Technologies that target cellular states

Abstract

In particular, this disclosure provides technologies that target KAT2. In some embodiments, this disclosure provides technologies for reducing the levels of KAT2 polypeptides in various systems. In some embodiments, this disclosure provides technologies for treating various diseases, disorders, or conditions associated with KAT2 polypeptides, including various cancers.

Description

[Technical Field]

[0001] Related applications

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

[0002]

[0002] KAT2A (also known as General Control Non-Depressible 5 (GCN5)) and KAT2B (also known as p300 / CBP-related factor (PCAF)) are both multi-domain proteins containing an acetyltransferase domain and a bromodomain. Both KAT2A and KAT2B have been reported to modify histones and recognize modified histones, and therefore have been reported to function as epigenetic proteins. They have been reported to be involved 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. Conditional knockout of KAT2A in mice carrying additional mutations that cause acute myeloid leukemia has been reported to delay the onset of leukemia, deplete leukemia stem cells, and shift the fate of leukemia cells from self-renewal to differentiation, thereby making the disease less invasive. See, for example, Domingues AP et al., eLife 9:e51754, 2020. [Overview of the project] [Means for solving the problem]

[0003]

[0003] In particular, this disclosure encompasses the recognition that various conditions, disorders, or diseases are associated with certain cellular states. For example, many types of normal cells typically experience a proliferative plastic cellular state, then eventually differentiate, lean towards a specific cellular state, and cease to proliferate, while many cancer cells exist in a plastic and proliferative state (which may also be called a plastic state) through, for example, 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 conditions, disorders, or diseases by targeting those associated cellular states. In some embodiments, this disclosure provides techniques for targeting the plastic state of cancer cells. In some embodiments, this disclosure identifies driving factors associated with the plastic state of cancer cells. In some embodiments, the driving factors fix cancer cells in a plastic and proliferative state. In some embodiments, the driving factor contributes to maintaining cancer cells in a plastic and proliferative state. In some embodiments, the provided technique returns cancer cells to a normal cellular state and / or inhibits their growth and proliferation.

[0004]

[0004] In some embodiments, KAT2A and / or KAT2B have been identified as driving factors for the plasticity state of various cancer cells, such as small cell lung cancer, neuroendocrine prostate cancer, and acute myeloid leukemia. In some embodiments, the Disclosure provides compounds useful for modulating KAT2 (e.g., KAT2A and / or KAT2B) by, for example, degrading KAT2 (e.g., increasing its degradation), for example, by reducing KAT2 activity. In some embodiments, the techniques provided (e.g., compounds, compositions, or methods) can reduce the level of KAT2 protein. In some embodiments, the techniques provided can reduce the level of KAT2A. In some embodiments, the techniques provided can reduce the level of KAT2B. In some embodiments, the techniques provided can reduce the levels of both KAT2A and KAT2B. In some embodiments, the techniques provided can selectively reduce the level of one of KAT2A and KAT2B compared to the other. In some embodiments, the provided technology can selectively reduce the level of KAT2A compared to the level of KAT2B. In some embodiments, the provided compounds are useful, among other things, for treating and / or preventing 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 a technology for preventing or treating conditions, disorders, or diseases related to KAT2A and / or KAT2B. In some embodiments, the provided technology provides a technology for preventing or treating conditions, disorders, or diseases related to KAT2A. In some embodiments, the provided technology provides a technology for preventing or treating conditions, disorders, or diseases related to KAT2B.

[0005]

[0005] In some embodiments, the provided compound comprises a protein-binding portion that can bind to a KAT2 protein (e.g., KAT2A and / or KAT2B) and an E3 ligase-binding portion that can bind to an E3 ubiquitin ligase. In some embodiments, the protein-binding portion binds to the bromodomain of KAT2A and / or KAT2B. In some embodiments, the provided compound can recruit the KAT2 protein to an E3 ubiquitin ligase, thereby promoting (or otherwise inhibiting) the degradation of the KAT2 protein (e.g., KAT2A and / or KAT2B). 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.

[0006]

[0006] In some embodiments, the present disclosure relates to compounds of formula I: PBM-Linker-LBM I The present invention provides either a pharmaceutically acceptable salt thereof (wherein PBM, linker, 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.

[0007]

[0007] In some embodiments, the compound provided is a compound of formula III or a salt thereof. In some embodiments, the compound provided is a compound of formula IIIA or a salt thereof. In some embodiments, the compound provided is a compound of formula IIIB, IIIB-1, or IIIB-2, or a salt thereof. In some embodiments, the compound provided is a compound of formula IIIC or a salt thereof. In some embodiments, the compound provided is a compound of formula IIID or a salt thereof. In some embodiments, the compound provided is a compound of formula IV, IVA, or IVA-1, or a salt thereof. In some embodiments, the compound provided is a compound of formula V, VA, VA-1, VB, or VB-1, or a salt thereof. In some embodiments, the compound provided is a compound of formula VI, VIA, or VIA-1, or a salt thereof. In some embodiments, the compound provided is a compound of formula VII or VIA, or a salt thereof. In some embodiments, the compound provided is a compound of formula VIII or VIIIA, or a salt thereof. In some embodiments, the compound provided is a compound of formula X, XA, XA-1, XA-2, or XB, or a salt thereof. In some embodiments, the compound provided is a compound of formula XI or XIA, or a salt thereof. In some embodiments, the compound provided is a compound of formula XII, XIA, XIIB, or XIIB-1, or a salt thereof. In some embodiments, the compound provided is a compound of formula XIII or XIIIA, or a salt thereof. In some embodiments, the compound provided is a compound of formula XIV, or a salt thereof. In some embodiments, the compound provided 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 to KAT2A and / or KAT2B, as well as 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 level of KAT2A and / or KAT2B.In some embodiments, such compounds are useful for preventing and / or treating conditions, disorders, or diseases associated with KAT2A and / or KAT2B.

[0008]

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

[0009]

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

[0010]

[0010] In some embodiments, the Disclosure provides a method for preventing a condition, disorder, or disease, comprising the step of administering or delivering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject susceptible to the condition, disorder, or disease. In some embodiments, the Disclosure provides a method for treating a condition, disorder, or disease, comprising the step of administering or delivering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject suffering from the condition, disorder, or disease. In some embodiments, a pharmaceutical composition is administered for administering or delivering the compound or a salt thereof. In some embodiments, the condition, disorder, or disease is related to 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. [Brief explanation of the drawing]

[0011] [Figure 1]

[0011] The provided compound can offer a variety of activities, including inhibiting tumor growth in vivo. (Figure 1A) This figure shows that the provided compound can inhibit tumor growth in vivo. Nude Balb / c mice were inoculated with NCI-H1048 cells in Matrigel. Tumors were allowed to grow to approximately 200 mm3, and then the mice were randomly divided into two groups. The mice were administered either vehicle or 30 mg / kg of compound 22 intraperitoneally (ip) once a week. Tumor size was measured every 3-4 days, and the mice were sacrificed when the vehicle tumor reached 2000 mm3. Error bars are SEM. Administration was started 17 days after tumor inoculation. (Figure 1B) This figure shows that the provided technology can reduce KAT2A and KAT2B levels as well as histone acetylation levels. As shown, such reductions are confirmed by Western blot data of small cell lung cancer NCI-H1048 cells treated with various concentrations of compound 22 for 24 hours. The vehicle is DMSO. (Figure 1C) This figure shows that the provided technology can inhibit cell growth. Cell count data compared to a DMSO control after 8 days of treatment with compound 22 is presented as an example to confirm the inhibition. GI50 = 6 nM. (Figure 1D) This figure shows that the provided technology can inhibit tumor growth in vivo. Nude Balb / c mice inoculated with H1048 tumors were administered either the vehicle (HbCD) or compound 22 intraperitoneally (qw ip) once a week. Mean tumor volume + / - SEM from 6 mice is shown. A significant 70% inhibition of tumor growth was observed at 30 mg / kg, and the treatment was well-tolerated. See also Figure 1A. (Figure 1E) This figure shows that the provided technology is well-tolerated. Constant body weight compared to starting body weight is presented as an example to confirm tolerability and safety. (Figure 1F) This figure shows that the provided technology can reduce tumor KAT2A and KAT2B levels as well as histone acetylation levels in vivo. Western blots from tumors 168 hours after the last dose showed a significant decrease in KAT2A and KAT2B, as well as histone acetylation.(Figure 1G) This figure shows that the provided technology can modulate cellular state and induce differentiation. The box plot of epithelial GSEA demonstrates significant upregulation in tumors treated with compound 22 compared to the vehicle. [Figure 2]

[0012] The provided compounds can offer a variety of activities. (Figure 2A) This figure shows that the provided technique can reduce KAT2A and KAT2B levels as well as histone acetylation levels. As shown, this reduction is confirmed by Western blot data of acute myeloid leukemia MOLM-13 cells treated with compound 22 for 48 hours. (Figure 2B) This figure shows that the provided technique can inhibit cell growth. Cell count data after 8 days of treatment with compound 22 compared to a DMSO control are presented as an example to confirm the inhibition. GI50 = 1.2 nM. (Figure 2C) This figure shows that the provided technique can modulate cellular state and induce differentiation. Monocytic differentiation was observed by flow cytometry analysis of CD86 at 48 hours. EC50 = 0.3 nM. [Figure 3]

[0013] The provided compounds can offer a variety of activities. (Figure 3A) This figure shows that the provided technique can reduce KAT2A and KAT2B levels as well as histone acetylation levels. As shown, such reductions are confirmed by Western blotting of neuroendocrine prostate cancer LASCPC-01 cells treated with compound 22 for 24 hours. (Figure 3B) This figure shows that the provided technique can inhibit cell growth. Cell viability (Cell Titer Glo) data compared to DMSO control after 7 days of treatment with compound 22 are presented as an example to confirm the inhibition. GI50 = 5 nM. (Figure 3C) This figure shows that the provided technique can modulate cellular state and induce differentiation. Box plots of epithelial GSEA demonstrate significant upregulation in cells treated with compound 22 compared to DMSO. (Figure 3D) This figure shows that the provided technique can reduce KAT2A and KAT2B levels as well as histone acetylation levels, including those in organoids from major neuroendocrine prostate cancer patients. As shown, this reduction was confirmed by Western blotting of NEPC primary patient organoids treated with compound 22 for 72 hours. The concentration is nM. (Figure 3E) This figure shows that the provided technique can inhibit cell growth. Cell viability data compared to DMSO control after 21 days of treatment with compound 22 are presented as an example to confirm the inhibition. GI50 = 3nM. (Figure 3F) This figure shows that the provided technique can modulate cellular state and induce differentiation. Box plots of GSEA of microglia demonstrated significant upregulation (both epithelial and neuronal components). [Modes for carrying out the invention]

[0012]

[0014] Certain technologies provided in this disclosure, such as compounds, compositions, and methods, include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein.

[0013] definition

[0015] As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of this disclosure, chemical elements are identified in accordance with the Periodic Table, CAS versions, and Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are incorporated herein by reference in their entirety, “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th edition, edited by Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0014]

[0016] Unless otherwise indicated, structures described herein represent all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, and all geometric or conformatoric forms of the structure. For example, where a stereocenter is present, in some embodiments, the R and / or S configuration of such a stereocenter is considered part of the disclosure. Thus, in some embodiments, a single stereochemical isomer of the provided compound, as well as / or enantiomers, diastereomers, and / or geometric (or conformatoric) mixtures, are within the scope of the disclosure. For example, in some cases, Tables 1 and 2 show one or more stereoisomers of the compound, and unless otherwise indicated, each stereoisomer is represented individually and / or as a mixture. Unless otherwise indicated, tautomeric forms of the provided compound are within the scope of the disclosure.

[0015]

[0017] Unless otherwise indicated, structures described herein mean that they contain compounds that differ only in the presence of one or more isotopically enriched atoms. For example, substitution of hydrogen with deuterium or tritium, or carbon 13 C or 14 Compounds having this structure, including substitution with carbon-enriched carbon, are within the scope of this disclosure.

[0016]

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

[0017]

[0019] Alkyl: The term "alkyl," used alone or as part of a larger moiety, has (unless otherwise specified) from 1 to 12, from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 4, from 1 to 3, or from 1 to 2 carbon atoms (e.g., C 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~4 , C 1~3 , or C 1~2) refers to saturated, possibly substituted, linear or branched hydrocarbon groups. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0018]

[0020] Carbocyclyl: The terms “carbocyclyl,” “carbocyclic,” and “carbocyclic ring” as used herein refer to a monocyclic, bicyclic, or polycyclic ring system of saturated or partially unsaturated cyclic aliphatic rings having 3 to 14 members, as described herein, and the aliphatic ring system may be substituted as described herein. Examples of carbocyclic groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “alicyclic)” is a monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, and may be substituted, or a monocyclic C5-C8 hydrocarbon that may be substituted. 10 (For example, C7~C 10 Or C8~C 10 The term "cycloalkyl" refers to a bicyclic hydrocarbon. The term "cycloalkyl" refers to a saturated ring system that may be substituted with about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl group has 3 to 6 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system that contains at least one carbon-carbon double bond and has about 3 to about 10 carbon atoms, and may be substituted with 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0019]

[0021] Alkenyl: Used alone or as part of a larger term, the term "alkenyl" has at least one double bond and (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2~12 , C 2~10 , C 2~8 , C 2~6 , C 2~4 , or C 2~3 This refers to a linear or branched hydrocarbon chain that may be substituted. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0020]

[0022] Alkynyl: Used alone or as part of a larger term, the term "alkynyl" has at least one triple bond and (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2~12 , C 2~10 , C 2~8 , C 2~6 , C 2~4 , or C 2~3 ) refers to a linear or branched hydrocarbon group that may be substituted. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0021]

[0023] Aryl: The term "aryl" refers to a ring with a total of 6 to 14 members (for example, C 6~14 The term "aryl" refers to monocyclic and bicyclic ring systems in which at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, "aryl" refers to aromatic ring systems, including but not limited to phenyl and naphthyl, which may have one or more substituents. Unless otherwise specified, the "aryl" group is a hydrocarbon.

[0022]

[0024] Heteroaliphatic: The term "heteroaliphatic," as used herein, is given its common meaning in the art and refers to an aliphatic group 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 heteroalkyl. In some embodiments, the heteroaliphatic group is heteroalkenyl.

[0023]

[0025] Heteroaryl: Used alone or as part of a larger phrase, such as "heteroaralkyl" or "heteroarcoxy," the terms "heteroaryl" and "heteroar-" refer to monocyclic or bicyclic ring groups having 6, 10, or 14 π electrons shared in a cyclic arrangement, and having 5 to 10 ring atoms with 1 to 5 heteroatoms in addition to the carbon atoms (e.g., 5-6 membered monocyclic heteroaryls or 9-10 membered bicyclic heteroaryls). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthylidinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-” also, as used herein, include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazine-3(4H)-one, and benzoisoxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which may include a substituted ring.

[0024]

[0026] Heteroatoms: As used herein, the term "heteroatom" means nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen.

[0025]

[0027] Heterocyclic: As used herein, the terms “heterocyclic,” “heterocyclyl,” and “heterocyclic ring” are interchangeable and refer to stable 3- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic parts that are saturated or partially unsaturated and have one or more heteroatoms, e.g., 1- to 4, in addition to the carbon atoms. In some embodiments, these refer to 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic parts that are saturated or partially unsaturated and have one or more heteroatoms, e.g., 1- to 4, in addition to the carbon atoms. When used with respect to the ring atoms of a heterocyclic ring, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or NR +This can be (such as N-substituted pyrrolidinyl). Heterocyclic rings can be bonded to their pendant group with any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. Heterocyclyl groups can be monocyclic, dicyclic, tricyclic, or polycyclic, preferably monocyclic, dicyclic, or tricyclic, more preferably monocyclic or bicyclic. Bicyclic heterocyclic rings also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or alicyclic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. Bicyclic heterocyclic rings can also be spirocyclic ring systems (e.g., 7- to 11-membered spirocyclic fused heterocyclic rings having one or more heteroatoms defined on top of the carbon atom (e.g., 1, 2, 3, or 4 heteroatoms)).

[0026]

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

[0027]

[0029] Patient or Subject: As used herein, the terms “patient” or “subject” refer to any organism to which the provided composition is administered, or may be administered, for example, for experimental, diagnostic, preventive, 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 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 one or more symptoms of a disorder or condition. 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, a particular treatment to diagnose and / or treat a disease, disorder, or condition.

[0028]

[0030] Specific Binding: As used herein, the term “specific binding” refers to the ability to distinguish possible binding partners in the environment in which binding occurs. A binder that interacts with a particular target in the presence of other possible targets is said to “specifically bind” to the target it interacts with. 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 over a range of concentrations.

[0029]

[0031] Substituted or Optionally Substituted: As described herein, the compounds of this disclosure may contain “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of a specified moiety are replaced with appropriate substituents (i.e., optional groups as described below), whether preceded by the term “optionally substituted.” “Substituted” applies to one or more hydrogens that are explicit or implicit from the structure (e.g.,

[0030] [ka] at least

[0031] [ka] referring to;

[0032] [ka] at least

[0033] [ka] This refers to the group. Unless otherwise indicated, a “may be substituted” group may have appropriate substituents at each substituted position of the group, and if two or more positions of any given structure may be substituted with two or more substituents selected from a specified group, the substituents may be the same or different at all positions. The substituent combinations envisioned by the present invention preferably result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to a compound that remains substantially unchanged when subjected to conditions that enable their manufacture, detection, and in certain embodiments their 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. A group described as “may be substituted” may be unsubstituted or “substituted” as described above.

[0034]

[0032] Suitable monovalent substituents on the replaceable carbon atoms of the "may be substituted" group are, independently, halogens;-(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R°, -O-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 CH(OR°)2;-(CH2) 0~4 SR°;R° may be substituted -(CH2) 0~4 It may be substituted with Ph;R°-(CH2) 0~4 O(CH2) 0~1 It may be substituted with Ph;R° - CH=CHPh;R° - (CH2) 0~4 O(CH2) 0~1 -Pyridyl;-NO2;-CN;-N3;-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)(NH)R°;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-(C 1~4 (Linear or branched alkylene) ON(R°)2; or -(C 1~4 The linear or branched alkylene is C(O)ON(R°)2, where each R° may be substituted as defined below, independently of hydrogen and C. 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R° may, together with their intervening atoms, 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 is substituted as defined below.

[0035]

[0033] Suitable monovalent substituents on R° (or the ring formed by combining two independent occurrences of R° with their intervening atoms) are independently halogen, -(CH2) 0-2 R ● , -(haloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● ), -O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● 、 -(C 1~4 linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ●is unsubstituted or, if "halo" is present upfront, substituted only with one or more halogens, C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or independently selected from 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 atoms of R° include =O and =S.

[0036]

[0034] Suitable divalent substituents on the saturated carbon atoms of a "may be 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 each independent occurrence of R * is hydrogen, C 1~6 aliphatic which may be substituted as defined below, or selected from an unsubstituted 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 bonded to an adjacent substitutable carbon of a "may be substituted" group include -O(CR * 2) 2~3 O- (where each independent occurrence of R * is hydrogen, C 1~6 aliphatic which may be substituted as defined below, or selected from an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0037]

[0035] Suitable substituents on the aliphatic group of R * include halogen, -R ●,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● It is either unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 A 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0038]

[0036] Suitable substituents on the substituted nitrogen of the "may be substituted" group include -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † These are listed, and each R † C may be substituted independently with hydrogen as defined below. 1~6 Aliphatic, or an unsubstituted 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, R † The two independent occurrences, together with their intervening atoms, form an unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039]

[0037] R† Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● It is either unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 A 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0040]

[0038] Treat: As used herein, the term “treat” (similarly “treatment” or “treating”) means any administration of treatment that partially or completely alleviates, improves, revives, inhibits, delays the onset of, reduces the severity of, and / or reduces 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 for subjects who do not show signs of the disease, disorder, and / or condition in question, and / or for subjects who show only initial signs of the disease, disorder, and / or condition. Alternatively or further, such treatment may be for subjects who show one or more established signs of the disease, disorder, and / or condition in question. In some embodiments, treatment may be for subjects who have been diagnosed with the disease, disorder, and / or condition in question.

[0041]

[0039] When used in this disclosure, unless otherwise evident from the context, (i) the term "a" or "an" may be understood to mean "at least one"; (ii) the term "or" may be understood to mean "and / or"; (iii) the terms "comprise," "comprising," "include" and "including" (whether used with "not limited to these" or not, whether they exist alone or together with one or more additional components or processes) (iv) The term “another” may be understood to mean at least one or more additional / secondary components or processes; (v) The terms “about” and “approximately” may be understood to allow for a standard deviation that will be understood by those skilled in the art; (vi) Where a range is provided, the endpoint is included. Unless otherwise evident from the context, isomers of the compound are included. As will be understood by those skilled in the art, a compound may be provided, administered or delivered in various forms, e.g., salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, esters, prodrugs, tautomers, etc.

[0042] A certain compound

[0040] In some embodiments, the Disclosure provides compounds useful for preventing or treating a variety of conditions, disorders or diseases, including cancer. In some embodiments, the Disclosure provides compounds useful for inhibiting cell proliferation, for example, cancer cell proliferation. In some embodiments, the Disclosure provides compounds useful for reducing tumor growth. In some embodiments, the Disclosure provides compounds useful for lowering KAT2A levels and / or KAT2B levels. In some embodiments, the Disclosure provides compounds useful for inhibiting one or more functions of KAT2A and / or KAT2B. In some embodiments, the Disclosure provides compounds that can bind to KAT2A and / or KAT2B and can bind to E3 ligase. Certain compounds are described below as examples.

