. In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is a phenyl group. In some embodiments, R is an optionally substituted 10-membered aryl group. In some embodiments, R is an optionally substituted naphthyl group. In some embodiments, R is a naphthyl group.

[1268] In some embodiments, R is an optionally substituted 5 to 10 (e.g., 5 to 9, 5 to 6, 5, 6, 7, 8, 9, or 10) heteroaryl group having 1 to 5 (e.g., 1 to 5, 1 to 4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, R is a 5 to 10 (e.g., 5 to 9 or 5, 6, 9, or 10) heteroaryl group having 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, the heteroaryl ring is monocyclic. In some embodiments, the heteroaryl ring is bicyclic. In some embodiments, the heteroaryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 5 or 6-membered aromatic ring having 0 to 4 heteroatoms (e.g., heteroatoms independently selected from N, O, and S), wherein at least one monocyclic unit contains 1 to 4 heteroatoms. In some embodiments, R is a 5-membered monocyclic heteroaryl group optionally substituted with 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a 6-membered monocyclic heteroaryl group optionally substituted with 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a 9-membered bicyclic heteroaryl group optionally substituted with 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a 10-membered bicyclic heteroaryl group optionally substituted with 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, the heteroaryl ring has one heteroatom. In some embodiments, the heteroaryl ring has two or more heteroatoms. In some embodiments, the heteroaryl ring has three or more heteroatoms. In some embodiments, the heteroaryl ring has four or more heteroatoms. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[1269] In some embodiments of any of the forms described herein, each R is independently hydrogen, optionally substituted C. 1-6 Aliphatic, or optionally substituted C 3-7 Alicyclic. In some embodiments, each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C. 1-6 Alkyl group. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C. 1-6 Aliphatic. In some embodiments, R is optionally substituted C. 1-6 Alkyl group. In some embodiments, R is C. 1-6 Alkyl group. In some embodiments, R is optionally substituted C. 1-2 Alkyl group. In some embodiments, R is C. 1-2Alkyl (e.g., methyl). In some embodiments, each R is C 1-2 Alkyl group (e.g., methyl). In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is an optionally substituted C-aryl group. 3-7 Alicyclic compound. In some embodiments, R is optionally substituted C. 3-7 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 3- to 7-membered monocyclic heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 4- to 6-membered monocyclic heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S.

[1270] As described herein, various groups may be optionally substituted. Substituents are commonly used in chemistry, including for the development of various therapeutic agents. Many substituents can be utilized according to this disclosure. In some embodiments, the optionally substituted group is unsubstituted. In some embodiments, the optionally substituted group is substituted. In some embodiments, the substituents are those that result in the formation of compounds having the desired properties, activities, uses, etc., as described herein. In some embodiments, the compound is stable for therapeutic uses as described herein. The term "stable" as used herein means that the compound is substantially unchanged when subjected to conditions that allow it to be generated, detected, and in some embodiments, recovered, purified, and used for one or more purposes disclosed herein. In some embodiments, the substituent is a hydrocarbon group. In some embodiments, the substituent contains a heteroatom. In some embodiments, the substituent contains multiple heteroatoms. In some embodiments, each atom in the substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus, and silicon. In some embodiments, each atom in the substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some implementations, each atom in the substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and nonhalogenated heteroatoms in the substituents is about 1 or no more than about 1; in some embodiments, it is about 2 or no more than about 2; in some embodiments, it is about 3 or no more than about 3; in some embodiments, it is about 4 or no more than about 4; in some embodiments, it is about 5 or no more than about 5; in some embodiments, it is about 6 or no more than about 6; in some embodiments, it is about 7 or no more than about 7; in some embodiments, it is about 8 or no more than about 8; in some embodiments, it is about 9 or no more than about 9; in some embodiments, it is about 10 or no more than about 10; in some embodiments, it is about 11 or no more than about 11; in some embodiments, it is about 12 or no more than about 12; in some embodiments, it is about 13 or no more than about 13; in some embodiments, it is about 14 or no more than about 14; in some embodiments, it is about 15 or no more than about 15; in some embodiments, it is about 20 or no more than about 20. In some embodiments, the total number of carbons and nonhalogenated heteroatoms in each substituent independently does not exceed about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the total number of carbons and nonhalogenated heteroatoms in each substituent independently does not exceed about 15. In some embodiments, the total number of carbons and nonhalogenated heteroatoms in each substituent independently does not exceed about 10. In some embodiments, the total number of carbons and nonhalogenated heteroatoms in each substituent independently does not exceed about 6.This document describes substituents of various sizes, including those exemplified in a variety of compounds. In some embodiments, each optional substituent on the substituted group (e.g., ring A, ring B, R, etc.) is independently a halogen, C. 1-4 Alkyl, -OH, -CN, -NO2, C 1-4 Halogenated alkyl groups (e.g., -CF3) , where each R SB Independently -H, C 1-4 Alkyl or C 1-4 Haloalkyl. In some embodiments, each optional substituent on the substituent group (e.g., ring A, ring B, R, etc.) is independently a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -OH. In some embodiments, each optional substituent on the substituent group (e.g., ring A, ring B, R, etc.) is independently a halogen or C. 1-4 Alkyl groups. As examples, many substituents are exemplified in the compounds described herein, for example in Table 1.

[1271] In some embodiments of any of the types described herein, the connector is in R d R e R f or R g One of the connections is with the bracketed part, or the connector is on an R. i When two Rs i When the groups are together, the ring formed connects to the bracket portion. In some embodiments, the connector is at R d R e R f or R g One of the connections is with the bracketed portion. In some implementations, the connector is in an R... i When two Rs i When the groups are together, the ring formed is connected to the bracket portion. In some embodiments, the connector is connected to a position having -H or a monovalent substituent (e.g., halogen, alkyl, etc.). In some embodiments, the connector is connected to a position having -H (e.g., for compounds with a PBM-H or LBM-H structure, the connector may replace -H to form a PBM-connector or LBM-connector structure, respectively).

