Pyridazinone derivatives as inducers of KAT2 degradation for the treatment of proliferative disorders

Abstract

Provided herein are heterocyclic phenyl compounds useful as KAT2 degradation inducers, as well as compositions and methods of use thereof.

Description

[Technical Field]

[0001] Related Applications

[0001] This application claims priority to and the benefit of U.S. patent application Ser. No. 63 / 403,401, filed September 2, 2022, and U.S. patent application Ser. No. 63 / 460,764, filed April 20, 2023, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] KAT2A (also known as general control nondepressible 5 (GCN5)) and KAT2B (also known as p300 / CBP-associated factor (PCAF)) are multidomain proteins containing both an acetyltransferase domain and a bromodomain. Because both KAT2A and KAT2B can modify histones and recognize modified histones, they are considered epigenetic proteins. They are known 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 have been implicated in 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 with additional acute myeloid leukemia-causing mutations has been shown to delay leukemia development, deplete leukemia stem cells, and shift leukemia cell fate from self-renewal to differentiation, making the disease less aggressive. See, e.g., Domingues AP et al., eLife 9:e51754, 2020. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure provides compounds useful for modulating KAT2, e.g., decreasing KAT2 activity, e.g., by degrading (e.g., increasing the degradation of) KAT2 (e.g., KAT2A and / or KAT2B). In some embodiments, the provided compounds are useful for treating and / or preventing, inter alia, diseases, disorders, or conditions associated with KAT2 (e.g., KAT2A and / or KAT2B), e.g., KAT2 (e.g., KAT2A and / or KAT2B) protein levels and / or activity.

[0004]

[0004] Provided compounds include a protein-binding moiety capable of binding to a KAT2 protein (e.g., KAT2A and / or KAT2B) and an E3 ligase-binding moiety capable of binding to an E3 ubiquitin ligase. In some embodiments, provided compounds can recruit a KAT2 protein to an E3 ubiquitin ligase, thereby promoting (or otherwise inhibiting) the degradation of the KAT2 protein (e.g., KAT2A and / or KAT2B).

[0005] In some embodiments, the present disclosure provides a compound of formula I: PBM-Linker-LBM I or a pharmaceutically acceptable salt thereof, wherein PBM, linker, and LBM are as defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0006] Compounds and Definitions The compounds of the present disclosure include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Edition, Smith, MB and March, J., editors, John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0007]

[0007] Unless otherwise indicated, structures depicted herein are meant to represent all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, and all geometric or conformational isomeric forms of the structure. For example, if a stereocenter is present, in some embodiments, the R and / or S configurations of such stereocenters are considered part of the present disclosure. Thus, in some embodiments, single stereochemical isomers and / or enantiomeric, diastereomeric, and / or geometric (or conformational) mixtures of the provided compounds are within the scope of the present disclosure. For example, in some cases, Tables 1 and 2 depict one or more stereoisomers of a compound, and represent each stereoisomer alone and / or as a mixture unless otherwise indicated. Unless otherwise indicated, tautomeric forms of the provided compounds are within the scope of the present disclosure.

[0008] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13 C or 14Compounds having this structure including substitutions with C-enriched carbons are within the scope of this disclosure.

[0009] Aliphatic: The term "aliphatic" refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic" or "alicyclic"). Unless otherwise specified, an aliphatic group contains 1-12 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms (e.g., C 1~6 In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1~5 In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1~4 In yet other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms (e.g., C 1~3 ), and in still other embodiments, the aliphatic group contains 1-2 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 fully saturated or contains one or more units of unsaturation.

[0010] Alkyl: The term "alkyl," used alone or as part of a larger moiety, means (unless otherwise specified) an alkyl group having 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms (e.g., C 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~4 , C 1~3 , or C 1~2) refers to a saturated, optionally substituted, straight-chain or branched hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0011] Carbocyclyl: The terms "carbocyclyl," "carbocycle," and "carbocyclic ring," as used herein, refer to a saturated or partially unsaturated cycloaliphatic monocyclic, bicyclic, or polycyclic ring system as described herein, having 3 to 14 members, wherein the aliphatic ring system may be substituted as described herein. Carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, "carbocyclyl" (or "alicyclic") refers to an optionally substituted monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, or an optionally substituted C5-C6 hydrocarbon. 10 It refers to a bicyclic hydrocarbon. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl group has 3 to 6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0012] Alkenyl: The term "alkenyl," used alone or as part of a larger moiety, refers to an alkyl group having at least one double bond and (unless otherwise specified) 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C2~12 , C 2~10 , C 2~8 , C 2~6 , C 2~4 , or C 2~3 ) refers to an optionally substituted straight or branched hydrocarbon chain. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0013] Alkynyl: The term "alkynyl," used alone or as part of a larger moiety, refers to an alkynyl group having at least one triple bond and (unless otherwise specified) 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C 2~12 , C 2~10 , C 2~8 , C 2~6 , C 2~4 , or C 2~3 ) refers to an optionally substituted straight or branched chain hydrocarbon group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0014] Aryl: The term "aryl" refers to an alkyl group having a total of 6 to 14 ring members (e.g., C 6~14 ) 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, naphthyl, and the like, which may bear one or more substituents. Unless otherwise specified, "aryl" groups are hydrocarbons.

[0015] Heteroaryl: The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to a monocyclic or bicyclic ring group having 5 to 10 ring atoms (e.g., a 5- or 6-membered monocyclic heteroaryl or a 9- or 10-membered bicyclic heteroaryl) with 6, 10, or 14 pi electrons shared in the cyclic arrangement and having 1 to 5 heteroatoms in addition to the carbon atoms. Exemplary heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzisoxazolyl. The terms "heteroaryl" and "heteroar-," as used herein, also 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, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzisoxazolyl. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include optionally substituted rings.

[0016] Heteroatom: The term "heteroatom," as used herein, refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0017] Heterocycle: As used herein, the terms "heterocycle," "heterocyclyl," and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, e.g., 1 to 4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(such as N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. 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. A heterocyclyl group can be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. Bicyclic heterocyclic rings also include groups in which a 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. The bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., a 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) as defined above).

[0018] Partially unsaturated: As used herein, the term "partially unsaturated," when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties as defined herein.

[0019] Patient or Subject: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition is or can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient or subject is suffering from or 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 undergoing or has undergone a particular therapy to diagnose and / or treat a disease, disorder, or condition.

[0020] Specific binding: As used herein, the term "specific binding" refers to the ability to distinguish between possible binding partners in the environment in which binding occurs. A binding agent that interacts with a particular target in the presence of other possible targets is said to "specifically bind" to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining the degree and / or rate of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining the degree and / or rate of dissociation of the binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or determining the ability of the binding agent to compete with an alternative interaction between its partner and another entity. In some embodiments, specific binding is assessed by performing such detection or determination across a range of concentrations.

[0021] Substituted or optionally substituted: As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent (i.e., as described below for optionally substituted groups). "Substituted" applies to one or more hydrogens that are explicit or implicit from the structure (e.g.,

[0022] [ka] At least

[0023] [ka] refers to;

[0024] [ka] At least

[0025] [ka] Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that remain substantially unchanged when subjected to conditions that permit their preparation, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as "substituted" preferably have 1 to 4 substituents, more preferably 1 or 2 substituents. Groups described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0026] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(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°; optionally substituted with R° -(CH2) 0~4 Ph; optionally substituted with R° -(CH2) 0~4 O(CH2) 0~1 Ph; optionally substituted with R° -CH=CHPh; optionally substituted with 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 linear or branched alkylene)C(O)ON(R°), where each R° is optionally substituted as defined below and independently represents hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, two independent occurrences of R° taken together with their intervening atoms form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0027] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with their intervening atoms) are independently halogen, —(CH 2 ), 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -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 ● and each R ●is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0028] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═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-(wherein, R * Each independent occurrence of is hydrogen, optionally substituted as defined below. 1~6 aliphatic or unsubstituted 3-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2) 2~3 O-(wherein, R * Each independent occurrence of is hydrogen, optionally substituted as defined below. 1~6 aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029]

[0025] R * Suitable substituents on the aliphatic group include halogen, -R ●,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, when preceded by "halo", is substituted only with one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † are listed, and each R † are independently hydrogen, optionally substituted as defined below, C 1~6 an aliphatic or unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, R † two independent occurrences of, taken together with their intervening atoms, form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031]

[0027] R† Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, when preceded by "halo", is substituted only with one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] Treat: As used herein, the term "treat" (also "treatment" or "treating") refers to any administration of a therapy 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, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of subjects who do not exhibit signs of the associated disease, disorder, and / or condition and / or who exhibit only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of subjects who exhibit one or more established signs of the associated disease, disorder, and / or condition. In some embodiments, treatment may be of subjects who have been diagnosed with the associated disease, disorder, and / or condition.

[0033] Provided compounds

[0029] In some embodiments, the present disclosure provides a KAT2 degrader inducer compound comprising a KAT2 protein binding moiety, a linker, and an E3 ubiquitin ligase binding moiety.

[0034] In some embodiments, the present disclosure provides a compound of formula I PBM-Linker-LBM I or a pharmaceutically acceptable salt thereof (In the formula, PBM is KAT2 protein binding moiety; The linker is an optional linking moiety; LBM is the E3 ubiquitin ligase binding moiety) to provide.

[0035] In some embodiments, the present disclosure provides a compound of formula II

[0036] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is

[0037] [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 bond or a divalent C 1~3 a straight or branched hydrocarbon chain; Each R 1 are independently optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is hydrogen, halogen, -CN, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; Each R3 are independently hydrogen, halogen, or optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 4 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 5 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic, or R 2 and R 5 together with the atoms to which they are attached form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; X is O or NR 7 and; R 7 is hydrogen or optionally substituted C 1~6 aliphatic, or R 4 and R 7 are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is hydrogen or optionally substituted C 1~6 It is aliphatic; The linker is a covalent bond or an optionally substituted divalent linear or branched saturated or unsaturated 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)-, - may be replaced by -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-, -SON(R)-, -N(R)SO2-, or -Cy-; each Cy independently represents an optionally substituted, mono- or polycyclic, 3- to 16-membered, bivalent ring system that is fully saturated, partially saturated, or aromatic and that contains 0-6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C 1~6 Aliphatic, Phenyl, C 3~7 an optionally substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding moiety) to provide.

[0038] In some embodiments, the present disclosure provides: Ring A is

[0039] [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 bond or a divalent C 1~3 a straight or branched hydrocarbon chain; Each R 1 are independently optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; Each R 3 are independently hydrogen, halogen, or optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 4 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 5 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic, or R 2 and R 5 are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; X is O or NR 7 and; R 7 is hydrogen or optionally substituted C 1~6 aliphatic, or R 4 and R 7are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is hydrogen or optionally substituted C 1~6 It is aliphatic; The linker is a covalent bond or an optionally 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)-, - may be replaced by -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-, -SON(R)-, -N(R)SO2-, or -Cy-; each Cy independently represents an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system that is fully saturated, partially saturated, or aromatic and contains 0-6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C 1~6 Aliphatic, Phenyl, C 3~7 an optionally substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; LBM is an E3 ubiquitin ligase binding moiety; Provided is a compound of Formula II, or a pharmaceutically acceptable salt thereof:

[0040] In some embodiments, the present disclosure provides a compound of formula IIA:

[0041] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 1 , R 1 , R 9 , n, the linker, and LBM, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein.

[0042] In some embodiments, the present disclosure provides a compound of formula IIA-1, IIA-2, IIA-3, or IIA-4:

[0043] [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , X, Z, the linker, and LBM, both alone and in combination, are defined above for Formula II and as described in classes and subclasses herein. In some embodiments, the present disclosure provides compounds of formula IIA-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compounds of formula IIA-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compounds of formula IIA-3, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compounds of formula IIA-4, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the present disclosure provides a compound of formula IIA-1:

[0045] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is optionally substituted C 1~6 It is aliphatic; Z is N or CR 3 and; R 2 is hydrogen, halogen, -CN, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; Each R 3 are independently hydrogen or halogen; R 4 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 9 is hydrogen; The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 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 an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, a 4- to 7-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 6- to 11-membered bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or an optionally substituted C 1~6 It is aliphatic; LBM is

[0046] [ka] and; Ring C is an optionally substituted group selected from phenyl, a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and a 9- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; Each R a is hydrogen; L 2 is a covalent bond, —CH2—, —O—, or —N(R)—; Y is N or CH to provide.

[0047] In some embodiments, the present disclosure provides a compound of formula IIA-1:

[0048] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is C 1~6 is alkyl; Z is N or CR 3 and; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, or C 3~6 is cycloalkyl; Each R 3 are independently hydrogen or halogen; R 4 is C 1~6 is alkyl; R 9 is hydrogen; The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 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 an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, a 4- to 7-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 6- to 11-membered bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C 1~6 is alkyl; LBM is

[0049] [ka] and; Ring C is an optionally substituted group selected from phenyl, a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and a 9- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; Each R a is hydrogen; L 2 is a covalent bond, —CH2—, —O—, or —N(R)—; Y is N or CH to provide.

[0050] In some embodiments, the present disclosure provides a compound of formula IIA-5:

[0051] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 , the linker, and the LBM, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein.

[0052] In some embodiments, the present disclosure provides a compound of formula IIA-6:

[0053] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 , the linker, and the LBM, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein.

[0054] In some embodiments, the present disclosure provides a compound of formula III:

[0055] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein; Ring C is an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system, which is fully saturated, partially saturated, or aromatic, and which contains 0-6 heteroatoms independently selected from N, O, and S; Each R a are independently hydrogen or optionally substituted C 1~6 Aliphatic or two R a the groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a linear or branched C 1~3 a hydrocarbon chain in which one methylene may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; Y is N or CH to provide.

[0056] In some embodiments, the present disclosure provides a compound of formula IIIA:

[0057] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein; Each R b is hydrogen, or two R on the same carbon b the groups taken together form oxo or join to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) to provide.

[0058] In some embodiments, the present disclosure provides a compound of formula IIIB:

[0059] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 , R b , R c , m, and the linker, both alone and in combination, are as defined above for formula IIIA and as described in classes and subclasses herein.

[0060] In some embodiments, the present disclosure provides a compound of formula IIIB-1 or IIIB-2:

[0061] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 and the linker, both alone and in combination, is as defined above for Formula II and as described in classes and subclasses herein. In some embodiments, the present disclosure provides compounds of formula IIIB-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides compounds of formula IIIB-2, or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the present disclosure provides a compound of formula IIIC:

[0063] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , L 2 , R 1 , R 9 , Y, n, and the linker, both alone and in combination, are as defined above for Formula III and as described in classes and subclasses herein; each B is independently selected from N, C, and CH, provided that no more than two Bs are N; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) to provide.

[0064] In some embodiments, the present disclosure provides a compound of formula IIID:

[0065] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, B, L 2 , R 1 , R 9 , R c , Y, m, and the linker, both alone and in combination, are as defined above for formula IIIC and as described in classes and subclasses herein.

[0066] In some embodiments, the present disclosure provides a compound of formula IIID:

[0067] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is

[0068] [ka] and; R 1 is optionally substituted C 1~6 It is aliphatic; Z is N or CR 3 and; R 2 is hydrogen, halogen, -CN, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; Each R 3 are independently hydrogen or halogen; R 4 is optionally substituted C 1~6 It is aliphatic; R 9 is hydrogen; The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 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 an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, a 4- to 7-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a 6- to 11-membered bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or an optionally substituted C 1~6 It is aliphatic; L 2 is a covalent bond, —CH2—, —O—, or —N(R)—; Y is N or CH; each B is independently selected from N, C, and CH, provided that no more than two Bs are N; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) to provide.

[0069] In some embodiments, the present disclosure provides a compound of formula IIID:

[0070] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is

[0071] [ka] and; R 1 is C1~6 is alkyl; Z is N or CR 3 and; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, or C 3~6 is cycloalkyl; Each R 3 are independently hydrogen or halogen; R 4 is C 1~6 is alkyl; R 9 is hydrogen; The linker is

[0072] [ka] and; L 6 and L 7 are both covalent bonds; Cy is

[0073] [ka] Selected from; portion

[0074] [ka] teeth,

[0075] [ka] and; L 2 is a covalent bond; Y is CH; each B is independently selected from N, C, and CH, provided that no more than two Bs are N; Each R c is a halogen, -O(C 1~6 alkyl), and C1~6 independently selected from alkyl; m is 0, 1, 2, or 3) to provide.

[0076] In some embodiments, the present disclosure provides a compound of formula IV:

[0077] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein; The linker is R d , R e , R f , or R g One of the following is attached to the part enclosed in brackets; Each R that is not a linker attachment point d are independently hydrogen, —C(O)R, optionally substituted C 1~6 aliphatic, or The Two R's d are joined together with the atoms to which they are attached to form a 5- or 6-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S, which may be fused to a phenyl or a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, and S; Each R that is not a linker attachment point e are independently hydrogen or optionally substituted C 1~6 It is aliphatic; R f When not the attachment point of the linker, C is hydrogen or optionally substituted 1~6 It is aliphatic; Each R that is not a linker attachment point g are independently halogen, -OR, -CN, or optionally substituted C1~6 It is aliphatic; R h is hydrogen, halogen, or optionally substituted C 1~6 It is aliphatic; p is 0, 1, 2, or 3) to provide.

[0078] In some embodiments, the present disclosure provides a compound of formula IVA:

[0079] [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 the linker, both alone and in combination, are as defined above for formula IV and as described in classes and subclasses herein.

[0080] In some embodiments, the present disclosure provides a compound of formula IVA-1:

[0081] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 , R d , R e , R f , R g , R h , p, and the linker, both alone and in combination, are as defined above for formula IV and as described in classes and subclasses herein.

[0082] In some embodiments, the present disclosure provides a compound of formula V:

[0083] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein; The linker consists of one R i or two R's i The ring formed when the groups are taken together is attached to the part enclosed in brackets; Each R that is not a linker attachment point i are independently halogen, optionally substituted C 1~6 aliphatic, -C(O)N(R)2, or -N(R)C(O)R; The Two R's i groups, together with the atoms to which they are attached, are joined to form an optionally substituted phenyl or 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; R j is C 1~6 Aliphatic and C 3~7 an optionally substituted group selected from alicyclic; R j is R i and, together with the atom to which they are attached, form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S; R k is optionally substituted C 1~6 It is aliphatic; r is 1, 2, 3, 4, or 5; (q is 1 or 2) to provide.

[0084] In some embodiments, the present disclosure provides a compound of formula VA:

[0085] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , R i , R j , R k , n, q, r, and the linker, both alone and in combination, are as defined above for Formula V and as described in classes and subclasses herein.

[0086] In some embodiments, the present disclosure provides a compound of formula VA-1:

[0087] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 , R i , R j , R k , q, r, and the linker, both alone and in combination, are as defined above for Formula V and as described in classes and subclasses herein.

[0088] In some embodiments, the present disclosure provides a compound of formula VB:

[0089] [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 the linker, both alone and in combination, are as defined above for Formula V and as described in classes and subclasses herein.

[0090] In some embodiments, the present disclosure provides a compound of formula VB-1:

[0091] [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 the linker, both alone and in combination, are as defined above for Formula V and as described in classes and subclasses herein.

[0092] In some embodiments, the present disclosure provides a compound of formula VI:

[0093] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein; R m is optionally substituted C 1~6 It is aliphatic; Each R n are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; s is 0, 1, 2, 3, 4, or 5) to provide.

[0094] In some embodiments, the present disclosure provides a compound of formula VIA:

[0095] [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 the linker, both alone and in combination, are as defined above for Formula VI and as described in classes and subclasses herein.

[0096] In some embodiments, the present disclosure provides a compound of formula VIA-1:

[0097] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 , R m , R n , s, and the linker, both alone and in combination, are as defined above for Formula VI and as described in classes and subclasses herein.

[0098] In some embodiments, the present disclosure provides a compound of formula VII:

[0099] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein; Each R p are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; Each R q are independently halogen, -OR, -CN, or optionally substituted C1~6 It is aliphatic; Each R r are independently hydrogen or optionally substituted C 1~6 It is aliphatic; Each R s are independently halogen, -OR, -CN, or optionally substituted C 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.

[0100] In some embodiments, the present disclosure provides a compound of formula VIIA:

[0101] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 , R p , R q , R r , R s , u, t, and the linker, both alone and in combination, are as defined above for Formula VII and as described in classes and subclasses herein.

[0102] In some embodiments, the present disclosure provides a compound of formula VIII:

[0103] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, ring B, L 1 , R 1 , R 9 , n, and linker, both alone and in combination, are as defined above for Formula II and as described in classes and subclasses herein; Each R t are independently hydrogen or optionally substituted C 1~6aliphatic, or Both R t groups, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered alicyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S; Each R u are independently hydrogen, halogen, -CN, or optionally substituted C 1~6 It is aliphatic; Each R v are independently halogen, -OR, -CN, or optionally substituted C 1~6 aliphatic, or R u and R v an example of which, together with the atoms to which they are attached, combine to form an optionally substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each R w are independently halogen, -OR, -CN, or optionally substituted C 1~6 aliphatic, or R u and R w an example of which, together with the atoms to which they are attached, combine to form an optionally 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.

[0104] In some embodiments, the present disclosure provides a compound of formula VIIIA:

[0105] [ka] or a pharmaceutically acceptable salt thereof (wherein ring A, R 1 , R 9 , R t , R u , R v , R w, v, and linkers, both alone and in combination, are as defined above for Formula VIII and as described in classes and subclasses herein.