[0043]

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

[0044]

[0042] In some embodiments, the present disclosure relates to compounds of formula I: PBM-Linker-LBM I or a pharmaceutically acceptable salt thereof (In the formula, PBM is either the KAT2 protein binding site or

[0045] [ka] and; The linker is an optional linking part, or a covalently bonded or substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; LBM is either the E3 ubiquitin ligase binding site or

[0046] [ka] and; Ring A is,

[0047] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; L 3 , L 4 , and L 5 Each of these is independently a divalent C1-6 hydrocarbon chain that may be covalently bonded or substituted; Each R8 It is independently -R'; R 9 is -R'; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L 2 C may be covalently bonded or substituted. 1~3 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is,

[0048] [ka] ,or

[0049] [ka] A substitutable base selected from; Y is either N or CH; Each R aThese are independently halogen, -CN, or -R'; Linker is R d , R e , R f , or R g One of them, which is linked to the part enclosed in parentheses, or the linker is one R i or two R's i A ring formed when the bases are together, bonded to the part enclosed in parentheses; Each R is not a linker joint point. d Independently, it is either -R' or Two R's d However, together with the atoms to which they are bonded, they form a 5-6 membered ring having 1-3 heteroatoms independently selected from N, O, and S, which may be condensed or substituted with phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Each R is not a linker joint point. e It is independently -R; R f If it is not a linker joint point, then it is -R; Each R is not a linker joint point. g These are independently halogen, -CN, R, or -OR; p is 0, 1, 2, or 3; R h is halogen or -R; Each R is not a linker joint point. i These are independently halogen, -R, -C(O)N(R')2, or -N(R)C(O)R, or Two R's i The groups, together with the atoms to which they are bonded, form a 5-6 membered ring having phenyl, or 1-3 heteroatoms independently selected from N, O, and S, which may be bonded and substituted; R j is -R, or R j R iIn one example, it combines with its intervening atoms to form a substituted 5-7 membered ring having 1-2 heteroatoms independently selected from N, O, and S; R k is -R; r is 1, 2, 3, 4, or 5; q is either 1 or 2; R m is -R; R n , R p , R q , R r , R s , and R u Each of these is independently a halogen, -CN, -R, or -OR; s is 0, 1, 2, 3, 4, or 5; t is 0, 1, 2, 3, 4, or 5; Each u is independently 0, 1, 2, 3, 4, or 5; Each R t Independently, is R, or Both R t The groups, together with the atoms to which they are bonded, form a substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; Each R v These are independently halogen, -CN, -R or -OR, or R u and R v One example is that together with those intervening atoms, they bond to form a substituted or otherwise 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; Each R w These are independently halogen, -CN, -R or -OR, or R u and R w One example is that together with those intervening atoms, they bond to form a substituted or otherwise 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; Each v is independently 0, 1, 2, 3, 4, or 5; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0050]

[0043] In some embodiments, the present disclosure relates to compounds of formula I: PBM-Linker-LBM I or a pharmaceutically acceptable salt thereof (In the formula, PBM is the KAT2 protein binding site; A linker is an optional linking part; LBM is the E3 ubiquitin ligase binding site. To provide.

[0051]

[0044] In some embodiments, PBM is

[0052] [ka] And LBM is,

[0053] [ka] In some embodiments, PBM is

[0054] [ka] And LBM is,

[0055] [ka] In some embodiments, PBM is

[0056] [ka] And LBM is,

[0057] [ka] That is the case.

[0058]

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

[0059]

[0046] In some embodiments, the present disclosure relates to compounds of formula II.

[0060] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0061] [ka] Selected from; Ring B is a 5-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L 1 is a covalent or divalent C 1~3 It is a straight-chain or branched hydrocarbon chain; Each R 1 C may be substituted independently. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 C may be hydrogen, halogen, -CN, or substituted C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; Each R 3 These are independently hydrogen, halogen, and possibly substituted C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 4 C is hydrogen, which may be substituted. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 5 C may be hydrogen, halogen, or substituted C 1~6 Aliphatic or substituted C 3~6 Is it alicyclic, or R 2 and R 5They, together with the atoms to which they are bonded, form a substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 C is hydrogen, which may be substituted. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; X is O or NR 7 and; R 7 C is hydrogen or may be substituted. 1~6 It is aliphatic, or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 C is hydrogen or may be substituted. 1~6 It is aliphatic; The linker is a divalent linear or branched saturated or unsaturated C1-C, which may be covalent or substituted. 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- may be substituted; Each Cy is independently a monocyclic or polycyclic 3-16 membered divalent ring system, which may be substituted, and this ring system is fully saturated, partially saturated, or aromatic, and this ring system contains 0-6 heteroatoms independently selected from N, O, and S; Each R is independently either hydrogen or C 1~6Aliphatic, phenyl, C 3~7 A substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryls having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclines having 1-2 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding site. To provide.

[0062]

[0047] In some embodiments, this disclosure is, Ring A is

[0063] [ka] Selected from; Ring B is a 5-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L 1 However, covalent or divalent C 1~3 It is a straight-chain or branched hydrocarbon chain; Each R 1 C may be substituted independently. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 However, hydrogen, halogens, and substituted C may be present. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; Each R 3 C may be independently hydrogen, halogen, or substituted. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 4 However, hydrogen may be substituted in C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 5 However, hydrogen, halogens, and substituted C may be present. 1~6 Aliphatic or substituted C 3~6 Is it alicyclic, or R 2 and R 5 However, together with the atoms to which they are bonded, they form a substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 However, hydrogen may be substituted in C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; X is O or NR 7 and; R 7 C may be hydrogen or substituted. 1~6 It is aliphatic, or R 4 and R 7 However, together with the atoms to which they are bonded, they form a substituted 5-6 membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 C may be hydrogen or substituted. 1~6 It is aliphatic; The linker may be covalent or substituted divalent linear or branched saturated or unsaturated C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- may be substituted; Each Cy independently is a monocyclic or polycyclic 3-16 membered divalent ring system, which may be substituted, and this ring system is fully saturated, partially saturated, or aromatic, and this ring system contains 0-6 heteroatoms independently selected from N, O, and S; Each R independently represents hydrogen or C 1~6 Aliphatic, phenyl, C 3~7 A substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryls having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclines having 1-2 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding site. The present invention provides a compound of formula II, or a pharmaceutically acceptable salt thereof.

[0064]

[0048] In some embodiments, the present disclosure relates to compounds of formula IIA:

[0065] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 1 , R 1 , R 9 , n, linker, and LBM, both individually and in combination, provide (as defined above for Formula II and as described in the Classes and Subclasses herein).

[0066]

[0049] In some embodiments, the present disclosure relates to compounds of formula IIA-1, IIA-2, IIA-3, or IIA-4:

[0067] [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 9 X, Z, linker, and LBM, both individually and in combination, provide compounds (as defined above for Formula II and as described in the Classes and Subclasses herein). In some embodiments, the Disclosure provides compounds of Formula IIA-1 or pharmaceutically acceptable salts thereof. In some embodiments, the Disclosure provides compounds of Formula IIA-2 or pharmaceutically acceptable salts thereof. In some embodiments, the Disclosure provides compounds of Formula IIA-3 or pharmaceutically acceptable salts thereof. In some embodiments, the Disclosure provides compounds of Formula IIA-4 or pharmaceutically acceptable salts thereof.

[0068]

[0050] In some embodiments, the present disclosure relates to compounds of formula IIA-1:

[0069] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 C may be substituted. 1~6 It is aliphatic; Z is N or CR 3 and; R 2 C may be hydrogen, halogen, -CN, or substituted C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; Each R 3 These are independently hydrogen or halogen; R 4 C is hydrogen, which may be substituted. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 9 is hydrogen; The linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 10A hydrocarbon chain in which one or more methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-; Each Cy is independently a substituted group selected from a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from phenyl, N, O, and S; a monocyclic 4-7 member heterocyclil having 1-2 heteroatoms independently selected from N, O, and S; and a bicyclic 6-11 member heterocyclil having 1-3 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or a substituted C 1~6 It is aliphatic; LBM is

[0070] [ka] and; The ring C is an optional substituted group selected from a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from phenyl, N, O, and S, and a 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; Each R a is hydrogen; L 2 The bond is a covalent bond, -CH2-, -O-, or -N(R)-; Y is either N or CH. To provide.

[0071]

[0051] In some embodiments, the present disclosure relates to compounds of formula IIA-1:

[0072] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1is C 1~6 It is alkyl; Z is N or CR 3 and; R 2 Hydrogen, halogen, -CN, C 1~6 Alkyl, or C 3~6 It is a cycloalkyl; Each R 3 These are independently hydrogen or halogen; R 4 is C 1~6 It is alkyl; R 9 is hydrogen; The linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 10 A hydrocarbon chain in which one or more methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-; Each Cy is independently a substituted group selected from a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from phenyl, N, O, and S; a monocyclic 4-7 member heterocyclil having 1-2 heteroatoms independently selected from N, O, and S; and a bicyclic 6-11 member heterocyclil having 1-3 heteroatoms independently selected from N, O, and S; Each R is independently either hydrogen or C 1~6 It is alkyl; LBM is

[0073] [ka] and; The ring C is an optional substituted group selected from a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from phenyl, N, O, and S, and a 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; Each R a is hydrogen; L 2 The bond is a covalent bond, -CH2-, -O-, or -N(R)-; Y is either N or CH. To provide.

[0074]

[0052] In some embodiments, the present disclosure relates to compounds of formula IIA-5:

[0075] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 Linkers and LBMs, both individually and in combination, provide (as defined above for Formula II and as described in the Classes and Subclasses herein).

[0076]

[0053] In some embodiments, the present disclosure relates to compounds of formula IIA-6:

[0077] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 Linkers and LBMs, both individually and in combination, provide (as defined above for Formula II and as described in the Classes and Subclasses herein).

[0078]

[0054] In some embodiments, the present disclosure relates to compounds of formula II-1:

[0079] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0080] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding site; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0081]

[0055] In some embodiments, the present disclosure relates to compounds of formula III:

[0082] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0083] [ka] Selected from; Ring B is a 5-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; L 1 is a covalent or divalent C 1~3 It is a straight-chain or branched hydrocarbon chain; Each R 1 C may be substituted independently. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 C may be hydrogen, halogen, -CN, or substituted C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; Each R 3 These are independently hydrogen, halogen, and possibly substituted C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 4 C is hydrogen, which may be substituted. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 5 C may be hydrogen, halogen, or substituted C 1~6 Aliphatic or substituted C 3~6 Is it alicyclic, or R 2 and R 5They, together with the atoms to which they are bonded, form a substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 C is hydrogen, which may be substituted. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; X is O or NR 7 and; R 7 C is hydrogen or may be substituted. 1~6 It is aliphatic, or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 C is hydrogen or may be substituted. 1~6 It is aliphatic; The linker is a divalent linear or branched saturated or unsaturated C1-C, which may be covalent or substituted. 20 It is a hydrocarbon chain, and one or more methylene units are independent of each other. They may also be replaced by -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted monocyclic or polycyclic 3-16 membered divalent ring system, the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; Ring C is a monocyclic or polycyclic 3-16 membered divalent ring system, which may be substituted; the ring system is fully saturated, partially saturated, or aromatic; and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; L 2 C is covalent, linear, or branched. 1~3 A hydrocarbon chain in which one methylene group may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; Y is either N or CH; Each R a These are independently hydrogen atoms or C atoms which may be substituted. 1~6 It is either aliphatic or has two R's a The groups, together with the atoms to which they are bonded, form 3- to 6-membered saturated or partially unsaturated rings; Each R is independently either hydrogen or C 1~6 Aliphatic, phenyl, C 3~7 A substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryls having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclines having 1-2 heteroatoms independently selected from N, O, and S; Ring A, Ring B, L 1 , R 1 , R 9 (The linkers, both individually and in combination, are defined above for Formula II and are as described in the Classes and Subclasses herein.) To provide.

[0084]

[0056] In some embodiments, the present disclosure relates to compounds of formula IIIA:

[0085] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9, n, and linker, both individually and in combination, are defined above for Formula II and as described in the Classes and Subclasses herein; Each R b is hydrogen, or two R on the same carbon b The groups combine to form an oxo, or bond to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; (m is 0, 1, 2, or 3) To provide.

[0086]

[0057] In some embodiments, the present disclosure relates to compounds of formula IIIB:

[0087] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 , R b , R c , m, and linker, both individually and in combination, provide (as defined above for Formula IIIA and as described in the Classes and Subclasses herein).

[0088]

[0058] In some embodiments, the present disclosure relates to compounds of formula IIIB-1 or IIIB-2:

[0089] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9, and linkers, both alone and in combination, provide (as defined above for formula II and as described in the classes and subclasses herein). In some embodiments, the disclosure provides compounds of formula IIIB-1 or pharmaceutically acceptable salts thereof. In some embodiments, the disclosure provides compounds of formula IIIB-2 or pharmaceutically acceptable salts thereof.

[0090]

[0059] In some embodiments, the present disclosure relates to compounds of formula IIIC:

[0091] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , L 2 , R 1 , R 9 Y, n, and linker are defined above for Formula III, both individually and in combination, as described in the Classes and Subclasses herein; Each B is independently selected from N, C, and CH, except that two or fewer B are N; Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; (m is 0, 1, 2, or 3) To provide.

[0092]

[0060] In some embodiments, the present disclosure relates to compounds of formula IIID:

[0093] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, B, L 2 , R 1 , R 9 , R cY, m, and linker, both individually and in combination, provide (as defined above for formula IIIC and as described in the classes and subclasses herein).

[0094]

[0061] In some embodiments, the present disclosure relates to compounds of formula IIID:

[0095] [ka] or a pharmaceutically acceptable salt (In the formula, Ring A is,

[0096] [ka] and; R 1 C may be substituted. 1~6 It is aliphatic; Z is N or CR 3 and; R 2 C may be hydrogen, halogen, -CN, or substituted C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; Each R 3 These are independently hydrogen or halogen; R 4 C may be substituted. 1~6 It is aliphatic; R 9 is hydrogen; The linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 10 A hydrocarbon chain in which one or more methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-; Each Cy is independently a substituted group selected from a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from phenyl, N, O, and S; a monocyclic 4-7 member heterocyclil having 1-2 heteroatoms independently selected from N, O, and S; and a bicyclic 6-11 member heterocyclil having 1-3 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or a substituted C 1~6 It is aliphatic; L 2 The bond is a covalent bond, -CH2-, -O-, or -N(R)-; Y is either N or CH; Each B is independently selected from N, C, and CH, except that two or fewer B are N; Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; (m is 0, 1, 2, or 3) To provide.

[0097]

[0062] In some embodiments, the present disclosure relates to compounds of formula IIID:

[0098] [ka] or a pharmaceutically acceptable salt (In the formula, Ring A is,

[0099] [ka] and; R 1 is C 1~6 It is alkyl; Z is N or CR 3 and; R 2 Hydrogen, halogen, -CN, C 1~6Alkyl, or C 3~6 It is a cycloalkyl; Each R 3 These are independently hydrogen or halogen; R 4 is C 1~6 It is alkyl; R 9 is hydrogen; Linker,

[0100] [ka] and; L 6 and L 7 They are both covalent bonds; Church

[0101] [ka] Selected from; portion

[0102] [ka] teeth,

[0103] [ka] and; L 2 It is a covalent bond; Y is CH; Each B is independently selected from N, C, and CH, except that two or fewer B are N; Each R c is halogen, -O(C 1~6 Alkyl, and C 1~6 Selected independently of alkyl; (m is 0, 1, 2, or 3) To provide.

[0104]

[0063] In some embodiments, the present disclosure relates to compounds of formula III-1:

[0105] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0106] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L 2 C may be covalently bonded or substituted. 1~3A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is,

[0107] [ka] ,or

[0108] [ka] A substitutable base selected from; Y is either N or CH; Each R a These are independently halogen, -CN, or -R'; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10(The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0109]

[0064] In some embodiments, the present disclosure relates to compounds of formula IIIE:

[0110] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0111] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L 2C may be covalently bonded or substituted. 1~3 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is either N or CH; Each R a These are independently halogen, -CN, or -R'; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0112]

[0065] In some embodiments, the present disclosure relates to compounds of formula IIIF:

[0113] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0114] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L 2 C may be covalently bonded or substituted. 1~3 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is either N or CH; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0115]

[0066] In some embodiments, the present disclosure relates to compounds of formula IIIG:

[0116] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0117] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; L 6 is a covalent bond, -C(O)- or possibly substituted -CH2-; Cy is a substituted or otherwise substituted 3-16 membered divalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L 2 C may be covalently bonded or substituted. 1~3A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is,

[0118] [ka] ,or

[0119] [ka] A substitutable base selected from; Y is either N or CH; Each R a These are independently halogen, -CN, or -R'; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10(The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0120]

[0067] In some embodiments, the present disclosure relates to compounds of formula IIIH:

[0121] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0122] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; L 6 is a covalent bond, -C(O)- or possibly substituted -CH2-; Cy is a substituted or otherwise substituted 3-16 membered divalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L 2 C may be covalently bonded or substituted. 1~3A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is either N or CH; Each R a These are independently halogen, -CN, or -R'; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0123]

[0068] In some embodiments, the present disclosure relates to compounds of formula IIIJ:

[0124] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0125] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; L 6is a covalent bond, -C(O)- or possibly substituted -CH2-; Cy is a substituted or otherwise substituted 3-16 membered divalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L 2 C may be covalently bonded or substituted. 1~3 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is either N or CH; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10(The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0126]

[0069] In some embodiments, the present disclosure relates to compounds of formula IIIK:

[0127] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0128] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; L 6 is a covalent bond, -C(O)- or possibly substituted -CH2-; Cy is a substituted or otherwise substituted 3-16 membered divalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; L 2 C may be covalently bonded or substituted. 1~3 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0129]

[0070] In some embodiments, the present disclosure relates to compounds of formula IIIL:

[0130] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0131] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b and R b1 These are independently halogen, -CN, -R', or -OR; t' is 0, 1, 2, or 3; L 2 C may be covalently bonded or substituted. 1~3 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is,

[0132] [ka] ,or

[0133] [ka] A substitutable base selected from; Y is either N or CH; Each R a These are independently halogen, -CN, or -R'; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0134]

[0071] In some embodiments, the present disclosure relates to compounds of formula IIIM:

[0135] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0136] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; L 6 is a covalent bond, -C(O)- or possibly substituted -CH2-; Cy is a substituted or otherwise substituted 3-16 membered divalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b and R b1 These are independently halogen, -CN, -R', or -OR; t' is 0, 1, 2, or 3; L 2 C may be covalently bonded or substituted. 1~3A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Ring E is,

[0137] [ka] ,or

[0138] [ka] A substitutable base selected from; Y is either N or CH; Each R a These are independently halogen, -CN, or -R'; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10(The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0139]

[0072] In some embodiments, the present disclosure relates to compounds of formula IIIN:

[0140] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0141] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; L 6 is a covalent bond, -C(O)- or possibly substituted -CH2-; Cy is a substituted or otherwise substituted 3-16 membered divalent ring system having 0-6 heteroatoms independently selected from N, O, and S; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R b and R b1 These are independently halogen, -CN, -R', or -OR; t' is 0, 1, 2, or 3; L 2 C may be covalently bonded or substituted. 1~3A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Y is either N or CH; Each R a These are independently halogen, -CN, or -R'; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0142]

[0073] In some embodiments, the present disclosure relates to compounds of formula IV:

[0143] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1, R 1 , R 9 , n, and linker, both individually and in combination, are defined above for Formula II and as described in the Classes and Subclasses herein; Linker is R d , R e , R f , or R g It is one of them, and is connected to the part enclosed in parentheses; Each R is not a linker joint point. d These are independently hydrogen, -C(O)R, and possibly substituted C. 1~6 It is aliphatic, or Two R's d However, together with the atoms to which they are bonded, they form a 5-6 membered ring having 1-3 heteroatoms independently selected from N, O, and S, which may be condensed or substituted with phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Each R is not a linker joint point. e C is independently hydrogen or may be substituted. 1~6 It is aliphatic; R f If it is not a linker bond point, then hydrogen or a substituted C 1~6 It is aliphatic; Each R is not a linker joint point. g C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; R h C is hydrogen, halogen, or may be substituted. 1~6 It is aliphatic; p is 0, 1, 2, or 3. To provide.

[0144]

[0074] In some embodiments, the present disclosure relates to compounds of formula IVA:

[0145] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , R d , R e , R f , R g , R h p, n, and linker, both individually and in combination, provide (as defined above for Formula IV and as described in the Classes and Subclasses herein).

[0146]

[0075] In some embodiments, the present disclosure relates to compounds of formula IVA-1:

[0147] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 , R d , R e , R f , R g , R h , p, and linker, both individually and in combination, provide (as defined above for Formula IV and as described in the Classes and Subclasses herein).

[0148]

[0076] In some embodiments, the present disclosure relates to compounds of formula IV-1:

[0149] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0150] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; Linker is R d , R e , R f , or R g It is one of them, and is connected to the part enclosed in parentheses; Each R is not a linker joint point. d Independently, it is either -R' or Two R's d However, together with the atoms to which they are bonded, they form a 5-6 membered ring having 1-3 heteroatoms independently selected from N, O, and S, which may be condensed or substituted with phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Each R is not a linker joint point. e It is independently -R; R f If it is not a linker joint point, then it is -R; Each R is not a linker joint point. g These are independently halogen, -CN, R, or -OR; p is 0, 1, 2, or 3; Rh is halogen or -R; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0151]

[0077] In some embodiments, the compound of formula IV-1 is the compound of formula IVD:

[0152] [ka] (In the formula, the variable parts, both individually and in combination, are as defined above for formula IVB and as described in the classes and subclasses herein.) That is the case.