[1272] LBM

[1273] In some implementations, LBM is In some implementations, LBM is In some implementations, LBM is In some implementations, LBM is In some implementations, LBM is In some implementations, LBM is In some embodiments described herein, LBM is the E3 ubiquitin ligase-binding moiety, i.e., LBM is the portion capable of binding E3 ubiquitin ligase. Generally, LBM is considered capable of binding E3 ubiquitin ligase if it specifically (i.e., preferentially) associates with the E3 ubiquitin ligase when in contact with at least one other protein in the presence of the ligase. In some embodiments, LBM is considered capable of binding the protein if it specifically associates with the E3 ubiquitin ligase in cells (e.g., in vitro or in vivo). In some embodiments, LBM-H compound or its salt, or LBM-linker-H compound or its salt, is considered capable of binding the K+ of the E3 ubiquitin ligase in an assay (e.g., surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC)). D If the concentration is approximately 1 μM or less, LBM is considered capable of binding to E3 ubiquitin ligases. In some embodiments, the LBM-H compound or its salt, or the LBM-linker-H compound or its salt, exhibits IC50 in competitive or functional assays (e.g., time-resolved fluorescence resonance energy transfer (TR-FRET)). 50 The amount is approximately 1 μM or less. LBMs can bind to any suitable E3 ubiquitin ligase, including cereblon, Von Hippel-Lindau protein, apoptosis protein inhibitors, MDM2, RNF114, DCAF16, DCAF15, KEAP1, FEM1B, aryl hydrocarbon receptors, etc. Some parts of E3 ubiquitin ligases capable of binding are known in the art – see, for example, The entire contents of each of these references are incorporated herein by reference. In some embodiments, techniques for identifying or evaluating LBMs are described in one or more of these references. Certain available LBMs and techniques are described below:

[1274] .

[1275] In some implementations, LBM is The variables, both individually and in combination, are defined as categories and subcategories herein and described within those categories and subcategories. In some embodiments, certain LBM types and species may provide improved properties and / or activity, such as improved stability, improved selectivity (e.g., KAT2A versus KAT2B), improved bioavailability, improved potency, and / or improved half-life. In some embodiments, LBMs have the following structures: The variables, both individually and in combination, are defined as categories and subcategories as described herein. In some implementations, the LBM has the following structure. The variables, both individually and in combination, are defined as categories and subcategories as described herein. In some implementations, the LBM has the following structure. The variables, both individually and in combination, are defined as categories and subcategories as described herein. In some implementations, the LBM has the following structure. The variables, both individually and in combination, are defined as categories and subcategories as described herein. In some implementations, the LBM has the following structure. The variables, both individually and in combination, are defined as categories and subcategories as described herein. In some implementations, the LBM has the following structure. The variables, both individually and in combination, are defined as in the categories and subcategories herein and described therein. In some embodiments, ring C is an optionally substituted benzene ring. In some embodiments, ring C is an optionally substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted naphthalene ring having 1 to 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 to 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 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, L 2 It is a covalent bond. In some implementations, L 2 It is -NH-. In some implementations, L 2 Yes -O-. In some implementations, L 2 It is -C(O)-NH-, where -C(O)- is bonded to the cyclic C. In some embodiments, L 2 It is -C(O)-NH-, where -NH- is bonded to the ring C. In some embodiments, L 2 Atoms adjacent to the atoms bonded to the joint are bonded. In some embodiments, in the case of L... 2 The shortest path from the bonded atom to the atom bonded to the linker, in relation to L 2 There is one atom between the bonded atom and the atom bonded to the linker. In some embodiments, in the atom bonded to L...2 The shortest path from the bonded atom to the atom bonded to the linker, in relation to L 2 There are two atoms between the bonded atom and the atom bonded to the linker. In some implementations, in the atom bonded to L... 2 The shortest path from the bonded atom to the atom bonded to the linker, in relation to L 2 There are three atoms between the bonded atom and the atom bonded to the linker. In some implementations, in the atom bonded to L... 2 The shortest path from the bonded atom to the atom bonded to the linker, in relation to L 2 There are four atoms in pairs between the bonded atom and the atom bonded to the linker. For example, in some embodiments, LBM is optionally substituted.

[1276] In some implementations, LBM is... .

[1277] In some embodiments of any of the forms described herein, LBM is a hydroxycerebroside (CRBN) binding moiety, that is, LBM is a moiety capable of binding hydroxycerebroside.

[1278] In some embodiments of any of the forms described herein, the LBM has the following structure:

[1279]

[1280] Where R b R c The groups A and m are defined individually and in combination as described herein for formula IIIA and in the categories and subclasses described herein; and each A is independently N, C, or CH, provided that no more than two A groups are N. It should be understood that when A is a connection point to the rest of the molecule, A is C.

[1281] In some embodiments of any of the forms described herein, the LBM has the following structure:

[1282]

[1283] Where R b R c And m, both individually and in combination, are defined in this paper as for Equation IIIA and are described in the categories and subclasses herein.

[1284] In some implementations of any of the forms described herein, LBM is selected from:

[1285] .

[1286] In some embodiments of any of the forms described herein, the LBM has the following structure:

[1287]

[1288] Among them, B and L 2 R c Y and m, individually and in combination, are defined herein as for formula IIIC and described in the categories and subclasses herein. It should be understood that B is C when B is the point of connection to the rest of the molecule.