[0106] In some embodiments, the present disclosure provides a compound of formula IX:

[0107] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is

[0108] [ka] Selected from; L 3 , L 4 , and L 5 each independently represents a covalent bond or an optionally substituted divalent C 1~6 a straight or branched hydrocarbon chain; Z is N or CR 3 and; R 2 is hydrogen, halogen, -CN, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; Each R 3 are independently hydrogen, halogen, or optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 4 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 5 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic, or R 2and R 5 together with the atoms to which they are attached form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; X is O or NR 7 and; R 7 is hydrogen or optionally substituted C 1~6 aliphatic, or R 4 and R 7 are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; Each R 8 are independently hydrogen or optionally substituted C 1~6 It is aliphatic; R 9 is hydrogen or optionally substituted C 1~6 It is aliphatic; The linker is a covalent bond or an optionally 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)-, - may be replaced by -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-, -SON(R)-, -N(R)SO2-, or -Cy-; each Cy independently represents an optionally substituted, mono- or polycyclic, 3- to 16-membered, bivalent ring system that is fully saturated, partially saturated, or aromatic and that contains 0-6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C 1~6 Aliphatic, Phenyl, C 3~7 an optionally substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding moiety) to provide.

[0109] In some embodiments, the present disclosure provides: Ring A is

[0110] [ka] Selected from; L 3 , L 4 , and L 5 each independently represents a covalent bond or an optionally substituted divalent C 1~6 a straight or branched hydrocarbon chain; Z is N or CR 3 and; R 2 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; Each R 3 are independently hydrogen, halogen, or optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 4 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 5 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic, or R 2 and R 5 are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; X is O or NR 7 and; R 7 is hydrogen or optionally substituted C 1~6 aliphatic, or R 4 and R 7 are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; Each R 8 are independently hydrogen or optionally substituted C 1~6 It is aliphatic; R 9 is hydrogen or optionally substituted C 1~6 It is aliphatic; The linker is a covalent bond or an optionally substituted divalent linear or branched saturated or unsaturated 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)-, - may be replaced by -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-, -SON(R)-, -N(R)SO2-, or -Cy-; each Cy independently represents an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system that is fully saturated, partially saturated, or aromatic and contains 0-6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C 1~6 Aliphatic, Phenyl, C 3~7 an optionally substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; LBM is an E3 ubiquitin ligase binding moiety; Provided is a compound of formula IX, or a pharmaceutically acceptable salt thereof:

[0111] In some embodiments, the present disclosure provides a compound of formula IXA, IXB, IXC, or IXD:

[0112] [ka] or a pharmaceutically acceptable salt thereof (wherein, L 3 , L 4 , L 5 , R 2 , R 3 , R 4 , R 5, R 6 , R 8 , R 9 , X, Z, the linker, and LBM, both alone and in combination, are defined above for formula IX and as described in classes and subclasses herein. In some embodiments, the disclosure provides a compound of formula IXA, or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula IXB, or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula IXC, or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound of formula IXD, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the present disclosure provides a compound of formula X:

[0114] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 and the linker, both alone and in combination, is as defined above for formula IX and as described in classes and subclasses herein; Ring C is an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system, which is fully saturated, partially saturated, or aromatic, and which contains 0-6 heteroatoms independently selected from N, O, and S; Each R a are independently hydrogen or optionally substituted C 1~6 Aliphatic or two R a the groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a linear or branched C 1~3a hydrocarbon chain in which one methylene may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; Y is N or CH to provide.

[0115] In some embodiments, the present disclosure provides a compound of formula XA:

[0116] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 and the linker, both alone and in combination, is as defined above for formula IX and as described in classes and subclasses herein; Each R b is hydrogen, or two R on the same carbon b the groups taken together form oxo or join to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) to provide.

[0117] In some embodiments, the present disclosure provides a compound of formula XA-1 or XA-2:

[0118] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9and the linker, both alone and in combination, is as defined above for formula IX and as described in classes and subclasses herein. In some embodiments, the present disclosure provides a compound of formula XA-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula XA-2, or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the present disclosure provides a compound of formula XB:

[0120] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 2 , L 3 , L 4 , L 5 , R 8 , R 9 , Y, and the linker, both alone and in combination, are as defined above for formula X and as described in classes and subclasses herein; each B is independently selected from N, C, and CH, provided that no more than two Bs are N; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) to provide.

[0121] In some embodiments, the present disclosure provides a compound of formula XI:

[0122] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9and the linker, both alone and in combination, is as defined above for formula IX and as described in classes and subclasses herein; The linker is R d , R e , R f , or R g One of the following is attached to the part enclosed in brackets; Each R that is not a linker attachment point d are independently hydrogen, —C(O)R, or optionally substituted C 1~6 aliphatic, or The Two R's d are joined together with the atoms to which they are attached to form a 5- or 6-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S, which may be fused to a phenyl or a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, and S; Each R that is not a linker attachment point e are independently hydrogen or optionally substituted C 1~6 It is aliphatic; R f When not the attachment point of the linker, C is hydrogen or optionally substituted 1~6 It is aliphatic; Each R that is not a linker attachment point g are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; R h is hydrogen, halogen, or optionally substituted C 1~6 It is aliphatic; p is 0, 1, 2, or 3) to provide.

[0123] In some embodiments, the present disclosure provides a compound of formula XIA:

[0124] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 , R d , R e , R f , R g , R h , p, and the linker, both alone and in combination, are as defined above for formula XI and as described in classes and subclasses herein.

[0125] In some embodiments, the present disclosure provides a compound of formula XII:

[0126] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 and the linker, both alone and in combination, is as defined above for formula IX and as described in classes and subclasses herein; The linker consists of one R i or two R's i The ring formed when the groups are taken together is attached to the part enclosed in brackets; Each R that is not a linker attachment point i are independently halogen, optionally substituted C 1~6 aliphatic, -C(O)N(R)2, or -N(R)C(O)R; The Two R's i groups, together with the atoms to which they are attached, are joined to form an optionally substituted phenyl or 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; R j is C 1~6 Aliphatic and C 3~7an optionally substituted group selected from alicyclic; R j is R i and, together with the atom to which they are attached, form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S; R k is optionally substituted C 1~6 It is aliphatic; r is 1, 2, 3, 4, or 5; (q is 1 or 2) to provide.

[0127] In some embodiments, the present disclosure provides a compound of formula XIIA:

[0128] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 , R i , R j , R k , q, r, and the linker, both alone and in combination, are as defined above for Formula XII and as described in classes and subclasses herein.

[0129] In some embodiments, the present disclosure provides a compound of formula XIIB:

[0130] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R, R 8 , R 9 , R i , R j , Rk , q, r, and the linker, both alone and in combination, are as defined above for Formula XII and as described in classes and subclasses herein.

[0131] In some embodiments, the present disclosure provides a compound of formula XIIB-1:

[0132] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R, R 8 , R 9 , R j , R k and the linkers, both alone and in combination, are as defined above for Formula XII and as described in classes and subclasses herein.

[0133] In some embodiments, the present disclosure provides a compound of formula XIII:

[0134] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 and the linker, both alone and in combination, is as defined above for formula IX and as described in classes and subclasses herein; R m is optionally substituted C 1~6 It is aliphatic; Each R n are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; s is 0, 1, 2, 3, 4, or 5) to provide.

[0135] In some embodiments, the present disclosure provides a compound of formula XIIIA:

[0136] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 , R m , R n , s, and the linker, both alone and in combination, are as defined above for Formula XIII and as described in classes and subclasses herein.

[0137] In some embodiments, the present disclosure provides a compound of formula XIV:

[0138] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 and the linker, both alone and in combination, is as defined above for formula IX and as described in classes and subclasses herein; Each R p are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; Each R q are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; Each R r are independently hydrogen or optionally substituted C 1~6 It is aliphatic; Each R sare independently halogen, -OR, -CN, or optionally substituted C 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.

[0139] In some embodiments, the present disclosure provides a compound of formula XV:

[0140] [ka] or a pharmaceutically acceptable salt thereof (wherein rings A, L 3 , L 4 , L 5 , R 8 , R 9 and the linker, both alone and in combination, is as defined above for formula IX and as described in classes and subclasses herein; Each R t are independently hydrogen or optionally substituted C 1~6 aliphatic, or Both R t groups, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered alicyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S; Each R u are independently hydrogen, halogen, -CN, or optionally substituted C 1~6 It is aliphatic; Each R v are independently halogen, -OR, -CN, or optionally substituted C 1~6 aliphatic, or R u and R v an example of which, together with the atoms to which they are attached, combine to form an optionally substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each Rw are independently halogen, -OR, -CN, or optionally substituted C 1~6 aliphatic, or R u and R w an example of which, together with the atoms to which they are attached, combine to form an optionally 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.

[0141] In some embodiments of any formula described herein, the PBM is a KAT2 protein binding moiety, i.e., a moiety capable of binding to a KAT2 protein. In some embodiments, the PBM is a KAT2A protein binding moiety, i.e., a moiety capable of binding to a KAT2 protein. In some embodiments, the PBM is a KAT2B protein binding moiety, i.e., a moiety capable of binding to a KAT2B protein. Typically, a PBM is believed to be capable of binding to a KAT2 protein (e.g., KAT2A and / or KAT2B) when it specifically (i.e., preferentially) associates with the KAT2 protein when contacted with the KAT2 protein in the presence of at least one other protein. In some embodiments, it is believed that a PBM is capable of binding to a KAT2 protein when it specifically associates with the protein inside a cell (e.g., in vitro or in vivo).

[0142] In some embodiments, the PBM shares significant structural identity with a reference compound or portion thereof that can bind to the KAT2 protein. For example, in some embodiments, the PBM comprises the same or similar structure as the reference compound, except that the PBM comprises a point of attachment to a linker. In some embodiments, the reference compound has a K of less than 1 μM in a biophysical assay, such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). dIn some embodiments, the reference compound has an IC of less than 1 μM in a competition or functional assay, such as time-resolved fluorescence resonance energy transfer (TR-FRET). 50 In some embodiments, the reference compound has a DC of less than 30 nM in the Western blot assay of Example B1. 50 In some embodiments, the reference compound is a compound described in WO 2016 / 036954, WO 2016 / 036873, WO 2016 / 112298, Chaikuad, A. et al., J. Med. Chem., 2016, 59, 1648-53, Humphreys, P. G. et al., J. Med. Chem., 2017, 60, 2, 695-709, or Moustakim, M. et al., Angew. Chem. Int. Ed., 2017, 56, 827-31, the entire contents of each of which are incorporated herein by reference. In some embodiments, the reference compound is GSK4027:

[0143] [ka] In some embodiments, the reference compound is

[0144] [ka] is.

[0145] In some embodiments, the PBM has the following structure:

[0146] [ka] (In the formula, ring A, ring B, L 1 , R 1 , R 9 and n, both alone and in combination, are as defined herein for Formula II and as described in classes and subclasses herein.

[0147] In some embodiments, the PBM has the following structure:

[0148] [ka] (In the formula, rings A, L 1 , R 1 , R 9 and n, both alone and in combination, are as defined herein for Formula II and as described in classes and subclasses herein.

[0149] In some embodiments, the PBM has the following structure:

[0150] [ka] (In the formula, rings A, R 1 , and R 9 are as defined herein for Formula II, both alone and in combination, and as described in classes and subclasses herein.

[0151] In some embodiments, the PBM has the following structure:

[0152] [ka] (In the formula, rings A, R 1 , and R 9 are as defined herein for Formula II, both alone and in combination, and as described in classes and subclasses herein.

[0153] In some embodiments, the PBM has the following structure:

[0154] [ka] (In the formula, rings A, R 1 , and R 9 are as defined herein for Formula II, both alone and in combination, and as described in classes and subclasses herein.

[0155] In some embodiments, the PBM is:

[0156] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , X, and Z, alone and in combination, are as defined herein for Formula II and as described in classes and subclasses herein. is selected from.

[0157] In some embodiments, the PBM has the following structure:

[0158] [ka] (In the formula, rings A, L 3 , L 4 , L 5 , R 8 , and R 9 are as defined herein for Formula IX, both alone and in combination, and as described in classes and subclasses herein.

[0159] In some embodiments, the PBM is:

[0160] [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, alone and in combination, are as defined herein for formula IX and as described in classes and subclasses herein. is selected from.

[0161] In some embodiments, the PBM is:

[0162] [ka] is selected from.

[0163] In some embodiments of any of the formulas described herein, ring A is:

[0164] [ka] In some embodiments, ring A is

[0165] [ka] In some embodiments, ring A is

[0166] [ka] In some embodiments, ring A is

[0167] [ka] In some embodiments, ring A is

[0168] [ka] In some embodiments, ring A is

[0169] [ka] In some embodiments, ring A is

[0170] [ka] In some embodiments, ring A is

[0171] [ka] In some embodiments, ring A is

[0172] [ka] In some embodiments, ring A is

[0173] [ka] In some embodiments, ring A is selected from:

[0174] [ka] is selected from.

[0175] In some embodiments of any of the formulas described herein, ring A is:

[0176] [ka] In some embodiments, ring A is

[0177] [ka] In some such embodiments, R 2 and R 5 together with the atoms to which they are attached, combine to form an optionally substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, ring A is

[0178] [ka] is.

[0179] In some embodiments of any of the formulas described herein, ring A is:

[0180] [ka] In some embodiments, ring A is

[0181] [ka] In some embodiments, ring A is

[0182] [ka] In some such embodiments, R 2 and R 5 are joined together with the atoms to which they are attached to form an optionally 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 7together with the atoms to which they are attached form an optionally substituted 5-6 membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, ring A is

[0183] [ka] is selected from.

[0184] In some embodiments of any of the formulas described herein, ring A is:

[0185] [ka] In some embodiments, ring A is

[0186] [ka] is.

[0187] 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 (e.g., CH).

[0188] In some embodiments of any of the formulas described herein, R 2 is hydrogen, halogen, —CN, or optionally substituted C 1~6 In some embodiments, R 2 But hydrogen, halogen, -CN, C 1~6 Alkyl, or C 3~6 In some embodiments, R 2 is hydrogen, halogen, or optionally substituted C 1~6 In some embodiments, R 2 is halogen or C 1~6In some embodiments, R 2 is chloro, bromo, or methyl. 2 is hydrogen. In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo. In some embodiments, R 2 is -CN. In some embodiments, R 2 may be substituted C 1~6 In some embodiments, R 2 may be substituted C 1~6 In some embodiments, R 2 C 1~2 In some embodiments, R is alkyl (e.g., methyl or ethyl). 2 may be substituted C 3~6 In some embodiments, R 2 may be substituted C 3~6 In some embodiments, R 2 C 3~4 It is cycloalkyl (eg, cyclopropyl).

[0189] In some embodiments of any of the formulas described herein, each R 3 are independently hydrogen, halogen, or optionally substituted C 1~6 In some embodiments, each R 3 is hydrogen. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is bromo. In some embodiments, R 3 may be substituted C 1~6 In some embodiments, R3 may be substituted C 1~6 In some embodiments, R 3 C 1~2 In some embodiments, R 3 may be substituted C 3~6 In some embodiments, R 3 may be substituted C 3~6 In some embodiments, R 3 C 3~4 It is cycloalkyl (eg, cyclopropyl).

[0190] In some embodiments of any of the formulas described herein, R 4 is hydrogen or optionally substituted C 1~6 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 may be substituted C 1~6 In some embodiments, R 4 may be substituted C 1~6 In some embodiments, R 4 C 1~6 In some embodiments, R 4 may be substituted C 1~2 In some embodiments, R 4 C 1~2 In some embodiments, R 4 may be substituted C 3~6 In some embodiments, R 4 may be substituted C 3~6 In some embodiments, R 4 C 3~4 It is cycloalkyl (eg, cyclopropyl).

[0191] In some embodiments of any of the formulas described herein, R 5 is hydrogen, halogen, or optionally substituted C1~6 In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is halogen. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 is bromo. In some embodiments, R 5 may be substituted C 1~6 In some embodiments, R 5 may be substituted C 1~6 In some embodiments, R 5 C 1~2 In some embodiments, R 5 may be substituted C 3~6 In some embodiments, R 5 may be substituted C 3~6 In some embodiments, R 5 C 3~4 It is cycloalkyl (eg, cyclopropyl).

[0192] In some embodiments of any of the formulas described herein, R 2 and R 5 are joined together with the atoms to which they are attached to form an optionally 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 which, together with the atoms to which they are attached, have attached thereto 0-2 heteroatoms independently selected from N, O, and S, and one or more halogens, -R°, -OR°, -N(R°)2, and -CN on substitutable carbon atoms, and one or more -R on substitutable nitrogen atoms. † and -C(O)R † In some embodiments, R 2 and R 5are joined together with the atoms to which they are attached to form an optionally substituted 5-membered aromatic ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 and R 5 are linked to form an optionally substituted pyrrole. In some embodiments, R 2 and R 5 are joined together with the atoms to which they are attached to form an optionally substituted 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 and R 5 are bonded to form an optionally substituted phenyl or pyridine.

[0193] In some embodiments of any of the formulas described herein, R 6 is hydrogen or optionally substituted C 1~6 In some embodiments, R 6 is hydrogen. In some embodiments, R 6 may be substituted C 1~6 In some embodiments, R 6 may be substituted C 1~6 In some embodiments, R 6 C 1~6 In some embodiments, R 6 may be substituted C 1~2 In some embodiments, R 6 C 1~2 In some embodiments, R 6 may be substituted C 3~6 In some embodiments, R 6 may be substituted C 3~6 In some embodiments, R 6 C 3~4 It is cycloalkyl (eg, cyclopropyl).

[0194] 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 are joined together with the atoms to which they are attached to form an optionally substituted 5- or 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.

[0195] In some embodiments of any of the formulas described herein, R 7 is hydrogen or optionally substituted C 1~6 In some embodiments, R 7 is hydrogen. In some embodiments, R 7 may be substituted C 1~6 In some embodiments, R 7 may be substituted C 1~6 In some embodiments, R 7 C 1~6 In some embodiments, R 7 may be substituted C 1~2 In some embodiments, R 7 C 1~2 It is alkyl (eg, methyl).

[0196] In some embodiments of any of the formulas described herein, R 4 and R 7 are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 and R 7which, together with the atoms to which they are attached, have 2-3 heteroatoms bonded thereto, independently selected from N, O, and S, and one or more halogens, -R°, -OR°, -N(R°)2, and -CN on substitutable carbon atoms, and one or more -R on substitutable nitrogen atoms. † and -C(O)R † In some embodiments, R 4 and R 7 together with the atoms to which they are attached have 2-3 heteroatoms independently selected from N, O, and S bonded thereto, and one or more C 1~6 In some embodiments, R 4 and R 7 are joined together with the atoms to which they are attached to form a 5-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 and R 7 is linked to form an optionally substituted triazole. In some embodiments, R 4 and R 7 together with the atoms to which they are attached to form a six-membered aromatic ring having two to three heteroatoms independently selected from N, O, and S.

[0197] In some embodiments of any of the formulas described herein, R 9 is hydrogen or optionally substituted C 1~6 In some embodiments, R 9 is hydrogen. In some embodiments, R 9 may be substituted C 1~6 In some embodiments, R 9 may be substituted C 1~6 In some embodiments, R 9 C 1~6 In some embodiments, R 9 may be substituted C 1~2In some embodiments, R 9 C 1~2 It is alkyl (eg, methyl).

[0198] In some embodiments of any formula described herein, ring B is a 5-6 membered heterocyclyl having one heteroatom independently selected from N, O, and S. In some embodiments, ring B is a 5-6 membered heterocyclyl having one to two heteroatoms independently selected from N, O, and S, where at least one heteroatom is N. In some embodiments, ring B is a 5-membered heterocyclyl having one to two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is a 6-membered heterocyclyl having one to two heteroatoms independently selected from N, O, and S. In some embodiments, ring B is piperidine. In some embodiments, ring B is

[0199] [ka] In some embodiments, ring B is

[0200] [ka] is.

[0201] In some embodiments of any of the formulas described herein, L 1 is a covalent bond. In some embodiments, L 1 is a divalent C 1~3 In some embodiments, L 1 is a divalent C 1~3 In some embodiments, L 1 is a divalent C 1~2 In some embodiments, L 1 is -CH2-.

[0202] In some embodiments of any of the formulas described herein, each R 1 are independently optionally substituted C 1~6 Alkyl or optionally substituted C 3~6 In some embodiments, R 1 may be substituted C 1~6 In some embodiments, R 1 may be substituted C 1~6 In some embodiments, R 1 C 1~6 In some embodiments, R 1 may be substituted C 1~2 In some embodiments, R 1 C 1~2 In some embodiments, R 1 may be substituted C 3~6 In some embodiments, R 1 may be substituted C 3~6 In some embodiments, R 1 C 3~4 It is cycloalkyl (eg, cyclopropyl).

[0203] In some embodiments of any formula described herein, n is 0, 1, or 2. In some embodiments, n is 0 or 1. 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.

[0204] In some embodiments of any of the formulas described herein, L 3 is a covalent bond or an optionally substituted divalent C 1~3 In some embodiments, L 3 is a covalent bond. In some embodiments, L 3 is an optionally substituted divalent C 1~6In some embodiments, L 3 is a divalent C 1~6 In some embodiments, L 3 is an optionally substituted divalent C 1~3 In some embodiments, L 3 is a divalent C 1~3 In some embodiments, L 3 is selected from —CH2— and —CH(CH3)—.

[0205] In some embodiments of any of the formulas described herein, L 4 is a covalent bond or an optionally substituted divalent C 1~3 In some embodiments, L 4 is a covalent bond. In some embodiments, L 4 is an optionally substituted divalent C 1~6 In some embodiments, L 4 is a divalent C 1~6 In some embodiments, L 4 is an optionally substituted divalent C 1~3 In some embodiments, L 4 is a divalent C 1~3 In some embodiments, L 4 is selected from —CH2— and —CH(CH3)—.

[0206] In some embodiments of any of the formulas described herein, L 5 is a covalent bond or an optionally substituted divalent C 1~3 In some embodiments, L 5 is a covalent bond. In some embodiments, L 5 is an optionally substituted divalent C 1~6 In some embodiments, L 5 is a divalent C1~6 In some embodiments, L 5 is an optionally substituted divalent C 1~3 In some embodiments, L 5 is a divalent C 1~3 In some embodiments, L 5 is selected from —CH2— and —CH(CH3)—.