[0153]

[0078] In some embodiments, the present disclosure relates to compounds of formula V:

[0154] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9, n, and linker, both individually and in combination, are defined above for Formula II and as described in the Classes and Subclasses herein; The linker is one R i or two R's i A ring formed when the bases are together, bonded to the part enclosed in parentheses; Each R is not a linker joint point. i C may be substituted with a halogen, independently. 1~6 It is aliphatic, -C(O)N(R)2, or -N(R)C(O)R, or Two R's i The groups, together with the atoms to which they are bonded, form a 5-6 membered heteroaryl ring having phenyl, or 1-3 heteroatoms independently selected from N, O, and S, which may be bonded and substituted; R j C 1~6 Aliphatic and C 3~7 A group that may be substituted, selected from alicyclic groups, or R j R i In one example, it combines with the atom to which it is bonded to form a substituted or otherwise substituted 5-7 membered heteroring having 1-2 heteroatoms independently selected from N, O, and S; R k C may be substituted. 1~6 It is aliphatic; r is 1, 2, 3, 4, or 5; (q is either 1 or 2) To provide.

[0155]

[0079] In some embodiments, the present disclosure relates to compounds of formula VA:

[0156] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , Ri , R j , R k n, q, r, and linker, both individually and in combination, provide (as defined above for formula V and as described in the Classes and Subclasses herein).

[0157]

[0080] In some embodiments, the present disclosure relates to compounds of formula VA-1:

[0158] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 , R i , R j , R k q, r, and linker, both individually and in combination, provide (as defined above for formula V and as described in the Classes and subclasses herein).

[0159]

[0081] In some embodiments, the present disclosure relates to compounds of formula VB:

[0160] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R, R 1 , R 9 , R i , R j , R k n, q, r, and linker, both individually and in combination, provide (as defined above for formula V and as described in the Classes and Subclasses herein).

[0161]

[0082] In some embodiments, the present disclosure relates to compounds of formula VB-1:

[0162] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R, R 1 , R 9 , R j , R k , n, and linkers, both individually and in combination, provide (as defined above for formula V and as described in the Classes and subclasses herein).

[0083] In some embodiments, the present disclosure relates to compounds of formula V-1:

[0163] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0164] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; The linker is one R i or two R's i A ring formed when the bases are together, bonded to the part enclosed in parentheses; Each R is not a linker joint point. iThese are independently halogen, -R, -C(O)N(R')2, or -N(R)C(O)R, or Two R's i The groups, together with the atoms to which they are bonded, form a 5-6 membered ring having phenyl, or 1-3 heteroatoms independently selected from N, O, and S, which may be bonded and substituted; R j is -R, or R j R i In one example, it combines with the atom to which it is bonded to form a substituted 5-7 membered ring having 1-2 heteroatoms independently selected from N, O, and S; R k is -R; r is 1, 2, 3, 4, or 5; q is either 1 or 2; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0165]

[0084] In some embodiments, the compound of formula V-1 is the compound of formula VC:

[0166] [ka] (In the formula, the variable parts, both individually and in combination, are as defined above for formula V-1 and as described in the classes and subclasses herein.) That is the case.

[0167]

[0085] In some embodiments, the compound of formula V-1 is the compound of formula VD:

[0168] [ka] (In the formula, the variable parts, both individually and in combination, are as defined above for formula V-1 and as described in the classes and subclasses herein.) That is the case.

[0169]

[0086] In some embodiments, the compound of formula V-1 is the compound of formula VE:

[0170] [ka] (In the formula, the variable parts, both individually and in combination, are as defined above for formula V-1 and as described in the classes and subclasses herein.) That is the case.

[0171]

[0087] In some embodiments, the present disclosure relates to compounds of formula VI:

[0172] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both individually and in combination, are defined above for Formula II and as described in the Classes and Subclasses herein; R m C may be substituted. 1~6 It is aliphatic; Each R n C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; (s is 0, 1, 2, 3, 4, or 5) To provide.

[0173]

[0088] In some embodiments, the present disclosure relates to compounds of formula VIA:

[0174] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , R m , R n ,n,s, and linkers, both individually and in combination, provide (as defined above for Formula VI and as described in the Classes and Subclasses herein).

[0175]

[0089] In some embodiments, the present disclosure relates to compounds of formula VIA-1:

[0176] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 , R m , R n , s, and linkers, both individually and in combination, provide (as defined above for Formula VI and as described in the Classes and Subclasses herein). In some embodiments, this disclosure relates to compounds of formula VI-1:

[0177] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0178] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; R m is R; Each R n These are independently halogen, -CN, -R, or -OR; s is 0, 1, 2, 3, 4, or 5; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0179]

[0090] In some embodiments, the present disclosure relates to compounds of formula VIB:

[0180] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, both alone and in combination, the variable is as defined above for formula VI-1 and as described in the classes and subclasses herein).

[0181]

[0091] In some embodiments, the present disclosure relates to compounds of formula VII:

[0182] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both individually and in combination, are defined above for Formula II and as described in the Classes and Subclasses herein; Each R p C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; Each R q C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; Each R r C is independently hydrogen or may be substituted. 1~6 It is aliphatic; Each R s C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; t is 0, 1, 2, 3, 4, or 5; (Each u is independently 0, 1, 2, 3, 4, or 5) To provide.

[0183]

[0092] In some embodiments, the present disclosure relates to compounds of formula VIIA:

[0184] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 , R p , R q , R r , R s u, t, and linker, both individually and in combination, provide (as defined above for Formula VII and as described in the Classes and Subclasses herein).

[0185]

[0093] In some embodiments, the present disclosure relates to compounds of formula VII-1:

[0186] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0187] [ka] Selected from; Ring B is a substituted or substituted 5-6 member heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L 1 This is a covalently bonded or possibly substituted divalent C 1~3 It is a hydrocarbon chain; Each R 1 It is independently -R; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; The linker is a covalent or possibly substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 A substituted group selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and a 3-10 membered monocyclic heterocycline having 1-5 heteroatoms independently selected from N, O, and S; Each R p C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; Each R q C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; Each R r C is independently hydrogen or may be substituted. 1~6 It is aliphatic; Each R s C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; t is 0, 1, 2, 3, 4, or 5; (Each u is independently 0, 1, 2, 3, 4, or 5) To provide.

[0188]

[0094] In some embodiments, the present disclosure relates to compounds of formula VIIB:

[0189] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 , R p , R q , R r , R s u, t, and linker, both individually and in combination, provide (as defined above for Formula VII-1 and as described in the Classes and Subclasses herein).

[0190]

[0095] In some embodiments, the present disclosure relates to compounds of formula VIII:

[0191] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both individually and in combination, are defined above for Formula II and as described in the Classes and Subclasses herein; Each R t C is independently hydrogen or may be substituted. 1~6 It is aliphatic, or Both R t The groups, together with the atoms to which they are bonded, form a substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each R u These are independently hydrogen, halogen, -CN, or possibly substituted C 1~6 It is aliphatic; Each R v C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic, or R u and R vOne example is that together with the atoms to which they are bonded, they form a substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each R w C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic, or R u and R w One example is that together with the atoms to which they are bonded, they form a substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; (Each v is independently 0, 1, 2, 3, 4, or 5) To provide.

[0192]

[0096] In some embodiments, the present disclosure relates to compounds of formula VIIIA:

[0193] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A and R) 1 , R 9 , R t , R u , R v , R w , v, and linkers, both alone and in combination, provide (as defined above for formula VIII and as described in the Classes and Subclasses herein).

[0194]

[0097] In some embodiments, the present disclosure relates to compounds of formula VIII-1:

[0195] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0196]

Chem.

[0197]

[0098] In some embodiments, the present disclosure relates to compounds of formula VIIIB:

[0198] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring F, R 1 , R 9 , R t , R u , R v , R w, v, and linkers, both individually and in combination, provide (as defined above for formula VIII-1 and as described in the classes and subclasses herein).

[0199]

[0099] In some embodiments, the present disclosure relates to compounds of formula IX:

[0200] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0201] [ka] Selected from; L 3 , L 4 , and L 5 Each of these may independently be covalently bonded or substituted divalent C 1~6 It is a straight-chain or branched hydrocarbon chain; Z is N or CR 3 and; R 2 However, hydrogen, halogen, -CN, and C may be substituted. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; Each R 3 C may be independently hydrogen, halogen, or substituted. 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 4 However, hydrogen may be substituted in C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; R 5 However, hydrogen, halogens, and substituted C may be present. 1~6 Aliphatic or substituted C 3~6 Is it alicyclic, or R2 and R 5 However, together with the atoms to which they are bonded, they form a substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 However, hydrogen may be substituted in C 1~6 Aliphatic or substituted C 3~6 It is alicyclic; X is O or NR 7 and; R 7 C may be hydrogen or substituted. 1~6 It is aliphatic, or R 4 and R 7 However, together with the atoms to which they are bonded, they form a substituted 5-6 membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; Each R 8 C may be independently hydrogenated or substituted. 1~6 It is aliphatic; R 9 C may be hydrogen or substituted. 1~6 It is aliphatic; The linker may be covalent or substituted divalent linear or branched saturated or unsaturated C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- may be substituted; Each Cy is independently a monocyclic or polycyclic 3- to 16-membered divalent ring system which may be substituted, the ring system being fully saturated, partially saturated, or aromatic, and the ring system containing from 0 to 6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C 1~6 an aliphatic group, phenyl, C 3~7 a cycloaliphatic group, a 5- to 6-membered monocyclic heteroaryl having from 1 to 4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having from 1 to 2 heteroatoms independently selected from N, O, and S, each being a group which may be substituted; where LBM is an E3 ubiquitin ligase binding moiety) is provided.

[0202]

[0100] In some embodiments, the present disclosure provides a compound of formula IX, or a pharmaceutically acceptable salt thereof (wherein ring A is

[0203]

Chemical formula

[0204]

[0101] In some embodiments, the present disclosure relates to compounds of formula IXA, IXB, IXC, or IXD:

[0205] [ka] or a pharmaceutically acceptable salt thereof (wherein L 3 , L 4 , L 5 , R 2 , R 3 , R 4 , R 5 , R 6 , R8 , R 9 X, Z, linker, and LBM, both individually and in combination, provide compounds (as defined above for formula IX and as described in the classes and subclasses herein). In some embodiments, the disclosure provides compounds of formula IXA or pharmaceutically acceptable salts thereof. In some embodiments, the disclosure provides compounds of formula IXB or pharmaceutically acceptable salts thereof. In some embodiments, the disclosure provides compounds of formula IXC or pharmaceutically acceptable salts thereof. In some embodiments, the disclosure provides compounds of formula IXD or pharmaceutically acceptable salts thereof.

[0206]

[0102] In some embodiments, the present disclosure relates to compounds of formula IX-1:

[0207] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is,

[0208] [ka] Selected from; Z is N or CR 3 and; R 2 is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 is halogen, -CN, or -R, or R 2 and R 5 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6is -R'; X is O or NR 7 and; R 7 is -R' or R 4 and R 7 They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; L 3 , L 4 , and L 5 Each of these is independently a divalent C1-6 hydrocarbon chain that may be covalently bonded or substituted; Each R 8 It is independently -R'; Ring F is a substituted or otherwise 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; The linker is a covalently bonded or substituted divalent linear or branched saturated linker, or the linker is a covalently bonded or substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is independently a substituted or substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding site; Each R' is independently -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C1-8 aliphatic, C3- 10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 (The group may be substituted, selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S.) To provide.

[0209]

[0103] In some embodiments, the present disclosure relates to compounds of formula X:

[0210] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker, both individually and in combination, are defined above for formula IX and as described in the Classes and subclasses of the specification; Ring C is a monocyclic or polycyclic 3-16 membered divalent ring system, which may be substituted; the ring system is fully saturated, partially saturated, or aromatic; and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; Each Ra is independently a C1-6 aliphatic with hydrogen or substituted atoms, or two Ra groups, together with the atom to which they are bonded, form a 3-6 membered saturated or partially unsaturated ring. L 2 C is covalent, linear, or branched. 1~3A hydrocarbon chain in which one methylene group may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; Y is either N or CH. To provide.

[0211]

[0104] In some embodiments, the present disclosure relates to compounds of formula XA:

[0212] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linkers, both individually and in combination, are defined above for formula IX and as described in the Classes and subclasses herein; Each R b is hydrogen, or two R on the same carbon b The groups combine to form an oxo, or bond to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; (m is 0, 1, 2, or 3) To provide.

[0213]

[0105] In some embodiments, the present disclosure relates to compounds of formula XA-1 or XA-2:

[0214] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9, and linkers, both alone and in combination, provide (as defined above for formula IX and as described in the classes and subclasses herein). In some embodiments, the disclosure provides compounds of formula XA-1 or pharmaceutically acceptable salts thereof. In some embodiments, the disclosure provides compounds of formula XA-2 or pharmaceutically acceptable salts thereof.

[0215]

[0106] In some embodiments, the present disclosure relates to compounds of formula XB:

[0216] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 2 , L 3 , L 4 , L 5 , R 8 , R 9 Y and linker, both individually and in combination, are defined above for formula X and as described in the Classes and subclasses herein; Each B is independently selected from N, C, and CH, except that two or fewer B are N; Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; (m is 0, 1, 2, or 3)

[0217]

[0107] In some embodiments, the present disclosure relates to compounds of formula X-1, X-2, or X-3:

[0218] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined, both alone and in combination, as in formula I or IIIL, as described in the Classes and Subclasses herein).

[0219]

[0108] In some embodiments, the present disclosure relates to compounds of formula XA':

[0220] [ka] or a pharmaceutically acceptable salt thereof (wherein each R) c m is independently selected from halogen, -OR, -N(R)2, -CN, and -R; m is 0, 1, 2, or 3; other variable parts are defined, both individually and in combination, as shown in Formula I, and are as described in the Classes and Subclasses herein. In some embodiments, ring A is

[0221] [ka] Selected from; Z is N or CR 3 and; R 2 However, it is halogen, -CN, or -R; Each R 3 These are independently halogen, -CN, or -R; R 4 is -R'; R 5 However, whether it is halogen, -CN, or -R, R 2 and R 5 However, together with the atoms to which they are bonded, they form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is -R'; X is O or NR 7 and; R 7 Is -R' or R 4 and R 7However, together with the atoms to which they are bonded, they bond to form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is -R'; L 3 , L 4 , and L 5 Each of these is independently a divalent C1-6 hydrocarbon chain, which may be covalently bonded or substituted; Each R 8 They are independent and are -R'; Ring F is a substituted 3-16 membered ring having 0-6 heteroatoms independently selected from N, O, and S; The linker is a covalently bonded or substituted divalent linear or branched saturated linker, or the linker is a covalently bonded or substituted divalent C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; Each Cy is an independently substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Each R' independently is either -R, -C(O)R, or -S(O)2R, or two R's bonded to the same atom bond together with the atom to which they are bonded to form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R independently represents hydrogen or C1-8 aliphatic, C3-10 Alicyclic, C1-C8 heteroaliphatic, C6- having 1-3 heteroatoms independently selected from N, O, and S. 10 A substituted group selected from 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from aryl, N, O, and S, and a 3-10 membered monocyclic heterocycline having 1-5 heteroatoms independently selected from N, O, and S; Each R b is hydrogen, or two R on the same carbon b The groups combine to form an oxo, or bond to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c However, halogens, -OR, -N(R)2, -CN, and C which may be substituted. 1~6 Selected independently from aliphatic species; m is 0, 1, 2, or 3.

[0222]

[0109] In some embodiments, the present disclosure relates to compounds of formula XA-1' or XA-2':

[0223] [ka] or a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as in formula I, as described in the classes and subclasses herein). In some embodiments, rings A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker, both individually and in combination, are defined above for formula X-1 and as described in the classes and subclasses herein. In some embodiments, the disclosure provides compounds of formula XA-1' or pharmaceutically acceptable salts thereof. In some embodiments, the disclosure provides compounds of formula XA-2' or pharmaceutically acceptable salts thereof.

[0224]

[0110] In some embodiments, the present disclosure relates to compounds of formula XB':

[0225] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring F, L) 2 , L 3 , L 4 , L 5 , R 8 , R 9 Y, and linker, both individually and in combination, are defined above for formula X-1 and as described in the Classes and subclasses herein; Each B is independently selected from N, C, and CH, except that two or fewer B are N; Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; m provides (where m is 0, 1, 2, or 3).

[0226]

[0111] In some embodiments, the present disclosure relates to compounds of formula XI:

[0227] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker, both individually and in combination, are defined above for formula IX and as described in the Classes and subclasses of the specification; Linker is R d , R e , R f , or R g It is one of them, and is connected to the part enclosed in parentheses; Each R is not a linker joint point. dThese are independently hydrogen, -C(O)R, or possibly substituted C 1~6 It is aliphatic, or Two R's d However, together with the atoms to which they are bonded, they form a 5-6 membered ring having 1-3 heteroatoms independently selected from N, O, and S, which may be condensed or substituted with phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Each R is not a linker joint point. e C is independently hydrogen or may be substituted. 1~6 It is aliphatic; R f If it is not a linker bond point, then hydrogen or a substituted C 1~6 It is aliphatic; Each R is not a linker joint point. g C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; R h C is hydrogen, halogen, or may be substituted. 1~6 It is aliphatic; Provide p (where p is 0, 1, 2, or 3).

[0228]

[0112] In some embodiments, the present disclosure relates to compounds of formula XIA:

[0229] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , R d , R e , R f , R g , R h, p, and linker, both individually and in combination, provide (as defined above for Formula XI and as described in the Classes and Subclasses herein).

[0230]

[0113] In some embodiments, the present disclosure relates to compounds of formula XI-1:

[0231] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0232]

[0114] In some embodiments, the present disclosure relates to compounds of formula XIB:

[0233] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0234]

[0115] In some embodiments, the present disclosure relates to compounds of formula XII:

[0235] [ka] or a pharmaceutically acceptable salt thereof (In the formula, rings A, L 3 , L 4 , L 5 , R 8 , R 9 , and linkers, both individually and in combination, are defined above for formula IX and as described in the Classes and subclasses herein; The linker is one R i or two R's iA ring formed when the bases are together, bonded to the part enclosed in parentheses; Each R is not a linker joint point. i C may be substituted with a halogen, independently. 1~6 It is aliphatic, -C(O)N(R)2, or -N(R)C(O)R, or Two R's i The groups, together with the atoms to which they are bonded, form a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from phenyl or N, O, and S, which may be bonded and substituted; R j C 1~6 Aliphatic and C 3~7 A group that may be substituted, selected from alicyclic groups, or R j R i In one example, it combines with the atom to which it is bonded to form a substituted or otherwise substituted 5-7 membered heteroring having 1-2 heteroatoms independently selected from N, O, and S; R k C may be substituted 1~6 It is aliphatic; r is 1, 2, 3, 4, or 5; Provides (q is 1 or 2).

[0236]

[0116] In some embodiments, the present disclosure relates to compounds of formula XIIA:

[0237] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , R i , R j , R kq, r, and linker, both individually and in combination, provide (as defined above for Formula XII and as described in the Classes and Subclasses herein).

[0238]

[0117] In some embodiments, the present disclosure relates to compounds of formula XIIB:

[0239] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R, R 8 , R 9 , R i , R j , R k q, r, and linker, both individually and in combination, provide (as defined above for Formula XII and as described in the Classes and Subclasses herein).

[0240]

[0118] In some embodiments, the present disclosure relates to compounds of formula XIIB-1:

[0241] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R, R 8 , R 9 , R j , R k The linkers, both individually and in combination, provide (as defined above for Formula XII and as described in the Classes and Subclasses herein).

[0242]

[0119] In some embodiments, the present disclosure relates to compounds of formula XII-1:

[0243] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0244]

[0120] In some embodiments, the present disclosure relates to compounds of formula XIIA':

[0245] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0246]

[0121] In some embodiments, the present disclosure relates to compounds of formula XIIB':

[0247] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0248]

[0122] In some embodiments, the present disclosure relates to a compound of formula XIIB-1':

[0249] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0250]

[0123] In some embodiments, the present disclosure relates to compounds of formula XIII:

[0251] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linkers, both individually and in combination, are defined above for formula IX and as described in the Classes and subclasses herein; R m C may be substituted. 1~6 It is aliphatic; Each R n C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; (s is 0, 1, 2, 3, 4, or 5) To provide.

[0252]

[0124] In some embodiments, the present disclosure relates to compounds of formula XIIIA:

[0253] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , R m , R n , s, and linkers, both individually and in combination, provide (as defined above for Formula XIII and as described in the Classes and Subclasses herein).

[0254]

[0125] In some embodiments, the present disclosure relates to compounds of formula XIII-1:

[0255] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0256]

[0126] In some embodiments, the present disclosure relates to compounds of formula XIIIB:

[0257] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring F, L) 3 , L 4 , L 5 , R 8 , R 9 , R m , R n , s, and linkers, both individually and in combination, provide (as defined above for Formula XIII-1 and as described in the Classes and Subclasses herein).

[0258]

[0127] In some embodiments, the present disclosure relates to compounds of formula XIV:

[0259] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linkers, both individually and in combination, are defined above for formula IX and as described in the Classes and subclasses herein; Each R p C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; Each R q C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; Each R rC is independently hydrogen or may be substituted. 1~6 It is aliphatic; Each R s C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic; t is 0, 1, 2, 3, 4, or 5; Each u independently provides (0, 1, 2, 3, 4, or 5).

[0260]

[0128] In some embodiments, the present disclosure relates to compounds of formula XIV-1:

[0261] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0262]

[0129] In some embodiments, the present disclosure relates to compounds of formula XV:

[0263] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linkers, both individually and in combination, are defined above for formula IX and as described in the Classes and subclasses herein; Each R t C is independently hydrogen or may be substituted. 1~6 It is aliphatic, or Both R t The groups, together with the atoms to which they are bonded, form a substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each R u These are independently hydrogen, halogen, -CN, or possibly substituted C 1~6 It is aliphatic; Each R v C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic, or R u and R v One example is that together with the atoms to which they are bonded, they form a substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each R w C may be independently a halogen, -OR, -CN, or substituted. 1~6 It is aliphatic, or R u and R w One example is that together with the atoms to which they are bonded, they form a substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each v independently provides (0, 1, 2, 3, 4, or 5).