[1289] In some embodiments of any of the forms described herein, the LBM has the following structure:

[1290]

[1291] Among them, B and L 2 R c Y and m, individually and in combination, are defined in this paper as for Equation IIIC and described in the categories and subclasses herein.

[1292] In some embodiments of any of the forms described herein, the LBM has the following structure:

[1293]

[1294] Among them, B and L 2 R c Y and m, individually and in combination, are defined in this paper as for Equation IIIC and described in the categories and subclasses herein.

[1295] In some implementations of any of the forms described herein, LBM is selected from:

[1296]

[1297] Among them, B and L 2 R c And m, both individually and in combination, are defined in this paper as for formula IIIC and described in the categories and subclasses herein.

[1298] In some implementations of any of the forms described herein, LBM is selected from:

[1299] .

[1300] In some implementations of any of the forms described herein, LBM is selected from:

[1301] .

[1302] In some implementation schemes, R a It is a halogen (e.g., -F, -Cl, or -Br). In some implementations, R a Yes -CN. In some implementations, R a It is -R', as described herein. In some implementations, R a It is -R, as described herein. In some implementations, R a It is -R, but not hydrogen. In some embodiments of any of the formulations described herein, each R a Independently hydrogen or optionally substituted C 1-6 Aliphatic. In some implementations, each R a Independently hydrogen or optionally substituted C 1-6 Alkyl group. In some embodiments, each R a Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, each R a Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl or C 6-10 Aryl. In some implementations, each R a Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, or 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, each R a Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl having 1 to 5 heteroatoms independently selected from N, O, and S, or 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, each R a It is hydrogen. In some implementations, R a It is hydrogen. In some implementations, R a It is an optional substituted C 1-6 Aliphatic. In some implementations, R a It is an optional substituted C1-6 Alkyl group. In some embodiments, R a It is C 1-6 Alkyl group. In some embodiments, R a It is an optional, substituted C 1-2 Alkyl group. In some embodiments, R a It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R a It is an optional, substituted C 3-6 Alicyclic group. In some implementations, R a It is an optional, substituted C 3-6 Cycloalkyl. In some embodiments, R a It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R a It is C 6-10 Aryl. In some implementations, R a It is phenyl. In some embodiments, R a It is naphthyl. In some embodiments, R a It is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R a It is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R a It is a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R a It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S.

[1303] In some implementations, two R a Each group is -R', and there are two R groups. a The groups, together with the atoms they are attached to, form optionally substituted rings as described herein. In some embodiments, the two R groups... a The groups, together with the atoms they are attached to, combine to form 3- to 6-membered saturated or partially unsaturated rings (e.g., carbon rings or heterocycles having 1 to 2 independent heteroatoms selected from N, O, and S). In some embodiments, the two R groups... a The groups, together with the atoms they are attached to, combine to form a 3- to 6-membered saturated ring (e.g., a carbon ring or a heterocycle having one or two independent heteroatoms selected from N, O, and S). In some embodiments, the two R groups... a Groups combine with the atoms they are attached to to form 3 to 4-membered saturated rings (e.g., carbon rings or heterocycles having 1 to 2 heteroatoms independently selected from N, O and S).

[1304] In some embodiments of any of the forms described herein, Y is N. In some embodiments, Y is CH.

[1305] In some implementations, L 2 It is a covalent bond. In some implementations, L 2 It is an optional, substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by:

[1306]

[1307] In some implementations, L 2 It is an optional substituted linear C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by:

[1308] In some embodiments of any of the forms described herein, L 2 It is a covalent bond or an optional substituted straight or branched chain C 1-3 Hydrocarbon chain. In some implementations, L 2 Is it a covalent bond, a straight chain, or a branched chain? 1-3 Hydrocarbon chain. In some implementations, L 2 Is it a covalent bond, a straight chain, or a branched chain? 1-3 A hydrocarbon chain in which one methylene group is replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 It is a covalent bond. In some implementations, L 2 Is it a straight chain or a branched chain C? 1-3 The hydrocarbon chain, wherein one methylene group is optionally replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 It is a C1 hydrocarbon chain, wherein one methylene group is optionally replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 It is a straight-chain or branched C2 hydrocarbon chain, wherein one methylene group is optionally replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 It is a straight-chain or branched C3 hydrocarbon chain, wherein one methylene group is optionally replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2 It is a covalent bond, -CH2-, -O-, or -N(R)-. In some implementations, L 2 It is -CH2-. In some implementations, L 2 It is -CH2-, -O-, or -N(R)-. In some implementations, L 2 It is -CH2-, -O-, or -N(H)-. In some implementations, L 2 It is -O- or -S-. In some implementations, L 2 Yes -O-. In some implementations, L 2 Yes -S-. In some implementations, L 2 It is -N(R)-. In some implementations, L 2 It is -N(H)-. In some implementations, L 2 It is -SO2-. In some implementations, -C(O)N(R)- or -N(R)C(O)-. In some implementations, L 2 It is -C(O)N(R)-. In some implementations, L 2 It is -N(R)C(O)-. In some implementations, L 2 It is -C(O)NH-. In some implementations, L 2 It is -NHC(O)-. In some implementations, L 2 It is -S(O)-. In some implementations, L 2 It is -S(O)N(R)-. In some implementations, L 2 It is -N(R)S(O)-. In some implementations, L 2 It is -S(O)NH-. In some implementations, L 2 It is -NHS(O)-. In some implementations, L 2 It is -S(O)2-. In some implementations, L 2 It is -N(R)S(O)2-. In some implementations, L 2 It is -S(O)2N(R)-. In some implementations, L 2 It is -NHS(O)2-. In some implementations, L 2 It is -S(O)2NH-. In some implementations, L 2 It is -Cy-, as described in this article. In some implementations, L 2 It is -Cy-, where -Cy- is of the Aryan family.