[0207] In some embodiments of any of the formulas described herein, each R 8 are independently hydrogen or optionally substituted C 1~6 In some embodiments, R 8 is hydrogen. In some embodiments, R 8 may be substituted C 1~6 In some embodiments, R 8 may be substituted C 1~6 In some embodiments, R 8 C 1~6 In some embodiments, R 8 may be substituted C 1~2 In some embodiments, R 8 C 1~2 In some embodiments, each R 8 C 1~2 It is alkyl (eg, methyl).

[0208] In some embodiments of any formula described herein, a linker is a linking moiety (i.e., any suitable divalent moiety that connects a PBM to an LBM). In some embodiments, the linker is of a particular length (e.g., measured by number of atoms). When describing the length of a 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, which is 14 atoms long (counted as indicated by the numbers in italics):

[0209] [ka] .

[0210] In some embodiments, the linker is 2 to 16 atoms in length. In some embodiments, the linker is 2 to 13 atoms in length. In some embodiments, the linker is 2 to 10 atoms in length. In some embodiments, the linker is 2 to 8 atoms in length. In some embodiments, the linker is 2 to 7 atoms in length. In some embodiments, the linker is 0 to 16 atoms in length. In some embodiments, the linker is 0 to 13 atoms in length. In some embodiments, the linker is 0 to 10 atoms in length. In some embodiments, the linker is 0 to 7 atoms in length. In some embodiments, the linker is 4 to 16 atoms in length. In some embodiments, the linker is 4 to 13 atoms in length. In some embodiments, the linker is 4 to 10 atoms in length. In some embodiments, the linker is 4 to 8 atoms in length. In some embodiments, the linker is 4 to 7 atoms in length. In some embodiments, the linker is less than 14 atoms in length. In some embodiments, the linker is less than 11 atoms in length. In some embodiments, the linker is less than 9 atoms in length. In some embodiments, the linker is less than 8 atoms in length.

[0211]

[0115] In some embodiments of any of the formulas described herein, the linker is a covalent bond.

[0212] In some embodiments of any of the formulas described herein, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated 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)-, - In some embodiments, the linker is an optionally substituted divalent, linear or branched, saturated or unsaturated C-C alkyl group. 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 In some embodiments, the linker is an optionally substituted divalent, linear or branched, saturated or unsaturated C-C alkyl group. 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 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-, -SON(R)-, -N(R)SO2-, or -Cy-.

[0213] In some embodiments, the linker is an optionally substituted, 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)-, - In some embodiments, the linker is an optionally substituted divalent, linear or branched, saturated or unsaturated C-C alkyl group. 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 In some embodiments, the linker is an optionally substituted divalent, linear or branched, saturated or unsaturated C-C alkyl group. 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 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-, -SON(R)-, -N(R)SO2-, or -Cy-.

[0214] In some embodiments, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 In some embodiments, the linker 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 an optionally substituted divalent linear or branched saturated or unsaturated C1-C 20In some embodiments, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C hydrocarbon chain, wherein at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. 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-.

[0215] In some embodiments, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 10 In some embodiments, the linker 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 an optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 In some embodiments, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C hydrocarbon chain, wherein at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. 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-.

[0216] In some embodiments, the linker comprises an ether moiety (e.g., —O—). In some embodiments, the linker comprises an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20In some embodiments, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 10 It is a hydrocarbon chain in which at least one methylene unit is replaced by -O-.

[0217] In some embodiments, the linker comprises an amine moiety (e.g., —N(R)—). In some embodiments, the linker comprises an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 A hydrocarbon chain in which at least one methylene unit is -N(R)- (e.g., -NH- or -N(C 1~6 In some embodiments, the linker is an optionally substituted 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 is replaced by alkyl)-).

[0218] In some embodiments, the linker comprises a carbonyl moiety. In some embodiments, the linker comprises an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 In some embodiments, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 10 It is a hydrocarbon chain in which at least one methylene unit is replaced by -C(O)-.

[0219] In some embodiments, the linker comprises an ester moiety. In some embodiments, the linker comprises an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20In some embodiments, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C2 hydrocarbon chain, in which at least one methylene unit is replaced by -OC(O)- or -C(O)O-. 10 It is a hydrocarbon chain in which at least one methylene unit is replaced by -OC(O)- or -C(O)O-.

[0220] In some embodiments, the linker comprises an amide moiety. In some embodiments, the linker comprises an optionally 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 In some embodiments, the linker is an optionally substituted 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 In some embodiments, the linker is an optionally substituted 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 In some embodiments, the linker is an optionally substituted divalent linear or branched saturated or unsaturated C1-C alkyl group. 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 is replaced by alkyl)C(O)—).

[0221] In some embodiments, the linker comprises a divalent ring moiety (e.g., -Cy-). In some embodiments, the linker comprises an optionally substituted divalent linear or branched saturated or unsaturated C1-C20 In some embodiments, the linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 10 is a hydrocarbon chain in which at least one methylene unit is replaced by -Cy-. In some such embodiments, Cy is not phenyl.

[0222] In some embodiments, the linker comprises a triple bond. In some embodiments, the linker comprises an optionally substituted, divalent, linear or branched, partially unsaturated C1-C2 alkyl group containing at least one triple bond. 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)-, - In some embodiments, the linker is an optionally substituted divalent linear or branched, partially unsaturated C1-C2 alkyl group containing at least one triple bond. 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)-, - In some embodiments, the linker is an optionally substituted divalent linear or branched, partially unsaturated C1-C2 alkyl group containing at least one triple bond. 20 In some embodiments, the linker 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 an optionally substituted divalent linear or branched, partially unsaturated C1-C linker 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-.

[0223] In some embodiments of any of the formulas described herein, the linker has the following structure:

[0224] [ka] wherein Cy, both alone and in combination, is as defined herein for Formula II and as described in classes and subclasses herein; M 1 and M 2are each independently absent, —CH—, —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 independently represents a covalent bond or an optionally substituted 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(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-, -SON(R)-, -N(R)SO-, or -Cy- It has.

[0225] In some embodiments of any of the formulas described herein, the linker is:

[0226] [ka] is selected from.

[0227] In some embodiments of any of the formulas described herein, the linker is:

[0228] [ka] is.

[0229] In some embodiments of any of the formulas described herein, the linker is:

[0230] [ka] is selected from.

[0231] In some embodiments of any of the formulas described herein, the linker has the following structure:

[0232] [ka] (In the formula, M 1 and M 2 are each independently absent, —CH—, —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 independently represents a covalent bond or an optionally substituted 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(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-, -SON(R)-, -N(R)SO-, or -Cy- It has.

[0233] In some embodiments of any of the formulas described herein, the linker is:

[0234] [ka] is selected from.

[0235] In some embodiments of any of the formulas described herein, the linker has the following structure:

[0236] [ka] (In the formula, M 1 and M 2 are each independently absent, —CH—, —O—, —N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, or —N(R)C(O)—; L 8 is a covalent bond or an optionally substituted divalent straight-chain 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)-, -SO-, -SON(R)-, -N(R)SO-, or -Cy- It has.

[0237] In some embodiments of any of the formulas described herein, the linker is:

[0238] [ka] is selected from.

[0239] In some embodiments of any of the formulas described herein, M 1 is —CH—, —O—, —N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, or —N(R)C(O)—. In some embodiments, M 1 is absent. In some embodiments, M 1 is -CH2-. In some embodiments, M 1 is —O—. In some embodiments, M 1 is —N(R)— (e.g., —N(H)— or —N(CH3)—). In some embodiments, M 1 is —C(O)—. In some embodiments, M 1 is -OC(O)-. In some embodiments, M 1 is —C(O)O—. In some embodiments, M 1 is —C(O)N(R)— (e.g., —C(O)N(H)— or —C(O)N(CH)—). In some embodiments, M 1 is —N(R)C(O)— (e.g., —N(H)C(O)— or —N(CH3)C(O)—).

[0240] In some embodiments of any of the formulas described herein, M 2 is —CH—, —O—, —N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, or —N(R)C(O)—. In some embodiments, M 2 is absent. In some embodiments, M 2 is -CH2-. In some embodiments, M 2 is —O—. In some embodiments, M 2 is —N(R)— (e.g., —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 2is —C(O)N(R)— (e.g., —C(O)N(H)— or —C(O)N(CH)—). In some embodiments, M 2 is —N(R)C(O)— (e.g., —N(H)C(O)— or —N(CH3)C(O)—).

[0241] In some embodiments of any of the formulas described herein, L 6 is a covalent bond.

[0242] In some embodiments, L 6 optionally substituted 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)-, - In some embodiments, L may be replaced by -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-, -SON(R)-, -N(R)SO-, or -Cy-. 6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 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( In some embodiments, L 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)-, -SO-, -SON(R)-, -N(R)SO-, or -Cy-.6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 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( and 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-, -SON(R)-, -N(R)SO2-, or -Cy-.

[0243] In some embodiments, L 6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 is a hydrocarbon chain, wherein 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 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 is 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-. 6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least two methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-.

[0244] In some embodiments, L 6optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 is a hydrocarbon chain, wherein 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 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 In some embodiments, L is 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)-. 6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least two methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0245] In some embodiments, L 6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 In some embodiments, L is a hydrocarbon chain, wherein one or more methylene units may be independently replaced by -O-. 6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 In some embodiments, L is a hydrocarbon chain in which at least one methylene unit is replaced by -O-. 6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 It is a hydrocarbon chain in which at least two methylene units are replaced by -O-.

[0246] In some embodiments, L 6 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10In some embodiments, L 6 is an optionally substituted divalent straight-chain or branched saturated C1-C 10 In some embodiments, L 6 is an optionally substituted divalent linear or branched saturated or unsaturated C1-C6 hydrocarbon chain. 6 is an optionally substituted divalent linear or branched saturated C1 to C6 hydrocarbon chain.

[0247] In some embodiments of any of the formulas described herein, L 7 is a covalent bond.

[0248] In some embodiments, L 7 optionally substituted 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)-, - In some embodiments, L may be replaced by -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-, -SON(R)-, -N(R)SO-, or -Cy-. 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 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( In some embodiments, L 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)-, -SO-, -SON(R)-, -N(R)SO-, or -Cy-. 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 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( and 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-, -SON(R)-, -N(R)SO2-, or -Cy-.

[0249] In some embodiments, L 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 is a hydrocarbon chain, wherein 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 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10is 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-. 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least two methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-.

[0250] In some embodiments, L 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 is a hydrocarbon chain, wherein 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 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 In some embodiments, L is 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)-. 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 A hydrocarbon chain in which at least two methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0251] In some embodiments, L 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10In some embodiments, L is a hydrocarbon chain, wherein one or more methylene units may be independently replaced by -O-. 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 In some embodiments, L is a hydrocarbon chain in which at least one methylene unit is replaced by -O-. 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 It is a hydrocarbon chain in which at least two methylene units are replaced by -O-.

[0252] In some embodiments, L 7 optionally substituted divalent linear or branched saturated or unsaturated C1-C 10 In some embodiments, L 7 is an optionally substituted divalent straight-chain or branched saturated C1-C 10 In some embodiments, L 7 is an optionally substituted divalent linear or branched saturated or unsaturated C1-C6 hydrocarbon chain. 7 is an optionally substituted divalent linear or branched saturated C1 to C6 hydrocarbon chain.

[0253] In some embodiments of any of the formulas described herein, L 6 and L 7 Both are covalent bonds.

[0254] In some embodiments of any of the formulas described herein, L 8 is a covalent bond.

[0255] In some embodiments, L 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15a 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)-, - In some embodiments, L may be replaced by -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-, -SON(R)-, -N(R)SO-, or -Cy-. 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 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( In some embodiments, L 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)-, -SO-, -SON(R)-, -N(R)SO-, or -Cy-. 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15A 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( and 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-, -SON(R)-, -N(R)SO2-, or -Cy-.

[0256] In some embodiments, L 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 is a hydrocarbon chain, wherein 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 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 is 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-. 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 A hydrocarbon chain in which at least two methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-.

[0257] In some embodiments, L 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15is a hydrocarbon chain, wherein 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 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 In some embodiments, L is 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)-. 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 A hydrocarbon chain in which at least two methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0258] In some embodiments, L 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 In some embodiments, L is a hydrocarbon chain, wherein one or more methylene units may be independently replaced by -O-. 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 In some embodiments, L is a hydrocarbon chain in which at least one methylene unit is replaced by -O-. 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 It is a hydrocarbon chain in which at least two methylene units are replaced by -O-.

[0259] In some embodiments, L 8 optionally substituted divalent linear or branched saturated or unsaturated C1-C 15 In some embodiments, L 8is an optionally substituted divalent straight-chain or branched saturated C1-C 15 In some embodiments, L 8 is an optionally substituted divalent linear or branched saturated or unsaturated C1-C6 hydrocarbon chain. 8 is an optionally substituted divalent linear or branched saturated C1 to C6 hydrocarbon chain.

[0260] In some embodiments of any of the formulas described herein, the linker is: -CH2-,

[0261] [ka]

[0262] [ka]

[0263] [ka]

[0264] [ka] is selected from.

[0265] In some embodiments of any of the formulas described herein, the linker is:

[0266] [ka] isn't it.

[0267] In some embodiments of any of the formulas described herein, each Cy is independently an optionally substituted monocyclic or bicyclic 3- to 11-membered bivalent ring system that is fully saturated, partially saturated, or aromatic and that contains 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently selected from phenyl, C 9~10 bicyclic aryl, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic C 3~7 and optionally substituted groups selected from alicyclic, 5- to 10-membered bicyclic alicyclic, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0268] In some embodiments, Cy is optionally substituted phenyl. In some embodiments, Cy is phenyl. In some embodiments, Cy is not phenyl.

[0269] In some embodiments, Cy is optionally substituted C 9~10 In some embodiments, Cy is an optionally substituted C 13~16 It is a polycyclic aryl.

[0270] In some embodiments, Cy is an optionally substituted 5- or 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted triazole. In some embodiments, Cy is an optionally substituted 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted pyridine, pyridazine, or pyrimidine.

[0271] In some embodiments, Cy is an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 10-16 membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

[0272] In some embodiments, Cy is an optionally substituted monocyclic C 3~7 In some embodiments, Cy is an optionally substituted monocyclic C 3~7 In some embodiments, Cy is an optionally substituted monocyclic C 4~6 cycloalkyl (eg, cyclobutane, cyclopentane, or cyclohexane).

[0273] In some embodiments, Cy is an optionally substituted 5- to 10-membered bicyclic alicyclic. In some embodiments, Cy is an optionally substituted 6- to 10-membered bicyclic alicyclic. In some embodiments, Cy is an optionally substituted 6- to 10-membered bicyclic bridged, fused, or spirocyclic alicyclic.

[0274]

[0165] In some embodiments, Cy is an optionally substituted monocyclic 4- to 7-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 5- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 4-membered heterocyclyl having 1 heteroatom independently selected from N, O, and S. In some embodiments, Cy is azetidine. In some embodiments, Cy is an optionally substituted monocyclic 5-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is pyrrolidine. In some embodiments, Cy is an optionally substituted monocyclic 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is piperidine or piperazine. In some embodiments, Cy is an optionally substituted monocyclic 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0275] In some embodiments, Cy is an optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 6- to 11-membered bridged, fused, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7- to 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered bridged bicyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 8-membered spirocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 9-membered spirocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 10-membered spirocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 11-membered spirocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is

[0276] [ka] In some embodiments, Cy is an optionally substituted bicyclic 10-16 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is

[0277] [ka] is selected from.

[0278] In some embodiments of any of the formulas described herein, each R is independently hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~7 In some embodiments, each R is independently hydrogen or an optionally substituted C 1~6 In some embodiments, each R is independently hydrogen or an optionally substituted C 1~6 In some embodiments, R is an alkyl. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C 1~6 In some embodiments, R is an optionally substituted C 1~6 In some embodiments, R is C 1~6 In some embodiments, R is an optionally substituted C alkyl. 1~2 In some embodiments, R is C 1~2 In some embodiments, each R is C 1~2 In some embodiments, R is an optionally substituted alkyl (e.g., methyl). In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted C 3~7 In some embodiments, R is an optionally substituted C 3~7In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, R is an optionally substituted 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S.

[0279] In some embodiments of any formula described herein, the LBM is an E3 ubiquitin ligase-binding moiety, i.e., a moiety capable of binding to an E3 ubiquitin ligase. Typically, an LBM is capable of binding to an E3 ubiquitin ligase when it specifically (i.e., preferentially) associates with the E3 ubiquitin ligase when contacted with the E3 ubiquitin ligase in the presence of at least one other protein. In some embodiments, an LBM is capable of binding to an E3 ubiquitin ligase when it specifically associates with the E3 ubiquitin ligase in a cell (e.g., in vitro or in vivo). An LBM may be capable of binding to any suitable E3 ubiquitin ligase, including cereblon, von Hippel-Lindau protein, inhibitor of apoptosis protein, MDM2, RNF114, DCAF16, DCAF15, KEAP1, FEM1B, aryl hydrocarbon receptor, etc. Some moieties capable of binding to E3 ubiquitin ligases are known in the art. See, for example, Sun, X. et al., Signal Transduction and Targeted Therapy, 2019, 4, 64; Ishida, T. et al., SLAS Discovery, 2021, 26(4), 484-502; Bricelj, A. et al., Frontiers in Chemistry, 2021, 9, Article 707317; Min, J. et al., Angew. Chem. Int. Ed., 2021, 60, 26663-70; and WO 2019 / 140387, the contents of each of which are incorporated herein by reference in their entirety.

[0280]

[0169] In some embodiments of any formula described herein, the LBM is a cereblon (CRBN) binding moiety, ie, a moiety that can bind to cereblon.

[0281] In some embodiments of any formula described herein, the LBM has the following structure:

[0282] [ka] (In the formula, rings C, L 2 , and R a are as defined herein for Formula III and as described in classes and subclasses herein, both alone and in combination.

[0283] In some embodiments of any formula described herein, the LBM has the following structure:

[0284] [ka] (In the formula, R b , R c and m, alone or in combination, are as defined herein for formula IIIA and as described in classes and subclasses herein; and each A is independently N, C, or CH, with the proviso that no more than two A groups are N. It is understood that A is C when it is the point of attachment to the rest of the molecule.

[0285] In some embodiments of any formula described herein, the LBM has the following structure:

[0286] [ka] (In the formula, R b , R c and m, alone or in combination, is as defined herein for formula IIIA and as described in classes and subclasses herein.

[0287] In some embodiments of any formula described herein, the LBM is:

[0288] [ka] is selected from.

[0289] In some embodiments of any formula described herein, the LBM has the following structure:

[0290] [ka] (In the formula, B, L 2 , R c , Y, and m, alone or in combination, are as defined herein for formula IIIC and as described in classes and subclasses herein. It is understood that when B is the point of attachment to the rest of the molecule, it is C.

[0291] In some embodiments of any formula described herein, the LBM has the following structure:

[0292] [ka] (In the formula, B, L 2 , R c , Y, and m, both alone and in combination, are as defined herein for formula IIIC and as described in classes and subclasses herein.

[0293] In some embodiments of any formula described herein, the LBM has the following structure:

[0294] [ka] (In the formula, B, L 2 , R c , Y, and m, both alone and in combination, are as defined herein for formula IIIC and as described in classes and subclasses herein.

[0295] In some embodiments of any formula described herein, the LBM is:

[0296] [ka] (In the formula, B, L 2 , R c and m, alone or in combination, is as defined herein for formula IIIC and as described in the classes and subclasses herein. is selected from.

[0297] In some embodiments of any formula described herein, the LBM is:

[0298] [ka]

[0299] [ka]

[0300] [ka] is selected from.

[0301] In some embodiments of any of the formulas described herein, each R a are independently hydrogen or optionally substituted C 1~6 In some embodiments, each R a are independently hydrogen or optionally substituted C 1~6 In some embodiments, each R a is hydrogen. In some embodiments, R a is hydrogen. In some embodiments, R a may be substituted C 1~6 In some embodiments, R a may be substituted C 1~6 In some embodiments, Ra C 1~6 In some embodiments, R a may be substituted C 1~2 In some embodiments, R a C 1~2 In some embodiments, two R a In some embodiments, two R groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring (e.g., a carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S). a In some embodiments, two R groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated ring (e.g., a carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S). a The groups, together with the atoms to which they are attached, combine to form a 3- to 4-membered saturated ring (e.g., a carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S).

[0302] In some embodiments of any formula described herein, Y is N. In some embodiments, Y is CH.

[0303] In some embodiments of any of the formulas described herein, L 2 is a covalent bond or a linear or branched C 1~3 In some embodiments, L 2 is a covalent bond or a linear or branched C 1~3 In some embodiments, L is a hydrocarbon chain in which one methylene is replaced with -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. 2 is a covalent bond. In some embodiments, L 2 Is linear or branched C 1~3It is a hydrocarbon chain, in which one methylene may be replaced with -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 is a C hydrocarbon chain, in which one methylene may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. 2 is a straight or branched C hydrocarbon chain, in which one methylene may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 is a straight or branched C hydrocarbon chain, in which one methylene may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L 2 is a covalent bond, —CH—, —O—, or —N(R)—. In some embodiments, L 2 is -CH2-. In some embodiments, L 2 is —CH—, —O—, or —N(R)—. In some embodiments, L 2 is —CH—, —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 In some embodiments, L is —SO—. In some embodiments, L is —C(O)N(R)— or —N(R)C(O)—. In some embodiments, L is —SO—. 2 is —C(O)N(R)—. In some embodiments, L 2 is -N(R)C(O)-.

[0304] In some embodiments of any formula described herein, Ring C is an optionally substituted monocyclic or bicyclic 3-10 membered bivalent ring system that is fully saturated, partially saturated, or aromatic and that contains 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is selected from phenyl, C 5~6 and optionally substituted groups selected from alicyclic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted phenyl or an optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted C3-C7 alicyclic or an optionally substituted 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0305] In some embodiments, Ring C is an optionally substituted phenyl. In some embodiments, Ring C is a phenyl.

[0306] In some embodiments, ring C is an optionally substituted 5- or 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 5- or 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 5-membered heteroaryl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is pyrrole. In some embodiments, ring C is an optionally substituted 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is pyridine, pyridone, or pyrimidine.