[0264]

[0130] In some embodiments, the present disclosure relates to compounds of formula XV-1:

[0265] [ka] The present invention provides either a pharmaceutically acceptable salt thereof (wherein the formula, the variable is defined both alone and in combination as shown in Formula I, as described in the Classes and Subclasses herein).

[0266] PBM

[0131] In some embodiments of any formula described herein, the PBM is a KAT2 protein-binding portion, i.e., a portion that can bind to the KAT2 protein. In some embodiments, the PBM is a KAT2A protein-binding portion, i.e., a portion that can bind to the KAT2A protein. In some embodiments, the PBM is a KAT2B protein-binding portion, i.e., a portion that can bind to the KAT2B protein. Typically, the PBM is considered to be able to bind to the KAT2 protein (e.g., KAT2A and / or KAT2B) if it specifically (i.e., preferentially) associates with the KAT2 protein when it comes into contact with the KAT2 protein in the presence of at least one other protein. In some embodiments, the PBM is considered to be able to bind to the KAT2 protein if it specifically associates with the protein intracellularly (e.g., in vitro or in vivo).

[0267]

[0132] In some embodiments, the PBM shares important structural identity with a reference compound or a portion thereof that can bind to the KAT2 protein. For example, in some embodiments, the PBM has the same or similar structure as the reference compound, except that it includes a linker binding site. In some embodiments, the reference compound has a K2 protein of less than 1 μM in biophysical assays such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). d The following characteristics are present: In some embodiments, the reference compound has an IC50 of less than 1 μM in competitive or functional assays such as time-resolved fluorescence resonance energy transfer (TR-FRET). 50 The following characteristics are present. In some embodiments, the reference compound is less than 30 nM DC in the Western blot assay of Example B1. 50The following features are present. In some embodiments, the reference compound binds to the KAT2 protein but does not cause KAT2 degradation, for example, when evaluated 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 a compound described in International Publication No. 2016 / 036954, International Publication No. 2016 / 036873, International Publication No. 2016 / 112298, Chaikuad, A. et al., J. Med. Chem., 2016, 59, 1648-53, Humphreys, PG et al., J. Med. Chem., 2017, 60, 2, 695-709, and Moustakim, M. et al., Angew. Chem. Int. Ed., 2017, 56, 827-31, the entire contents of which are incorporated herein by reference. Reference compounds may be useful for evaluating the binding properties of the PBMs of this disclosure, for example, by comparing the binding data of the PBMs of this disclosure with the binding data of the reference compounds. In some embodiments, reference compounds can be incorporated as PBMs (see, for example, GSK4027 incorporated as a PBM in various compounds). In some embodiments, PBMs are as described in International Publication 2024 / 003533, U.S. Patent Application Publication 20230391745, International Publication 2017 / 197046, or Bassi, Z. et al., ACS Chem. Biol. 2018, 13, 2862-2867, each of which is incorporated herein by reference in whole. In some embodiments, techniques for identifying or evaluating PBMs are described in one or more of such references. In some embodiments, PBM-H or a salt thereof, or a compound of PBM-linker-H or a salt thereof, is used to detect KAT2A protein at concentrations of approximately 1 μM or less than 1 μM in assays such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). DIf present, PBM is thought to be able to bind to the KAT2A protein. In some embodiments, compounds of PBM-H or its salt, or PBM-linker-H or its salt, exhibit an IC50 of approximately 1 μM or less than 1 μM in competitive or functional assays such as time-resolved fluorescence resonance energy transfer (TR-FRET). 50 It has.

[0268]

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

[0269] [ka] That is the case. In some embodiments, the reference compound is

[0270] [ka] That is the case.

[0271]

[0134] In some embodiments, PBM is

[0272] [ka] The structure (wherein the formula, the variable is as defined and described in the Classes and Subclasses herein, both individually and in combination) is as follows. In some embodiments, ring F is a substituted or otherwise 3- to 10-membered ring having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or otherwise 5- to 10 (e.g., 5-8, 5-6, 3, 4, 5, 6, 7, 8, 9, or 10)-membered ring having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or otherwise 5-membered ring having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or otherwise 6-membered ring having 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or otherwise fragrant ring. In some embodiments, ring F is a substituted or otherwise phenyl ring. In some embodiments, ring F is a substituted or possibly substituted five-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or possibly substituted six-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or possibly substituted five to six-membered saturated or partially unsaturated ring having 0 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or possibly 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 a substituted or possibly substituted bicyclic ring (e.g., 6 to 10, 6, 7, 8, 9, or 10-membered). In some embodiments, ring F is polycyclic.

[0273]

[0135] In some embodiments, PBM is

[0274] [ka] (wherein each variable part, both individually and in combination, is as defined and described in the Classes and Subclasses herein). In some embodiments, the PBM has the following structure:

[0275] [ka] (In the formula, ring A, ring B, L 1 , R 1 , R 9 , and n are defined herein for Formula II, both individually and in combination, as described herein in terms of the classes and subclasses.

[0276]

[0136] In some embodiments, the PBM has the following structure:

[0277] [ka] (In the formula, rings A, L 1 , R 1 , R 9 , and n are defined herein for Formula II, both individually and in combination, as described herein in terms of the classes and subclasses.

[0278]

[0137] In some embodiments, the PBM has the following structure:

[0279] [ka] (In the formula, rings A, R 1 , and R 9 (Both alone and in combination, as defined herein for Formula II, and as described herein in its classes and subclasses).

[0280]

[0138] In some embodiments, the PBM has the following structure:

[0281] [ka] (In the formula, rings A, R 1 , and R 9 (Both alone and in combination, as defined herein for Formula II, and as described herein in its classes and subclasses).

[0282]

[0139] In some embodiments, the PBM has the following structure:

[0283] [ka] (In the formula, rings A, R 1 , and R 9 (Both alone and in combination, as defined herein for Formula II, and as described herein in its classes and subclasses).

[0284]

[0140] In some embodiments, PBM is

[0285] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 X and Z, both individually and in combination, are defined herein for Formula II, as described herein in terms of its classes and subclasses. Selected from.

[0286]

[0141] In some embodiments, the PBM has the following structure:

[0287] [ka] (In the formula, rings A, L3 , L 4 , L 5 , R 8 , and R 9 (Both alone and in combination, as defined herein for formula IX, and as described herein in its classes and subclasses).

[0288]

[0142] In some embodiments, PBM is

[0289] [ka] (In the formula, L 3 , L 4 , L 5 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 X and Z, both individually and in combination, are defined herein for formula IX, as described herein in terms of its classes and subclasses. Selected from.

[0290]

[0143] In some embodiments, PBM is

[0291] [ka] Selected from.

[0292]

[0144] In some embodiments, PBM is

[0293] [ka]

[0294] [ka] Selected from.

[0295]

[0145] In some embodiments of any formula described herein (unless otherwise explicitly indicated, whether using or not the term "any formula described herein" or similar, the embodiments described should apply to all suitable formulas, structures, etc., including such variable parts or parts, for example, with respect to a variable part or section), ring A is

[0296] [ka] In some embodiments, ring A is

[0297] [ka] In some embodiments, ring A is

[0298] [ka] In some embodiments, ring A is

[0299] [ka] In some embodiments, ring A is

[0300] [ka] In some embodiments, ring A is

[0301] [ka] In some embodiments, ring A is

[0302] [ka] In some embodiments, ring A is

[0303] [ka] In some embodiments, ring A is

[0304] [ka] In some embodiments, ring A is

[0305] [ka] Selected from. In some embodiments, ring A is

[0306] [ka] Selected from.

[0307]

[0146] In some embodiments of any formula described herein, ring A is

[0308] [ka] In some embodiments, ring A is

[0309] [ka] In some such embodiments, R 2 and R 5However, together with the atoms to which they are bonded, they bond to form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, the formed ring is aromatic. In some embodiments, ring A is

[0310] [ka] That is the case.

[0311]

[0147] In some embodiments of any formula described herein, ring A is

[0312] [ka] In some embodiments, ring A is

[0313] [ka] In some embodiments, ring A is

[0314] [ka] In some such embodiments, R 2 and R 5 However, together with the atoms to which they are bonded, they bond to form a substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some such embodiments, R 4 and R 7 However, together with the atoms to which they are bonded, they bond to form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, the formed ring is aromatic. In some embodiments, ring A is

[0315] [ka] Selected from.

[0316]

[0148] In some embodiments of any formula described herein, ring A is

[0317] [ka] In some embodiments, ring A is

[0318] [ka] That is the case.

[0319]

[0149] In some embodiments of any formula described herein, Z is N or CH. In some embodiments, Z is N. In some embodiments, Z is CR 3 (For example, CH). In some embodiments, Z may be a substituted CH.

[0320]

[0150] In some embodiments, ring F is a substituted 3-16 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1, 2, 3, 4, 5, or 6) ring having 0-6 (e.g., 0, 1-6, 1-4, 1, 2, 3, 4, 5, or 6) heteroatoms independently selected from N, O, and S. In some embodiments, ring F is 3-10 membered. In some embodiments, it is 3 membered. In some embodiments, it is 4 membered. In some embodiments, it is 5 membered. In some embodiments, it is 6 membered. In some embodiments, it is 7 membered. In some embodiments, it is 8 membered. In some embodiments, it is 9 membered. In some embodiments, it is 10 membered. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is aromatic. In some embodiments, this has 1-6, 1-5, 1-4, 1-3, 1, 2, 3, or 4 heteroatoms. In some embodiments, it has no heteroatoms. In some embodiments, this is monocyclic. In some embodiments, this is bicyclic. In some embodiments, this 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 a substituted or 5-6 membered ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or phenyl ring. In some embodiments, ring F is a substituted or substituted pyridine ring. In some embodiments, ring F is a substituted or possibly 5-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or possibly 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, and S.In some embodiments, ring F is a substituted or possibly 6-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, ring F is a substituted or possibly 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 a heteroatom. In some embodiments, at least one monocyclic ring unit does not have a heteroatom.

[0321]

[0151] In some embodiments, ring F may be substituted with one or more halogens. In some embodiments, ring F may be substituted with one or more C1-C6 alkyl groups. In some embodiments, ring F may be substituted with a substituted -O(C1-C6 alkyl) group. In some embodiments, ring F is

[0322] [ka] In some embodiments, ring F is 1,4-phenylene, which may be substituted. In some embodiments, ring F is 1,4-phenylene. In some embodiments, ring F is

[0323] [ka] In some embodiments, ring F is

[0324] [ka] That is the case.

[0325]

[0152] In some embodiments, R 2 However, R is as described herein. In some embodiments, R 2 R is -R, but not hydrogen. In some embodiments of any formula described herein, R 2 However, hydrogen, halogen, -CN, or substituted C may be present. 1~6 It is aliphatic. In some embodiments, R 2 However, hydrogen, halogen, -CN, C 1~6 Alkyl, or C 3~6 It is cycloalkyl. In some embodiments, R 2 However, hydrogen, halogen, -CN, C 1~6 Alkyl, C 3~6 Cycloalkyl, or C6~ 10 It is an arrow. In some embodiments, R 2 However, hydrogen, halogen, -CN, C 1~6 Alkyl, C 3~6 Cycloalkyl, C6~ 10 An aryl or 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 However, hydrogen, halogen, -CN, C 1~6 Alkyl, C 3~6 Cycloalkyl, C6~ 10A 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from aryl, N, O, and S, or a 3-10 membered monocyclic heterocycline having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 However, hydrogen, halogen, or substituted C may be present. 1~6 It is aliphatic. In some embodiments, R 2 is halogen or C 1~6 It is alkyl. In some embodiments, R 2 However, it is chloro, bromo, or methyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 This is bromo. In some embodiments, R 2 is -CN. In some embodiments, R 2 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 2 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 2 C 1~2 Alkyl (e.g., methyl or ethyl). In some embodiments, R 2 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 2 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 2 C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R 2 C6~ 10 It is an arrow. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is naphthyl. In some embodiments, R 2However, it is a 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 However, it is a 5-6 member heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 However, it is a 3- to 10-membered monocyclic heterocycline having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 However, it is a 4-6 membered monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S.

[0326]

[0153] In some embodiments, R 3 However, R is as described herein. In some embodiments, R 3 is -R but not H. In some embodiments of any formula described herein, each R 3 C may independently be hydrogen, halogen, or substituted. 1~6 It is aliphatic. In some embodiments, each R 3 These independently produce hydrogen, halogen, -CN, and C. 1~6 Alkyl, or C 3~6 It is cycloalkyl. In some embodiments, each R 3 These independently produce hydrogen, halogen, -CN, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, or C6~ 10 It is an arrow. In some embodiments, each R 3 These independently produce hydrogen, halogen, -CN, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, C6~ 10 An aryl or 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R 3 These independently produce hydrogen, halogen, -CN, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, C6~ 10A 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from aryl, N, O, and S, or a 3-10 membered monocyclic heterocyclil having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R 3 is hydrogen. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 This is bromo. In some embodiments, R 3 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 3 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 3 C 1~2 It is alkyl (e.g., methyl). In some embodiments, R 3 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 3 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 3 C6~ 10 It is an arrow. In some embodiments, R 3 is phenyl. In some embodiments, R 3 is naphthyl. In some embodiments, R 3 However, it is a 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 3 However, it is a 5-6 member heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 3 However, it is a 3- to 10-membered monocyclic heterocycline having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 3However, it is a 4-6 membered monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S.

[0327]

[0154] In some embodiments, R 4 However, R is as described herein. In some embodiments, R 4 R is -R, but not hydrogen. In some embodiments of any formula described herein, R 4 However, C may be hydrogenated or substituted. 1~6 It is aliphatic. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 4 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 4 C 1~6 It is alkyl. In some embodiments, R 4 However, C may be substituted. 1~2 It is alkyl. In some embodiments, R 4 C 1~2 It is alkyl (e.g., methyl). In some embodiments, R 3 is methyl. In some embodiments, R 4 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 4 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 4 C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R 4 is -C(O)R. In some embodiments, R 4 -C(O)(C 1~6 It is alkyl. In some embodiments, R 4 is -S(O)2R. In some embodiments, R4 -S(O)2(C 1~6 It is alkyl.

[0328]

[0155] In some embodiments, R 5 However, R is as described herein. In some embodiments, R 5 R is -R, but not hydrogen. In some embodiments of any formula described herein, R 5 However, hydrogen, halogen, or substituted C may be present. 1~6 It is aliphatic. In some embodiments, R 5 However, hydrogen, halogen, -CN, C 1~6 Alkyl, or C 3~6 It is cycloalkyl. In some embodiments, R 5 However, hydrogen, halogen, -CN, C 1~6 Alkyl, C 3~6 Cycloalkyl, or C6~ 10 It is an arrow. In some embodiments, R 5 However, hydrogen, halogen, -CN, C 1~6 Alkyl, C 3~6 Cycloalkyl, C6~ 10 An aryl or 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 However, hydrogen, halogen, -CN, C 1~6 Alkyl, C 3~6 Cycloalkyl, C6~ 10 A 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from aryl, N, O, and S, or a 3-10 membered monocyclic heterocycline having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 This is bromo. In some embodiments, R 5 However, C may be substituted.1~6 It is aliphatic. In some embodiments, R 5 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 5 C 1~2 It is alkyl (e.g., methyl). In some embodiments, R 5 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 5 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 5 C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R 5 C6~ 10 It is an arrow. In some embodiments, R 5 is phenyl. In some embodiments, R 5 is naphthyl. In some embodiments, R 5 However, it is a 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 However, it is a 5-6 member heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 However, it is a 3- to 10-membered monocyclic heterocycline having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 5 However, it is a 4-6 membered monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S.

[0329]

[0156] In some embodiments, R 2 and R 5However, together with the atoms to which they are bonded, they bond to form a substituted or possibly substituted 5-6 membered ring having 0-2 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 1-2 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 a substituted or possibly substituted heteroaryl ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments of any formula described herein, R 2 and R 5 However, together with the atoms to which they are bonded, they bond to form a substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 and R 5 However, together with the atoms to which they are bonded, they have 0 to 2 heteroatoms that are independently selected from N, O, and S, and one or more halogens, -R°, -OR°, -N(R°)2, and -CN on the replaceable carbon atom, and one or more -R° on the replaceable nitrogen atom. † and -C(O)R † It forms a 5-6 member aromatic ring which may be substituted with R. 2 and R 5 However, together with the atoms to which they are bonded, they bond to form a substituted, possibly five-membered aromatic ring having one or two heteroatoms independently selected from N, O, and S. In some embodiments, R 2 and R 5 It forms pyrroles which may be bound and substituted. In some embodiments, R 2 and R 5However, together with the atoms to which they are bonded, they bond to form a substituted, possibly six-membered aromatic ring having 0 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 and R 5 R forms a phenyl or pyridine which may be bonded and substituted. In some embodiments, R 2 and R 5 A phenyl ring may be bonded and substituted. In some embodiments, R 2 and R 5 A pyridine ring may be bonded and substituted. In some embodiments, R 2 and R 5 They may be combined and substituted.

[0330] [ka] It forms.

[0331]

[0157] In some embodiments, R 6 However, R is as described herein. In some embodiments, R 6 R is -R, but not hydrogen. In some embodiments of any formula described herein, R 6 C may be hydrogen or substituted. 1~6 It is aliphatic. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 6 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 6 C 1~6 It is alkyl. In some embodiments, R 6 However, C may be substituted. 1~2 It is alkyl. In some embodiments, R 6 C 1~2 It is alkyl (e.g., methyl). In some embodiments, R 6is methyl. In some embodiments, R 6 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 6 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 6 C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R 6 is -C(O)R. In some embodiments, R 6 -C(O)(C 1~6 It is alkyl. In some embodiments, R 6 is -S(O)2R. In some embodiments, R 6 -S(O)2(C 1~6 It is alkyl.

[0332]

[0158] In some embodiments of any formula described herein, X is O. In some embodiments, X is NR 7 In some embodiments, X is NR 7 If R 4 and R 7 However, together with the atoms to which they are bonded, they bond to form a substituted 5-6 membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.

[0333]

[0159] In some embodiments, R 7 However, R is as described herein. In some embodiments, R 7 R is -R, but not hydrogen. In some embodiments of any formula described herein, R 7 C may be hydrogen or substituted. 1~6 It is alkyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 7 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 7 C1~6 It is alkyl. In some embodiments, R 7 However, C may be substituted. 1~2 It is alkyl. In some embodiments, R 7 C 1~2 It is alkyl (e.g., methyl). In some embodiments, R 7 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 7 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 7 However, C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R 7 is -C(O)R. In some embodiments, R 7 -C(O)(C 1~6 It is alkyl. In some embodiments, R 7 is -S(O)2R. In some embodiments, R 7 -S(O)2(C 1~6 It is alkyl.

[0334]

[0160] In some embodiments, R 4 and R 7 However, together with the atoms to which they are bonded, they bond to form a substituted 5-6 membered ring having 2-3 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 formula described herein, R 4 and R 7 However, together with the atoms to which they are bonded, they bond to form a substituted 5-6 membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4and R 7 However, together with the atoms to which they are bonded, they have 2-3 heteroatoms that are independently selected from N, O, and S, with one or more halogens, -R°, -OR°, -N(R°)2, and -CN on the replaceable carbon atom, and one or more -R° on the replaceable nitrogen atom. † and -C(O)R † It forms a 5-6 member aromatic ring which may be substituted with R. 4 and R 7 However, together with the atoms to which they are bonded, they have 2-3 heteroatoms that are independently selected from N, O, and S, and one or more C 1~6 It forms a 5-6 membered aromatic ring which may be substituted with alkyl. In some embodiments, R 4 and R 7 However, together with the atoms to which they are bonded, they bond to form a five-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 and R 7 It forms a triazole which may be bound and substituted. In some embodiments, R 4 and R 7 However, together with the atoms to which they are bonded, they bond to form a six-membered aromatic ring having two to three heteroatoms independently selected from N, O, and S. In some embodiments, the formed ring may be substituted.

[0335] [ka] In some embodiments, the formed ring is

[0336] [ka] That is the case.

[0337]

[0161] In some embodiments, R 9 However, R is as described herein. In some embodiments, R9 R is -R, but not hydrogen. In some embodiments of any formula described herein, R 9 C may be hydrogen or substituted. 1~6 It is alkyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 9 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 9 C 1~6 It is alkyl. In some embodiments, R 9 However, C may be substituted. 1~2 It is alkyl. In some embodiments, R 9 C 1~2 It is alkyl (e.g., methyl). In some embodiments, R 9 is methyl. In some embodiments, R 9 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 9 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 9 C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R 9 is -C(O)R. In some embodiments, R 9 -C(O)(C 1~6 It is alkyl. In some embodiments, R 9 is -S(O)2R. In some embodiments, R 9 -S(O)2(C 1~6 It is alkyl.

[0338]

[0162] In some embodiments, ring B is a substituted or otherwise substituted five-membered heterocycline having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a substituted or otherwise substituted five-membered saturated heterocycline having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a substituted or otherwise substituted five-membered partially unsaturated heterocycline having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a substituted or otherwise substituted six-membered heterocycline having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a substituted or otherwise substituted nine-membered saturated heterocycline having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a substituted or otherwise substituted five-membered partially unsaturated heterocycline 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 a substituted piperidine ring.

[0339] [ka] In some embodiments, ring B is

[0340] [ka] In some embodiments of any formula described herein, ring B is a 5-6 membered heterocycline having one heteroatom independently selected from N, O, and S. In some embodiments, ring B is a 5-6 membered heterocycline having one or two heteroatoms independently selected from N, O, and S, with at least one heteroatom being N. In some embodiments, ring B is a 5 membered heterocycline having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a 6 membered heterocycline having one or two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is piperidine. In some embodiments,

[0341] [ka] but,

[0342] [ka] In some embodiments,

[0343] [ka] but,

[0344] [ka] That is the case.