[1309] In some implementations, ring E is In some implementations, ring E is In some implementations, ring E is .

[1310] In some implementations, ring E is optionally replaced. In some implementations, ring E is In some implementations, ring E is optionally replaced. In some implementations, ring E is In some implementations, ring E is optionally replaced. In some implementations, ring E is In some embodiments, one stereoisomer binds more strongly to the E3 ubiquitin ligase than the other. In some embodiments, the stereoisomer can be converted to the other, for example, during storage, at application, or after application. In some embodiments, targeting ring E and L... 2 Or the carbon at the C-ring bond, the compound can be provided or applied in stereochemically pure form or as a mixture of two stereoisomers. In some embodiments, targeting the E and L rings... 2 For the carbon center at the ring C bond, the stereochemical purity of the compound in the composition 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, for any other chiral center, the stereochemical purity of the compound in the composition is about or at least about 90% or 95%.

[1311] In some implementations, ring E is optionally replaced. In some implementations, ring E is .

[1312] In some embodiments of any of the formulations described herein, ring C is an optionally substituted monocyclic or bicyclic 3- to 10-membered divalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is optionally substituted with a group selected from: phenyl, C 5-6Alicyclic compounds, comprising 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S; 5- to 6-membered heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S; and 9- to 10-membered bicyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is optionally substituted with a group selected from: phenyl, 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is optionally substituted with a phenyl or optionally substituted with 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, the ring C is an optionally substituted C3-C7 alicyclic group or an optionally substituted 3- to 7-membered heterocyclic group having one or two heteroatoms independently selected from N, O and S.

[1313] In some embodiments, ring C is an optionally substituted 3 to 16 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 3 to 15, 3 to 10, 5 to 10, 3 to 8, 3 to 7, or 5 to 6) member ring having 0 to 6 (e.g., 0, 1 to 6, 1 to 4, 1, 2, 3, 4, 5, or 6) heteroatoms independently selected from N, O, and S.

[1314] In some embodiments, ring C is an optionally substituted benzene ring. In some embodiments, ring C is a benzene ring. In some embodiments, ring C is an optionally substituted 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 5- to 6-membered heteroaryl group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 5-membered heteroaryl group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is pyrrole. In some embodiments, ring C is an optionally substituted 6-membered heteroaryl group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is pyridine, pyridone, or pyrimidine.

[1315] In some embodiments, the ring C is an optionally substituted C3-C7 alicyclic compound. In some embodiments, the ring C is an optionally substituted C3-C7 cycloalkyl compound. In some embodiments, the ring C is an optionally substituted C5-C6 alicyclic compound. In some embodiments, the ring C is an optionally substituted C5-C6 cycloalkyl compound. In some embodiments, the ring C is cyclohexane.

[1316] In some embodiments, ring C is an optionally substituted 3- to 7-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is a 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is piperidine or piperazine.

[1317] In some embodiments, ring C is an optionally substituted 9- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 9-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted phthalimide, isoindoline-1-one, indazole, benzo[d][1,2,3]triazole, or benzo[d] The ring C is 1,3-dihydro-2H-benzo[d]imidazol-2-one, or isoquinoline. In some embodiments, the ring C is optionally substituted phthalimide or isoindolin-1-one. In some embodiments, the ring C is optionally substituted 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. For example, in some embodiments, the ring C is optionally substituted. In some implementations, ring C is... In some embodiments, the carbon atom is bonded to the linker. In some embodiments, the ring C is optionally substituted. In some implementations, ring C is... In some implementations, the carbon atoms in the benzene ring are bonded to the linker.

[1318] In some embodiments, ring C is an optionally substituted 10- to 16-membered polycyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 11-membered tricyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S (e.g., 6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione).

[1319] In some implementations, ring C is ,in:

[1320] Each A can be N, C, or CH independently, provided that no more than two A groups are N;

[1321] Each R b It is hydrogen, or two Rs on the same carbon atom. b Groups together form oxo groups or combine to form 3 to 6-membered saturated or partially unsaturated rings;

[1322] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 aliphatic;

[1323] m can be 0, 1, 2, or 3.

[1324] In some implementations, ring C is .

[1325] In some implementations, ring C is selected from: .

[1326] In some implementations, ring C is ,in:

[1327] Each B is independently selected from N, C, and CH, provided that no more than two Bs are N;

[1328] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[1329] m can be 0, 1, 2, or 3.

[1330] In some implementations, ring C is ,in:

[1331] Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and

[1332] m can be 0, 1, 2, or 3.

[1333] In some implementations, ring C is selected from: In some implementations, ring C is selected from: .

[1334] In some implementations, ring C is optionally substituted. In some implementations, ring C is optionally substituted. In some implementations, ring C is... In some implementations, ring C is optionally substituted. In some implementations, ring C is... .