[0307]

[0185] In some embodiments, ring C is an optionally substituted C3-C7 alicyclic. In some embodiments, ring C is an optionally substituted C3-C7 cycloalkyl. In some embodiments, ring C is an optionally substituted C5-C6 alicyclic. In some embodiments, ring C is an optionally substituted C5-C6 cycloalkyl. In some embodiments, ring C is cyclohexane.

[0308] In some embodiments, ring C is an optionally substituted 3- to 7-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 4- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is a 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is piperidine or piperazine.

[0309] In some embodiments, ring C is an optionally substituted 9- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted 9-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring C is an optionally substituted phthalimide, isoindolin-1-one, indazole, benzo[d][1,2,3]triazole, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-benzo[d]imidazol-2-one, or isoquinoline. In some embodiments, ring C is an optionally substituted phthalimide or isoindolin-1-one. In some embodiments, ring C is an optionally substituted 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S.

[0310] In some embodiments, Ring C is an optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted 11-membered tricyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S (e.g., 6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione).

[0311] In some embodiments, Ring C is:

[0312] [ka] (In the formula, each A is independently N, C, or CH, provided that no more than two A groups are N; Each R b is hydrogen, or two R on the same carbon b the groups taken together form oxo or join to form a 3- to 6-membered saturated or partially unsaturated ring; Each Rc is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) is.

[0313] In some embodiments, Ring C is:

[0314] [ka] is.

[0315] In some embodiments, Ring C is:

[0316] [ka] is selected from.

[0317] In some embodiments, Ring C is:

[0318] [ka] (In the formula, each B is independently selected from N, C, and CH, provided that no more than two Bs are N; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) is.

[0319] In some embodiments, Ring C is:

[0320] [ka] (In the formula, Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) is.

[0321] In some embodiments, Ring C is:

[0322] [ka] In some embodiments, Ring C is selected from:

[0323] [ka] is selected from.

[0324] In some embodiments, Ring C is:

[0325] [ka]

[0326] [ka] is selected from.

[0327] In some embodiments of any formula described herein, each A is CH. In some embodiments, one A is N and the other A group is CH. In some embodiments, two A groups are N and the other A group is CH. When A is CH, R is, as defined herein. c may be substituted with, resulting in a ring that is -C(R c It will be understood that when A is the point of attachment to the rest of the molecule, it is also understood to be a C.

[0328] In some embodiments of any of the formulas described herein, each R b is hydrogen. In some embodiments, two R b In some embodiments, two R groups on the same carbon atom form an oxo group. b The group is attached to a 3- to 6-membered saturated or partially unsaturated ring (e.g., C 3~6 In some embodiments, two R on the same carbon form a heterocyclic ring (cycloaliphatic, cycloaliphatic, or 3-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S). b The group is bonded to C 3~6 In some embodiments, two R on the same carbon form a cycloalkyl (e.g., cyclopropyl). b The groups are joined to form a 3-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0329] In some embodiments of any of the formulas described herein, each B is selected from the group consisting of CH, CR c In some embodiments, one B is N and the other B group is CH or C. In some embodiments, two B groups are N and the other B group is CH or C. In some embodiments, B is N. In some embodiments, B is CH. In some embodiments, B is CR c In some embodiments, B is C. It is understood that B is C when it is the point of attachment to the rest of the molecule.

[0330] In some embodiments of any of the formulas described herein, each R c But halogen, -OH, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -CN, and optionally substituted C 1~6 In some embodiments, each R cBut halogen, -OH, -O(C 1~6 alkyl), -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl), -CN, and optionally substituted C 1~6 In some embodiments, each R c But halogen, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), C 1~6 Alkyl, and C 1~6 In some embodiments, each R c But halogen, -O(C 1~6 alkyl), C 1~6 Alkyl, and C 1~6 In some embodiments, each R c But halogen, -O(C 1~6 alkyl), and C 1~6 In some embodiments, R c is halogen (e.g., fluoro or chloro). In some embodiments, R c -OR (e.g., -OH, -O(C 1~6 alkyl), or -O(C 1~6 haloalkyl). In some embodiments, R c is —OCH or —OCF. In some embodiments, R c is -N(R)2 (e.g., -NH2, NH(C 1~6 alkyl), or -N(C 1~6 In some embodiments, R c is -CN. In some embodiments, R c may be substituted C 1~6 In some embodiments, R c may be substituted C 1~6 In some embodiments, R c C optionally substituted with one or more halogens 1~6 In some embodiments, R c C 1~6In some embodiments, R c may be substituted C 1~2 In some embodiments, R c optionally substituted with one or more halogens, optionally substituted C 1~2 In some embodiments, R c C 1~2 In some embodiments, R c C 1~6 In some embodiments, R c C 1~2 Haloalkyl (e.g., -CF3).

[0331] In some embodiments of any formula described herein, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0332]

[0201] In some embodiments of any formula described herein, the LBM is a von Hippel-Lindau protein (VHL) binding moiety, ie, a moiety that can bind to von Hippel-Lindau protein.

[0333] In some embodiments of any formula described herein, the LBM has the following structure:

[0334] [ka] (In the formula, R d , R e , R f , R g , R h and p, alone or in combination, is as defined herein for formula IV and as described in classes and subclasses herein. It has.

[0335] In some embodiments of any formula described herein, the LBM is:

[0336] [ka] (In the formula, R d , R e , R f , R g , R h and p, alone or in combination, is as defined herein for formula IV and as described in classes and subclasses herein. is selected from.

[0337] In some embodiments of any formula described herein, the LBM has the following structure:

[0338] [ka] (In the formula, R d , R e , R f , R g , R h and p, alone or in combination, is as defined herein for formula IV and as described in classes and subclasses herein. It has.

[0339] In some embodiments of any formula described herein, the LBM has the following structure:

[0340] [ka] (In the formula, R d , R e , R f , R g , R hand p, alone or in combination, is as defined herein for formula IV and as described in classes and subclasses herein. It has.

[0341] In some embodiments of any of the formulas described herein, the LBM moiety (e.g., VHL binding moiety) is R d In some embodiments, the LBM moiety (e.g., the VHL binding moiety) is attached to the linker at R e In some embodiments, the LBM moiety (e.g., the VHL binding moiety) is attached to the linker at R f In some embodiments, the LBM moiety (e.g., the VHL binding moiety) is attached to the linker at R g is attached to the linker.

[0342] In some embodiments of any formula described herein, each R that is not the point of attachment of a linker d are independently hydrogen, —C(O)R, or optionally substituted C 1~6 In some embodiments, R d is hydrogen. In some embodiments, R d is —C(O)R. In some embodiments, R d is -C(O) (optionally substituted C 1~6 In some embodiments, R d is -C(O) (optionally substituted C 3~6 In some embodiments, R d may be substituted C 1~6 In some embodiments, R d may be substituted C 1~6 In some embodiments, R d C 1~6 In some embodiments, R d may be substituted C 1~2 In some embodiments, R d C 1~2In some embodiments, two R d are joined together with the atoms to which they are attached to form a 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S, which may be fused to a phenyl or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, two R d are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, two R d are joined together with the atoms to which they are attached to form an optionally substituted 5- or 6-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S, or a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, and S, which is fused to a phenyl.

[0343] In some embodiments of any formula described herein, each R that is not the point of attachment of a linker e are independently hydrogen or optionally substituted C 1~6 In some embodiments, each R e may be substituted C 1~6 In some embodiments, each R e may be substituted C 1~6 In some embodiments, R e is hydrogen. In some embodiments, R e may be substituted C 1~6 In some embodiments, R e may be substituted C 1~6 In some embodiments, R e C 1~6 In some embodiments, R e may be substituted C 1~2 In some embodiments, Re C 1~2 It is alkyl (eg, methyl).

[0344] In some embodiments of any of the formulas described herein, R f is not the attachment point of the linker, hydrogen or optionally substituted C 1~6 In some embodiments, R f is hydrogen. In some embodiments, R f may be substituted C 1~6 In some embodiments, R f may be substituted C 1~6 In some embodiments, R f C 1~6 In some embodiments, R f may be substituted C 1~2 In some embodiments, R f C 1~2 It is alkyl (eg, methyl).

[0345] In some embodiments of any formula described herein, each R that is not the point of attachment of a linker g are independently halogen, -OR, -CN, or optionally substituted C 1~6 In some embodiments, R g is halogen (e.g., fluoro or chloro). In some embodiments, R g -OR (e.g., -OH or -O(C 1~6 In some embodiments, R g is -CN. In some embodiments, R g may be substituted C 1~6 In some embodiments, R g may be substituted C 1~6 In some embodiments, R g C 1~6 In some embodiments, R g may be substituted C 1~2In some embodiments, R g C 1~2 It is alkyl (eg, methyl).

[0346] In some embodiments of any of the formulas described herein, R h is hydrogen, halogen, or optionally substituted C 1~6 In some embodiments, R h is hydrogen. In some embodiments, R h is halogen (e.g., fluoro or chloro). In some embodiments, R h may be substituted C 1~6 In some embodiments, R h may be substituted C 1~6 In some embodiments, R h C 1~6 In some embodiments, R h may be substituted C 1~2 In some embodiments, R h C 1~2 It is alkyl (eg, methyl).

[0347] In some embodiments of any formula described herein, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0348]

[0213] In some embodiments of any formula described herein, the LBM is an inhibitor of apoptosis protein (IAP) binding moiety, ie, a moiety that can bind to an inhibitor of apoptosis protein.

[0349] In some embodiments of any formula described herein, the LBM has the following structure:

[0350] [ka] (In the formula, R i , R j , R k , r, and q, both alone and in combination, are as defined herein for Formula V and as described in classes and subclasses herein. It has.

[0351] In some embodiments of any formula described herein, the LBM is:

[0352] [ka] (In the formula, R i , R j , R k , r, and q, alone or in combination, are as defined herein for formula V and as described in classes and subclasses herein; ring D is a ring formed by two R i The ring formed when groups, together with the atoms to which they are attached, are bonded is selected from.

[0353] In some embodiments of any formula described herein, the LBM has the following structure:

[0354] [ka] (In the formula, R i , R j , R k , r, and q, both alone and in combination, are as defined herein for Formula V and as described in classes and subclasses herein. It has.

[0355] In some embodiments of any formula described herein, the LBM is:

[0356] [ka] (In the formula, R i , R j , R k , r, and q, alone or in combination, are as defined herein for formula V and as described in classes and subclasses herein; ring D is a ring formed by two R i The ring formed when groups, together with the atoms to which they are attached, are bonded is selected from.

[0357] In some embodiments of any formula described herein, the LBM has the following structure:

[0358] [ka] (In the formula, R, R i , R j , R k , r, and q, both alone and in combination, are as defined herein for Formula V and as described in classes and subclasses herein. It has.

[0359] In some embodiments of any formula described herein, the LBM has the following structure:

[0360] [ka] (In the formula, R, R j , and R k are as defined herein for Formula V, both alone and in combination, and as described in the classes and subclasses herein. It has.

[0361] In some embodiments of any formula described herein, the LBM has the following structure:

[0362] [ka] (In the formula, R m , R n and s, both alone and in combination, are as defined herein for Formula VI and as described in the classes and subclasses herein. It has.

[0363] In some embodiments of any formula described herein, the LBM has the following structure:

[0364] [ka] (In the formula, R m , R n and s, both alone and in combination, are as defined herein for Formula VI and as described in the classes and subclasses herein. It has.

[0365] In some embodiments of any of the formulas described herein, the LBM moiety (e.g., the IAP binding moiety) is R i In some embodiments, the LBM moiety (e.g., the IAP binding moiety) is attached to the linker at two R i The groups, together with the atoms to which they are attached, are attached to the linker in a ring that is formed upon bonding.

[0366] In some embodiments of any formula described herein, each R that is not the point of attachment of a linker i are independently halogen, optionally substituted C 1~6 aliphatic, -C(O)N(R), or -N(R)C(O)R. In some embodiments, R i is halogen (e.g., fluoro or chloro). In some embodiments, R i may be substituted C 1~6 In some embodiments, Ri may be substituted C 1~6 In some embodiments, R i C 1~6 In some embodiments, R i may be substituted C 1~2 In some embodiments, R i C 1~2 In some embodiments, R i is —C(O)N(R). In some embodiments, at least one R i is —C(O)N(R). In some embodiments, R i is —N(R)C(O)R. In some embodiments, two R i In some embodiments, two R groups, taken together with the atoms to which they are attached, form an optionally substituted phenyl or 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. i In some embodiments, two R groups, together with the atoms to which they are attached, are joined to form an optionally substituted phenyl. i The groups, together with the atoms to which they are attached, combine to form an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S.

[0367] In some embodiments of any of the formulas described herein, R j But C 1~6 Aliphatic and C 3~7 In some embodiments, R is an optionally substituted group selected from alicyclic. j may be substituted C 1~6 In some embodiments, R j may be substituted C 1~6 In some embodiments, R j C 1~6 In some embodiments, R is alkyl (e.g., tert-butyl or isopropyl). jmay be substituted C 1~2 In some embodiments, R j C 1~2 In some embodiments, R j may be substituted C 3~7 In some embodiments, R j may be substituted C 3~7 In some embodiments, R j C 3~7 In some embodiments, R is cycloalkyl (e.g., cyclohexyl). j R i and combine with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S.

[0368] In some embodiments of any of the formulas described herein, R k may be substituted C 1~6 In some embodiments, R k C 1~6 In some embodiments, R k may be substituted C 1~2 In some embodiments, R k C 1~2 It is alkyl (eg, methyl).

[0369] In some embodiments of any formula described herein, r is 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5.

[0370] In some embodiments of any formula described herein, q is 1. In some embodiments, q is 2.

[0371] In some embodiments of any of the formulas described herein, R m may be substituted C 1~6 In some embodiments, R m C 1~6 In some embodiments, R m may be substituted C 1~2 In some embodiments, R m C 1~2 It is alkyl (eg, methyl).

[0372] In some embodiments of any of the formulas described herein, each R n are independently halogen, -OR, -CN, or optionally substituted C 1~6 In some embodiments, R n is halogen (e.g., fluoro or chloro). In some embodiments, R n is -OR. In some embodiments, R n is -CN. In some embodiments, R n may be substituted C 1~6 In some embodiments, R n may be substituted C 1~6 In some embodiments, R n C 1~6 In some embodiments, R n may be substituted C 1~2 In some embodiments, R n C 1~2 It is alkyl (eg, methyl).

[0373] In some embodiments of any formula described herein, s is 0, 1, or 2. In some embodiments, s is 1, 2, or 3. In some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5.

[0374]

[0231] In some embodiments of any formula described herein, the LBM is an MDM2 binding moiety, ie, a moiety that can bind to MDM2.

[0375] In some embodiments of any formula described herein, the LBM has the following structure:

[0376] [ka] (In the formula, R p , R q , R r , R s , u, and t, both alone and in combination, are as defined herein for Formula VII and as described in the classes and subclasses herein. It has.

[0377] In some embodiments of any formula described herein, the LBM has the following structure:

[0378] [ka] (In the formula, R t , R u , R v , R w and v, alone or in combination, are as defined herein for Formula VIII and as described in the classes and subclasses herein. It has.

[0379] In some embodiments of any of the formulas described herein, each R p are independently halogen, -OR, -CN, or optionally substituted C 1~6 In some embodiments, each R p is halogen (e.g., chloro). In some embodiments, R p is halogen (e.g., chloro or fluoro). In some embodiments, R p is -OR. In some embodiments, R p is -CN. In some embodiments, R p may be substituted C 1~6 In some embodiments, R p may be substituted C 1~6 In some embodiments, R p C 1~6 In some embodiments, R p may be substituted C 1~2 In some embodiments, R p C 1~2 It is alkyl (eg, methyl).

[0380] In some embodiments of any of the formulas described herein, each R q are independently halogen, -OR, -CN, or optionally substituted C 1~6 In some embodiments, each R q is halogen (e.g., chloro). In some embodiments, R q is halogen (e.g., chloro or fluoro). In some embodiments, R q is -OR. In some embodiments, R q is -CN. In some embodiments, R q may be substituted C 1~6 In some embodiments, R q may be substituted C 1~6 In some embodiments, R q C1~6 In some embodiments, R q may be substituted C 1~2 In some embodiments, R q C 1~2 It is alkyl (eg, methyl).

[0381] In some embodiments of any of the formulas described herein, each R r are independently hydrogen or optionally substituted C 1~6 In some embodiments, R r is hydrogen. In some embodiments, R r may be substituted C 1~6 In some embodiments, R r may be substituted C 1~6 In some embodiments, R r C 1~6 In some embodiments, R r may be substituted C 1~2 In some embodiments, R r C 1~2 In some embodiments, each R r is methyl.

[0382] In some embodiments of any of the formulas described herein, each R s are independently halogen, -OR, -CN, or optionally substituted C 1~6 In some embodiments, each R s is halogen (e.g., chloro). In some embodiments, R s is halogen (e.g., chloro or fluoro). In some embodiments, R s -OR(e.g., -O(C 1~6 In some embodiments, R s is -CN. In some embodiments, R s may be substituted C 1~6 In some embodiments, Rs may be substituted C 1~6 In some embodiments, R s C 1~6 In some embodiments, R s may be substituted C 1~2 In some embodiments, R s C 1~2 It is alkyl (eg, methyl).

[0383] In some embodiments of any formula described herein, t is 0, 1, or 2. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 0 or 1. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5.

[0384] In some embodiments of any formula described herein, each u is independently 0, 1, or 2. In some embodiments, each u is independently 1, 2, or 3. In some embodiments, each u is independently 0 or 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.

[0385] In some embodiments of any of the formulas described herein, each R t are independently hydrogen or optionally substituted C 1~6 In some embodiments, R t is hydrogen. In some embodiments, R t may be substituted C 1~6 In some embodiments, R t may be substituted C 1~6 In some embodiments, R tC 1~6 In some embodiments, R is alkyl (e.g., tert-butyl or isobutyl). t may be substituted C 1~2 In some embodiments, R t C 1~2 In some embodiments, at least one R t may be substituted C 1~6 In some embodiments, both R t The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, both R t C groups, together with the atoms to which they are attached, may be bonded and substituted 3~7 Alicyclic (e.g., C such as cyclohexyl) 3~7 In some embodiments, both R t The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S.

[0386] In some embodiments of any formula described herein, each R u are independently hydrogen, halogen, —CN, or optionally substituted C 1~6 In some embodiments, R u is hydrogen. In some embodiments, at least one R u is hydrogen. In some embodiments, R u is halogen (e.g., fluoro or chloro). In some embodiments, R u is -CN. In some embodiments, R u may be substituted C 1~6 In some embodiments, R u may be substituted C 1~6 In some embodiments, Ru C 1~6 In some embodiments, R u may be substituted C 1~2 In some embodiments, R t C 1~2 It is alkyl (eg, methyl).

[0387] In some embodiments of any of the formulas described herein, each R v are independently halogen, -OR, -CN, or optionally substituted C 1~6 In some embodiments, each R v is halogen (e.g., chloro). In some embodiments, R v is halogen (e.g., chloro or fluoro). In some embodiments, R v -OR(e.g., -O(C 1~6 In some embodiments, R v is -CN. In some embodiments, R v may be substituted C 1~6 In some embodiments, R v may be substituted C 1~6 In some embodiments, R v C 1~6 In some embodiments, R v may be substituted C 1~2 In some embodiments, R v C 1~2 In some embodiments, R u and R v together with the atoms to which they are attached form an optionally substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R u and R vWhen taken together with the atoms to which they are attached, R u and R v An example of the following is a heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, which is optionally substituted with 3 to 7 members, together with the atoms to which they are attached.

[0388] In some embodiments of any of the formulas described herein, each R w are independently halogen, -OR, -CN, or optionally substituted C 1~6 In some embodiments, each R w is halogen (e.g., chloro). In some embodiments, R w is halogen (e.g., chloro or fluoro). In some embodiments, R w -OR(e.g., -O(C 1~6 In some embodiments, R w is -CN. In some embodiments, R w may be substituted C 1~6 In some embodiments, R w may be substituted C 1~6 In some embodiments, R w C 1~6 In some embodiments, R w may be substituted C 1~2 In some embodiments, R w C 1~2 In some embodiments, R u and R w together with the atoms to which they are attached form an optionally substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R u and R wWhen taken together with the atoms to which they are attached, R u and R w An example of the following is a heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, which is optionally substituted with 3 to 7 members, together with the atoms to which they are attached.

[0389] In some embodiments of any formula described herein, each v is independently 0, 1, or 2. In some embodiments, each v is independently 1, 2, or 3. In some embodiments, each v is independently 0 or 1. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 5.

[0390] In some embodiments of any formula described herein, the compound is:

[0391] [ka] isn't it.