[0345]

[0163] In some embodiments of any formula described herein, L 1 In some embodiments, L 1 However, divalent C may be substituted. 1~3 It is a hydrocarbon chain. In some embodiments, L 1 However, divalent saturated C may be substituted. 1~3 It is a hydrocarbon chain. In some embodiments, L1 However, divalent partial unsaturated C may be substituted. 1~3 It is a hydrocarbon chain. In some embodiments, L 1 However, divalent linear carbon may be substituted. 1~3 It is a hydrocarbon chain. In some embodiments, L 1 However, bivalent branched C may be substituted. 1~3 It is a hydrocarbon chain. In some embodiments, L 1 However, divalent C 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 1 However, divalent C 1~3 It is a straight-chain hydrocarbon chain. In some embodiments, L 1 However, divalent C 1~2 It is a straight-chain hydrocarbon chain. In some embodiments, L 1 L may be substituted. In some embodiments, L 1 It is -CH2-.

[0346]

[0164] In some embodiments, R 1 However, R is as described herein. In some embodiments, R 1 is -R, but not hydrogen. In some embodiments of any formula described herein, each R 1 C may be substituted independently. 1~6 Alkyl or optionally substituted C 3~6 It is cycloalkyl. In some embodiments, each R 1 These independently consist of hydrogen or C1-8 aliphatic, C6- 10 Ariel, C3~ 10 The group may be substituted, selected from alicyclic, 5-10 membered heteroaryls having 1-5 heteroatoms independently selected from N, O, and S, and 3-10 membered monocyclic heterocyclines having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 1 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 1 C1~6 It is alkyl. In some embodiments, R 1 However, C may be substituted. 1~2 It is alkyl. In some embodiments, R 1 C 1~2 It is alkyl (e.g., methyl). In some embodiments, R 1 is methyl. In some embodiments, R 1 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 1 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 1 C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R 1 -CH2-C 3~6 It is alicyclic. In some embodiments, R 1 is -CH2-cyclopropyl. In some embodiments, R 1 C6~ 10 It is an arrow. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is naphthyl. In some embodiments, R 1 However, it is a 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 However, it is a 5-6 member heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 However, it is a 3- to 10-membered monocyclic heterocycline having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 However, it is a 4-6 membered monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S.

[0347]

[0165] In some embodiments of any formula 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.

[0348]

[0166] In some embodiments, L 3 However, divalent linear C1-6 may be substituted (for example, C 1~3 , C1, C2, C3, C4, C5 or C6) hydrocarbon chains. In some embodiments, L 3 However, bivalent branched C1~6 may be substituted (for example, C 1~3 , C1, C2, C3, C4, C5 or C6) hydrocarbon chains. In some embodiments of any formula described herein, L 3 However, the divalent C may be covalently bonded or substituted. 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 3 In some embodiments, L 3 is a divalent C 1~6 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 3 However, divalent C may be substituted. 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 3 is a divalent C 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 3 However, it is a -CH2- which may be substituted. In some embodiments, L 3 However, it is selected 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-.

[0349]

[0167] In some embodiments, L 4 However, divalent linear carbon may be substituted. 1~6 (For example, C1~3 , C1, C2, C3, C4, C5 or C6) hydrocarbon chains. In some embodiments, L 4 However, bivalent branched C may be substituted. 1~6 (For example, C 1~3 , C1, C2, C3, C4, C5 or C6) hydrocarbon chains. In some embodiments of any formula described herein, L 4 However, the divalent C may be covalently bonded or substituted. 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 4 In some embodiments, L 4 However, divalent C may be substituted. 1~6 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 4 is a divalent C 1~6 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 4 However, divalent C may be substituted. 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 4 is a divalent C 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 4 However, it is a -CH2- which may be substituted. In some embodiments, L 4 However, it is selected from -CH2- and -CH(CH3)-. In some embodiments, L 4 It is -CH2-.

[0350]

[0168] In some embodiments, L 5 However, divalent linear carbon may be substituted. 1~6 (For example, C 1~3 , C1, C2, C3, C4, C5 or C6) hydrocarbon chains. In some embodiments, L 5 However, bivalent branched C may be substituted. 1~6 (For example, C 1~3 , C1, C2, C3, C4, C5 or C6) hydrocarbon chains. In some embodiments of any formula described herein, L 5 However, the divalent C may be covalently bonded or substituted. 1~3It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 5 In some embodiments, L 5 However, divalent C may be substituted. 1~6 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 5 is a divalent C 1~6 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 5 However, divalent C may be substituted. 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 5 is a divalent C 1~3 It is a straight-chain or branched hydrocarbon chain. In some embodiments, L 5 However, it is a -CH2- which may be substituted. In some embodiments, L 5 However, it is selected from -CH2- and -CH(CH3)-. In some embodiments, L 5 It is -CH2-.

[0351]

[0169] In some embodiments, R 8 However, R is as described herein. In some embodiments, R 8 is -R, but not hydrogen. In some embodiments of any formula described herein, each R 8 C may be independently hydrogenated or substituted. 1~6 It is alkyl. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R 8 However, C may be substituted. 1~6 It is alkyl. In some embodiments, R 8 C 1~6 It is alkyl. In some embodiments, R 8 However, C may be substituted. 1~2 It is alkyl. In some embodiments, R 8 C 1~2 Alkyl (e.g., methyl). In some embodiments, each R 8 C 1~2It is alkyl (e.g., methyl). In some embodiments, R 8 However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R 8 However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R 8 C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R 8 is -C(O)R. In some embodiments, R 8 -C(O)(C 1~6 It is alkyl. In some embodiments, R 8 is -S(O)2R. In some embodiments, R 8 -S(O)2(C 1~6 It is alkyl. In some embodiments, two R 8 The base is the same. In some embodiments, these are different. In some embodiments, there are two R 8However, together with the nitrogen atom to which they are bonded, they form a substituted 3-16 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1, 2, 3, 4, or 5) membered ring having 1-5 (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, the formed ring is 3-10 membered. In some embodiments, the formed ring is 3-6 membered. In some embodiments, the formed ring is 3 membered. In some embodiments, it is 4 membered. In some embodiments, it is 5 membered. In some embodiments, it is 6 membered. In some embodiments, it is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, it is saturated, or at least one monocyclic unit is saturated. In some embodiments, it is partially unsaturated, or at least one monocyclic unit is partially unsaturated. In some embodiments, it is aromatic, or at least one monocyclic unit is aromatic. In some embodiments, it is heteroaromatic, or at least one monocyclic unit is heteroaromatic.

[0352] Linker

[0170] In some embodiments of any formula described herein, the linker is a connecting portion (i.e., any suitable divalent portion connecting the PBM to the LBM). In some embodiments, the linker is a covalent bond. In some embodiments, the linker is a divalent C1-C which may be substituted. 20 (For example, C1~C 15 , C1~C 10 , C1~C6, C1~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 C20 ) A hydrocarbon chain (which can be straight or branched, and saturated or partially unsaturated, and may contain one or more (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) hydrocarbon rings) in which one or more (e.g., 1-10, 1-8, 1-6, 1-5, 1-3, 1-2, 2-10, 2-5, 2-3, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(N The linkers may be replaced by -OR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the various linkers described herein can provide superior properties, such as improved potency, improved half-life, improved stability, and / or reduced toxicity.

[0353]

[0171] In some embodiments, the linker is of a specific length (e.g., measured by the number of atoms). When describing the length of the linker, it will be understood that the longest continuous chain of atoms is used. For example, in some embodiments, the linker has the following structure with a length of 14 atoms (counted as shown in the italicized numbers):

[0354] [ka] .

[0355]

[0172] In some embodiments, the linker has an atomic length of 2 to 16 atoms. In some embodiments, the linker has an atomic length of 2 to 13 atoms. In some embodiments, the linker has an atomic length of 2 to 10 atoms. In some embodiments, the linker has an atomic length of 2 to 8 atoms. In some embodiments, the linker has an atomic length of 2 to 7 atoms. In some embodiments, the linker has an atomic length of 0 to 16 atoms. In some embodiments, the linker has an atomic length of 0 to 13 atoms. In some embodiments, the linker has an atomic length of 0 to 10 atoms. In some embodiments, the linker has an atomic length of 0 to 7 atoms. In some embodiments, the linker has an atomic length of 4 to 16 atoms. In some embodiments, the linker has an atomic length of 4 to 13 atoms. In some embodiments, the linker has an atomic length of 4 to 10 atoms. In some embodiments, the linker has an atomic length of 4 to 8 atoms. In some embodiments, the linker has an atomic length of 4 to 7 atoms. In some embodiments, the linker has an atomic length of less than 14 atoms. In some embodiments, the linker has an atomic length of less than 11 atoms. In some embodiments, the linker has an atomic length of less than 9 atoms. In some embodiments, the linker is less than 8 atomic lengths.

[0356]

[0173] Alternatively, or further, in some embodiments, the shortest path length of the linker (the number of atoms in the chain from one end of the linker to the other (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, this is 0. In some embodiments, this is about 1 to 16 atoms. In some embodiments, this is about 1 to 10 atoms. In some embodiments, this is 1 atom. In some embodiments, this is about 2 or about 2 or fewer atoms. In some embodiments, this is about 2 or about 2 or fewer atoms. In some embodiments, this is about 3 or about 3 or fewer atoms. In some embodiments, this is about 4 or fewer than 4 atoms. In some embodiments, this is about 5 or fewer than 5 atoms. In some embodiments, this is about 6 or fewer than 6 atoms. In some embodiments, this is about 7 or fewer than 7 atoms. In some embodiments, this is about 8 or fewer than 8 atoms. In some embodiments, this is about 9 or fewer than 9 atoms. In some embodiments, this is about 10 or fewer than 10 atoms. In some embodiments, this is about 11 or fewer than 11 atoms. In some embodiments, this is about 12 or fewer than 12 atoms. In some embodiments, this is about 13 or fewer than 13 atoms. In some embodiments, this is about 14 or fewer than 14 atoms.

[0357]

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

[0358]

[0175] In some embodiments of any formula described herein, the linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 20A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C The linker may be replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the linker may be a divalent linear or branched saturated or unsaturated C1~C which may be substituted. 20 A hydrocarbon chain in which at least one methylene unit is -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C The linker is replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the linker is replaced by divalent linear or branched saturated or unsaturated C1~C, which may be substituted. 20A hydrocarbon chain in which at least two methylene units are -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C It is replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.

[0359]

[0176] In some embodiments, the linker may be a divalent linear or branched saturated or unsaturated C1-C 10 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C The linker may be replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the linker may be a divalent linear or branched saturated or unsaturated C1~C which may be substituted. 10A hydrocarbon chain in which at least one methylene unit is -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C The linker is replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the linker is replaced by divalent linear or branched saturated or unsaturated C1~C, which may be substituted. 10 A hydrocarbon chain in which at least two methylene units are -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C It is replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.

[0360]

[0177] In some embodiments, the linker may be a divalent linear or branched saturated or unsaturated C1-C 20 A hydrocarbon chain in which one or more methylene units may be 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, the linker may be a substituted divalent linear or branched saturated or unsaturated C1-C 20A hydrocarbon chain in which at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, the linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 20 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)-, -N(R)C(O)-, or -Cy-.

[0361]

[0178] In some embodiments, the linker may be a divalent linear or branched saturated or unsaturated C1-C 10 (For example, C1~C8, C1~C6, C1~C5, C1~C4, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 ) is a hydrocarbon chain in which one or more methylene units may be 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, the linker is a divalent linear or branched saturated or unsaturated C1-C which may be substituted. 10 A hydrocarbon chain in which at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, the linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 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)-, -N(R)C(O)-, or -Cy-.

[0362]

[0179] As illustrated herein, in various embodiments, the linker of the provided compound is short (e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 atoms or less; often having a length of about 8, 9, or 10 atoms or about 8, 9, or 10 atoms or less and / or shortest path length) and provides rigidity (e.g., about 0, 1, 2, 3, 4, or 5 or about 0, 1, 2, 3, 4, or 5 acyclic continuous sp in the shortest path chain) and provides rigidity (e.g., about 0, 1, 2, 3, 4, or 5 or about 0, 1, 2, 3, 4, or 5 sp 3 A shortest path chain containing atoms, with approximately 0, 1, 2, 3, 4, or 5 acyclic continuous atoms, or a shortest path chain containing approximately 0, 1, 2, 3, 4, or 5 acyclic continuous atoms, with approximately 0, 1, 2, 3, 4, or 5 acyclic sp atoms. 3 A ring-continuous sp² having atoms, approximately 0, 1, 2, 3, 4, or 5 acyclic atoms in the shortest path chain, or approximately 0, 1, 2, 3, 4, or 5 or less acyclic atoms in the shortest path chain, where each atom is independently C, N, O, or S. 3 A shortest path chain containing approximately 0, 1, 2, 3, 4, or 5 acyclic continuum atoms, each atom independently being C, N, O, or S, and containing approximately 0, 1, 2, 3, 4, or 5 acyclic sp[ing] atoms. 3 (Having C, N, O, or S atoms, or having about 0, 1, 2, 3, 4, or 5 or less acyclic C, N, O, or S atoms in the shortest path chain). In some embodiments, acyclic continuous sp in the shortest path chain of the linker. 3 The number of atoms is approximately 5 or less. In some embodiments, acyclic continuous sp is present in the shortest path chain of the linker. 3 The number of atoms is approximately 4 or less. In some embodiments, acyclic continuous sp is present in the shortest path chain of the linker. 3 The number of atoms is approximately 3 or less. In some embodiments, acyclic continuous sp is present in the shortest path chain of the linker. 3The number of atoms is approximately 2 or less. In some embodiments, acyclic sp is present in the shortest path chain of the linker. 3 The number of atoms is approximately 5 or less. In some embodiments, acyclic sp is present in the shortest path chain of the linker. 3 The number of atoms is approximately 4 or less. In some embodiments, acyclic sp is present in the shortest path chain of the linker. 3 The number of atoms is approximately 3 or less. In some embodiments, acyclic sp is present in the shortest path chain of the linker. 3 The number of atoms is approximately 2 or less. In some embodiments, acyclic sp is present in the shortest path chain of the linker. 3 The number of atoms is approximately 1 or less. In some embodiments, acyclic sp is present in the shortest path chain of the linker. 3 The number of atoms is 0. In some embodiments, acyclic sp is present in the shortest path chain of the linker. 3 The number of C, O, and S atoms is about 5 or less. In some embodiments, acyclic sp in the shortest path chain of the linker. 3 The number of C, O, and S atoms is about 4 or less. In some embodiments, acyclic sp in the shortest path chain of the linker. 3 The number of C, O, and S atoms is about 3 or less. In some embodiments, acyclic sp in the shortest path chain of the linker. 3 The number of C, O, and S atoms is about 2 or less. In some embodiments, acyclic sp in the shortest path chain of the linker. 3 The number of C, O, and S atoms is about 1 or less. In some embodiments, acyclic sp in the shortest path chain of the linker. 3The number of C, O, and S atoms is 0. In some embodiments, the number of acyclic C, O, and S atoms in the linker's shortest path chain is about 5 or less. In some embodiments, the number of acyclic C, O, and S atoms in the linker's shortest path chain is about 4 or less. In some embodiments, the number of acyclic C, O, and S atoms in the linker's shortest path chain is about 3 or less. In some embodiments, the number of acyclic C, O, and S atoms in the linker's shortest path chain is about 2 or less. In some embodiments, the number of acyclic C, O, and S atoms in the linker's shortest path chain is about 1 or less. In some embodiments, the number of acyclic atoms in the linker's shortest path chain is 0. In some embodiments, the number of acyclic atoms in the linker's shortest path chain is about 5 or less. In some embodiments, the number of acyclic atoms in the linker's shortest path chain is about 4 or less. In some embodiments, the number of acyclic atoms in the linker's shortest path chain is about 3 or less. In some embodiments, the number of acyclic atoms in the linker's shortest path chain is about 2 or less. In some embodiments, the number of acyclic atoms in the linker's shortest path chain is about 1 or less. In some embodiments, the number of acyclic atoms in the linker's shortest path chain is 0. As those skilled in the art will understand, one or more shortest path chains of a linker may exist. In some embodiments, the linker contains one or more (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) -Cy- atoms in its shortest path chain. In some embodiments, the linker contains one or more (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) -Cy- atoms in its shortest path chain. In some embodiments, each -Cy- atom is independently present in the linker's shortest path chain. In some embodiments, the -Cy- atoms are monocyclic. In some embodiments, -Cy- is bicyclic. In some embodiments, -Cy- is spiro-bicyclic. In some embodiments, -Cy- is polycyclic. In some embodiments, -Cy- is saturated. In some embodiments, -Cy- is partially unsaturated. In some embodiments, -Cy- is aromatic. In some embodiments, -Cy- is monocyclic with 3 to 10 members (e.g., 3 to 8, 3 to 6, 3 to 5, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10).In some embodiments, -Cy- has 6 to 16 members (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) and is bicyclic. In some embodiments, -Cy- has 6 to 16 members (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) and is spiro-bicyclic. In some embodiments, -Cy- has 10 to 12 members and is bicyclic. In some embodiments, -Cy- has 10 to 12 members and is spiro-bicyclic. In some embodiments, -Cy- is 11-membered and bicyclic. In some embodiments, -Cy- is 11-membered and spiro-bicyclic. In some embodiments, each monocyclic ring unit of -Cy- is independently 3 to 10 members (e.g., 3 to 8, 3 to 6, 3 to 5, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, each monocyclic ring unit of -Cy- is independently 3 to 8 members (e.g., 3 to 6, 3 to 5, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, each monocyclic ring unit of -Cy- is independently 3 to 6 members (e.g., 3 to 5, 5 to 6, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, each monocyclic ring unit of -Cy- is independently 5 or 6 members. In some embodiments, the monocyclic ring units of -Cy- are saturated. In some embodiments, the monocyclic ring units of -Cy- are partially unsaturated. In some embodiments, the monocyclic ring units of -Cy- are aromatic. In some embodiments, each monocyclic ring unit of -Cy- is independently saturated or partially unsaturated. In some embodiments, each monocyclic ring unit of -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 of -Cy- is nitrogen. In some embodiments, it has been observed that the spirocyclic ring of the linker can provide various 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, e.g., pharmacokinetic properties. In some embodiments, for example, when evaluated by rodent PK assays, the basic nitrogen atoms of the linker, e.g., -Cy- (e.g., piperidine and / or piperazine rings), result in improved solubility, improved dissolution rate, and / or longer T. 1 / 2 It has been observed that this can be provided. Various embodiments of the linker are described herein, for example, below or in various compounds.

[0363]

[0180] In some embodiments, the linker is a substituted divalent C1-C5 (e.g., C1-C4, C1-C3, C1-C2, C1, C2, C3, C4, or C5) hydrocarbon chain (which may be linear or branched, and saturated or partially unsaturated), where one or more (e.g., 1, 2, 3, 4, or 5) methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, These may be replaced by -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the linker is a substituted divalent C1-C3 (e.g., C1-C2, C1, C2, or C3) hydrocarbon chain (which may be linear or branched, and saturated or partially unsaturated), where one or more (e.g., 1, 2, 3, 4, or 5) methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, - These may be replaced by C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.In some embodiments, the linker is a substituted divalent linear C1-C3 (e.g., C1-C2, C1, C2, or C3) hydrocarbon chain, where one or more (e.g., 1, 2, 3, 4, or 5) methylene units are independently -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)- These may be replaced by -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the linker is a substituted divalent linear C1-C3 (e.g., C1-C2, C1, C2, or C3) alkylene chain, where one or more (e.g., 1, 2, 3, 4, or 5) methylene units are independently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(NR)-, or -Cy-. In some embodiments, the linker further has a limited number of acyclic atoms in its shortest path chain as described herein, for example, the number of acyclic atoms in its shortest path chain being about 0, 1, 2, 3, 4, or 5 or about 0, 1, 2, 3, 4, or 5 or less (as illustrated herein, in various embodiments about 2 or about 2 or less, and in various embodiments about 1 or about 1 or less).For example, in some embodiments, the linker is -C(O)-Cy-, with -C(O)- bonded to the PBM; in some embodiments, the linker is -CH2-Cy-, with -CH2- bonded to the PBM; in some embodiments, the linker is -CH2-O-, with -CH2- bonded to the PBM; and in some embodiments, the linker is -Cy-O-, with -Cy- bonded to the PBM.

[0364]

[0181] In some embodiments, about 1 to 10 or less than or equal to 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 replaced as described herein. In some embodiments, about 5 or less than or equal to 5 methylene units are independently replaced as described herein. In some embodiments, about 4 or less than or equal to 4 methylene units are independently replaced as described herein. In some embodiments, about 3 or less than or equal to 3 methylene units are independently replaced as described herein. In some embodiments, about 2 or less than or equal to 2 methylene units are independently replaced as described herein. In some embodiments, about 1 or less than or equal to 1 methylene unit is replaced as described herein.

[0365]

[0182] In some embodiments, the linker includes an ether moiety (e.g., -O-). In some embodiments, the linker may be 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 -O-. In some embodiments, the linker is a divalent straight or branched saturated or unsaturated C1-C, which may be substituted. 10 It is a hydrocarbon chain in which at least one methylene unit is replaced by -O-.

[0366]

[0183] In some embodiments, the linker includes an amine moiety (e.g., -N(R)-). In some embodiments, the linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 20 A hydrocarbon chain in which at least one methylene unit is -N(R)- (e.g., -NH- or -N(C) 1~6 It is replaced by alkyl(-). In some embodiments, the linker may be substituted with divalent linear or branched saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least one methylene unit is -N(R)- (e.g., -NH- or -N(C) 1~6 It is replaced by alkyl)-). In some embodiments, the methylene unit is replaced by -NH-.