[1335] In some implementations, ring C is in relation to L 2 (As understood by those skilled in the art, when L) 2A substituent is located at a position adjacent to the bonded position (e.g., ortho position for a benzene ring) when the bond is covalent. For example, in some embodiments, a substituent is present at the position adjacent to the bonded position (e.g., ortho position for a benzene ring). 2 Substituents at positions adjacent to the bonded site (e.g., R) b R b1 or R c The is -OR, -R, or halogen. In some embodiments, it is -OR, where R is as described herein. In some embodiments, it is -OR, where R is optionally substituted C. 1-4 Aliphatic. In some embodiments, it is -OR, where R is an optionally substituted C. 1-4 Alkyl group. In some embodiments, it is -OR, where R is C. 1-4 Aliphatic. In some implementations, it is -OR, where R is C 1-4 Alkyl group. In some embodiments, it is -OR, where R is C. 1-4 Halogenated alkyl group. In some embodiments, it is -OCF3. In some embodiments, it is -OMe. In some embodiments, it is -R, as described herein. In some embodiments, it is optionally substituted C. 1-4 Aliphatic. In some embodiments, it is optionally substituted C. 1-4 Alkyl group. In some embodiments, it is C10. 1-4 Aliphatic. In some implementations, it is C 1-4 Alkyl group. In some embodiments, it is C10. 1-4 Haloalkyl. In some embodiments, it is methyl. In some embodiments, it is -CF3. In some embodiments, it is halogen. In some embodiments, it is -F. In some embodiments, it is -Cl. In some embodiments, it is -Br. For example, in some embodiments, the ring C is... The carbon atoms marked with * are associated with L 2 Bonding. In some implementations, ring C is a bicyclic or multicyclic ring, and ring C is bonded to L. 2 (As understood by those skilled in the art, when L) 2 When it is a covalent bond, there are two ring atoms bonded at positions adjacent to the ring E. For example, in some embodiments, the ring C is... The carbon atoms marked with * are associated with L 2 Bonding. In some implementations, yes , where R b1 It is not hydrogen. In some embodiments, compounds containing such a ring C can selectively degrade KAT2A relative to KAT2B (e.g., the DC of KAT2A when evaluated).50 DC smaller than KAT2B 50 (e.g., as in embodiment B1).

[1336] In some implementations, ring C is selected from:

[1337] .

[1338] In some implementations, ring C is selected from:

[1339] .

[1340] In some embodiments of any of the formulations described herein, ring F is an optionally substituted 3- to 16-membered ring having 0 to 6 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 4- to 10-membered divalent ring system having 0 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 5- to 6-membered divalent ring system having 0 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted 6-membered divalent ring system having 0 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is an optionally substituted phenyl group.

[1341] In some embodiments of any of the formulations described herein, each A is CH. In some embodiments, one A is N, and the other A groups are CH. In some embodiments, two A groups are N, and the other A groups are CH. It should be understood that when A is CH, it can be R as defined herein. c The substitution makes the ring contain -C(R) c - Part. It should also be understood that when A is the point of connection with the rest of the molecule, A is C.

[1342] In some implementation schemes, R b Let R' be R', as described herein. In some implementations, R... b It is -R, as described herein. In some implementations, R b It is -R, but not hydrogen. In some implementations, R... b It is -OR, where R is as described herein. In some embodiments of any of the forms described herein, each R b It is hydrogen. In some embodiments of any of the forms described herein, each R b Independently, it is halogen, -CN, -R, or -OR. In some implementations, each R... bIndependently hydrogen, halogen, or optionally substituted C 1-6 Aliphatic. In some implementations, each R b Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, each R b Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl or C 6-10 Aryl. In some implementations, each R b Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, or 5- to 10-membered heteroaryl groups having 1 to 5 independent heteroatoms selected from N, O, and S. In some embodiments, each R b Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 The aryl group is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S, or a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, each R b It is hydrogen independently. In some implementations, R b It is a halogen. In some implementations, R b It is fluorine. In some implementations, R b It is chlorine. In some implementations, R b It is bromine. In some implementations, R b It is an optional, substituted C 1-6 Aliphatic. In some implementations, R b It is an optional, substituted C 1-6 Alkyl group. In some embodiments, R b It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R b It is an optional, substituted C 3-6 Alicyclic group. In some implementations, R b It is an optional, substituted C 3-6 Cycloalkyl. In some embodiments, R b It is C 3-4 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R b It is C 6-10 Aryl. In some implementations, R b It is phenyl. In some embodiments, R b It is naphthyl. In some embodiments, Rb It is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R b It is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, R b It is a 3- to 10-membered monocyclic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R b It is a 4- to 6-membered monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from N, O and S.

[1343] In some implementations, two R on the same carbon b The groups together form an oxo group. In some embodiments, two R groups on the same carbon atom... b Groups combine to form 3 to 6-membered saturated or partially unsaturated rings (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 3-6 Alicyclic groups or 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, two R atoms on the same carbon atom... b Groups combine to form C 3-6 Cycloalkyl groups (e.g., cyclopropyl). In some embodiments, the two R groups on the same carbon atom... b The groups are combined to form 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms independently selected from N, O, and S.

[1344] In some implementation schemes, R b1 It is R b As described herein. In some implementations, R b1 It is not hydrogen. In some embodiments, it is -OR, where R is as described herein. In some embodiments, it is -OR, where R is optionally substituted C. 1-4 Aliphatic. In some embodiments, it is -OR, where R is an optionally substituted C. 1-4 Alkyl group. In some embodiments, it is -OR, where R is C. 1-4 Aliphatic. In some implementations, it is -OR, where R is C 1-4 Alkyl group. In some embodiments, it is -OR, where R is C. 1-4 Halogenated alkyl group. In some embodiments, it is -OCF3. In some embodiments, it is -OMe. In some embodiments, it is -R, as described herein. In some embodiments, it is optionally substituted C. 1-4 Aliphatic. In some embodiments, it is optionally substituted C. 1-4 Alkyl group. In some embodiments, it is C10. 1-4 Aliphatic. In some implementations, it is C 1-4Alkyl group. In some embodiments, it is C10. 1-4 Alkyl halide. In some embodiments, it is methyl. In some embodiments, it is -CF3. In some embodiments, it is halogen. In some embodiments, it is -F. In some embodiments, it is -Cl. In some embodiments, it is -Br.