[0392]

[0246] In some embodiments, the disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0393] [Table 1-1]

[0394] [Table 1-2]

[0395] [Table 1-3]

[0396]

Table 1-4

[0397]

Table 1-5

[0398]

Table 1-6

[0399]

Table 1-7

[0400]

Table 1-8

[0401]

Table 1-9

[0402]

Table 1-10

[0403]

Table 1-11

[0404]

Table 1-12

[0405]

Table 1-13

[0406]

Table 1-14

[0407]

Table 1-15

[0408]

Table 1-16

[0409]

Table 1-17

[0410]

Table 1-18

[0411]

Table 1-19

[0412]

Table 1-20

[0413]

Table 1-21

[0414]

Table 1-22

[0415]

Table 1-23

[0416]

Table 1-24

[0417]

Table 1-25

[0418]

Table 1-26

[0419]

Table 1-27

[0420]

Table 1-28

[0421]

Table 1-29

[0422]

Table 1-30

[0423]

Table 1-31

[0424]

Table 1-32

[0425]

Table 1-33

[0426]

Table 1-34

[0427]

Table 1-35

[0428]

Table 1-36

[0429]

Table 1-37

[0430]

Table 1-38

[0431]

Table 1-39

[0432]

Table 1-40

[0433]

Table 1-41

[0434]

Table 1-42

[0435]

Table 1-43

[0436]

Table 1-44

[0437]

Table 1-45

[0438]

Table 1-46

[0439]

Table 1-47

[0440]

Table 1-48

[0441]

Table 1-49

[0442]

Table 1-50

[0443]

Table 1-51

[0444]

Table 1-52

[0445]

Table 1-53

[0446]

Table 1-54

[0447]

Table 1-55

[0448]

Table 1-56

[0449]

Table 1-57

[0450]

Table 1-58

[0451]

Table 1-59

[0452]

Table 1-60

[0453]

Table 1-61

[0454]

Table 1-62

[0455]

Table 1-63

[0456]

Table 1-64

[0457]

Table 1-65

[0458]

Table 1-66

[0459]

Table 1-67

[0460]

Table 1-68

[0461]

Table 1-69

[0462]

Table 1-70

[0463]

Table 1-71

[0464]

Table 1-72

[0465]

Table 1-73

[0466]

Table 1-74

[0467]

Table 1-75

[0468]

Table 1-76

[0469]

Table 1-77

[0470]

Table 1-78

[0471]

Table 1-79

[0472]

Table 1-80

[0473]

Table 1-81

[0474]

Table 1-82

[0475]

Table 1-83

[0476]

Table 1-84

[0477]

Table 1-85

[0478]

Table 1-86

[0479]

Table 1-87

[0480]

Table 1-88

[0481]

Table 1-89

[0482]

Table 1-90

[0483]

Table 1-91

[0484]

Table 1-92

[0485]

Table 1-93

[0486]

Table 1-94

[0487]

Table 1-95

[0488]

Table 1-96

[0489]

Table 1-97

[0490]

Table 1-98

[0491]

Table 1-99

[0492]

Table 1-100

[0493]

Table 1-101

[0494] Table 1-102

[0495]

Table 1-103

[0496]

Table 1-104

[0497]

Table 1-105

[0498]

Table 1-106

[0499] Table 1-107

[0500]

Table 1-108

[0501]

Table 1-109

[0502]

Table 1-110

[0503]

Table 1-111

[0504]

Table 1-112

[0505]

Table 1-113

[0506]

Table 1-114

[0507]

Table 1-115

[0508]

Table 1-116

[0509]

Table 1-117

[0510]

Table 1-118

[0511]

Table 1-119

[0512]

Table 1-120

[0513]

Table 1-121

[0514] Table 1-122

[0515]

Table 1-123

[0516]

Table 1-124

[0517]

Table 1-125

[0518]

Table 1-126

[0519]

Table 1-127

[0520] Table 1-128

[0521]

Table 1-129

[0522] Table 1-130

[0523]

Table 1-131

[0524] Table 1-132

[0525]

Table 1-133

[0526] Table 1-134

[0527] Table 1-135

[0528]

Table 1-136

[0529]

Table 1-137

[0530]

Table 1-138

[0531]

Table 1-139

[0532] Table 1-140

[0533]

Table 1-141

[0534] Table 1-142

[0535] Table 1-143

[0536] Table 1-144

[0537]

Table 1-145

[0538] [Table 1-146]

[0539] [Table 1-147]

[0540] [Table 1-148]

[0541] [Table 1-149]

[0542] [Table 1-150]

[0543] [Table 1-151]

[0544] [Table 1-152]

[0545] [Table 1-153]

[0546] [Table 1-154]

[0547]

[0247] In some embodiments, the disclosure provides a compound selected from Table 2, or a pharmaceutically acceptable salt thereof.

[0548]

Table 2-1

[0549]

Table 2-2

[0550]

Table 2-3

[0551]

Table 2-4

[0552]

Table 2-5

[0553]

Table 2-6

[0554]

Table 2-7

[0555]

Table 2-8

[0556]

Table 2-9

[0557]

Table 2-10

[0558]

Table 2-11

[0559]

Table 2-12

[0560]

Table 2-13

[0561]

Table 2-14

[0562]

Table 2-15

[0563]

Table 2-16

[0564]

Table 2-17

[0565]

Table 2-18

[0566]

Table 2-19

[0567] In some embodiments, the present disclosure encompasses the recognition that provided compounds exhibit certain desirable characteristics, for example, compared to other known compounds (such as GSK983, GSK699, and / or GSK702, as described in Bassi, ZI et al., ACS Chem. Biol., 2018, 13, 2862-67). For example, in some embodiments, provided compounds are more potent than certain known compounds in one or more assays described herein, e.g., the Western blot assay of Example B1. In some embodiments, provided compounds are more soluble than certain known compounds, e.g., as measured by kinetic and / or thermodynamic solubility assays. In some embodiments, provided compounds have improved metabolic stability compared to certain known compounds, e.g., as measured by intrinsic clearance using an in vitro liver microsomal stability assay and / or in vivo pharmacokinetic analysis. In some embodiments, provided compounds have improved permeability, e.g., as measured by MDCK and / or Caco2 permeability assays. Without wishing to be bound by theory, provided compounds exhibiting an appropriate balance of any two or more of these properties may, in some embodiments, exhibit a high AUC, T 1 / 2 It will be appreciated that the compound may be particularly suitable for development as a drug, as evidenced by pharmacokinetic properties such as β-glucan, MRT, or CL.

[0568] In some embodiments, the present disclosure encompasses the recognition that provided compounds can degrade KAT2A, KAT2B, or both KAT2A and KAT2B. It will be appreciated that in some embodiments, compounds that can degrade both KAT2A and KAT2B will provide benefits over compounds that degrade only KAT2A or KAT2B. In other embodiments, compounds that selectively degrade KAT2A over KAT2B will be desirable. In other embodiments, compounds that selectively degrade KAT2B over KAT2A will be desirable.

[0569] In some embodiments, the provided compounds are provided and / or utilized in salt form (e.g., pharmaceutically acceptable salt form). Reference to the compounds provided herein is understood to include reference to salts thereof unless otherwise indicated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge et al., J. Pharmaceutical Sciences, 66:1-19 (1977), describe pharmaceutically acceptable salts in detail.

[0570]

[0251] Throughout this disclosure, unless otherwise indicated, it will be understood that references to compounds of formula I are also intended to include the species of compounds of formulae II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5, IIA-6, III, IIIA, IIIB, IIIB-1, IIIB-2, IIIC, IIID, IV, IVA, IVA-1, V, VA, VA-1, VB, VB-1, VI, VIA, VIA-1, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, IXC, IXD, X, XA, XA-1, XA-2, XB, XI, XIA, XII, XIIA, XIIB, XIIB-1, XIII, XIIIA, XIV, and XV, and the species of such formulae disclosed herein.

[0571] Preparation of the provided compounds

[0252] The provided compounds can generally be produced by the processes described in the following schemes and examples. In some embodiments, provided compounds (e.g., compounds with amide-containing linkers) are prepared according to the following scheme:

[0572] [ka] wherein PBM, linker, LBM, and R are as defined in the formulas herein. Thus, in some embodiments, compound A is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 in the presence of a suitable coupling agent (e.g., N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate), optionally in the presence of a suitable base (e.g., N-methylimidazole). In some embodiments, intermediate A.1 has the following structure:

[0573] [ka] In some embodiments, intermediate A.1 has the following structure:

[0574] [ka] It has.

[0575] In some embodiments, provided compounds (e.g., compounds having amide-containing linkers) are prepared according to the following scheme:

[0576] [ka] wherein PBM, linker, LBM, and Cy are as defined in the formulas herein. Thus, in some embodiments, compound B is prepared by a process comprising contacting intermediate A.1 with intermediate B.1 in the presence of a suitable coupling agent (e.g., N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate), optionally in the presence of a suitable base (e.g., N-methylimidazole). In some embodiments, intermediate A.1 has the following structure:

[0577] [ka] In some embodiments, intermediate A.1 has the following structure:

[0578] [ka] It has.

[0579] In some embodiments, provided compounds (e.g., compounds having linkers that include esters) are prepared according to the following scheme:

[0580] [ka] wherein PBM, linker, and LBM are as defined in the formula herein. Thus, in some embodiments, compound C is prepared by a process comprising contacting intermediate A.1 with intermediate C.1 in the presence of a suitable coupling agent (e.g., N,N'-diisopropylcarbodiimide), optionally in the presence of a suitable base (e.g., 4-dimethylaminopyridine). In some embodiments, intermediate A.1 has the following structure:

[0581] [ka] In some embodiments, intermediate A.1 has the following structure:

[0582] [ka] It has.

[0583]

[0255] In some embodiments, provided compounds are prepared according to the following scheme:

[0584] [ka] wherein PBM, linker, LBM, and Cy are as defined in the formulas herein. Thus, in some embodiments, compound D is prepared by a process comprising contacting intermediate D.1 with intermediate B.1, optionally in the presence of a suitable acid (e.g., AcOH) and in the presence of a suitable reducing agent (e.g., NaCNBH3). In some embodiments, intermediate D.1 has the following structure:

[0585] [ka] In some embodiments, intermediate D.1 has the following structure:

[0586] [ka] It has.

[0587]

[0256] In some embodiments, provided compounds are prepared according to one of the following schemes:

[0588] [ka] wherein PBM, linker, LBM, and Cy are as defined in the formulas herein. Thus, in some embodiments, compound D is prepared by a process comprising contacting intermediate E.1 with intermediate B.1, optionally in the presence of a suitable base (e.g., Cs2CO3). In some embodiments, compound E is prepared by a process comprising contacting intermediate E.1 with intermediate C.1, optionally in the presence of a suitable base (e.g., Cs2CO3). In some embodiments, intermediate E.1 has the following structure:

[0589] [ka] In some embodiments, intermediate E.1 has the following structure:

[0590] [ka] It has.

[0591] In some embodiments, provided compounds (e.g., compounds having a linker comprising a triazole ring) are prepared according to the following scheme:

[0592] [ka] wherein PBM, linker, and LBM are as defined in the formula herein. Thus, in some embodiments, compound F is prepared by a process comprising contacting intermediate F.1 with intermediate F.2, optionally in the presence of a suitable catalyst (e.g., a copper catalyst). In some embodiments, intermediate F.1 has the following structure:

[0593] [ka] In some embodiments, intermediate F.1 has the following structure:

[0594] [ka] It has.

[0595] composition

[0258] The present disclosure also provides compositions that include or deliver the compounds provided herein. In some embodiments, the present disclosure provides compositions that include a compound provided herein together with one or more other ingredients.

[0596] In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., a compound of Formula I, II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5, IIA-6, III, IIIA, IIIB, IIIB-1, IIIB-2, IIIC, IIID, IV, IVA, IVA-1, V, VA, VA-1, VB, VB-1, VI, VIA, VIA-1, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, IXC, IXD, X, XA, XA-1, XA-2, XB, XI, XIA, XII, XIIA, XIIB, XIIB-1, XIII, XIIIA, XIV, and XV).

[0597] In some embodiments, provided compositions are pharmaceutical compositions that comprise and / or deliver a compound provided herein (e.g., a compound of Formula I, II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5, IIA-6, III, IIIA, IIIB, IIIB-1, IIIB-2, IIIC, IIID, IV, IVA, IVA-1, V, VA, VA-1, VB, VB-1, VI, VIA, VIA-1, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, IXC, IXD, X, XA, XA-1, XA-2, XB, XI, XIA, XII, XIIA, XIIB, XIIB-1, XIII, XIIIA, XIV, and XV), and further comprise a pharmaceutically acceptable carrier.

[0598] Pharmaceutical compositions typically contain an amount of an active agent (e.g., a compound described herein) effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, flow agents, anti-adherents, and / or anti-static agents, etc. Provided pharmaceutical compositions can be in a variety of forms, including oral dosage forms, topical creams, topical patches, iontophoretic forms, suppositories, nasal sprays and / or inhalers, eye drops, intraocular injection forms, depot forms, and injection and infusion solutions.

[0599]

[0262] The provided pharmaceutical compositions may be prepared by any suitable available technique.

[0600] In some embodiments, provided compounds are formulated into unit dosage forms for ease of administration and uniformity of dosage. The phrase "unit dosage form," as used herein, refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, a unit dosage form contains an entire dose of the agent. In some embodiments, two or more unit dosage forms are administered to achieve the entire dose. In some embodiments, administration of multiple unit dosage forms is required, or is expected to be required, to achieve the intended effect. A unit dosage form can be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, capsule, etc.) containing a predetermined amount of one or more active agents, a sustained-release formulation containing a predetermined amount of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents.

[0601]

[0264] The provided compositions may be administered according to a dosing regimen (i.e., including a single dose or multiple doses separated in time, administered via a particular route of administration) that is effective (e.g., has been demonstrated to be effective) for treating (e.g., delaying the onset and / or reducing the incidence and / or intensity of) a disease or disorder described herein, for example.

[0602]

[0265] The present disclosure also provides methods for preparing the pharmaceutical compositions provided herein. In some embodiments, the provided methods include: (i) providing a provided compound or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with a suitable excipient to obtain a pharmaceutical composition.

[0603] use The present disclosure provides the use of the compounds and compositions described herein. In some embodiments, the provided compounds and compositions are useful in medicine (e.g., as treatments). In some embodiments, the provided compounds and compositions are useful in research, for example, as analytical tools and / or control compounds in biological assays.

[0604] In some embodiments, provided compounds are useful as KAT2 degradation inducers and / or inhibitors. In some embodiments, provided compounds promote the degradation of KAT2A. In some embodiments, provided compounds promote the degradation of KAT2B.

[0605] In some embodiments, the present disclosure provides methods of degrading and / or inhibiting KAT2 (e.g., KAT2A and / or KAT2B), comprising contacting KAT2 with a provided compound. In some embodiments, the contacting occurs in a cell. In some embodiments, the contacting occurs in a subject (e.g., a human subject).

[0606] In some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject suffering from or susceptible to a disease, disorder, or condition associated with KAT2 (e.g., KAT2A and / or KAT2B).

[0607] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with KAT2 (e.g., KAT2A and / or KAT2B), comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the provided method is for treating cancer. In some embodiments, the cancer is characterized by a solid tumor. In some embodiments, the cancer is characterized by a hematological tumor. In some embodiments, the cancer is selected from hematopoietic cancers, including leukemia, lymphoma (e.g., Hodgkin's and non-Hodgkin's), myeloma, and myeloproliferative disorders; sarcoma, melanoma, adenoma, carcinoma of solid tissue, squamous cell carcinoma of the oral cavity, pharynx, larynx, and lung, genitourinary cancers such as liver cancer, prostate, cervical, bladder, uterine, and endometrial cancer, and benign lesions such as renal cell carcinoma, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, endocrine system cancer, thyroid cancer, parathyroid cancer, head and neck cancer, breast cancer, gastrointestinal cancer, and nervous system cancer, papilloma, etc. In some embodiments, the provided method is for treating leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia). In some embodiments, the provided methods are for treating a disease, disorder, or condition selected from acute myeloid leukemia (AML), neuroblastoma, non-small cell lung cancer (NCSLC), small cell lung cancer (SCLC), colorectal cancer, melanoma, and prostate cancer.

[0608] In some embodiments, provided compounds or compositions are administered as part of a combination therapy. As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents) simultaneously. In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "administrations" of a first regimen are administered before any administration of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may involve administering one or more agents or modalities in combination with a subject receiving other agents or modalities. For clarity, combination therapy does not require that individual agents be administered together (or necessarily simultaneously) in a single composition, although in some embodiments, two or more agents, or active portions thereof, may be administered together in a combination composition.

[0609] For example, in some embodiments, a provided compound or composition is administered to a subject who is undergoing or has undergone one or more additional treatments (e.g., anti-cancer treatments and / or treatments to address one or more side effects of such anti-cancer treatments or to otherwise provide palliative care).

[0610] Illustrative Embodiments

[0273] The following listed embodiments are non-limiting but illustrate certain aspects of the present disclosure: 1. Compounds of Formula I: PBM-Linker-LBM I (In the formula, PBM is KAT2 protein binding moiety; The linker is an optional linking moiety; LBM is the E3 ubiquitin ligase binding moiety). 2. The compound of embodiment 1, wherein the PBM is a KAT2A protein binding moiety. 3. The compound of embodiment 1, wherein the PBM is a KAT2B protein binding moiety. 4. The compound of any one of embodiments 1 to 3, wherein the linker is less than 14 atoms in length. 5. The compound of any one of embodiments 1 to 4, wherein the linker is less than 11 atoms in length. 6. The compound of any one of embodiments 1-5, wherein LBM is a CRBN binding moiety. 7. The compound of any one of embodiments 1-5, wherein LBM is a VHL binding moiety. 8. The compound of any one of embodiments 1-5, wherein LBM is an IAP binding moiety. 9. The compound of any one of embodiments 1-5, wherein LBM is an MDM2 binding moiety. 10. Compound of Formula II:

[0611] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is

[0612] [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 bond or a divalent C 1~3 a straight or branched hydrocarbon chain; Each R 1 are independently optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 and; R 2is hydrogen, halogen, -CN, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; Each R 3 are independently hydrogen, halogen, or optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 4 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 5 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic, or R 2 and R 5 together with the atoms to which they are attached form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; X is O or NR 7 and; R 7 is hydrogen or optionally substituted C 1~6 aliphatic, or R 4 and R 7 are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R 9 is hydrogen or optionally substituted C 1~6 It is aliphatic; The linker is a covalent bond or an optionally substituted divalent linear or branched saturated or unsaturated 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)-, - may be replaced by -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-, -SON(R)-, -N(R)SO2-, or -Cy-; each Cy independently represents an optionally substituted, mono- or polycyclic, 3- to 16-membered, bivalent ring system that is fully saturated, partially saturated, or aromatic and that contains 0-6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C 1~6 Aliphatic, Phenyl, C 3~7 an optionally substituted group selected from an alicyclic, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or a 3- to 7-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding moiety). 11.R 2 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 The compound of embodiment 10, which is alicyclic. 12. Ring A is

[0613] [ka] 12. The compound of embodiment 10 or 11, wherein 13. Ring A is

[0614] [ka] 13. The compound of embodiment 12, selected from: 14. Ring A is

[0615] [ka] 14. The compound of embodiment 13, selected from: 15. Ring A is

[0616] [ka] 12. The compound of embodiment 10 or 11, wherein 16.R 2 and R 5 taken together with the atoms to which they are attached to form an optionally substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. 17. Ring A is

[0617] [ka] 17. The compound of embodiment 16, wherein 18. Ring A is

[0618] [ka] 12. The compound of embodiment 10 or 11, wherein 19.R 2 and R 5 taken together with the atoms to which they are attached to form an optionally substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. 20. Ring A is

[0619] [ka] 20. The compound of embodiment 19, selected from: 21.X is NR 7 and R 4 and R 7 taken together with the atoms to which they are attached to form an optionally substituted 5- or 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. 22. Ring A is

[0620] [ka] 22. The compound of embodiment 21, wherein: 23. Ring A is

[0621] [ka] 12. The compound of embodiment 10 or 11, wherein 24. Ring A is

[0622] [ka] 24. The compound of embodiment 23, wherein 25.R 9 The compound of any one of embodiments 10 to 24, wherein is hydrogen. 26. The compound according to any one of embodiments 10 to 25, wherein ring B is a 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 27. Ring B is

[0623] [ka] 27. The compound of embodiment 26, wherein 28. Ring B is

[0624] [ka] 28. The compound of embodiment 27, wherein 29.L 1 The compound of any one of embodiments 10 to 28, wherein is a covalent bond. 30.Each R 1 are independently optionally substituted C 1~6 The compound of any one of embodiments 10 to 29, wherein is alkyl. 31.Each R 1 independently, C 1~6 The compound of embodiment 28, wherein R is alkyl. 32. The compound according to any one of embodiments 10 to 31, wherein n is 0 or 1. 33.R 2 is halogen or C 1~6 The compound of any one of embodiments 10 to 32, wherein is alkyl. 34.R 2 The compound of any one of embodiments 10 to 33, wherein is halogen. 35.Each R 3 The compound of any one of embodiments 10 to 34, wherein is hydrogen. 36.R 4 may be substituted C 1~6 The compound of any one of embodiments 10 to 35, wherein is alkyl. 37.R 6 may be substituted C 1~6 The compound of any one of embodiments 10 to 36, wherein is alkyl. 38. The compound according to any one of embodiments 10 to 37, wherein X is O. 39.X is NR 7 38. The compound of any one of embodiments 10 to 37, wherein 40. The linker is an optionally substituted divalent linear or branched saturated or unsaturated 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)NR-, -N(R 40. The compound of any one of embodiments 10-39, optionally replaced by -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-, -SON(R)-, -N(R)SO2-, or -Cy-. 41. The linker is an optionally substituted, 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(NR)NR 41. The compound of embodiment 40, wherein the compound is optionally replaced by -, -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-, -SON(R)-, -N(R)SO2-, or -Cy-. 42. The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 The compound of embodiment 40, which is a hydrocarbon chain, wherein at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. 43. The linker is an optionally substituted divalent linear or branched saturated or unsaturated C1-C 20The compound of embodiment 42, which is a hydrocarbon chain wherein at least two methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. 44. The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 The compound according to any one of embodiments 40 to 43, wherein the hydrocarbon chain is at least one methylene unit replaced by -C(O)N(R)-. 45. The compound according to any one of embodiments 40 to 44, wherein the linker comprises at least one triple bond. 46. ​​The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 The compound according to any one of embodiments 40 to 45, which is a hydrocarbon chain, wherein at least one methylene unit is replaced by -Cy-. 47. The linker

[0625] [ka] (In the formula, M 1 and M 2 are each independently absent, —CH—, —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 independently represents a covalent bond or an optionally substituted divalent linear or branched saturated or unsaturated C1-C 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)-, -SO-, -SON(R)-, -N(R)SO-, or -Cy- 47. The compound of any one of embodiments 10 to 46, wherein 48. The linker