[0367]

[0184] In some embodiments, the linker includes a carbonyl moiety. In some embodiments, the linker may be 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 -C(O)-. In some embodiments, the linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 10 It is a hydrocarbon chain in which at least one methylene unit is replaced by -C(O)-.

[0368]

[0185] In some embodiments, the linker includes an ester moiety. In some embodiments, the linker may be 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 -OC(O)- or -C(O)O-. In some embodiments, the linker is a divalent linear or branched saturated or unsaturated C1-C, which may be substituted. 10 It is a hydrocarbon chain in which at least one methylene unit is replaced by -OC(O)- or -C(O)O-.

[0369]

[0186] In some embodiments, the linker includes an amide moiety. In some embodiments, the linker may be a substituted divalent linear or branched saturated or unsaturated C1-C 20 A hydrocarbon chain in which at least one methylene unit is -C(O)N(R)- (e.g., -C(O)NH- or -C(O)N(C 1~6 It is replaced by alkyl(-). In some embodiments, the linker may be substituted with divalent linear or branched saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least one methylene unit is -C(O)N(R)- (e.g., -C(O)NH- or -C(O)N(C 1~6 It is replaced by alkyl(-). In some embodiments, the linker may be substituted with divalent linear or branched saturated or unsaturated C1-C 20 A hydrocarbon chain in which at least one methylene unit is -N(R)C(O)- (e.g., -N(H)C(O)- or -N(C 1~6 It is replaced by alkyl)C(O)-). In some embodiments, the linker may be substituted with divalent linear or branched saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least one methylene unit is -N(R)C(O)- (e.g., -N(H)C(O)- or -N(C 1~6 It is replaced by alkyl)C(O)-). In some embodiments, the methylene unit is replaced by -C(O)NH-.

[0370]

[0187] In some embodiments, the linker includes a divalent ring moiety (e.g., -Cy-). In some embodiments, the linker may be 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 a divalent linear or branched saturated or unsaturated C1-C1 which may be substituted. 10It is a hydrocarbon chain in which at least one methylene unit is replaced by -Cy-. In some such embodiments, Cy is not phenyl.

[0371]

[0188] In some embodiments, the linker includes a triple bond. In some embodiments, the linker includes at least one triple bond in a substituted divalent linear or branched partially unsaturated C1-C 20 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C The linker may be replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the linker may be replaced by a divalent linear or branched partially unsaturated C1~C that includes at least one triple bond. 10 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C The linker may be replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, the linker may be replaced by a divalent linear or branched partially unsaturated C1~C that includes at least one triple bond. 20A hydrocarbon chain in which one or more methylene units may be 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, the linker may be a substituted divalent straight or branched partially unsaturated C1-C2 containing at least one triple bond. 10 A hydrocarbon chain in which one or more methylene units may be independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-.

[0372]

[0189] In some embodiments of any formula described herein, the linker has the following structure:

[0373] [ka] (wherein Cy, both alone and in combination, is as defined herein for Formula II and as described herein for its classes and subclasses; M 1 and M 2 Each of these is independently nonexistent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; L 6 and L 7 Each of these is independently a divalent linear or branched saturated or unsaturated C1-C, which may be covalently bonded or substituted. 10A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- should be used as substitutes.) It has.

[0374]

[0190] In some embodiments of any formula described herein, the linker has the following structure:

[0375] [ka] (wherein Cy, both alone and in combination, is as defined herein for Formula II and as described herein for its classes and subclasses; M 1 and M 2 Each of these is independently nonexistent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; L 6 and L 7Each is independently a divalent linear or branched saturated or unsaturated C1-C5 (e.g., C1-C4, C1-C3, C1-C2, C2-C4, C1, C2, C3, C4, or C5) hydrocarbon chain which may be covalently bonded or substituted, and one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, (These will likely be replaced by -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-) It has.

[0376]

[0191] In some embodiments of any formula described herein, the linker is

[0377] [ka] Selected from.

[0378]

[0192] In some embodiments of any formula described herein, the linker is

[0379] [ka] That is the case.

[0380]

[0193] In some embodiments of any formula described herein, the linker is

[0381] [ka] Selected from.

[0382]

[0194] In some embodiments of any formula described herein, the linker has the following structure:

[0383] [ka] (In the formula, M 1 and M 2 Each of these is independently nonexistent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; L 6 and L 7 Each of these is independently a divalent linear or branched saturated or unsaturated C1-C, which may be covalently bonded or substituted. 10 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- should be used as substitutes.) It has.

[0384]

[0195] In some embodiments of any formula described herein, the linker is

[0385] [ka] Selected from.

[0386]

[0196] In some embodiments of any formula described herein, the linker has the following structure:

[0387] [ka] (In the formula, M 1 and M 2 Each of these is independently nonexistent, -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; L 8 This refers to a covalent or substituted divalent linear or branched saturated or unsaturated C1-C 15 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- should be used as substitutes.) It has.

[0388]

[0197] In some embodiments of any formula described herein, the linker is

[0389] [ka] Selected from.

[0390]

[0198] In some embodiments, the linker is -M 1 -L 6 -L 7 -M 2 - is

[0391]

[0199] In some embodiments of any formula described herein, M 1 However, these are -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 embodiments, M 1 However, it is a -CH2- which may be substituted. In some embodiments, M 1 is -CH2-. In some embodiments, M 1 is -O-. In some embodiments, M 1 is -N(R)- (for example, -N(H)- or -N(CH3)-). In some embodiments, M 1 is -C(O)-. In some embodiments, M 1 is -OC(O)-. In some embodiments, M 1 is -C(O)O-. In some embodiments, M 1 is -C(O)N(R)- (for example, -C(O)N(H)- or -C(O)N(CH3)-). In some embodiments, M 1 is -N(R)C(O)- (for example, -N(H)C(O)- or -N(CH3)C(O)-). In some embodiments, the variable part is covalent and can be appropriately considered non-existent as understood by those skilled in the art. In some embodiments, M 1 It is coupled to PBM.

[0392]

[0200] In some embodiments of any formula described herein, M 2 However, these are -CH2-, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, M 2 It does not exist. In some embodiments, M 2 is -CH2-. In some embodiments, M 2 is -O-. In some embodiments, M 2is -N(R)- (for example, -N(H)- or -N(CH3)-). In some embodiments, M 2 is -C(O)-. In some embodiments, M 2 is -OC(O)-. In some embodiments, M 2 is -C(O)O-. In some embodiments, M 2 is -C(O)N(R)- (for example, -C(O)N(H)- or -C(O)N(CH3)-). In some embodiments, M 2 is -N(R)C(O)- (for example, -N(H)C(O)- or -N(CH3)C(O)-). In some embodiments, M 2 It is coupled to the LBM.

[0393]

[0201] In some embodiments of any formula described herein, L 6 This is a covalent bond.

[0394]

[0202] In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- may be substituted. In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10A hydrocarbon chain in which at least one methylene unit is -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C( It is replaced by NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which at least two methylene units are -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C It is replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.

[0395]

[0203] In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which one or more methylene units may be 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 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10A hydrocarbon chain in which at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 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)-, -N(R)C(O)-, or -Cy-.

[0396]

[0204] In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which one or more methylene units may be 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 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 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)-.

[0397]

[0205] In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10A hydrocarbon chain in which one or more methylene units may be independently replaced by -O-. In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 It is a hydrocarbon chain in which at least one methylene unit is replaced by -O-. In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 It is a hydrocarbon chain in which at least two methylene units are replaced by -O-.

[0398]

[0206] In some embodiments, L 6 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 It is a hydrocarbon chain. In some embodiments, L 6 However, divalent linear or branched saturated C1-C may be substituted. 10 It is a hydrocarbon chain. In some embodiments, L 6 However, it is a divalent linear or branched saturated or unsaturated C1-C6 hydrocarbon chain which may be substituted. In some embodiments, L 6 However, it is a divalent, linear or branched saturated C1-C6 hydrocarbon chain that may be substituted.

[0399]

[0207] In some embodiments, L 6 However, it is a -CH2- which may be substituted. In some embodiments, L 6 is -CH2-. In some embodiments, L 6 is -C(O)-. In some embodiments, L 6 It is coupled to PBM.

[0400]

[0208] In some embodiments of any formula described herein, L 7 This is a covalent bond.

[0401]

[0209] In some embodiments, L 7However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- may be substituted. In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which at least one methylene unit is -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C It is replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10A hydrocarbon chain in which at least two methylene units are -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C It is replaced by (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.

[0402]

[0210] In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which one or more methylene units may be 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 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 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)-, -N(R)C(O)-, or -Cy-.

[0403]

[0211] In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10A hydrocarbon chain in which one or more methylene units may be 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 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 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)-.

[0404]

[0212] In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 A hydrocarbon chain in which one or more methylene units may be independently replaced by -O-. In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 It is a hydrocarbon chain in which at least one methylene unit is replaced by -O-. In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 It is a hydrocarbon chain in which at least two methylene units are replaced by -O-.

[0405]

[0213] In some embodiments, L 7 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 10 It is a hydrocarbon chain. In some embodiments, L 7However, divalent linear or branched saturated C1-C may be substituted. 10 It is a hydrocarbon chain. In some embodiments, L 7 However, it is a divalent linear or branched saturated or unsaturated C1-C6 hydrocarbon chain which may be substituted. In some embodiments, L 7 However, it is a divalent, linear or branched saturated C1-C6 hydrocarbon chain that may be substituted.

[0406]

[0214] In some embodiments, L 7 It is coupled to the LBM.

[0407]

[0215] In some embodiments of any formula described herein, L 6 and L 7 Both are covalent bonds.

[0408]

[0216] In some embodiments of any formula described herein, L 8 This is a covalent bond.

[0409]

[0217] In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C (NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy- may be substituted. In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15A hydrocarbon chain in which at least one methylene unit is -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C( It is replaced by NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15 A hydrocarbon chain in which at least two methylene units are -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C( It is replaced by NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.

[0410]

[0218] In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15 A hydrocarbon chain in which one or more methylene units may be 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 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15A hydrocarbon chain in which at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 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)-, -N(R)C(O)-, or -Cy-.

[0411]

[0219] In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15 A hydrocarbon chain in which one or more methylene units may be 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 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15 A hydrocarbon chain in which at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 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)-.

[0412]

[0220] In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15A hydrocarbon chain in which one or more methylene units may be independently replaced by -O-. In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15 It is a hydrocarbon chain in which at least one methylene unit is replaced by -O-. In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15 It is a hydrocarbon chain in which at least two methylene units are replaced by -O-.

[0413]

[0221] In some embodiments, L 8 However, divalent linear or branched saturated or unsaturated C1-C may be substituted. 15 It is a hydrocarbon chain. In some embodiments, L 8 However, divalent linear or branched saturated C1-C may be substituted. 15 It is a hydrocarbon chain. In some embodiments, L 8 However, it is a divalent linear or branched saturated or unsaturated C1-C6 hydrocarbon chain which may be substituted. In some embodiments, L 8 However, it is a divalent, linear or branched saturated C1-C6 hydrocarbon chain that may be substituted.

[0414]

[0222] In some embodiments of any formula described herein, the linker is -CH2-,

[0415] [ka]

[0416] [ka]

[0417] [ka]

[0418] [ka] Selected from.

[0419]

[0223] As described herein and illustrated by various compounds, the linkers are of short length (e.g., the shortest path chain length is about 8, 9, or 10 atoms or less) and / or contain few structurally flexible chain atoms, for example, about 1, 2, 3, or 4 or less, or 0 acyclic sp in its shortest path chain. 3 It contains C, N, O, or S atoms. In some embodiments, there are about 1, 2, or 3 or about 1, 2, or 3 or fewer acyclic atoms in its shortest path chain. In some embodiments, there are about 2 or about 2 or fewer acyclic atoms in its shortest path chain. In some embodiments, there is about 1 or about 1 or fewer acyclic atoms in its shortest path chain (for example,

[0420] [ka] (For example). In some embodiments, two acyclic sps in the shortest path chain of the linker 3 The number of interatomic bonds is approximately 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5 or 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5 or less; in some embodiments, this is 0 (for example,

[0421] [ka] Like this); in some embodiments, this is 1 (for example,

[0422] [ka] (For example). In particular, such linkers can provide increased structural rigidity and / or various benefits and advantages. In some embodiments, the ring is monocyclic or bicyclic, often spiro-bicyclic, and each monocyclic ring unit independently has about 3, 4, 5, or 6 members. In some embodiments, the ring independently contains 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 linker contains, for example, one or more basic nitrogen atoms in its shortest path chain. For example, in some embodiments, the linker is

[0423] [ka] In some embodiments, the linker is

[0424] [ka] In some embodiments, the linker is

[0425] [ka] In some embodiments, the linker is

[0426] [ka] In some embodiments, the linker is

[0427] [ka] In some embodiments, the linker is

[0428] [ka] In some embodiments, the linker is

[0429] [ka] In some embodiments, the linker is

[0430] [ka] In some embodiments, the linker is

[0431] [ka] In some embodiments, the linker is

[0432] [ka] In some embodiments, the linker is

[0433] [ka] In some embodiments, the linker is

[0434] [ka] In some embodiments, the linker is

[0435] [ka] In some embodiments, the linker is

[0436] [ka] In some embodiments, the linker's -C(O)- is bonded to the PBM. In some embodiments, the linker is -CH2-O-. In some embodiments, the linker is

[0437] [ka] In some embodiments, the linker is coupled to the LBM at O.

[0438]

[0224] In some embodiments of any formula described herein, the linker is

[0439] [ka] isn't it.

[0440]

[0225] In some embodiments of any formula described herein, each Cy is independently a monocyclic or bicyclic 3- to 11-membered divalent ring system which may be substituted, and which is fully saturated, partially saturated, or aromatic, and which contains 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently phenyl, C 9~10 Bicyclic aryl, 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 8-10 member bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic C 3~7The group may be substituted, selected from alicyclic, 5-10 membered bicyclic alicyclic, monocyclic 4-7 membered heterocyclil having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6-11 membered heterocyclil having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy may be substituted, selected from 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from phenyl, N, O, and S, monocyclic 4-7 membered heterocyclil having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6-11 membered heterocyclil having 1-3 heteroatoms independently selected from N, O, and S.

[0441]

[0226] In some embodiments, Cy is a phenyl compound that may be substituted. In some embodiments, Cy is a phenyl compound. In some embodiments, Cy is not a phenyl compound.

[0442]

[0227] In some embodiments, Cy may be replaced by C 9~10 It is a biring aryl group. In some embodiments, Cy may be substituted with C. 13~16 It is a polycyclic aryl structure.

[0443]

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

[0444]

[0229] In some embodiments, Cy is a substituted or alternatively substituted 8-10 member bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted or alternatively substituted 10-16 member polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

[0445]

[0230] In some embodiments, Cy may be a monocyclic C which may be substituted. 3~7 It is alicyclic. In some embodiments, Cy may be substituted with monocyclic C. 3~7 It is a cycloalkyl group. In some embodiments, Cy is a monocyclic C group which may be substituted. 4~6 These are cycloalkyl compounds (e.g., cyclobutane, cyclopentane, or cyclohexane).

[0446]

[0231] In some embodiments, Cy is a 5-10 member bicyclic alicyclic compound which may be substituted. In some embodiments, Cy is a 6-10 member bicyclic alicyclic compound which may be substituted. In some embodiments, Cy is a bicyclic 6-10 member crosslinked, condensed, or spirocyclic alicyclic compound which may be substituted.

[0447]

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

[0448]

[0233] In some embodiments, Cy is a substituted bicyclic 6- to 11-membered heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted bicyclic 6- to 11-membered bridged, condensed, or spiro-ring heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted bicyclic 7- to 11-membered spiro-ring heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted bicyclic 7-membered spiro-ring heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted bicyclic 7-membered bridged heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted bicyclic 8-membered spiro-ring heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted bicyclic 9-membered spiro-ring heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted bicyclic 10-membered spiro-ring heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is a substituted bicyclic 11-membered spiro-ring heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is,

[0449] [ka] A group which may be substituted, selected from the following. In some embodiments, Cy is

[0450] [ka] Selected from: In some embodiments, Cy is a substituted or alternative bicyclic 10-16 member heterocycline having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, -Cy- is spiro-cyclic. In some embodiments, -Cy- is a substituted or alternative spiro-cyclic diamine. In some embodiments, -Cy- is a substituted or alternative spiro-cyclic diamine bonded to the rest of the compound by two amino groups.

[0451]

[0234] In some embodiments, Cy is

[0452] [ka] A group which may be substituted, selected from the following. In some embodiments, Cy is

[0453] [ka] Selected from. In some embodiments, the linker includes -Cy-. In some embodiments, the linker is -Cy-.

[0454]

[0235] Rings are utilized in many of the formulas and compounds of this disclosure. In some embodiments, each monocyclic ring unit of a ring (e.g., -Cy-, in a particular R embodiment, ring B, ring C, or ring F) is independently 3 to 10 members (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), independently saturated, partially unsaturated, or aromatic, and independently having 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 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 6 members. In some embodiments, the monocyclic ring unit is 3 members. In some embodiments, the monocyclic ring unit is 4 members. In some embodiments, the monocyclic ring unit has 5 members. In some embodiments, the monocyclic ring unit has 6 members. 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 has no 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 embodiments, each monocyclic ring unit independently has a nitrogen atom.

[0455]

[0236] Various variable parts may be R' as described herein. In some embodiments, R' is hydrogen.

[0456]

[0237] In some embodiments, R' is -R as described herein. In some embodiments, R' is -C(O)R (wherein R is as described herein). In some embodiments, R' is -C(O)OR (wherein R is as described herein). In some embodiments, R' is -S(O)2R (wherein R is as described herein). In some embodiments, two R' groups on the same atom, or two groups that are or may be R', can come together with that atom to form a ring that may be substituted as described herein. In some embodiments, two R' atoms bonded to the same atom, together with the atom to which they are bonded, form a substituted 3-16 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1, 2, 3, 4, or 5) membered ring having 1-5 (e.g., 1-2, 1-3, 1-4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, two R' groups on the same atom may independently combine with that atom to form a substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 5-10, 3-8, 3-7, or 5-6) membered ring having 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms in addition to that atom. In some embodiments, the formed ring is substituted (in addition to the groups bonded to the intervening atom). In some embodiments, the formed ring is unsubstituted. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered. In some embodiments, the formed ring is 8-membered. In some embodiments, the formed ring is 9-membered. In some embodiments, the formed ring is 10-membered. 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, this is polycyclic. In some embodiments, each monocyclic unit is independently saturated, partially unsaturated, or aromatic and is a 3-10 (e.g., 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered ring having 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, each monocyclic unit is independently saturated, partially unsaturated, or aromatic and is a 3-10 (e.g., 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered ring having 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic ring unit is independently 3-7 membered. In some embodiments, each monocyclic ring unit is independently 3-6 membered. In some embodiments, each monocyclic ring unit is independently 5 to 7 members. In some embodiments, each monocyclic ring unit is independently saturated or partially unsaturated. 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, 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 addition to the intercalating atoms. In some embodiments, there are no additional heteroatoms. In some embodiments, there is one additional heteroatom. In some embodiments, there are two additional heteroatoms. In some embodiments, there are three additional heteroatoms. In some embodiments, there are four additional heteroatoms. In some embodiments, there are five additional heteroatoms. In some embodiments, there are six or more additional heteroatoms. In some embodiments, the additional heteroatom is nitrogen. In some embodiments, the additional heteroatom is oxygen. In some embodiments, the additional heteroatom is sulfur.

[0457]

[0238] Various variable parts may be R as described herein. Various embodiments of R may be other variable parts that may be R (e.g., R 1 , R 2This is described extensively in this specification, including in various sections concerning , or R').

[0458]

[0239] In some embodiments, R is -H. In some embodiments, R is not -H.

[0459]

[0240] In some embodiments, R may be replaced by 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) are aliphatic. In some embodiments, R may be substituted with C 1~6 It is aliphatic. In some embodiments, R may be substituted with C. 1~6 It is alkyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted n-propyl. In some embodiments, R is optionally substituted isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is t-butyl. In some embodiments, R is pentyl. In some embodiments, R is hexyl.

[0460]

[0241] In some embodiments, R may be a substituted C having 1 to 3 (e.g., 1, 2, or 3) 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. In some embodiments, R may be substituted with C having 1 to 3 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, and S. 1~6 It is heteroaliphatic. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[0461]

[0242] In some embodiments, R may be replaced by C 3~10 (For example, C 4~10 , C 3~9 , C 3~7 , or 3, 4, 5, 6, 7, 8, 9, or 10-membered alicyclic groups. 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 3-10 (e.g., C 4~10 , C 3~9 , C 3~7 , or 3, 4, 5, 6, 7, 8, 9, or 10) a alicyclic ring. In some embodiments, the alicyclic group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is optionally substituted cycloheptyl. In some embodiments, R is cyclopropyl. In some embodiments, R is cyclobutyl. In some embodiments, R is cyclopentyl. In some embodiments, R is cyclohexyl. In some embodiments, R is cycloheptyl.

[0462]

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

[0463]

[0244] In some embodiments, R may be replaced by C 6~10 (For example, C6 or C 10 ) is an aryl. In some embodiments, R may be a substituted C6 aryl. In some embodiments, R may be a substituted C 10It is an aryl ring. 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. In some embodiments, R is a phenyl ring. In some embodiments, R is an optionally substituted 10-membered aryl ring. In some embodiments, R is an optionally substituted naphthyl ring. In some embodiments, R is a naphthyl ring.