[1345] In some implementations, t' is 0. In some implementations, t' is 1. In some implementations, t' is 2. In some implementations, t' is 3.

[1346] In some embodiments of any of the forms described herein, each B is CH, CR 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. In some embodiments, B is CR. c In some implementations, B is C. It should be understood that B is C when it is the point of connection to the rest of the molecule.

[1347] In some implementations of any of the forms described herein, each R c Independently selected from halogens, -OH, -O(C 1-6 Alkyl), -O(C) 1-6 Halogenated alkyl groups), -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl groups, -CN and optionally substituted C 1-6 Alkyl group. In some embodiments, each R c Independently selected from halogens, -OH, -O(C 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl groups, -CN and optionally substituted C 1-6 Alkyl group. In some embodiments, each R c Independently selected from halogens, -O(C 1-6 Alkyl), -O(C) 1-6 (halogenated alkyl), C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... c Independently selected from halogens, -O(C 1-6 Alkyl), C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, each R... c Independently selected from halogens, -O(C 1-6alkyl) and C 1-6 Alkyl group. In some embodiments, R c It is a halogen (e.g., fluorine or chlorine). In some implementations, R c It is -OR (e.g., -OH, -O(C)). 1-6 alkyl) or -O(C 1-6 (Haloalkyl)). In some embodiments, R c It is -OCH3 or -OCF3. In some implementations, R c It is -N(R)2 (e.g., -NH2, NH(C)2). 1-6 alkyl) or -N(C) 1-6 Alkyl group 2). In some embodiments, R c Yes -CN. In some implementations, R c It is an optional, substituted C 1-6 Aliphatic. In some implementations, R c It is an optional, substituted C 1-6 Alkyl group. In some embodiments, R c C is a C that is optionally replaced by one or more halogens. 1-6 Alkyl group. In some embodiments, R c It is C 1-6 Alkyl group. In some embodiments, R c It is an optional, substituted C 1-2 Alkyl group. In some embodiments, R c It is an optional substituted C that is optionally replaced by one or more halogens. 1-2 Alkyl group. In some embodiments, R c It is C 1-2 Alkyl (e.g., methyl). In some embodiments, R c It is C 1-6 Halogenated alkyl groups. In some embodiments, R c It is C 1-2 Halogenated alkyl groups (e.g., -CF3).

[1348] In some embodiments of any of the formulas described herein, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodi...

Claims

1. A compound, said compound being selected from: ， Or its medicinal salt.

2. Compound of formula I or its pharmaceutically acceptable salt: in: PBM is the KAT2 protein binding site, or or ; The connector is an optional connecting part, either a covalent bond or an optional substituted divalent C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ;and LBM is the E3 ubiquitin ligase-binding site, or , ； in: Ring A is selected from: ； Ring B is a 5- to 6-membered heterocyclic group that is optionally substituted and has 1 to 2 heteroatoms independently selected from N, O and S; L 1 It is a covalent bond or an optional substituted divalent C 1-3 hydrocarbon chain; Each R 1 Independently, it is -R; n is 0, 1, 2, 3 or 4; Z is N or CR 3 ; R 2 It is a halogen, -CN, or -R; Each R 3 It is halogen, -CN, or -R independently; R 4 It is -R'; R 5 It is halogen, -CN or -R, or R 2 and R 5 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S; R 6 It is -R'; X is O or NR 7 ; R 7 It is -R', or R 4 and R 7 Together with the atoms to which they are attached, they can form optional substituted 5- to 6-membered rings with 2 to 3 independent heteroatoms selected from N, O, and S; L 3 L 4 and L 5 Each is independently a covalent bond or an optional substituted divalent C. 1-6 hydrocarbon chain; Each R 8 Independently, it is -R'; R 9 It is -R'; Each Cy is independently a 3- to 16-membered divalent ring that is optionally substituted and has 0 to 6 heteroatoms independently selected from N, O, and S; The C ring and the F ring are each independently substituted 3- to 16-membered rings with 0 to 6 heteroatoms independently selected from N, O and S; Each R b It can be halogen, -CN, -R', or -OR independently; t is 0, 1, 2, 3, or 4; L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ； Ring E is Or, optionally, selected from the alternatives. and group; Y is either N or CH; Each R a It is independently a halogen, -CN, or -R'; Connector at R d R e R f or R g One of the connections is with the bracketed part, or the connector is on an R. i In place or when two R i When groups are together, the ring formed is connected to the bracket portion; R at each connection point that is not the aforementioned connector d Independently, it is -R', or Two Rs d Together with the atoms to which they are attached, they combine to form optionally substituted 5- to 6-membered rings having 1 to 3 heteroatoms independently selected from N, O, and S, and said rings are optionally fused with phenyl or 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from N, O, and S. R at each connection point that is not the aforementioned connector e Independently, it is -R; When R f When it is not the connection point of the aforementioned connector, it is -R; R at each connection point that is not the aforementioned connector g It can be halogen, -CN, R, or -OR independently; p is 0, 1, 2, or 3; R h It is a halogen or -R; R at each connection point that is not the aforementioned connector i It is independently a halogen, -R, -C(O)N(R')2 or -N(R)C(O)R, or Two Rs i The groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl group or a 5- to 6-membered ring having 1 to 3 independent heteroatoms selected from N, O, and S; R j It's -R, or R j With an R i Examples and their intercalated atoms are combined together to form optional substituted 5- to 7-membered rings with 1 to 2 independent heteroatoms selected from N, O and S; R k It is -R; r is 1, 2, 3, 4 or 5; q is 1 or 2; R m It is -R; R n R p R q R r R s and R u Each can be independently halogenated, -CN, -R, or -OR; s is 0, 1, 2, 3, 4, or 5; t is 0, 1, 2, 3, 4, or 5; Each u is independently 0, 1, 2, 3, 4 or 5; Each R t Independently, it is R, or Two Rs t The groups, together with the atoms to which they are attached, combine to form optional substituted 3- to 7-membered rings with 0 to 2 independent heteroatoms selected from N, O, and S; Each R v It can be halogen, -CN, -R, or -OR independently, or R v and R u One example combines with their intercalating atoms to form an optionally substituted 3- to 7-membered ring with 0 to 2 independent heteroatoms selected from N, O, and S; Each R w It can be halogen, -CN, -R, or -OR independently, or R w and R u One example combines with their intercalating atoms to form an optionally substituted 3- to 7-membered ring with 0 to 2 independent heteroatoms selected from N, O, and S; Each v is independently 0, 1, 2, 3, 4 or 5; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom can combine with the atoms they are bonded to to form optionally substituted 3- to 16-membered rings with 1 to 5 heteroatoms independently selected from N, O, and S; and Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-8 aliphatic, C 3-10 Alicyclic alicyclic compounds, specifically C1-C8 heteroalicyclic compounds with 1 to 3 heteroatoms independently selected from N, O, and S. 6-10 Aryl groups, 5- to 10-membered heteroaryl groups having 1 to 5 heteroatoms independently selected from N, O, and S, and 3- to 10-membered monocyclic heterocyclic groups having 1 to 5 heteroatoms independently selected from N, O, and S.