[0626] [ka] 48. The compound of embodiment 47, selected from: 49. The linker

[0627] [ka] 49. The compound of embodiment 47 or 48, selected from: 50.L 6 The compound of any one of embodiments 47 to 49, wherein is a covalent bond. 51.L 7 The compound of any one of embodiments 47 to 50, wherein is a covalent bond. 52. The compound according to any one of embodiments 40 to 51, wherein Cy is optionally substituted phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 53. The compound according to any one of embodiments 40 to 51, wherein Cy is an optionally substituted monocyclic 5-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 54. The compound according to any one of embodiments 40 to 51, wherein Cy is an optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 55. Compounds according to embodiment 54, wherein Cy is a spirocyclic 6-7 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 56. Each R is independently hydrogen or optionally substituted C 1~6 The compound of any one of embodiments 10 to 55, wherein is alkyl. 57. The compound according to any one of embodiments 10-56, wherein LBM is a CRBN binding moiety. 58. The compound according to any one of embodiments 10-56, wherein LBM is a VHL binding moiety. 59. The compound according to any one of embodiments 10-56, wherein LBM is an IAP binding moiety. 60. The compound according to any one of embodiments 10-56, wherein LBM is an MDM2 binding moiety. 61. Compound of Formula IIA:

[0628] [ka] 61. The compound of any one of embodiments 10 to 60, which is: 62. Compounds of formula IIA-1, IIA-2, IIA-3, or IIA-4:

[0629] [ka] or a pharmaceutically acceptable salt thereof. 63. Compound of formula IIA-5:

[0630] [ka] 63. The compound of any one of embodiments 10 to 62, which is: 64. Compound of formula IIA-6:

[0631] [ka] 63. The compound of any one of embodiments 10 to 62, which is: 65. Compound of Formula III:

[0632] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring C is an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system, which is fully saturated, partially saturated, or aromatic, and which contains 0-6 heteroatoms independently selected from N, O, and S; Each R a are independently hydrogen or optionally substituted C 1~6 Aliphatic or two R a the groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a linear or branched C 1~3 a hydrocarbon chain in which one methylene may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; Y is N or CH 65. The compound of any one of embodiments 10 to 64, wherein 66. Ring C is optionally substituted phenyl, C 5~6Compounds of embodiment 65 which are alicyclic, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, or 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 67. Compounds according to embodiment 65, wherein Ring C is optionally substituted phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 68. Ring C is

[0633] [ka] (In the formula, each B is independently selected from N, C, and CH, provided that no more than two Bs are N; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) 68. The compound of embodiment 67, wherein 69. Ring C is

[0634] [ka] 69. The compound of embodiment 68, wherein 70. Compound of Formula IIIC:

[0635] [ka] 70. The compound of any one of embodiments 65 to 69, which is: or a pharmaceutically acceptable salt thereof. 71. Compound of formula IIID:

[0636] [ka] or a pharmaceutically acceptable salt thereof. 72. Compounds according to embodiment 65, wherein ring C is an optionally substituted C3-C7 alicyclic or 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 73. Compounds according to embodiment 65, wherein Ring C is an optionally substituted 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 74. Ring C is

[0637] [ka] (In the formula, each A is independently N, C, or CH, provided that no more than two A groups are N; Each R b is hydrogen, or two R on the same carbon b the groups taken together form oxo or join to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) 74. The compound of embodiment 73, wherein 75. Ring C is

[0638] [ka] 75. The compound of embodiment 74, wherein 76.L 2 The compound of any one of embodiments 65 to 75, wherein is a covalent bond. 77.L 2The compound of any one of embodiments 65 to 75, wherein is —CH 2 —. 78.L 2 The compound of any one of embodiments 65 to 75, wherein is —O— or —S—. 79.L 2 The compound of any one of embodiments 65 to 75, wherein is —C(O)N(R)— or —N(R)C(O)—. 80. The compound according to any one of embodiments 65 to 79, wherein Y is N. 81. A compound according to any one of embodiments 65 to 79, wherein Y is CH. 82.Each R c But halogen, -O(C 1~6 alkyl), C 1~6 Alkyl, and C 1~6 The compound of any one of embodiments 68 to 81, independently selected from haloalkyl. 83. Compound of Formula IIIA:

[0639] [ka] or a pharmaceutically acceptable salt thereof. 84. Compound of Formula IIIB:

[0640] [ka] or a pharmaceutically acceptable salt thereof. 85. Compounds of formula IIIB-1 or IIIB-2:

[0641] [ka] or a pharmaceutically acceptable salt thereof. 86.

[0642] [ka] 86. The compound of any one of embodiments 1 to 85, wherein 87. Compound of Formula IV:

[0643] [ka] or a pharmaceutically acceptable salt thereof (In the formula, The linker is R d , R e , R f , and R g One of the following is attached to the part enclosed in brackets; Each R that is not a linker attachment point d are independently hydrogen, —C(O)R, optionally substituted C 1~6 aliphatic, or The Two R's d are joined together with the atoms to which they are attached to form a 5- or 6-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S, which may be fused to a phenyl or a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, and S; Each R that is not a linker attachment point e are independently hydrogen or optionally substituted C 1~6 It is aliphatic; R f When not the attachment point of the linker, C is hydrogen or optionally substituted 1~6 It is aliphatic; Each R that is not a linker attachment point g are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; R h is hydrogen, halogen, or optionally substituted C 1~6 It is aliphatic; p is 0, 1, 2, or 3) 65. The compound of any one of embodiments 10 to 64, wherein 88. Compound of formula IVA:

[0644] [ka] or a pharmaceutically acceptable salt thereof) 88. The compound of embodiment 87, wherein 89. Compound of formula IVA-1:

[0645] [ka] or a pharmaceutically acceptable salt thereof. 90. Compound of Formula V:

[0646] [ka] or a pharmaceutically acceptable salt thereof (In the formula, The linker consists of one R i or two R's i The ring formed when the groups are taken together is attached to the part enclosed in brackets; Each R that is not a linker attachment point i are independently halogen, optionally substituted C 1~6 aliphatic, -C(O)N(R)2, or -N(R)C(O)R; The Two R's i groups, together with the atoms to which they are attached, are joined to form an optionally substituted phenyl or 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; R j is C 1~6 Aliphatic and C 3~7 an optionally substituted group selected from alicyclic; R j is R iand, together with the atom to which they are attached, form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S; R k is optionally substituted C 1~6 It is aliphatic; r is 1, 2, 3, 4, or 5; (q is 1 or 2) 65. The compound of any one of embodiments 10 to 64, wherein 91. At least one R i The compound of embodiment 90, wherein is —C(O)N(R) 2 . 92. Two R's i Compounds according to embodiments 90 or 91, wherein the groups, together with the atoms to which they are attached, are joined to form an optionally substituted phenyl or 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. 93. Compound of formula VA:

[0647] [ka] 93. The compound of any one of embodiments 90 to 92, which is: 94. Compound of formula VA-1:

[0648] [ka] or a pharmaceutically acceptable salt thereof. 95. Compound of formula VB:

[0649] [ka] or a pharmaceutically acceptable salt thereof. 96. Compound of formula VB-1:

[0650] [ka] or a pharmaceutically acceptable salt thereof. 97. Compound of Formula VI:

[0651] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R m is optionally substituted C 1~6 It is aliphatic; Each R n are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; s is 0, 1, 2, 3, 4, or 5) 65. The compound of any one of embodiments 10 to 64, wherein 98. Compound of formula VIA:

[0652] [ka] or a pharmaceutically acceptable salt thereof. 99. Compound of formula VIA-1:

[0653] [ka] or a pharmaceutically acceptable salt thereof. 100. Compound of Formula VII:

[0654] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Each R p are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; Each R q are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; Each R r are independently hydrogen or optionally substituted C 1~6 It is aliphatic; Each R s are independently halogen, -OR, -CN, or optionally substituted C 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) 65. The compound of any one of embodiments 10 to 64, wherein 101. Compound of formula VIIA:

[0655] [ka] or a pharmaceutically acceptable salt thereof. 102. Compound of Formula VIII:

[0656] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Each R t are independently hydrogen or optionally substituted C 1~6 aliphatic, or Both R t groups, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered alicyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S; Each R uare independently hydrogen, halogen, -CN, or optionally substituted C 1~6 It is aliphatic; Each R v are independently halogen, -OR, -CN, or optionally substituted C 1~6 aliphatic, or R u and R v an example of which, together with the atoms to which they are attached, combine to form an optionally substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each R w are independently halogen, -OR, -CN, or optionally substituted C 1~6 aliphatic, or R u and R w an example of which, together with the atoms to which they are attached, combine to form an optionally 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) 65. The compound of any one of embodiments 10 to 64, wherein 103. Compound of Formula VIIIA:

[0657] [ka] or a pharmaceutically acceptable salt thereof. 104. Compound of formula IX:

[0658] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring A is

[0659] [ka] Selected from; L 3 , L 4 , and L 5 each independently represents a covalent bond or an optionally substituted divalent C 1~6 a straight or branched hydrocarbon chain; Z is N or CR 3 and; R 2 is hydrogen, halogen, -CN, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; Each R 3 are independently hydrogen, halogen, or optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 4 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; R 5 is hydrogen, halogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic, or R 2 and R 5 together with the atoms to which they are attached form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R 6 is hydrogen, optionally substituted C 1~6 Aliphatic or optionally substituted C 3~6 is alicyclic; X is O or NR 7 and; R 7 is hydrogen or optionally substituted C 1~6 aliphatic, or R 4 and R 7are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; Each R 8 are independently hydrogen or optionally substituted C 1~6 It is aliphatic; R 9 is hydrogen or optionally substituted C 1~6 It is aliphatic; The linker is a covalent bond or an optionally 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)-, - may be replaced by -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-, -SON(R)-, -N(R)SO2-, or -Cy-; each Cy independently represents an optionally substituted, mono- or polycyclic, 3- to 16-membered, bivalent ring system that is fully saturated, partially saturated, or aromatic and that contains 0-6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C 1~6 Aliphatic, Phenyl, C 3~7 an optionally substituted group selected from an alicyclic, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or a 3- to 7-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding moiety). 105.R 2 is hydrogen, halogen, -CN, optionally substituted C 1~6Aliphatic or optionally substituted C 3~6 The compound of embodiment 104, which is alicyclic. 106. Ring A is

[0660] [ka] 106. The compound of embodiment 104 or 105, wherein 107. Ring A is

[0661] [ka] The compound of embodiment 106, selected from: 108. Ring A is

[0662] [ka] 106. The compound of embodiment 104 or 105, wherein 109.R 2 and R 5 taken together with the atoms to which they are attached to form an optionally substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. 110. Ring A is

[0663] [ka] 110. The compound of embodiment 109, wherein 111. Ring A is

[0664] [ka] 106. The compound of embodiment 104 or 105, wherein 112.R 2 and R 5taken together with the atoms to which they are attached to form an optionally substituted 5- or 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. 113. Ring A is

[0665] [ka] The compound of embodiment 112, selected from: 114.X is NR 7 and R 4 and R 7 taken together with the atoms to which they are attached to form an optionally substituted 5- or 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. 115. Ring A is

[0666] [ka] The compound of embodiment 114, wherein 116. Ring A is

[0667] [ka] 106. The compound of embodiment 104 or 105, wherein 117. Ring A is

[0668] [ka] 117. The compound of embodiment 116, wherein 118.L 3 The compound of any one of embodiments 104 to 117, wherein is a covalent bond. 119.L 3 is an optionally substituted divalent C 1~3The compound according to any one of embodiments 104 to 117, wherein the hydrocarbon chain is a straight or branched chain. 120.L 4 The compound of any one of embodiments 104 to 119, wherein is a covalent bond. 121.L 4 is an optionally substituted divalent C 1~3 The compound of any one of embodiments 104 to 119, wherein the hydrocarbon chain is a straight or branched chain. 122.L 5 The compound of any one of embodiments 104 to 121, wherein is a covalent bond. 123.L 5 is an optionally substituted divalent C 1~3 The compound according to any one of embodiments 104 to 121, wherein the hydrocarbon chain is a straight or branched chain. 124.Each R 8 C 1~6 The compound of any one of embodiments 104 to 123, wherein is alkyl. 125.R 9 The compound of any one of embodiments 104 to 124, wherein is hydrogen. 126.R 2 The compound of any one of embodiments 104 to 125, wherein is halogen. 127.Each R 3 The compound of any one of embodiments 104 to 126, wherein is hydrogen. 128.R 4 may be substituted C 1~6 The compound of any one of embodiments 104 to 127, wherein is alkyl. 129.R 6 may be substituted C 1~6 The compound of any one of embodiments 104 to 128, wherein is alkyl. 130. A compound according to any one of embodiments 104 to 129, wherein X is O. 131.X is NR 7 130. The compound of any one of embodiments 104 to 129, wherein 132. The linker is an optionally 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) The compound of any one of embodiments 104 to 131, optionally replaced by 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—, —SON(R)—, —N(R)SO—, or -Cy-. 133. The linker is an optionally substituted, 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(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—, —SON(R)—, —N(R)SO—, or -Cy-. 134. The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 The compound of embodiment 132, which is a hydrocarbon chain wherein at least one methylene unit is replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. 135. The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 The compound of embodiment 134, which is a hydrocarbon chain wherein at least two methylene units are replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or -Cy-. 136. The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 The compound according to any one of embodiments 132 to 135, which is a hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)-. 137. The compound according to any one of embodiments 132 to 136, wherein the linker comprises at least one triple bond. 138. The linker is an optionally substituted, divalent, linear or branched, saturated or unsaturated C1-C 20 The compound according to any one of embodiments 132 to 137, which is a hydrocarbon chain, wherein at least one methylene unit is replaced by -Cy-. 139. Linker,

[0669] [ka] (In the formula, M 1 and M 2 are each independently absent, —CH—, —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 independently represents a covalent bond or an optionally substituted divalent linear or branched saturated or unsaturated C1-C 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)-, -SO-, -SON(R)-, -N(R)SO-, or -Cy- The compound of any one of embodiments 104 to 138, wherein 140. The linker

[0670] [ka] 140. The compound of embodiment 139, selected from: 141. The linker

[0671] [ka] 141. The compound of embodiment 139 or 140, selected from: 142.L 6 The compound of any one of embodiments 139 to 141, wherein is a covalent bond. 143.L 7 The compound of any one of embodiments 139 to 142, wherein is a covalent bond. 144. The compound according to any one of embodiments 132 to 143, wherein Cy is optionally substituted phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 145. The compound according to any one of embodiments 132 to 143, wherein Cy is an optionally substituted monocyclic 5-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 146. The compound according to any one of embodiments 132 to 143, wherein Cy is an optionally substituted bicyclic 6-11 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 147. Compounds according to embodiment 146, wherein Cy is a spirocyclic 6-7 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 148. Each R is independently hydrogen or optionally substituted C 1~6 The compound of any one of embodiments 104 to 147, wherein is alkyl. 149. The compound according to any one of embodiments 104-148, wherein LBM is a CRBN binding moiety. 150. The compound according to any one of embodiments 104-148, wherein LBM is a VHL binding moiety. 151. The compound according to any one of embodiments 104-148, wherein LBM is an IAP binding moiety. 152. The compound according to any one of embodiments 104-148, wherein LBM is an MDM2 binding moiety. 153. A compound of formula IXA, IXB, IXC, or IXD:

[0672] [ka] 153. The compound of any one of embodiments 104 to 152, which is: 154. Compound of formula X:

[0673] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Ring C is an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system, which is fully saturated, partially saturated, or aromatic, and which contains 0-6 heteroatoms independently selected from N, O, and S; Each R a are independently hydrogen or optionally substituted C 1~6 Aliphatic or two R a the groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a linear or branched C 1~3 a hydrocarbon chain in which one methylene may be replaced by -O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; Y is N or CH The compound of any one of embodiments 104 to 153, wherein 155. Ring C is optionally substituted phenyl, C 5~6 Compounds according to embodiment 154, which are alicyclic, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, or 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 156. Compounds according to embodiment 154, wherein Ring C is optionally substituted phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 157. Ring C is

[0674] [ka] (In the formula, each B is independently selected from N, C, and CH, provided that no more than two Bs are N; Each R cis halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) 157. The compound of embodiment 156, wherein 158. Ring C is

[0675] [ka] The compound of embodiment 157, wherein 159. Compound of formula IIIC:

[0676] [ka] 159. The compound of any one of embodiments 154 to 158, which is: 160. Compound of formula IIID:

[0677] [ka] 160. The compound of any one of embodiments 154 to 159, which is: 161. Compounds according to embodiment 154, wherein ring C is an optionally substituted C3-C7 alicyclic or 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 162. Compounds according to embodiment 154, wherein Ring C is an optionally substituted 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 163. Ring C is

[0678] [ka] (In the formula, each A is independently N, C, or CH, provided that no more than two A groups are N; Each R b is hydrogen, or two R on the same carbon b the groups taken together form oxo or join to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) 163. The compound of embodiment 162, wherein 164. Ring C is

[0679] [ka] The compound of embodiment 163, wherein 165.L 2 The compound of any one of embodiments 154 to 164, wherein is a covalent bond. 166.L 2 The compound of any one of embodiments 154 to 164, wherein is —CH 2 —. 167.L 2 The compound according to any one of embodiments 154 to 164, wherein is —O— or —S—. 168.L 2 The compound of any one of embodiments 154 to 164, wherein is —C(O)N(R)— or —N(R)C(O)—. 169. The compound according to any one of embodiments 154 to 168, wherein Y is N. 170. A compound according to any one of embodiments 154 to 168, wherein Y is CH. 171.Each R c But halogen, -O(C 1~6 alkyl), C 1~6 Alkyl, and C 1~6 The compound of any one of embodiments 68 to 81, independently selected from haloalkyl. 172. Compound of formula XA:

[0680] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Each R b is hydrogen, or two R on the same carbon b the groups taken together form oxo or join to form a 3- to 6-membered saturated or partially unsaturated ring; Each R c is halogen, -OR, -N(R)2, -CN, and optionally substituted C 1~6 independently selected from aliphatic; m is 0, 1, 2, or 3) 172. The compound of any one of embodiments 154 to 171, wherein 173. Compounds of formula XA-1 or XA-2:

[0681] [ka] or a pharmaceutically acceptable salt thereof. 174. Compound of formula XI:

[0682] [ka] or a pharmaceutically acceptable salt thereof (In the formula, The linker is R d , R e , R f , and R g One of the following is attached to the part enclosed in brackets; Each R that is not a linker attachment point d are independently hydrogen, —C(O)R, or optionally substituted C 1~6 aliphatic, or The Two R's dare joined together with the atoms to which they are attached to form a 5- or 6-membered ring having 1 to 3 heteroatoms independently selected from N, O, and S, which may be fused to a phenyl or a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O, and S; Each R that is not a linker attachment point e are independently hydrogen or optionally substituted C 1~6 It is aliphatic; R f When not the attachment point of the linker, C is hydrogen or optionally substituted 1~6 It is aliphatic; Each R that is not a linker attachment point g are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; R h is hydrogen, halogen, or optionally substituted C 1~6 It is aliphatic; p is 0, 1, 2, or 3) The compound of any one of embodiments 104 to 153, wherein 175. Compound of formula XIA:

[0683] [ka] or a pharmaceutically acceptable salt thereof. 176. Compound of formula XII:

[0684] [ka] 154. The compound of any one of embodiments 104 to 153, which is: 177. At least one R i The compound of embodiment 176, wherein is —C(O)N(R) 2 . 178. Two R's iCompounds according to embodiment 176 or 177, wherein the groups, together with the atoms to which they are attached, are joined to form an optionally substituted phenyl or 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. 179. Compound of formula XIIA:

[0685] [ka] or a pharmaceutically acceptable salt thereof. 180. Compound of formula XIIB:

[0686] [ka] 179. The compound of embodiment 176 or 179, which is: 181. Compound of formula XIIB-1:

[0687] [ka] or a pharmaceutically acceptable salt thereof. 182. Compound of formula XIII:

[0688] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R m is optionally substituted C 1~6 It is aliphatic; Each R n are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; s is 0, 1, 2, 3, 4, or 5) The compound of any one of embodiments 104 to 153, wherein 183. Compound of formula XIIIA:

[0689] [ka] or a pharmaceutically acceptable salt thereof. 184. Compound of formula XIV:

[0690] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Each R p are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; Each R q are independently halogen, -OR, -CN, or optionally substituted C 1~6 It is aliphatic; Each R r are independently hydrogen or optionally substituted C 1~6 It is aliphatic; Each R s are independently halogen, -OR, -CN, or optionally substituted C 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) The compound of any one of embodiments 104 to 153, wherein 185. Compound of formula XV:

[0691] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Each R tare independently hydrogen or optionally substituted C 1~6 aliphatic, or Both R t groups, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered alicyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S; Each R u are independently hydrogen, halogen, -CN, or optionally substituted C 1~6 It is aliphatic; Each R v are independently halogen, -OR, -CN, or optionally substituted C 1~6 aliphatic, or R u and R v an example of which, together with the atoms to which they are attached, combine to form an optionally substituted 3-7 membered alicyclic or heterocyclic ring having 1-2 heteroatoms independently selected from N, O, and S; Each R w are independently halogen, -OR, -CN, or optionally substituted C 1~6 aliphatic, or R u and R w an example of which, together with the atoms to which they are attached, combine to form an optionally 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) The compound of any one of embodiments 104 to 153, wherein 186. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. 187. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 186, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 188. A method for preparing a pharmaceutical composition according to embodiment 187, comprising: Providing a compound according to any one of embodiments 1 to 186, or a pharmaceutically acceptable salt thereof; formulating the compound with suitable excipients to obtain a pharmaceutical composition; A method comprising: 189. A method comprising administering a compound according to any one of embodiments 1 to 186, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 187, to a subject in need thereof. 190. A method for treating cancer, comprising administering to a subject in need thereof a compound according to any one of embodiments 1 to 186, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 187. 191. The method of embodiment 190, wherein the cancer is selected from acute myeloid leukemia, neuroblastoma, non-small cell lung cancer, small cell lung cancer, colorectal cancer, melanoma, and prostate cancer. 192. A method for degrading KAT2 in a subject, comprising administering to a subject in need thereof a compound described in any one of embodiments 1 to 186, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 187. 193. An in vitro method for degrading KAT2, comprising contacting a biological sample with a compound according to any one of embodiments 1 to 186, or a pharmaceutically acceptable salt thereof. [Example]

[0692] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods are directed to the synthesis of certain specific compounds of the present disclosure, it will be understood that the following general methods, and other methods known to those skilled in the art, can be applied to all compounds and each subclass and species of these compounds, as described herein. List of abbreviations

[0693] [Table 3-1]

[0694] [Table 3-2]

[0695] Analysis method The following analytical methods are representative of those used to purify and / or characterize the compounds described herein:

[0696]

[0276] Method A (preparative HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 μm, eluent A: 0.1% TFA in water, B: acetonitrile; flow rate: 25.0 mL / min; gradient: 0.0 min 5% B, 0.2-3.0 min 5-5% B, 3-40 min 60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-5% B, 48-55 min 5-5% B.