[0464]

[0245] In some embodiments, R is a substituted 5-10 (e.g., 5-9, 5-6, 5, 6, 7, 8, 9, or 10) membered heteroaryl having 1-5 (e.g., 1-5, 1-4, 1, 2, 3, 4, or 5) heteroatoms independently selected from N, O, and S. In some embodiments, R is a 5-10 (e.g., 5-9, or 5, 6, 9, or 10) membered heteroaryl having 1-4 (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. In some embodiments, 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 0-4 heteroatoms independently selected from, for example, N, O, and S, and at least one monocyclic unit contains 1-4 heteroatoms. In some embodiments, R is a substituted or alternatively substituted five-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a substituted or alternatively substituted six-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a substituted or alternatively substituted nine-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a substituted or alternatively substituted ten-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, the heteroaryl ring has 1 heteroatom. In some embodiments, the heteroaryl ring has 2 or more heteroatoms. In some embodiments, the heteroaryl ring has 3 or more heteroatoms. In some embodiments, the heteroaryl ring has 4 or more heteroatoms. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[0465]

[0246] In some embodiments of any formula described herein, each R is independently hydrogen, or C which may be substituted. 1~6 Aliphatic or substituted C 3~7 It is alicyclic. In some embodiments, each R may be independently hydrogen or substituted C 1~6 It is aliphatic. In some embodiments, each R is independently hydrogen or may be substituted with C 1~6 It is alkyl. In some embodiments, R is hydrogen. In some embodiments, R may be substituted C 1~6 It is aliphatic. In some embodiments, R may be substituted with C. 1~6 It is alkyl. In some embodiments, R is C 1~6 It is alkyl. In some embodiments, R may be substituted with C. 1~2 It is alkyl. In some embodiments, R is C 1~2 It is an alkyl group (e.g., methyl). In some embodiments, each R is C 1~2 It is an alkyl group (e.g., methyl). In some embodiments, R is a phenyl group which may be substituted. In some embodiments, R is a C group which may be substituted. 3~7 It is alicyclic. In some embodiments, R may be substituted with C. 3~7 The compound is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R is a substituted or substituted 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a substituted or substituted 5 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a substituted or substituted 6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is a substituted or substituted 3-7 member monocyclic heterocyclil having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R is a substituted or substituted 4-6 member monocyclic heterocyclil having 1-2 heteroatoms independently selected from N, O, and S.

[0466]

[0247] Various groups may be substituted as described herein. Substituents are routinely used in chemistry, including in the development of various therapeutic agents. Many substituents can be used in accordance with this disclosure. In some embodiments, groups that may be substituted are unsubstituted. In some embodiments, groups that may be substituted are substituted. In some embodiments, the substituents result in the formation of compounds for desired properties, activities, uses, etc., as described herein. In some embodiments, the compounds are stable for therapeutic use as described herein. The term “stable,” as used herein, means a compound that remains substantially unchanged when subjected to conditions that enable their manufacture, detection, and in certain embodiments, their recovery, purification, and use 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 of the substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus, and silicon. In some embodiments, each atom of the substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom of 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 non-halogen heteroatoms in the substituent is about 1 or less; in some embodiments, it is about 2 or less; in some embodiments, it is about 3 or less; in some embodiments, it is about 4 or less; in some embodiments, it is about 5 or less; in some embodiments, it is about 6 or less; in some embodiments, it is about 7 or less; in some embodiments, it is about 8 or less In some embodiments, this is about 9 or less; in some embodiments, this is about 10 or less; in some embodiments, this is about 11 or less; in some embodiments, this is about 12 or less; in some embodiments, this is about 13 or less; in some embodiments, this is about 14 or less; in some embodiments, this is about 15 or less; in some embodiments, this is about 20 or less. In some embodiments, the total number of carbons and non-halogen heteroatoms in each substituent is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or less. In some embodiments, the total number of carbons and non-halogen heteroatoms in each substituent is independently about 15 or less. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent is independently about 10 or less. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent is independently about 6 or less. Substituents of various sizes are described herein, including examples in various compounds. In some embodiments, each optional substituent on a substituted group (e.g., ring A, ring B, R, etc.) is independently halogen, C. 1~4 Alkyl, -OH, -CN, -NO2, C 1~4 Haloalkyl (e.g., -CF3), -OR SB , -N(R SB )2, -C(O)OR SB ,-C(O)N(R SB )2, or -S(O)2N(R SB)2(in the formula, each R SB These are independently -H, C 1~4 Alkyl or C 1~4 (It is a haloalkyl group). 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, C 1~4 It is a haloalkyl or -OH group. In some embodiments, each optional substituent on the substituted group (e.g., ring A, ring B, R, etc.) is independently a halogen or C 1~4 It is alkyl. Many substituents are exemplified in the compounds described herein, for example, in Table 1.

[0467]

[0248] In some embodiments of any formula described herein, the linker is R d , R e , R f , or R g One of them, which is linked to the part enclosed in parentheses, or the linker is one R i Or two R's i A ring formed when the groups are together, bonded to the part enclosed in parentheses. In some embodiments, the linker is R d , R e , R f , or R g In one of them, it is linked to the part enclosed in parentheses. In some embodiments, the linker is one R i or two R's i A ring formed when the groups are together, bonded to the portion enclosed in parentheses. In some embodiments, the linker is bonded to a position having -H or a monovalent substituent, such as a halogen or alkyl group. In some embodiments, the linker is bonded to a position having -H (for example, in the case of a compound with the structure PBM-H or LBM-H, the linker can replace -H to form the structure of a PBM-linker or LBM-linker, respectively).

[0468] LBM

[0249] In some embodiments, the LBM is

[0469] [ka] In some embodiments, the LBM is

[0470] [ka] In some embodiments, the LBM is

[0471] [ka] In some embodiments, the LBM is

[0472] [ka] In some embodiments, the LBM is

[0473] [ka] In some embodiments, the LBM is

[0474] [ka] In some embodiments of any formula described herein, LBM is the E3 ubiquitin ligase binding site, i.e., the site that can bind to E3 ubiquitin ligase. Typically, LBM is considered to be able to bind to E3 ubiquitin ligase if it specifically (i.e., preferentially) associates with E3 ubiquitin ligase when in contact with E3 ubiquitin ligase in the presence of at least one other protein. In some embodiments, LBM is considered to be able to bind to E3 ubiquitin ligase if it specifically associates with E3 ubiquitin ligase intracellularly (e.g., in vitro or in vivo). In some embodiments, compounds of LBM-H or a salt thereof, or LBM-linker-H or a salt thereof, are used to bind to approximately 1 μM or less of E3 ubiquitin ligase in assays such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). D If present, LBM is thought to be able to bind to E3 ubiquitin ligase. In some embodiments, compounds of LBM-H or its salt, or LBM-linker-H or its salt, exhibit an IC50 of approximately 1 μM or less than 1 μM in competitive or functional assays such as time-resolved fluorescence resonance energy transfer (TR-FRET). 50LBM has the following properties: LBM can bind to any suitable E3 ubiquitin ligase, including cereblon, von Hippel-Lindau protein, apoptosis inhibitory protein, MDM2, RNF114, DCAF16, DCAF15, KEAP1, FEM1B, aryl hydrocarbon receptor, etc. Some parts that can bind to E3 ubiquitin ligases are known in the art. For example, see Sun, X. et al., Signal Transduction and Targeted Therapy, 2019, 4, 64; Ishida, T. et al., SLAS Discovery, 2021, 26(4), 484-502; Bricelj, A. et al., Frontiers in Chemistry, 2021, 9, Article 707317; Min, J. et al., Angew. Chem. Int. Ed., 2021, 60, 26663-70; and International Publication No. 2019 / 140387, the entire contents of which are incorporated herein by reference. In some embodiments, techniques for identifying or evaluating LBMs are described in one or more of these references. Certain useful LBMs and technologies are described in International Publication Nos. 2017 / 197036, 2017 / 197046, 2017 / 197051, 2017 / 197055, 2017 / 197056, 2018 / 220149, 2018 / 237026, 2019 / 023553, 2019 / 043208, 2019 / 043214, 2019 / 043217, 2019 / 060693, and 2019 / 060742. International Publication Nos. 2019 / 099868, 2019 / 121562, 2019 / 133531, 2019 / 140380, 2019 / 140387, 2019 / 149922, 2019 / 191112, 2019 / 204354, 2019 / 236483, 2020 / 010177, 2020 / 010210, 2020 / 010227, 2020 / 051235, 2020 / 113233,International Publication Nos. 2020 / 132561, 2020 / 181232, 2020 / 206424, 2020 / 210630, 2020 / 251969, 2020 / 251971, 2020 / 251972, 2020 / 251974, 2020 / 264490, 2020 / 264499, 2021 / 011631, 2021 / 011634, 2021 / 011868, 2021 / 011 International Publication No. 871, International Publication No. 2021 / 083949, International Publication No. 2021 / 086785, International Publication No. 2021 / 119159, International Publication No. 2021 / 127190, International Publication No. 2021 / 127278, International Publication No. 2021 / 127283, International Publication No. 2021 / 127561, International Publication No. 2021 / 133917, International Publication No. 2021 / 133920, International Publication No. 2021 / 158634, International Publication No. 2021 / 178920, International Publication No. 2021 / 188696, International Publication No. 2021 / 188948, International Publication No. 2021 International Publication No. / 222366, International Publication No. 2021 / 231778, International Publication No. 2021 / 247897, International Publication No. 2021 / 247899, International Publication No. 2021 / 255212, International Publication No. 2021 / 255213, International Publication No. 2021 / 257914, International Publication No. 2022 / 027058, International Publication No. 2022 / 032026, International Publication No. 2022 / 032132, International Publication No. 2022 / 077010, International Publication No. 2022 / 081925, International Publication No. 2022 / 081927, International Publication No. 2022 / 081928, International Publication International Publication No. 2022 / 087216, International Publication No. 2022 / 125790, International Publication No. 2022 / 125800, International Publication No. 2022 / 125804, International Publication No. 2022 / 147465, International Publication No. 2022 / 174268, International Publication No. 2022 / 174269, International Publication No. 2022 / 178532, International Publication No. 2022 / 235945, International Publication No. 2022 / 236058, International Publication No. 2022 / 236339, International Publication No. 2022 / 251539, International Publication No. 2022 / 261250, International Publication No. 2023 / 039208,International Publication Nos. 2023 / 044046, 2023 / 049790, 2023 / 055952, 2023 / 076161, 2023 / 076556, 2023 / 107706, 2023 / 114933, 2023 / 137439, 2023 / 147594, 2023 / 154417, 2023 / 192578, 2023 / 192586, 2023 / 220 This is described in publications 425, International Publications 2023 / 239645, 2023 / 239697, 2023 / 239750, 2023 / 244764, 2023 / 250058, 2023 / 278402, 2023 / 278759, 2023 / 283372, 2023 / 283610, 2024 / 030628, 2024 / 039901, or 2024 / 039903.

[0475]

[0250] In some embodiments, the LBM is

[0476] [ka] (wherein the formula, the variable part is as defined and described in the Classes and Subclasses herein, both individually and in combination). In some embodiments, certain types and species of LBMs may provide improved properties and / or activity, such as improved stability, improved selectivity (e.g., to KAT2A rather than KAT2B), improved bioavailability, improved potency, and / or improved half-life. In some embodiments, the LBM has the following structure:

[0477] [ka] (wherein the formula, the variable part, both individually and in combination, is as defined and described in the Classes and Subclasses herein). In some embodiments, the LBM has the following structure:

[0478] [ka] (wherein the formula, the variable part, both individually and in combination, is as defined and described in the Classes and Subclasses herein). In some embodiments, the LBM has the following structure:

[0479] [ka] (wherein the formula, the variable part, both individually and in combination, is as defined and described in the Classes and Subclasses herein). In some embodiments, the LBM has the following structure:

[0480] [ka] (wherein the formula, the variable part, both individually and in combination, is as defined and described in the Classes and Subclasses herein). In some embodiments, the LBM has the following structure:

[0481] [ka] (wherein the formula, the variable part, both individually and in combination, is as defined and described in the Classes and Subclasses herein). In some embodiments, the LBM has the following structure:

[0482] [ka] (wherein the formula, the variable is as defined and described in the Classes and Subclasses herein, both individually and in combination). In some embodiments, ring C is an optionally substituted phenyl ring. In some embodiments, ring C is an optionally substituted 5-membered heteroaryl ring having 1 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 naphthyl 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 In some embodiments, L 2 is -NH-. In some embodiments, L 2 is -O-. In some embodiments, L 2 is -C(O)-NH- (where -C(O)- is bonded to ring C). In some embodiments, L 2 is -C(O)-NH- (wherein -NH- is bonded to ring C). In some embodiments, L 2 However, the linker is bonded to an atom adjacent to the atom to which it is bonded. In some embodiments, L 2 In the shortest path from the atom to which the linker is bonded to the atom to which the linker is bonded, L 2 There is one atom between the atom to which the linker is bonded and the atom to which the linker is bonded. In some embodiments, L 2 In the shortest path from the atom to which the linker is bonded to the atom to which the linker is bonded, L 2 Two atoms exist between the atom to which the linker is bonded and the atom to which the linker is bonded. In some embodiments, L 2In the shortest path from the atom to which the linker is bonded to the atom to which the linker is bonded, L 2 Three atoms exist between the atom to which the linker is bonded and the atom to which the linker is bonded. In some embodiments, L 2 In the shortest path from the atom to which the linker is bonded to the atom to which the linker is bonded, L 2 There are four atoms between the atom to which the linker is bonded and the atom to which the linker is bonded. For example, in some embodiments, the LBM may be substituted.

[0483] [ka] In some embodiments, the LBM is

[0484] [ka] That is the case.

[0485]

[0251] In some embodiments of any formula described herein, LBM is a cereblon (CRBN) binding portion, that is, a portion that can bind to cereblon.

[0486]

[0252] In some embodiments of any formula described herein, the LBM has the following structure:

[0487] [ka] (In the formula, R b , R c , and m, both individually and in combination, are as defined herein for formula IIIA and as described herein in its classes and subclasses; each A independently has N, C, or CH, except that two or fewer A groups are N. If A is a bonding site with the rest of the molecule, it will be understood to be C.

[0488]

[0253] In some embodiments of any formula described herein, the LBM has the following structure:

[0489] [ka] (In the formula, R b , R c , and m have, both individually and in combination, the same as defined herein for Formula IIIA and as described herein in its classes and subclasses.

[0490]

[0254] In some embodiments of any formula described herein, LBM is

[0491] [ka] Selected from.

[0492]

[0255] In some embodiments of any formula described herein, the LBM has the following structure:

[0493] [ka] (In the formula, B, L 2 , R c Y and m, both individually and in combination, have the following properties (as defined herein for formula IIIC, and as described herein for its classes and subclasses). It will be understood that C is the bond point with the rest of the molecule.

[0494]

[0256] In some embodiments of any formula described herein, the LBM has the following structure:

[0495] [ka] (In the formula, B, L 2 , R cY and m, both individually and in combination, have the following properties (as defined herein for Formula IIIC, and as described herein for its classes and subclasses).

[0496]

[0257] In some embodiments of any formula described herein, the LBM has the following structure:

[0497] [ka] (In the formula, B, L 2 , R c Y and m, both individually and in combination, have the following properties (as defined herein for Formula IIIC, and as described herein for its classes and subclasses).

[0498]

[0258] In some embodiments of any formula described herein, LBM is

[0499] [ka] (In the formula, B, L 2 , R c , and m are selected, both individually and in combination, from those defined herein for Formula IIIC (as described herein for its classes and subclasses).

[0500]

[0259] In some embodiments of any formula described herein, LBM is

[0501] [ka]

[0502] [ka]

[0503] [ka] Selected from.

[0504]

[0260] In some embodiments of any formula described herein, LBM is

[0505] [ka]

[0506] [ka]

[0507] [ka] Selected from.

[0508]

[0261] In some embodiments, R a is a halogen (e.g., -F, -Cl, or -Br). In some embodiments, R a is -CN. In some embodiments, R a However, this is -R' as described herein. In some embodiments, R a However, R is as described herein. In some embodiments, R a is -R, but not hydrogen. In some embodiments of any formula described herein, each R a C may be independently hydrogenated or substituted. 1~6 It is aliphatic. In some embodiments, each R a C may be independently hydrogenated or substituted. 1~6 It is alkyl. In some embodiments, each R a These independently produce hydrogen, halogen, -CN, and C. 1~6 Alkyl, or C 3~6 It is cycloalkyl. In some embodiments, each R aThese independently produce hydrogen, halogen, -CN, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, or C 6~10 It is an arrow. In some embodiments, each R a These independently produce hydrogen, halogen, -CN, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 An aryl or 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R a These independently produce hydrogen, halogen, -CN, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 A 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from aryl, N, O, and S, or a 3-10 membered monocyclic heterocyclil having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, each R a is hydrogen. In some embodiments, R a is hydrogen. In some embodiments, R a However, C may be substituted. 1~6 It is aliphatic. In some embodiments, R a However, C may be substituted. 1~6 It is alkyl. In some embodiments, R a C 1~6 It is alkyl. In some embodiments, R a However, C may be substituted. 1~2 It is alkyl. In some embodiments, R a C 1~2 It is alkyl (e.g., methyl). In some embodiments, R a However, C may be substituted. 3~6 It is alicyclic. In some embodiments, R a However, C may be substituted. 3~6 It is cycloalkyl. In some embodiments, R a C 3~4 It is a cycloalkyl (e.g., cyclopropyl). In some embodiments, R a C 6~10It is an arrow. In some embodiments, R a is phenyl. In some embodiments, R a is naphthyl. In some embodiments, R a However, it is a 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, R a However, it is a 5-6 member heteroaryl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, R a However, it is a 3- to 10-membered monocyclic heterocycline having 1 to 5 heteroatoms independently selected from N, O, and S. In some embodiments, R a However, it is a 4-6 membered monocyclic heterocycline having 1-3 heteroatoms independently selected from N, O, and S.

[0509]

[0262] In some embodiments, two R a Each of the groups, together with the atom to which they are bonded, forms an optionally substituted ring as described herein. In some embodiments, two R' groups a The groups, together with the atoms to which they are bonded, bond to form a 3- to 6-membered saturated or partially unsaturated ring (for example, a carbon ring or heterocycle having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two R groups a The groups, together with the atoms to which they are bonded, bond to form a 3- to 6-membered saturated ring (for example, a carbon ring or heterocycle having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two R groups a The groups, together with the atoms to which they are bonded, bond to form a 3-4 membered saturated ring (for example, a carbon ring or heterocycle having 1-2 heteroatoms independently selected from N, O, and S).

[0510]

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

[0511]

[0264] In some embodiments, L 2 In some embodiments, L 2 However, C may be substituted. 1~3 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR )NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L 2 However, linear C may be substituted. 1~3 A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR ) may be replaced by -NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments of any formula described herein, L 2 However, linear or branched C may be covalently bonded or substituted. 1~3 It is a hydrocarbon chain. In some embodiments, L 2 Covalent, linear, or branched C 1~3 It is a hydrocarbon chain. In some embodiments, L 2 Covalent, linear, or branched C 1~3A 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 In some embodiments, L 2 is linear or branched C 1~3 A hydrocarbon chain in which one methylene group may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 A is a C1 hydrocarbon chain, and one methylene group may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 The C2 hydrocarbon chain is either a straight-chain or a branched C2 hydrocarbon chain, and one methylene group may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 The C3 hydrocarbon chain is either a straight or branched C3 hydrocarbon chain, and one methylene group may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 The bond is covalent, -CH2-, -O-, or -N(R)-. In some embodiments, L 2 is -CH2-. In some embodiments, L 2 is -CH2-, -O-, or -N(R)-. In some embodiments, L 2 is -CH2-, -O-, or -N(H)-. In some embodiments, L 2 is -O- or -S-. In some embodiments, L 2 is -O-. In some embodiments, L 2 is -S-. In some embodiments, L 2 is -N(R)-. In some embodiments, L 2 is -N(H)-. In some embodiments, L 2 is -SO2-. In some embodiments, -C(O)N(R)- or -N(R)C(O)-. In some embodiments, L 2is -C(O)N(R)-. In some embodiments, L 2 is -N(R)C(O)-. In some embodiments, L 2 is -C(O)NH-. In some embodiments, L 2 is -NHC(O)-. In some embodiments, L 2 is -S(O)-. In some embodiments, L 2 is -S(O)N(R)-. In some embodiments, L 2 is -N(R)S(O)-. In some embodiments, L 2 is -S(O)NH-. In some embodiments, L 2 is -NHS(O)-. In some embodiments, L 2 is -S(O)2-. In some embodiments, L 2 is -N(R)S(O)2-. In some embodiments, L 2 is -S(O)2N(R)-. In some embodiments, L 2 is -NHS(O)2-. In some embodiments, L 2 is -S(O)2NH-. In some embodiments, L 2 This is -Cy- as described herein. In some embodiments, L 2 The compound is -Cy-, and -Cy- is aromatic.

[0512]

[0265] In some embodiments, ring E is

[0513] [ka] In some embodiments, ring E is

[0514] [ka] In some embodiments, ring E is

[0515] [ka] That is the case.

[0516]

[0266] In some embodiments, ring E may be substituted.

[0517] [ka] In some embodiments, ring E is

[0518] [ka] In some embodiments, ring E may be substituted.

[0519] [ka] In some embodiments, ring E is

[0520] [ka] In some embodiments, ring E may be substituted.

[0521] [ka] In some embodiments, ring E is

[0522] [ka] 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 stereoisomer, for example, during storage, administration, or after administration. In some embodiments, the compound has ring E as L 2Alternatively, with respect to the carbon bonded to ring C, it may be provided or administered as a stereochemically pure form or as a mixture of two stereoisomers. In some embodiments, ring E is L 2 The stereochemical purity of the compound in the composition with respect to the carbon center bonded to the ring C is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95%. In some embodiments, the stereochemical purity of the compound in the composition with respect to any other chiral center is about or at least about 90% or 95%.

[0523]

[0267] In some embodiments, ring E may be substituted.

[0524] [ka] In some embodiments, ring E is

[0525] [ka] That is the case.