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

4. The compound according to any one of claims 2 to 3, wherein PBM is 。 5. The compound of any one of claims 2 to 4, wherein ring F is an optionally substituted benzene ring.

6. The compound according to any one of claims 2 to 5, wherein R 2 It is halogen.

7. The compound of any one of claims 2 to 5, wherein ring A is .

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

9. The compound of any one of claims 2 to 5, wherein ring A is or .

10. The compound of claim 9, wherein R 6 It is an optional substituted C 1-6 Aliphatic and / or R 4 It is an optional substituted C 1-6 alkyl.

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

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

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

14. The compound according to any one of claims 2 to 11, wherein yes .

15. The compound of any one of claims 2 to 14, wherein each R 1 Independently, it is the optional substituted C 1-6 Alkyl group, preferably methyl group.

16. The compound according to any one of claims 2 to 15, wherein L 1 It is a covalent bond.

17. The compound according to any one of claims 2 to 16, wherein or Selected from 。 18. The compound of any one of the preceding claims, wherein the length of the joint is less than 14 atoms, or wherein the length of the joint is less than 11 atoms; and / or Where the shortest path length of the connector is approximately or no more than 14 atoms, or where the shortest path length of the connector is approximately or no more than 10 atoms; and / or where the non-cyclic continuous sp in the shortest path chain of the connector 3 The number of atoms is approximately or no more than approximately 5, 4, 3, 2, or 1; and / or therein is a non-cyclic continuous sp in the shortest path chain of the joint. 3 The number of atoms is approximately or no more than approximately 2; and / or therein are two non-cyclic sp atoms in the shortest path chain at the joint. 3 The number of bonds between atoms is approximately or no more than 5, 4, 3, 2, or 1; and / or two non-cyclic sp atoms in the shortest path chain at the joint. 3 The number of bonds between atoms is approximately or no more than 1; and / or the non-cyclic sp in the shortest path chain of the joint. 3 The number of C, O, and S atoms is approximately or no more than approximately 5, 4, 3, 2, or 1; and / or the non-cyclic sp atoms in the shortest path chain of the joint. 3 The number of atoms is about or no more than about 5, 4, 3, 2 or 1; and / or the non-cyclic sp in the shortest path chain of the joint. 3 The number of atoms is about or no more than about 1; and / or the number of non-cyclic atoms in the shortest path chain of the joint is about or no more than about 5, 4, 3, 2 or 1; and / or the number of non-cyclic atoms in the shortest path chain of the joint is about or no more than about 1.

19. The compound of any one of claims 2 to 17, wherein the linker is optionally a substituted divalent straight-chain or branched, saturated or unsaturated C1-C. 20 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ， Preferably: The linker is optionally a substituted divalent linear or branched chain, saturated or unsaturated C1-C. 20 Hydrocarbon chain, wherein at least one methylene unit is replaced by: -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)- or -Cy-; and in: The methylene unit is replaced by -C(O)-; the methylene unit is replaced by -Cy-, preferably wherein -Cy- is in the shortest path chain; and / or the methylene unit is replaced by -C(O)N(R)-.

20. The compound of any one of claims 2 to 17, wherein the connector is: ， in: M 1 and M 2 Each of these can be independently nonexistent, -CH2-, -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 Each is independently a covalent bond or an optionally substituted divalent straight or branched chain, saturated or unsaturated C1-C. 10 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: 。 21. The compound of any one of claims 2 to 17, wherein the connector is selected from... 。 22. The compound of any one of claims 2 to 17, wherein -Cy- is monocyclic and optionally 3 to 10-membered, or wherein -Cy- is bicyclic, optionally wherein -Cy- is 6, 7, 8, 9, 10, or 11-membered.

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

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

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

26. The compound of any one of claims 2 to 20, wherein the linker is selected from... and ; or the connector mentioned therein is selected from: 。 27. The compound of any one of claims 2 to 26, wherein LBM is an E3 ubiquitin ligase-binding moiety, or wherein LBM is a VHL-binding moiety, an IAP-binding moiety, or an MDM2-binding moiety.