[0697]

[0277] Method B (preparative HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 μm, eluent A: 10 mM ammonium bicarbonate in water, B: acetonitrile; flow rate: 25.0 mL / min; gradient: 0.0 min 5% B, 0.2-3.0 min 5-5% B, 3-40 min 60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-5% B, 48-55 min 5-5% B.

[0698]

[0278] Method C (preparative HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 μm, eluent A: 0.1% TFA in water, B: acetonitrile; flow rate: 25.0 mL / min; gradient: 0.0 min 10% B, 0.2-3.0 min 10-10% B, 3-40 min 10-60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-10% B, 48-55 min 10-10% B.

[0699] Method D (Combiflash®): Column: YMC, Dimensions: 4 g (amorphous silica, 40-63 μm, 60 Å), Eluent A: DCM, B: MeOH, Gradient: 0-5% MeOH / DCM over 30 min, Flow rate: 20.0 mL / min.

[0700] Method E (preparative HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 μm, eluent A: 10 mM ammonium bicarbonate in water, B: acetonitrile; flow rate: 25.0 mL / min; gradient: linear gradient.

[0701]

[0281] Method F (preparative HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 μm, eluent A: 0.1% formic acid in water, B: acetonitrile; flow rate: 25.0 mL / min; gradient: 0.0 min 2% B, 0.2-3.0 min 2-2% B, 3-50 min 2-55% B, 50-51 min 55-95% B, 51-57 min 95-95% B, 57-58 min 95-2% B, 58-65 min 2-2% B.

[0702]

[0282] Method G: Column: X-SELECT CSH-C18, (250 x 30 mm) 5 μm, eluent A: 0.1% formic acid in water, B: acetonitrile; flow rate: 25.0 mL / min; gradient: linear gradient.

[0703] Method H: Column: SYNERGY C18, (150 x 19 mm) 5 μm, Eluent A: 10 mM ammonium bicarbonate in H2O, B: acetonitrile; Flow rate: 25.0 mL / min; Gradient (time / % B): 0 / 10, 10 / 30, 20 / 40, 30 / 50, 40 / 60, 50 / 70, 55 / 98. Preparation of intermediates Preparation of Intermediate 1: 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid

[0704] Step 1: Methyl 4-(5-((tert-butoxycarbonyl)amino)pyridin-3-yl)benzoate

[0705] [ka]

[0706] To a stirred solution of 4-(methoxycarbonyl)phenyl)boronic acid (7.25 g, 40.29 mmol) and tert-butyl (5-bromopyridin-3-yl)carbamate (10.00 g, 36.63 mmol) in DME (150 mL) was added a solution of Na2CO3 (18.60 g, 175.80 mmol) in water (3 mL), and the reaction mixture was purged with argon for 30 minutes. To the resulting reaction mixture was added Pd(PPh3)4 (4.23 g, 3.66 mmol), and the reaction mixture was purged with argon again for 20 minutes. The reaction mixture was stirred at 90 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give methyl 4-(5-((tert-butoxycarbonyl)amino)pyridin-3-yl)benzoate (7.00 g, 58%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=9.77~9.69(m,1H), 8.63(brs,1H), 8.55(s,1H), 8.25(b rs,1H), 8.08(d,J=7.8Hz,2H), 7.82(d,J=8.3Hz,2H), 3.89(s,3H), 1.50(s,9H). LC-MS:m / z 329.2[M+H] + . Step 2: 3-((tert-butoxycarbonyl)amino)-5-(4-(methoxycarbonyl)phenyl)-1-methylpyridin-1-ium

[0707] [ka]

[0708] To a stirred solution of methyl 4-(5-((tert-butoxycarbonyl)amino)pyridin-3-yl)benzoate (7.50 g, 22.80 mmol, from step 1) in ACN (70 mL) was added MeI (2.10 mL, 34.20 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude compound was washed with diethyl ether to give 3-((tert-butoxycarbonyl)amino)-5-(4-(methoxycarbonyl)phenyl)-1-methylpyridin-1-ium (6.50 g, 83%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=10.57(brs,1H), 9.12(d,J=13.2Hz,2H), 8.64~8.52(m,1H), 8.19(d,J=8.3Hz,2H), 7.93(d,J=8.3Hz,2H), 4.42(s,3H), 3.91(s,3H), 1.53(s,9H). LC-MS:m / z 344.2[M+H] + . Step 3: Methyl 4-((cis)-5-((tert-butoxycarbonyl)amino)-1-methylpiperidin-3-yl)benzoate

[0709] [ka]

[0710] To a stirred solution of 3-((tert-butoxycarbonyl)amino)-5-(4-(methoxycarbonyl)phenyl)-1-methylpyridin-1-ium (2.50 g, 7.28 mmol, from step 2) in methanol (50 mL) was added PtO2 (1.25 g) at room temperature under a hydrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was filtered through Celite®. The filtrate was concentrated to give the crude compound. The crude compound was purified by column chromatography (5% methanol in DCM) to give compound methyl 4-((cis)-5-((tert-butoxycarbonyl)amino)-1-methylpiperidin-3-yl)benzoate (1.70 g, 68%) as an off-white solid together with compound methyl 4-((trans)-5-((tert-butoxycarbonyl)amino)-1-methylpiperidin-3-yl)benzoate. LC-MS: m / z 349.3 [M+H] + . Step 4: Methyl 4-((cis)-5-amino-1-methylpiperidin-3-yl)benzoate

[0711] [ka]

[0712] To a stirred solution of methyl 4-((cis)-5-((tert-butoxycarbonyl)amino)-1-methylpiperidin-3-yl)benzoate (3.40 g, 7.28 mmol, from step 3) in DCM (30 mL) was slowly added TFA (10 mL) at 0° C., and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was concentrated under reduced pressure and co-evaporated with DCM and methanol. The residue was diluted with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give crude methyl 4-((cis)-5-amino-1-methylpiperidin-3-yl)benzoate (2.00 g, 83%) as a yellow sticky solid, which was used directly in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ = 7.89 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H), 3.83 (s, 3H), 2.91-2.70 (m, 4H), 2.18 (s, 3H), 1.91 (d, J = 11.2 Hz, 1H), 1.79 (t, J = 11.0 Hz, 1H), 1.54 (t, J = 10.0 Hz, 1H), 1.21-1.09 (m, 1H). 2H peak merged with solvent peak. LC-MS: m / z 249.4 [M+H] + . Steps 5 and 6: Methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate

[0713] [ka]

[0714] To a stirred solution of methyl 4-((cis)-5-amino-1-methylpiperidin-3-yl)benzoate (3.00 g, 12.09 mmol, from Step 4) in DMSO (30 mL) was added K2CO3 (5.00 g, 36.29 mmol) followed by 4,5-dibromo-2-methylpyridazin-3(2H)-one (Intermediate 2, 4.86 g, 18.14 mmol), and the reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was dissolved in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (2% methanol in DCM) to give methyl 4-((cis)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate (0.84 g, 16%) as a pale yellow solid. This compound was purified by chiral SFC to give methyl 4-((3S,5S)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate and methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate (0.20 g, 24%). Chiral SFC conditions were as follows: Phenomenex Cellulose-3 column (250 mm × 21.2 mm, 5 μm); mobile phase: methanol; flow rate: 18 mL / min; diluent: methanol; loading: 80 mg / injection. Isomer 1 was separated at room temperature for 10.5 min and Isomer 2 for 18 min.

[0715] Isomer 1: Methyl 4-((3S,5S)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate: 1H NMR (400MHz, DMSO-d6) δ=7.96~7.85(m,3H), 7.42(d,J=7.8Hz,2H), 5.82(d,J=9.3Hz,1H), 4.03~3.91(m,1H), 3.84(s,3H), 3.59(s, 3H), 3.05(t,J=11.5Hz,1H), 2.95(d,J=7.3Hz,1H), 2.85(d,J=10.8Hz,1H), 2.25(s,3H), 2.07~1.87(m,3H), 1.72(q,J=11.7Hz,1H). LC-MS:m / z 435.0[M+H] + C-HPLC (Callum: Chiralcel OJ-H (250×4.5 mm, 5 μm); eluent A: CO2, B: 0.1% DEA in EtOH; A:B-40%B uniform concentration): retention time = 2.50 min; 100.00%. SOR: -19.16, solvent: MeOH, path length: 50 mm, concentration: 0.1 w / v%.

[0716]

[0290] Opposite sex 2:メチル4-((3R,5R)-5-((5-ブロモ-1-メチル-6-オキソ-1,6 -ジヒドロピリダジン-4-イル)アミノ)-1-メチルピペリジン-3-イル)ベンゾエート: 1 H NMR (400MHz, DMSO-d6) δ=7.95~7.85(m,3H), 7.42(d,J=8.3Hz,2H), 5.82(d,J=9.3Hz,1H), 4.02~3.89(m,1H), 3.84(s,3H), 3.5 9(s,3H), 3.05(t,J=11.5Hz,1H), 2.95(d,J=6.8Hz,1H), 2.90~2.80(m,1H), 2.25(s,3H), 2.09~1.87(m,3H), 1.80~1.66(m,1H). LC-MS:m / z 435.1[M+H] + C-HPLC (Calume: Chiralcel OJ-H (250×4.5mm, 5μm); eluent A: CO2, B: 0.1% DEA in EtOH; A:B-40% B uniform concentration): retention time = 3.26 minutes; 99.17%. SOR: 21.04, solvent: MeOH, path length: 50mm, concentration: 0.1% w / v. Step 7: 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid

[0717] [ka]

[0718] To a stirred solution of methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate (0.23 g, 0.52 mmol, from step 6) in ethanol (5 mL) and water (0.5 mL) was added lithium hydroxide (0.03 g, 0.63 mmol) and the reaction mixture was stirred at 70° C. for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude was acidified to pH 3 with 1 N HCl. The precipitated solid was filtered, washed, and concentrated to give 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.20 g, 91%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=13.13~12.82(m,1H), 11.34~11.09(m,1H), 7.96(d ,J=6.8Hz,3H), 7.43(d,J=8.3Hz,2H), 6.29(d,J=8.3Hz,1H), 4.53~4.36(m,1 H), 3.62(s,3H), 3.57~3.47(m,1H), 3.46~3.36(m,1H), 3.15~3.03(m,1H), 2. 93(d,J=8.8Hz,1H), 2.80(s,3H), 2.18(d,J=10.3Hz,1H), 2.12~2.01(m,1H). LC-MS: m / z 422.0 [M+H] + . Intermediate 1: Alternative preparation of 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid Step 1: tert-butyl (3R)-3-(pyridine-2-carbonylamino)piperidine-1-carboxylate

[0719] [ka]

[0720] To a stirred solution of picolinic acid (10 g, 50.00 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (7.40 g, 60.00 mmol), and DIPEA (13 mL, 75.00 mmol) in DCM (100 mL) was added HATU (23 g, 60.00 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 0.05 M HCl and saturated NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography to give tert-butyl (3R)-3-(pyridine-2-carbonylamino)piperidine-1-carboxylate (13.17 g, 72%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.63(d,J=3.9Hz,1H), 8.55(brs,1H), 8.07~7.98(m,2H), 7.61(t,J=5.6Hz,1H), 3.90 ~3.79(m,2H), 3.76~3.49(m,2H), 2.99(brs,2H), 1.82(brs,1H), 1.74~1.61(m,2H), 1.37(brs,9H);LC-MS:m / z 306.2[M+H] + . Step 2: tert-butyl (3R,5R)-3-(4-methoxycarbonylphenyl)-5-(pyridine-2-carbonylamino)piperidine-1-carboxylate

[0721] [ka]

[0722] A pressure vial (100 mL) equipped with a magnetic stir bar was charged with tert-butyl (3R)-3-(pyridine-2-carbonylamino)piperidine-1-carboxylate (10.00 g, 32.8 mmol, from Step 1), silver carbonate (9 g, 32.8 mmol), Pd(OAc)2 (0.74 g, 0.32 mmol), methyl 4-iodobenzoate (43 g, 164 mmol), 2,6-dimethylbenzoic acid (1.23 g, 8.2 mmol), and t-BuOH (100 mL). The vessel was flushed with argon, sealed with a crimp cap, and heated to 120 °C. After 24 h, the reaction vessel was removed from the oil bath, cooled to room temperature, and DCM was added to the reaction mixture. The progress of the reaction was monitored by TLC. The mixture was stirred vigorously for 10 minutes, and the solid was removed by filtration, which was rinsed with additional DCM. The combined filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give tert-butyl (3R,5R)-3-(4-methoxycarbonylphenyl)-5-(pyridine-2-carbonylamino)piperidine-1-carboxylate (8.00 g, 56%) as a white solid. LC-MS: m / z 438.12 [M−H] - . Step 3: Methyl 4-[(3R,5R)-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate

[0723] [ka]

[0724] To a stirred solution of tert-butyl (3R,5R)-3-(4-methoxycarbonylphenyl)-5-(pyridine-2-carbonylamino)piperidine-1-carboxylate (6.00 g, 13.66 mmol, from Step 2) in DCM (70 mL) was added TFA (12 mL) at 0° C. The resulting solution was then slowly warmed to room temperature and stirred for 7 h. The progress of the reaction was monitored by TLC. The solvent was removed under reduced pressure, and the crude product was redissolved in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford methyl 4-[(3R,5R)-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate (2.7 g, 58%) as a pale yellow solid, which was used in the next reaction without any further purification. 1 H NMR(400MHz,DMSO-d6)δ=8.65~8.63(m,1H), 8.52(d,J=8.6Hz,1H), 8.05~7 .97(m,2H), 7.92~7.89(m,2H), 7.62~7.58(m,1H), 7.41(d,J=8.3Hz,2H), 4 .06~4.00(m,1H), 3.84(s,3H), 3.08~2.95(m,3H), 2.91~2.85(m,1H), 2.55 (s,1H), 2.45(s,1H), 2.04(d,J=12.2Hz,1H), 1.93~1.85(m,1H);LC-MS:m / z 340.22[M+H] + . Step 4: Methyl 4-[(3R,5R)-1-methyl-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate

[0725] [ka]

[0726] To a stirred solution of methyl 4-[(3R,5R)-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate (7.0 g, 21 mmol, from Step 3) and glacial acetic acid (1 mL) in methanol (70 mL) was added 37% w / v formaldehyde (2.9 mL) and stirred for 5 hours. Sodium triacetoxyborohydride (6.53 g, 31 mmol) was then added over 30 minutes at 0° C. The resulting solution was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The biphasic solution was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by Combiflash® column chromatography to give methyl 4-[(3R,5R)-1-methyl-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate (5.5 g, 75%). 1 H NMR(400MHz,DMSO-d=)δ=8.67~8.53(m,2H), 8.08~7.95(m,2H), 7.91(d,J=8.3Hz,2H), 7.63~7.55(m,1H), 7.44(d,J=8.3Hz,2H), 4.2 1~4.06(m,1H), 3.84(s,3H), 3.09~2.90(m,2H), 2.85(d,J=9.8Hz,1H), 2.25(s,3H), 2.04~1.89(m,3H), 1.84~1.69(m,1H);LC-MS:m / z 354.12[M+H] + . Step 5: Methyl 4-((3R,5R)-5-amino-1-methylpiperidin-3-yl)benzoate

[0727] [ka]

[0728] To a stirred suspension of methyl 4-[(3R,5R)-1-methyl-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate (1.00 g, 2.80 mmol, from Step 4) in water (50 mL) was added 12 N HCl solution (5 mL) followed by zinc dust (2.76 g, 42.00 mmol) and DCM (50 mL) at 0° C. The reaction mixture was stirred at room temperature in a round-bottom flask for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, it was cooled to 0° C. and basified to pH 9 using NaOH (5 M). The mixture was then filtered through a Celite® bed and washed with DCM (20 mL × 3). The filtrate was extracted with DCM (20 mL × 3), all organic layers were combined, and the solvent was removed in vacuo. The crude material (700 mg) was purified by Combiflash column chromatography (DCM:MeOH:NHOH 80:20:03) to give methyl 4-((3R,5R)-5-amino-1-methylpiperidin-3-yl)benzoate (0.45 g, 64%) as an off-white solid. LC-MS: m / z 249.37 [M+H] + . Step 6: 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid

[0729] Following generally the procedures in steps 5 and 7 of the preparation of Intermediate 1 above, 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid was prepared from methyl 4-((3R,5R)-5-amino-1-methylpiperidin-3-yl)benzoate. Intermediate 2: Preparation of 4,5-dibromo-2-methylpyridazin-3(2H)-one

[0730] [ka]

[0731] To a stirred solution of 4,5-dibromopyridazin-3(2H)-one (20.00 g, 79.00 mmol) in DMF (200 mL) was added K2CO3 (21.00 g, 158.10 mmol) followed by methyl iodide (8.80 mL, 118.10 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was washed with diethyl ether to give 4,5-dibromo-2-methylpyridazin-3(2H)-one (14.00 g, 66.8%) as a colorless oil, which was used directly in the next reaction. 1 H NMR (400MHz, DMSO-d6) δ=8.12(s,1H), 3.67(s,3H). LC-MS:m / z 268.7[M+H] + . Intermediate 3: Preparation of tert-butyl 3-(4-hydroxy-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate Step 1: 2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione

[0732] [ka]

[0733] To a stirred solution of 4-hydroxyisobenzofuran-1,3-dione (5.00 g, 30.48 mmol) and 3-aminopiperidine-2,6-dione (5.00 g, 30.48 mmol) in acetic acid (10 mL) was added NaOAc (4.90 g, 60.97 mmol), and the reaction mixture was stirred at 100° C. for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered and washed with water. The crude compound was dissolved in acetone. Charcoal was added, and the reaction mixture was refluxed for 30 minutes. The reaction mixture was filtered through Celite® and washed with acetone. The filtrate was concentrated to give 2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione (6.5 g, 55%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=11.18(brs,1H), 11.08(s,1H), 7.65(dd,J=7.3,8.4Hz,1H), 7.32(d,J=6.8Hz, 1H), 7.26(d,J=8.4Hz,1H), 5.10~5.03(m,1H), 2.94~2.83(m,1H), 2.63~2.52(m,2H), 2.08~1.96(m,1H). LC-MS:m / z 275.2[M+H] + . Step 2: tert-butyl 3-(4-hydroxy-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate

[0734] [ka]

[0735] To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione (1.00 g, 3.64 mmol, from Step 1) in 1,4-dioxane (10 mL), di-tert-butyl dicarbonate (1.6 g, 7.2 mmol) followed by DMAP (0.43 g, 3.64 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. To the resulting reaction mixture, piperidine (0.30 g, 3.64 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography with (40% ethyl acetate in heptane) to give tert-butyl 3-(4-hydroxy-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate (0.8 g, 61.5%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=11.21(br s,1H), 7.66(t,J=7.8Hz,1H), 7.33(d,J=7.3Hz,1H), 7.26(d,J=8.3Hz,1H), 5.39~5.29(m,1H ), 3.20~3.02(m,1H), 2.83~2.73(m,1H), 2.66~2.52(m,1H), 2.13~2.02(m,1H), 1.48(s,9H). LC-MS:m / z 372.99[MH] + . Intermediate 4: Preparation of 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzaldehyde Step 1: 4-Bromo-5-[[(3R,5R)-5-[4-(hydroxymethyl)phenyl]-1-methyl-3-piperidyl]amino]-2-methyl-pyridazin-3-one

[0736] [ka]

[0737] To a stirred solution of methyl 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate (1.25 g, 2.87 mmol) in THF (25 mL) was added LAH (2 M in THF, 2.2 mL, 4.59 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NaSO solution, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (80% ethyl acetate in hexanes) to give 4-bromo-5-[[(3R,5R)-5-[4-(hydroxymethyl)phenyl]-1-methyl-3-piperidyl]amino]-2-methyl-pyridazin-3-one (0.98 g, 95%) as a pale yellow liquid. 1 H NMR(400MHz,DMSO-d6)δ=7.95~7.86(m,3H), 7.42(d,J=7.8Hz,2H), 5.86~5.81(m,1H), 4.02~3.90(m,1H), 3.86~3.82(m,3H) , 3.59(s,3H), 3.09~3.00(m,1H), 2.98~2.92(m,1H), 2.88~2.82(m,1H), 2.25(s,3H), 2.07~1.90(m,3H), 1.78~1.67(m,1H). LC-MS:m / z 407.2[M+H] + . Step 2: 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzaldehyde

[0738] [ka]

[0739] To a stirred solution of 4-bromo-5-[[(3R,5R)-5-[4-(hydroxymethyl)phenyl]-1-methyl-3-piperidyl]amino]-2-methyl-pyridazin-3-one (0.45 g, 1.10 mmol, from step 1) in DCM (15 mL) was added Dess-Martin periodinane (0.93 g, 2.21 mmol) at 0° C. and stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (80% ethyl acetate in hexanes) to give 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzaldehyde (0.4 g, 89%) as a pale yellow liquid. 1 H NMR(400MHz,DMSO-d6)δ=10.01~9.94(m,1H), 8.09~7.99(m,1H), 7.88(d,J=2.9Hz,2H), 7.51(d,J=7.8Hz,2H), 5.88~5. 79(m,1H), 4.05~3.89(m,1H), 3.59(s,3H), 3.07(t,J=11.2Hz,1H), 3.00~2.82(m,2H), 2.26(s,3H), 2.11~1.84(m,4H). LC-MS:m / z 406.82[M+H] + . Preparation of Intermediate 5: 5-[[4-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoyl]piperazin-1-yl]methyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione Step 1: 2-(2,6-dioxo-3-piperidyl)-5-methyl-isoindoline-1,3-dione