[0526]

[0268] In some embodiments of any formula described herein, ring C is a monocyclic or bicyclic 3- to 10-membered divalent ring system which may be substituted, and which is fully saturated, partially saturated, or aromatic, and which contains 0 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is phenyl, C 5~6The group is a substituted group selected from alicyclic, 5-6 membered heteroaryls having 1-4 heteroatoms independently selected from N, O, and S, 5-6 membered heterocyclils having 1-2 heteroatoms independently selected from N, O, and S, and 9-10 membered bicyclic heteroaryls having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, the ring C is a substituted group selected from phenyl, 5-6 membered heteroaryls having 1-4 heteroatoms independently selected from N, O, and S, and 9-10 membered bicyclic heteroaryls having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, the ring C is a substituted phenyl, or a substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, the ring C is a substituted C3-C7 alicyclic ring, or a substituted 3-7 membered heterocycline having 1-2 heteroatoms independently selected from N, O, and S.

[0527]

[0269] In some embodiments, the ring C is a 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) 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.

[0528]

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

[0529]

[0271] In some embodiments, ring C is a C3-C7 alicyclic compound which may be substituted. In some embodiments, ring C is a C3-C7 cycloalkyl compound which may be substituted. In some embodiments, ring C is a C5-C6 alicyclic compound which may be substituted. In some embodiments, ring C is a C5-C6 cycloalkyl compound which may be substituted. In some embodiments, ring C is a cyclohexane compound.

[0530]

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

[0531]

[0273] In some embodiments, ring C is a substituted or substituted 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is a substituted or substituted 9 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is a substituted or substituted phthalimide, isoindorin-1-one, indazole, benzo[d][1,2,3]triazole, benzo[d]oxazole-2(3H)-one, 1,3-dihydro-2H-benzo[d]imidazole-2-one, or isoquinoline. In some embodiments, ring C is a substituted or substituted phthalimide or isoindorin-1-one. In some embodiments, ring C is a substituted or substituted 10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. For example, in some embodiments, ring C may be substituted or

[0532] [ka] In some embodiments, ring C is

[0533] [ka] In some embodiments, carbon atoms are bonded to the linker. In some embodiments, the ring C may be substituted.

[0534] [ka] In some embodiments, ring C is

[0535] [ka] In some embodiments, the carbon atoms of the phenyl ring are bonded to the linker.

[0536]

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

[0537]

[0275] In some embodiments, ring C is

[0538] [ka] (In the formula, Each A is independently N, C, or CH, except that two or fewer A groups are N; Each R b is hydrogen, or two R on the same carbon b The groups combine to form an oxo, or bond to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; (m is 0, 1, 2, or 3) That is the case.

[0539]

[0276] In some embodiments, ring C is

[0540] [ka] That is the case.

[0541]

[0277] In some embodiments, ring C is

[0542] [ka] Selected from.

[0543]

[0278] In some embodiments, ring C is

[0544] [ka] (In the formula, Each B is independently selected from N, C, and CH, except that two or fewer B are N; Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; (m is 0, 1, 2, or 3) That is the case.

[0545]

[0279] In some embodiments, ring C is

[0546] [ka] (In the formula, Each R c C may be a halogen, -OR, -N(R)2, -CN, or substituted C 1~6 Selected independently from aliphatic species; (m is 0, 1, 2, or 3) That is the case.

[0547]

[0280] In some embodiments, ring C is

[0548] [ka] Selected from. In some embodiments, ring C is

[0549] [ka] Selected from.

[0550]

[0281] In...

Claims

【Request Item 1】 【Chemistry 1-1】 [Chemistry 1-2] [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] [Chemistry 1-6] [Chemistry 1-7] A compound selected from, or a pharmaceutically acceptable salt thereof.

2. Compound of formula I: PBM-Linker-LBM I or a pharmaceutically acceptable salt thereof (In the formula, PBM is either the KAT2 protein binding site or 【Chemistry 2】 And; The linker is an optional linking part, or a covalently bonded or substituted divalent C １ ~C ２０ A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR) ２ )-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R )C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO ２ -, -SO ２ N(R)-, -N(R)SO ２ It may be replaced by - or -Cy-; LBM is either the E3 ubiquitin ligase binding site or 【Transformation 3】 And; Ring A is, 【Chemistry 4】 Selected from; Ring B is a substituted or otherwise substituted 5-6 membered heterocycline having 1-2 heteroatoms independently selected from N, O, and S; L １ This is a divalent C which may be covalently bonded or substituted. １～３ It is a hydrocarbon chain; Each R １ is independently, -R; n is 0, 1, 2, 3, or 4; Z is N or CR ３ And; R ２ is a halogen, -CN, or -R; Each R ３ These are independently halogen, -CN, or -R; R ４ is -R'; R ５ is either halogen, -CN, or -R, or R ２ and R ５ They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 0-2 heteroatoms independently selected from N, O, and S; R ６ is -R'; X is O or NR ７ And; R ７ is -R', or R ４ and R ７ They, together with the atoms to which they are bonded, form a substituted 5-6 membered ring having 2-3 heteroatoms independently selected from N, O, and S; L ３ , L ４ , and L ５ Each of these is independently a divalent C which may be covalently bonded or substituted. １ ~ ６ It is a hydrocarbon chain; Each R ８ It is independently -R'; R ９ is -R'; Each Cy is independently a substituted 3-16 membered divalent ring having 0-6 heteroatoms independently selected from N, O, and S; Each of rings C and F is independently a substituted 3- to 16-membered ring having 0-6 heteroatoms independently selected from N, O, and S; Each R ｂ These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L ２ C may be covalently bonded or substituted. １～３ A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR) ２ )-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R )C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO ２ -, -SO ２ N(R)-, -N(R)SO ２ It may be replaced by - or -Cy-; Ring E is, 【Transformation 5】 ,or 【Transformation 6】 A optionally substituted group selected from; Y is either N or CH; Each R ａ These are independently halogen, -CN, or -R'; Linker is R ｄ , R ｅ , R ｆ , or R ｇ One of them is linked to the part enclosed in parentheses, or the linker is one R ｉ or two R's ｉ A ring formed when the bases are together, bonded to the part enclosed in parentheses; Each R is not a linker joint point. ｄ Independently, it is either -R' or Two R's ｄ However, together with the atoms to which they are bonded, they form a 5-6 membered ring having 1-3 heteroatoms independently selected from N, O, and S, which may be condensed or substituted with phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Each R is not a linker joint point. ｅ Independently, it is -R; R ｆ If it is not a linker joint point, then it is -R; Each R is not a linker joint point. ｇ These are independently halogen, -CN, R, or -OR; p is 0, 1, 2, or 3; R ｈ is halogen or -R; Each R is not a linker joint point. ｉ These are independently halogen, -R, and -C(O)N(R'). ２ , or -N(R)C(O)R, or Two R's ｉ The groups, together with the atoms to which they are bonded, form a 5-6 membered ring having phenyl, which may be bonded and substituted, or 1-3 heteroatoms independently selected from N, O, and S; R ｊ is -R, or R ｊ R ｉ In one example, it combines with their intervening atoms to form a substituted 5-7 membered ring having 1-2 heteroatoms independently selected from N, O, and S; R ｋ is -R; r is 1, 2, 3, 4, or 5; q is either 1 or 2; R ｍ is -R; R ｎ , R ｐ , R ｑ , R ｒ , R ｓ , and R ｕ Each of these is independently a halogen, -CN, -R, or -OR; s is 0, 1, 2, 3, 4, or 5; t is 0, 1, 2, 3, 4, or 5; Each u is independently 0, 1, 2, 3, 4, or 5; Each R ｔ Independently, R is or Both R ｔ The groups, together with the atoms to which they are bonded, bond to form a substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; Each R ｖ These are independently halogen, -CN, -R or -OR, or R ｕ and R ｖ One example is that together with these intervening atoms, they bond to form a substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; Each R ｗ These are independently halogen, -CN, -R or -OR, or R ｕ and R ｗ One example is that together with these intervening atoms, they bond to form a substituted 3-7 membered ring having 0-2 heteroatoms independently selected from N, O, and S; Each v is independently 0, 1, 2, 3, 4, or 5; Each R' is independent of -R, -C(O)R, or -S(O). ２ R, or two R' atoms bonded to the same atom, together with the atom to which they are bonded, form a substituted 3-16 membered ring having 1-5 heteroatoms independently selected from N, O, and S; Each R is independently either hydrogen or C １ ~ ８ aliphatic, C ３ ~ １０ C having alicyclic carbon atoms, 1 to 3 heteroatoms independently selected from N, O, and S. １ ~C ８ Heteroliphatic, C ６ ~ １０ The group is a substituted group selected from 5- to 10-membered heteroaryls having 1 to 5 heteroatoms independently selected from aryl, N, O, and S, and a 3- to 10-membered monocyclic heterocycline having 1 to 5 heteroatoms independently selected from N, O, and S.

3. The compound according to claim 1 or 2, wherein the PBM is a KAT2A protein-binding portion and / or a KAT2B protein-binding portion.

4. PBM, 【Transformation 7】 The compound according to claim 2 or 3.

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

6. R ２ The compound according to any one of claims 2 to 5, wherein is a halogen.

7. Ring A is 【Transformation 8】 The compound according to any one of claims 2 to 5.

8. Ring A is 【Chemistry 9】 A compound according to claim 7, selected from the above.

9. Ring A is 【Chemistry 10】 The compound according to any one of claims 2 to 5.

10. R ６ However, C may be substituted. １～６ It is aliphatic and / or R ４ However, C may be substituted. １～６ The compound according to claim 9, wherein it is alkyl.

11. Ring A is 【Chemistry 11】 A compound selected from any one of claims 2 to 5.

12. The compound according to any one of claims 2 to 11, wherein ring B is a substituted or otherwise substituted six-membered heterocycline having one or two heteroatoms independently selected from N, O, and S.

13. Ring B may be substituted. 【Chemistry 12】 The compound according to any one of claims 2 to 11. 【Request Item 14】 【Chemistry 13】 but, 【Chemistry 14】 The compound according to any one of claims 2 to 11.

15. Each R １ C may be substituted independently. １～６ The compound according to any one of claims 2 to 14, wherein the compound is alkyl, preferably methyl.

16. L １ The compound according to any one of claims 2 to 15, wherein the bond is covalent. 【Request Item 17】 【Chemistry 15】 but, 【Chemistry 16-1】 【Chemistry 16-2】 A compound according to any one of claims 2 to 16, selected from the above.

18. The linker is less than 14 atomic lengths, or the linker is less than 11 atomic lengths; and / or The shortest path length of the linker is about 14 atoms or less, or the shortest path length of the linker is about 10 atoms or less; and / or the number of acyclic non - contiguous sp ３ atoms in the shortest path chain of the linker is about 5, 4, 3, 2 or 1 or about 5, 4, 3, 2 or 1 or less; and / or the number of acyclic non - contiguous sp ３ atoms in the shortest path chain of the linker is about 2 or about 2 or less; and / or the number of bonds between two acyclic sp ３ atoms in the shortest path chain of the linker is about 5, 4, 3, 2 or 1 or 5, 4, 3, 2 or 1 or less; and / or the number of bonds between two acyclic sp ３ atoms in the shortest path chain of the linker is about 1 or 1 or less; and / or the number of acyclic sp ３ atoms in the shortest path chain of the linker for C, O, and S atoms is about 5, 4, 3, 2 or 1 or about 5, 4, 3, 2 or 1 or less; and / or the number of acyclic sp ３ atoms in the shortest path chain of the linker is about 5, 4, 3, 2 or 1 or about 5, 4, 3, 2 or 1 or less; and / or the number of acyclic sp ３ atoms in the shortest path chain of the linker is about 1 or about 1 or less; and / or the number of acyclic atoms in the shortest path chain of the linker is about 5, 4, 3, 2 or 1 or about 5, 4, 3, 2 or 1 or less; and / or the number of acyclic atoms in the shortest path chain of the linker is about 1 or about 1 or less, a compound according to any one of claims 1 to 17.

19. The linker is an optionally substituted divalent linear or branched saturated or unsaturated C １ -C ２０ hydrocarbon chain, and one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR ２ ), -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO ２ -, -SO ２ N(R)-, -N(R)SO ２ -, or -Cy- and may be replaced, preferably: The linker may be a divalent linear or branched saturated or unsaturated C. １ ~C ２０ A hydrocarbon chain in which 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-; The compound according to any one of claims 2 to 17, wherein the methylene unit is replaced by -C(O)-, the methylene unit is replaced by -Cy-, preferably the -Cy- is in the shortest path chain, and / or the methylene unit is replaced by -C(O)N(R)-.

20. Linker, 【Chemistry 17】 (In the formula, M １ and M ２ Each is independent of non-existence, -CH ２ -, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; L ６ and L ７ Each of these is independently a divalent linear or branched saturated or unsaturated C, which may be covalently bonded or substituted. １ ~C １０ A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR) ２ )-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO ２ -, -SO ２ N(R)-, -N(R)SO ２ (May be replaced by - or -Cy-) The compound according to any one of claims 2 to 17.

21. Linker, [Chemistry 18] A compound according to any one of claims 2 to 17, selected from the above.

22. The compound according to any one of claims 2 to 17, wherein the -Cy- is monocyclic and may have 3 to 10 members, or the -Cy- is bicyclic and may have 6, 7, 8, 9, 10, or 11 members.

23. The compound according to 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 according to any one of claims 2 to 23, wherein Cy is a substituted or otherwise monocyclic 5-6 membered heterocycline having 1-2 heteroatoms independently selected from N, O, and S.

25. The compound according to any one of claims 2 to 23, wherein Cy is a substituted or alternatively substituted bicyclic or spiro-ring 6-11 member heterocyclil having 1 to 3 heteroatoms independently selected from N, O, and S.

26. Linker, 【Chemistry 19】 Selected from, or the linker is -CH ２ - 【Chemistry 20-1】 【Chemistry 20-2】 【Chemistry 20-3】 【Chemistry 20-4】 【Chemistry 20-5】 A compound according to any one of claims 2 to 20, selected from the above.

27. The compound according to any one of claims 2 to 26, wherein the LBM is an E3 ubiquitin ligase binding site, or the LBM is a VHL binding site, an IAP binding site, or an MDM2 binding site.

28. LBM, 【Chemistry 21】 The compound according to any one of claims 2 to 27.

29. Compound of formula III-1: 【Chemistry 22】 or a pharmaceutically acceptable salt thereof (In the formula, Each R ｂ These are independently halogen, -CN, -R', or -OR; t is 0, 1, 2, 3, or 4; L ２ C may be covalently bonded or substituted. １～３ A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR) ２ )-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R )C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO ２ -, -SO ２ N(R)-, -N(R)SO ２ It may be replaced by - or -Cy-; Ring E is, 【Chemistry 23】 ,or 【Chemistry 24】 A optionally substituted group selected from; Y is either N or CH; Each R ａ (These are independently halogen, -CN, or -R'.) The compound according to any one of claims 2 to 27.

30. LBM, 【Chemistry 25】 The compound according to any one of claims 2 to 27.

31. Compounds of formula IIIL: 【Chemistry 26】 or a pharmaceutically acceptable salt thereof (In the formula, Each R ｂ and R ｂ１ These are independently halogen, -CN, -R', or -OR; t' is 0, 1, 2, or 3; L ２ C may be covalently bonded or substituted. １～３ A hydrocarbon chain in which one or more methylene units are independently -O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR) ２ )-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R )C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -S(O)-, -SO ２ -, -SO ２ N(R)-, -N(R)SO ２ It may be replaced by - or -Cy-; Ring E is, 【Chemistry 27】 ,or 【Chemistry 28】 A optionally substituted group selected from; Y is either N or CH; Each R ａ (These are independently halogen, -CN, or -R'.) The compound according to any one of claims 2 to 27.

32. R ｂ１ Is it not H, or R? ｂ１ However, C may be substituted. １～６ It is either aliphatic or halogen, or R ｂ１ The result is -OR, and R may be substituted. １～６ The compound according to any one of claims 2 to 31, wherein the compound is aliphatic.

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

34. The compound according to any one of claims 2 to 31, wherein ring C is a substituted or alternatively substituted five- or six-membered heteroaryl ring having one or two heteroatoms independently selected from N, O, and S, or ring C is a substituted or alternatively substituted nine- or ten-membered bicyclic heteroaryl ring having one or four heteroatoms independently selected from N, O, and S.

35. Ring E is 【Chemistry 29】 Either the ring E is substituted, or the ring E may be substituted. 【Transformation 30】 A compound according to any one of claims 2 to 34, selected from the above.

36. Ring C is 【Chemistry 31】 (In the formula, Each A is independently N, C, or CH, except that two or fewer A groups are N; Each R ｂ is hydrogen, or two R on the same carbon ｂ The groups combine to form an oxo, or bond to form a 3- to 6-membered saturated or partially unsaturated ring; Each R ｃ is halogen, -OR, -N(R) ２ , -CN, and C which may be substituted １～６ Selected independently from aliphatic species; m is 0, 1, 2, or 3. The compound according to any one of claims 2 to 35.

37. L ２ The compound according to any one of claims 2 to 36, wherein the bond is covalent.

38. LBM or 【Chemistry 32】 The part, 【Chemistry 33-1】 【Chemistry 33-2】 【Chemistry 33-3】 A compound according to any one of claims 2 to 37, selected from the above.

39. LBM, 【Transformation 34】 The compound according to any one of claims 2 to 35.

40. PBM, 【Chemistry 35】 The compound according to claim 2 or 3.

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

42. Ring A is 【Transformation 36】 A compound according to claim 41, selected from the above.

43. LBM, 【Chemistry 37】 The compound according to any one of claims 40 to 42.

44. A compound according to any one of claims 1 to 43, which is a pharmaceutically acceptable salt form.

45. The compound according to any one of claims 1 to 44, wherein the stereochemical purity of each chiral center in the PBM is at least about 90%.

46. The compound according to any one of claims 1 to 45, wherein the stereochemical purity of each chiral center is at least about 90%.

47. The compound according to any one of claims 1 to 46, wherein the purity of the compound by qNMR is at least about 90% (by weight).

48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

50. The composition according to claim 48 or 49, comprising a buffer or a component thereof, preferably the buffer being a citrate buffer and / or the pH of the buffer being about 2 to 6.

5.

51. A composition according to any one of claims 48 to 50, comprising cyclodextrin.

52. A composition according to any one of claims 48 to 50, which is substantially free of cyclodextrin.

53. A method for preparing the pharmaceutical composition described in claim 48, A step of preparing a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof; A step of formulating the compound with an appropriate excipient to obtain the pharmaceutical composition, A method that includes this.

54. A method for reducing KAT2A and / or KAT2B of a system, comprising the step of administering or delivering to the system an effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 48 to 52.

55. A method for modulating a dysregulated cellular condition associated with KAT2A and / or KAT2B, comprising the step of administering or delivering to cells an effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 48 to 52.

56. The method according to claim 55, wherein the dysregulated cellular condition is cancer, for example, acute myeloid leukemia, small cell lung cancer, or neuroendocrine prostate cancer.

57. The method according to claim 55 or 56, wherein the dysregulated cell state is induced to or facilitates a conversion to another cell state; the dysregulated cell state is more proliferative than the other cell state; the dysregulated cell state is less differentiated than the other cell state; the dysregulated cell state is blocked or reduced differentiation, or comprises blocked or reduced differentiation; the dysregulated cell state is dedifferentiated or comprises dedifferentiation; the dysregulated cell state is transdifferentiation, or comprises transdifferentiation; the dysregulated cell state is a dedifferentiated neuroendocrine cell state, or comprises a dedifferentiated neuroendocrine cell state; and / or the other cell state is a more differentiated epithelial cell state, or comprises a more differentiated epithelial cell state.

58. The method according to any one of claims 55 to 57, wherein the other cellular state comprises elevated levels of CD11b, CD14, CD15, and / or CD86 expression; the method increases myelodifferentiation and / or decreases stem, translation and replication; and / or the method increases myelodifferentiation and / or decreases the GSEA sign of stem, translation and / or replication.

59. The method according to any one of claims 55 to 58, which increases the GSEA sign of epithelium; and / or increases the GSEA sign of nerves; and / or increases monocytic differentiation; and / or increases nerve differentiation; and / or increases epithelial differentiation; and / or increases the level of CD11b+ cells; and / or increases the level of CD14+ cells; and / or increases the level of CD15+ cells; and / or increases the level of CD86+ cells.

60. A method for reducing histone acetylation of a system, comprising the step of administering or delivering to the system an effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 48 to 52.

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

62. A method for degrading target KAT2, comprising the step of administering a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 48 to 52, to a subject requiring such degradation.

63. A method for inducing or promoting cell differentiation of a system, comprising the step of administering or delivering to the system an effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 48 to 52; or a method for reducing or blocking dedifferentiation of a system, comprising the step of administering or delivering to the system an effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 48 to 52; or a method for reducing or blocking transdifferentiation of a system, comprising the step of administering or delivering to the system an effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 48 to 52.

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

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

66. The method according to any one of claims 54 to 64, wherein the system is a cancer cell or includes a cancer cell.

67. The method according to 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 condition, comprising the step of administering or delivering an effective amount of a compound or composition according to any one of claims 1 to 52 to a subject suffering from the disease, disorder, or condition.

69. The method according to claim 68, wherein the disease, disorder, or condition is related to KAT2A and / or KAT2B.

70. The method according to claim 68 or 69, wherein the disease, disorder, or condition is cancer, or the disease, disorder, or condition is selected from acute myeloid leukemia, neuroblastoma, non-small cell lung cancer, small cell lung cancer, colorectal cancer, melanoma, prostate cancer, neuroendocrine prostate cancer, castration-resistant prostate cancer, high-grade neuroendocrine carcinoma, high-grade neuroendocrine carcinoma of the GI duct, high-grade neuroendocrine carcinoma of the pancreas, and pancreatic cancer.

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

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