28. The compound of any one of claims 2 to 27, wherein LBM is .

29. The compound of any one of claims 2 to 27, wherein the compound is of formula III-1 or a pharmaceutically acceptable salt thereof: in: Each R b It can be halogen, -CN, -R', or -OR independently; t is 0, 1, 2, 3, or 4; L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ； Ring E is Or choose from the alternatives selected and group; Y is N or CH; and Each R a It is halogen, -CN, or -R' independently.

30. The compound of any one of claims 2 to 27, wherein LBM is .

31. The compound of any one of claims 2 to 27, wherein the compound is of formula IIIL or a pharmaceutically acceptable salt thereof: in: Each R b and R b1 It can be halogen, -CN, -R', or -OR independently; t' is 0, 1, 2, or 3; L 2 It is a covalent bond or an optionally substituted C 1-3 The hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by: ； Ring E is Or choose from the alternatives selected and group; Y is N or CH; and Each R a It is halogen, -CN, or -R' independently.

32. The compound according to any one of claims 2 to 31, wherein R b1 Not -H, or R in it b1 It is an optional substituted C 1-6 Aliphatic or halogenated, or R in which b1 It is -OR, where R is an arbitrarily substituted C. 1-6 Lipids.

33. The compound of any one of claims 2 to 31, wherein ring C is optionally a substituted benzene ring.

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

35. The compound of any one of claims 2 to 34, wherein ring E is Or, where ring E is optionally substituted and selected from... .

36. The compound of any one of claims 2 to 35, wherein the ring C is: in: Each A can be N, C, or CH independently, provided that no more than two A groups are N; Each R b It is hydrogen, or two Rs on the same carbon atom. b Groups together form oxo groups or combine to form 3 to 6-membered saturated or partially unsaturated rings; Each R c Independently selected from halogens, -OR, -N(R)2, -CN, and optionally substituted C. 1-6 Aliphatic; and m can be 0, 1, 2, or 3.

37. The compound according to any one of claims 2 to 36, wherein L 2 It is a covalent bond.

38. The compound of any one of claims 2 to 37, wherein LBM or Partially selected from: 。 39. The compound of any one of claims 2 to 35, wherein LBM is 。 40. The compound of any one of claims 2 to 3, wherein PBM is .

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

42. The compound of claim 41, wherein ring A is selected from... .

43. The compound of any one of claims 40 to 42, wherein LBM is .

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

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

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

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

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

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

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

5.

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

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

53. A method for preparing the pharmaceutical composition of claim 48, comprising: Provide a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 47; as well as The compound is formulated with a suitable excipient to obtain the pharmaceutical composition.

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

55. A method for regulating dysregulated cellular states associated with KAT2A and / or KAT2B, comprising administering or delivering to cells an effective amount of the compound or a pharmaceutically acceptable salt thereof, or a composition thereof, as described in any one of the preceding claims.

56. The method of claim 55, wherein the disordered cellular state is cancerous, such as acute myeloid leukemia, small cell lung cancer, or neuroendocrine prostate cancer.

57. The method of any one of claims 55 to 56, wherein the method induces or promotes the transformation of the disordered cell state into another cell state; wherein the disordered cell state is more proliferative than the other cell state; wherein the disordered cell state is less differentiated than the other cell state; wherein the disordered cell state is blocked or reduced differentiation, or includes blocked or reduced differentiation; wherein the disordered cell state is dedifferentiated or includes dedifferentiation; wherein the disordered cell state is transdifferentiated or includes transdifferentiation; wherein the disordered cell state is a dedifferentiated neuroendocrine cell state or includes a dedifferentiated neuroendocrine cell state; and / or wherein the other cell state is a more differentiated epithelial cell state or includes a more differentiated epithelial cell state.

58. The method of any one of claims 55 to 57, wherein the additional cell state comprises increased expression levels of CD11b, CD14, CD15 and / or CD86; wherein the method enhances myeloid differentiation and / or reduces stemness, translation and replication; and / or wherein the method enhances myeloid differentiation and / or reduces stemness, translation and / or replication of the GSEA tag.

59. The method of any one of claims 55 to 58, wherein the method enhances epithelial GSEA tags; and / or wherein the method enhances neural GSEA tags; and / or wherein the method enhances monocyte differentiation; and / or wherein the method enhances neural differentiation; and / or wherein the method enhances epithelial differentiation; and / or wherein the method enhances CD11b+ cell levels; and / or wherein the method enhances CD14+ cell levels; and / or wherein the method enhances CD15+ cell levels; and / or wherein the method enhances CD86+ cell levels.

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

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

62. A method for degrading KAT2 in a subject, comprising administering to the subject in which such degradation is desired the compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the preceding claims.

63. A method for inducing or promoting cell differentiation in a system, comprising administering or delivering to the system an effective amount of the compound or a pharmaceutically acceptable salt thereof, or a composition thereof; or a method for reducing or blocking dedifferentiation in a system, comprising administering or delivering to the system an effective amount of the compound or a pharmaceutically acceptable salt thereof, or a composition thereof; or a method for reducing or blocking transdifferentiation in a system, comprising administering or delivering to the system an effective amount of the compound or a pharmaceutically acceptable salt thereof, or a composition thereof.

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

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

66. The method of any one of claims 54 to 64, wherein the system is a cancer cell or contains cancer cells.

67. The method of any one of claims 54 to 64, wherein the system is acute myeloid leukemia cells or comprises acute myeloid leukemia cells.

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

69. The method of claim 68, wherein the disease, disorder, or ailment is related to KAT2A and / or KAT2B.

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

71. The compound, composition, or method according to any one of embodiments 1 to 689.

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