[0740] [ka]

[0741] To a stirred solution of 5-methylisobenzofuran-1,3-dione (5.00 g, 30.86 mmol) and 3-aminopiperidine-2,6-dione (6.3 g, 38.58 mmol) in acetic acid (60 mL) was added NaOAc (3.1 g, 38.58 mmol), and the reaction mixture was stirred at 100° C. for 12 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered, washed with water, and evaporated to dryness under reduced pressure to give 2-(2,6-dioxo-3-piperidyl)-5-methyl-isoindoline-1,3-dione (8.0 g, crude) as an off-white solid, which was used directly in the next reaction. 1 H NMR (400 MHz, DMSO-d6) δ = 11.11 (s, 1H), 7.84-7.75 (m, 2H), 7.72-7.67 (m, 1H), 5.13 (dd, J = 5.4, 12.9 Hz, 1H), 2.95-2.83 (m, 1H), 2.66-2.53 (m, 2H), 2.11-2.02 (m, 1H), 3H merged with the solvent peak. LC-MS: m / z 272.93 [M+H] + . Step 2: 5-(bromomethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

[0742] [ka]

[0743] To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-5-methyl-isoindoline-1,3-dione (0.50 g, 1.83 mmol, from Step 1) and NBS (0.39 g, 2.20 mmol) in ACN (10 mL) was added benzoyl peroxide (0.11 g, 3.60 mmol), and the reaction mixture was stirred at 90 °C for 4 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (30% ethyl acetate in hexane) to give 5-(bromomethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.37 g, 61%) as an off-white solid. LC-MS: m / z 353.0 [M+2H] + . Intermediate 6: Preparation of 4-bromo-5-[[(3R,5R)-5-[4-(chloromethyl)phenyl]-1-methyl-3-piperidyl]amino]-2-methyl-pyridazin-3-one

[0744] [ka]

[0745] To a stirred solution of 4-bromo-5-[[(3R,5R)-5-[4-(hydroxymethyl)phenyl]-1-methyl-3-piperidyl]amino]-2-methyl-pyridazin-3-one (0.08 g, 0.19 mmol, Step 1 of Intermediate 4) in DCM (10 mL) was added thionyl chloride (0.05 g, 0.39 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (50% ethyl acetate in hexane) to give 4-bromo-5-[[(3R,5R)-5-[4-(chloromethyl)phenyl]-1-methyl-3-piperidyl]amino]-2-methyl-pyridazin-3-one (0.08 g, 95%) as a pale yellow liquid. LC-MS: m / z 425.0 [M+H] + . Intermediate 7: Preparation of tert-butyl 3-(5-hydroxy-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate Step 1: 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione

[0746] [ka]

[0747] To a stirred solution of 5-hydroxyisobenzofuran-1,3-dione (2.00 g, 12.15 mmol) and 3-aminopiperidine-2,6-dione (1.99 g, 12.15 mmol) in acetic acid (20 mL) was added NaOAc (1.03 g, 12.68 mmol), and the reaction mixture was stirred at 100° C. for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered and washed with water. The crude compound was dissolved in acetone. Charcoal was added, and the reaction mixture was refluxed for 30 minutes. The reaction mixture was filtered through Celite® and washed with acetone. The filtrate was concentrated to give 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (3.0 g, 90%) as an off-white solid. LC-MS: m / z 275.0 [M+H] + . Step 2: tert-butyl 3-(5-hydroxy-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate

[0748] [ka]

[0749] To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (5.00 g, 18.24 mmol, from Step 1) in 1,4-dioxane (10 mL), di-tert-butyl dicarbonate (7.90 g, 36.49 mmol) followed by DMAP (2.22 g, 18.24 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. To the resulting reaction mixture, piperidine (1.55 g, 18.24 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography with (40% ethyl acetate in heptane) to give tert-butyl 3-(5-hydroxy-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate (3.0 g, 44%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=11.09(brs,1H), 7.79~7.71(m,1H), 7.21~7.11(m,2H), 5.36(dd,J=5.4,12 .7Hz,1H), 3.15~3.02(m,1H), 2.83~2.73(m,1H), 2.69~2.55(m,1H), 2.12~2.02(m,1H), 1.48(s,9H). LC-MS:m / z 373.2[MH] + . Preparation of Intermediate 8: 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid Step 1: Ethyl 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate

[0750] [ka]

[0751] To a stirred solution of ethyl 4-[(3R,5R)-5-amino-1-methyl-3-piperidyl]benzoate (12.00 g, 48.33 mmol, from step 5, alternative preparation of intermediate 1) and 4,5-dichloro-2-methyl-pyridazin-3-one (8.91 g, 48.33 mmol) in DMSO (60 mL) was added K2CO3 (20.00 g, 144.00 mmol) and CsF (0.74 g, 4.83 mmol), respectively, at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, respectively, then dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give ethyl 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate (5.50 g, 29%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.97(s,1H), 7.92(d,J=8.3Hz,2H), 7.41(d,J=8.1Hz ,2H), 6.16(d,J=9.2Hz,1H), 4.30(q,J=7.1Hz,2H), 3.98~3.94(m,1H), 3.58(s, 3H), 3.04(t,J=11.7Hz,1H), 2.97~2.84(m,2H), 2.25(s,3H), 2.07~1.95(m,2H) ), 1.91(t,J=11.1Hz,1H), 1.76~1.64(m,1H), 1.31(t,J=7.0Hz,3H);LC-MS:m / z 405.40[M+H] + . Step 2: 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid

[0752] [ka]

[0753] To a stirred solution of ethyl 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate (3.00 g, 7.40 mmol from step 1) in ethanol (10 mL), THF (10 mL), and HO (10 mL) was added LiOH·HO (0.35 g, 14.82 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated and washed with diethyl ether to give the crude product. The crude was diluted with water and acidified with 1N HCl (pH 3) to give a solid which was filtered and washed with diethyl ether to give 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid (2.10 g, 75%) as an off-white solid. LC-MS: m / z 377.20 [M+H] + . Intermediate 9: Preparation of 3-[1-oxo-5-(piperazin-1-ylmethyl)isoindolin-2-yl]piperidine-2,6-dione Step 1: 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbonitrile

[0754] [ka]

[0755] To a stirred solution of methyl 2-(bromomethyl)-4-cyanobenzoate (3.00 g, 11.80 mmol) in DMF (30 mL) was added 3-aminopiperidine-2,6-dione (2.33 g, 14.16 mmol) followed by TEA (8.20 mL, 59.03 mmol) at room temperature, and the reaction mixture was stirred at 85 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% MeOH / DCM) to give 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbonitrile (2.60 g, 82%) as a blue solid. 1 H NMR(400MHz,DMSO-d6)δ=11.03(s,1H), 8.16(s,1H), 8.01~7.98(m,1H), 7.93~7.90(m,1H), 5.15(dd,J=5.1,13.4Hz,1H), 4. 58~4.52(m,1H), 4.46~4.39(m,1H), 2.96~2.87(m,1H), 2.64~2.58(m,1H), 2.42(dd,J=4.5,13.0Hz,1H), 2.06~2.01(m,1H). LC-MS:m / z 270.1[M+H] + . Step 2: 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbaldehyde

[0756] [ka]

[0757] To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbonitrile (2.00 g, 7.43 mmol, from step 1) in HCOOH (20 mL) was added Raney nickel (2.52 g, 14.86 mmol) at room temperature, and the reaction mixture was stirred at 85° C. for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% MeOH / DCM) to give 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbaldehyde (1.8 g, 89%) as an off-white solid. LC-MS: m / z 273.34 [M+H] + . Step 3: tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]piperazine-1-carboxylate

[0758] [ka]

[0759] To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbaldehyde (2.80 g, 6.61 mmol, from Step 2) and tert-butyl piperazine-1-carboxylate (1.47 g, 7.94 mmol) in MeOH (20 mL) and DMSO (0.5 mL) was added AcOH (0.2 mL) and NaCNBH (0.83 g, 13.23 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, all volatiles were evaporated. The reaction mixture was quenched with saturated NaHCO solution, and the compound was extracted with DCM. The crude compound was purified by silica gel column chromatography (10% MeOH / DCM) to give tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]piperazine-1-carboxylate (1.60 g, 54%) as an off-white solid. LC-MS: m / z 441.1 [MH] - . Step 4: 3-[1-oxo-5-(piperazin-1-ylmethyl)isoindolin-2-yl]piperidine-2,6-dione

[0760] [ka]

[0761] To a stirred solution of tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]piperazine-1-carboxylate (1.60 g, 3.61 mmol, from step 3) in DCM (20 mL) was added TFA (5 mL) at 0° C., and the reaction mixture was stirred at room temperature for 5 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with diethyl ether followed by pentane and thoroughly dried to give 3-[1-oxo-5-(piperazin-1-ylmethyl)isoindolin-2-yl]piperidine-2,6-dione (1.10 g, 89%) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ=10.99(s,1H), 8.65(brs,1H), 7.75(d,J=7.3Hz,1H), 7.61(brs,1H), 7.52(d,J=7.3Hz,1H), 5.12(dd,J=4.6,13.0Hz,1H ), 4.50~4.30(m,2H), 3.39(q,J=7.0Hz,1H), 3.17(brs,4H), 3.01~2.85(m,2H), 2.77(brs,3H), 2.64~2.59(m,1H), 2.56~2.54(m,3H);LC-MS:m / z 343.26[M+H] + . Intermediate 10: Preparation of tert-butyl 4-[3-(p-tolylsulfonyloxy)prop-1-ynyl]piperidine-1-carboxylate Step 1: tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate

[0762] [ka]

[0763] To a stirred solution of triphenylphosphine (9.80 g, 37.55 mmol) in DCM (40 mL) was added CBr4 (6.22 g, 18.77 mmol) at 0° C. and stirred for 1 hour. To the resulting reaction mixture was added tert-butyl 4-formylpiperidine-1-carboxylate (2.00 g, 9.38 mmol) at 0° C. and stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (30% ethyl acetate in hexane) to give tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (0.70 g, 20%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=6.54~6.50(m,1H), 3.93~3.87(m,2H), 2.84~2.71(m ,2H), 2.43~2.35(m,1H), 1.62~1.57(m,2H), 1.39(s,9H), 1.32~1.26(m,2H). Step 2: tert-butyl 4-(3-hydroxyprop-1-ynyl)piperidine-1-carboxylate

[0764] [ka]

[0765] To a stirred solution of tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (4.00 g, 10.84 mmol, from Step 1) in THF (40 mL) was added 1.6 M n-butyllithium (27 ml, 43.36 mmol) at −78° C. and stirred for 1 hour. To the resulting reaction mixture was added paraformaldehyde (1.38 g, 43.36 mmol) at −78° C. and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (80% ethyl acetate in hexanes) to give tert-butyl 4-(3-hydroxyprop-1-ynyl)piperidine-1-carboxylate (1.0 g, 38%) as a pale yellow liquid. 1 H NMR(400MHz,DMSO-d6)δ=5.06(t,J=5.9Hz,1H), 4.04(dd,J=2.0,5.9Hz,2H), 3.69~3.53( m,2H), 3.04(t,J=9.4Hz,2H), 2.66~2.55(m,1H), 1.78~1.66(m,2H), 1.45~1.29(m,11H). Step 3: tert-butyl 4-[3-(p-tolylsulfonyloxy)prop-1-ynyl]piperidine-1-carboxylate

[0766] [ka]

[0767] A solution of tert-butyl 4-(3-hydroxyprop-1-ynyl)piperidine-1-carboxylate (1.00 g, 4.18 mmol, from Step 2) and p-toluenesulfonyl chloride (0.95 g, 5.02 mmol) in diethyl ether (50 mL) was stirred at 0° C. for 30 minutes. To the resulting reaction mixture, KOH (1.40 g, 25.08 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (30% ethyl acetate in heptane) to give (0.80 g, 48%) as a pale yellow liquid. LC-MS: m / z 338.2 [M+H] + (M-tBu). Intermediate 11: Preparation of 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine

[0768] [ka]

[0769] To a stirred solution of 1-bromo-4-iodo-benzene (0.50 g, 1.76 mmol) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.10 g, 2.65 mmol) in 1,4-dioxane (10 mL) was added NaCO (0.37 g, 3.53 mmol) dissolved in HO (3 mL) at room temperature. The reaction mixture was purged with argon for 30 minutes. To the resulting reaction mixture was added PdCl(dppf) (0.14 g, 0.17 mmol), and the reaction mixture was purged with argon again for 20 minutes. The reaction mixture was stirred in a sealed tube at 110 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (0.70 g, 44%) as an off-white solid, which was used directly in the next reaction. LC-MS: m / z 448.4 [M+H] + . Preparation of Intermediate 12: 4-chloro-5-(((3R,5R)-5-(4-(chloromethyl)phenyl)-1-methylpiperidin-3-yl)amino)-2-methylpyridazin-3(2H)-one

[0770] [ka]

[0771] Intermediate 12 was prepared similarly to Intermediate 6 using the ester of Intermediate 8. 1H NMR(400MHz,DMSO-d6)δ=8.00(s,1H), 7.46(d,J=7.8Hz,2H), 7.30(d,J=7.8Hz,2H), 6.56(d,J=8.3Hz,1H), 4.76(s,2H), 4.27(brs,1H) ), 3.61(s,3H), 3.56(d,J=10.8Hz,2H), 3.27~3.23(m,1H), 3.12~3.02(m,1H), 2.94~2.86(m,1H), 2.83(s,3H), 2.15(d,J=12.2Hz,1H). LC-MS:m / z 380.90[M+H] + . Preparation of Intermediate 13: 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzaldehyde

[0772] [ka]

[0773] Intermediate 13 was prepared similarly to Intermediate 4 using the ester of Intermediate 8. 1 H NMR(400MHz,DMSO-d6)δ=9.98(s,1H), 7.97(brs,1H), 7.87(d,J=7.8Hz,2H), 7.50(d,J=7.3Hz,2H), 6.13(d,J=7.8Hz,1H), 3.95( brs,1H), 3.58(brs,3H), 3.08(t,J=9.8Hz,1H), 2.96(d,J=9.3Hz,1H), 2.88(d,J=10.3Hz,1H), 2.27(brs,3H), 2.09~1.89(m,4H). LC-MS:m / z 361.2[M+H] + . Preparation of Intermediate 14: 5-(((3R,5R)-5-(4-(chloromethyl)phenyl)-1-methylpiperidin-3-yl)amino)-2,4-dimethylpyridazin-3(2H)-one

[0774] [ka]

[0775] Intermediate 14 was prepared in the same manner as Intermediate 6 using the ester of Intermediate 17. The crude material was used directly in the next step. Intermediate 15: Preparation of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione Step 1: 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione

[0776] [ka]

[0777] To a stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (2.50 g, 8.14 mmol) and 3-aminopiperidine-2,6-dione (1.93 g, 8.96 mmol) in ACN (25 mL) was added DIPEA (7.5 mL, 40.72 mmol) at room temperature. The reaction mixture was stirred at 85° C. for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (2.3 g, crude) as a blue solid, which was used directly in the next reaction. LC-MS: m / z 323.0 and 325.0 [M+H] + . Step 2: tert-Butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

[0778] [ka]

[0779] To a stirred solution of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (0.50 g, 1.54 mmol, from Step 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.57 g, 1.85 mmol) in DMF (5 mL) was added K2CO3 (0.42 g, 3.09 mmol) at room temperature. The reaction mixture was purged with argon for 30 minutes. To the resulting reaction mixture was added PdCl2(dppf) (0.13 g, 0.15 mmol), and the reaction mixture was purged again with argon for 20 minutes. The reaction mixture was stirred in a sealed tube at 110 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.0 g, crude) as a black solid, which was used directly in the next reaction. LC-MS: m / z 426.2 [M+H] + . Step 3: tert-Butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperidine-1-carboxylate

[0780] [ka]

[0781] To a stirred solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.80 g, 4.23 mmol, from Step 2) in dry THF (25 mL) was added Pd / C (1.0 g) at room temperature. The reaction mixture was stirred at 45° C. under 60 psi H gas pressure for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperidine-1-carboxylate (1.6 g, crude) as an off-white solid. LC-MS: m / z 372.2 [M+H] + [M-tBu]. Step 4: 3-[1-oxo-5-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione

[0782] [ka]

[0783] A mixture of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperidine-1-carboxylate (0.80 g, 1.87 mmol, from step 3) in 1,4-dioxane (10 mL) and 30% TFA in 1,4-dioxane (20 mL) was stirred at 0° C. for 5 minutes, followed by room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 3-[1-oxo-5-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione (1.1 g, HCl salt) as a white solid, which was used directly in the next reaction. 1H NMR(400MHz,DMSO-d6)δ=10.97(s,1H), 7.70(d,J=7.3Hz,1H), 7.46(s,1H), 7.38(d,J=7.8Hz,1H), 5.10(dd,J=3.9,12.7Hz,1H), 4.49~4.40(m,1H), 4. 34~4.28(m,1H), 3.56(s,1H), 3.36(d,J=11.7Hz,2H), 3.05~2.87(m,4H), 2. 60(d,J=16.6Hz,1H), 2.38(d,J=10.3Hz,1H), 2.04~1.88(m,5H);LC-MS:m / z 328.2[M+H] + . Intermediate 16: Preparation of 3-[1-oxo-4-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione Step 1: tert-Butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

[0784] [ka]

[0785] To a stirred solution of 3-(4-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (2.00 g, 6.19 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (6.7 g, 21.67 mmol) in DMF (40 mL) was added K2CO3 (3.00 g, 21.67 mmol), and the reaction mixture was purged with argon for 30 minutes. To the resulting reaction mixture was added PdCl2(dppf) (0.45 g, 0.61 mmol), and the reaction mixture was purged again with argon for 20 minutes. The reaction mixture was stirred in a sealed tube at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through Celite. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (40% ethyl acetate in hexane) to give tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.00 g, 38%) as an off-white solid. LC-MS: m / z 424 [MH] - . Step 2: tert-butyl 4-[[4-(2,6-dioxo-3-piperidyl)phenyl]methyl]piperazine-1-carboxylate

[0786] [ka]

[0787] A stirred solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.10 g, 0.23 mmol, from Step 1) in THF (5 mL) and 10% Pd / C (37 mg) was added at room temperature. The reaction mixture was heated at 50° C. for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% MeOH in DCM) to give tert-butyl 4-[[4-(2,6-dioxo-3-piperidyl)phenyl]methyl]piperazine-1-carboxylate (0.11 g, crude) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ=10.99(brs,1H), 7.62~7.48(m,3H), 5.14(d,J=10.2Hz,1H), 4.54(d,J=16.8Hz,1H), 4.37(d,J=15.3Hz,1H), 4.14~4.00(m ,2H), 3.38(brs,2H), 2.98~2.80(m,3H), 2.61(d,J=17.2Hz,1H), 2.02(br s,1H), 1.75(d,J=9.0Hz,2H), 1.63~1.53(m,2H), 1.42(s,9H);LC-MS:m / z 426[MH] - . Step 3: 3-[1-oxo-4-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione

[0788] [ka]

[0789] A mixture of tert-butyl 4-[[4-(2,6-dioxo-3-piperidyl)phenyl]methyl]piperazine-1-carboxylate (0.10 g, 0.16 mmol, from step 2) in DCM (2 mL) and 30% TFA in DCM (0.6 mL) was stirred at 0° C. for 5 minutes, followed by room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with diethyl ether followed by pentane and thoroughly dried to give 3-[1-oxo-4-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione (0.03 g, 39%) as a brown solid. LC-MS: m / z 326 [MH] - . Preparation of Intermediate 17: 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid Step 1: Ethyl 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate:

[0790] [ka]

[0791] To a stirred solution of ethyl 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate (5.00 g, 11.13 mmol, adapted from Intermediate 1, Step 6) in 1,4-dioxane (49 mL) and HO (1 mL) at room temperature, methylboronic acid (1.33 g, 22.25 mmol) was added, followed by CsCO (10.90 g, 33.30 mmol). The reaction mixture was purged with argon for 30 minutes. To the resulting reaction mixture was added PdCl(dppf)·DCM (0.85 g, 1.11 mmol), and the reaction mixture was purged with argon again for 20 minutes. The reaction mixture was stirred in a sealed tube at 90 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through a pad of Celite. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, respectively, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel column chromatography (10% MeOH / DCM) to obtain ethyl 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate (2.80 g, 65%) as a brown solid. LC-MS: m / z 385.20 [M+H] + . Step 2: 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid:

[0792] [ka]

[0793] To a stirred solution of ethyl 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate (2.50 g, 6.20 mmol) in ethanol (20 mL) and HO (4 mL) was added LiOH·HO (0.54 g, 22.54 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated, and the residue was washed with diethyl ether to give the crude product. The crude material was diluted with water and acidified with 1N aqueous HCl (pH 3) to give a solid, which was filtered and washed with diethyl ether to give 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid (2.10 g, 90%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ=7.89(d,J=7.8Hz,2H), 7.79(s,1H), 7.34(d,J=7.8Hz,2H), 5.59~5.47(m,1H), 3.91~3.79(m,2H), 3 .53(s,3H), 3.08~2.82(m,3H), 2.26(s,3H), 2.04(d,J=11.7Hz,1H), 1.92(t,J=10.8Hz,2H), 1.86(s,3H), -COOH proton does not exist. LC-MS:m / z 356.90[M+H] + . Intermediate 18: Preparation of methyl 4-((3R,5R)-5-((3-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate Step 1: Methyl 4-[(3R,5R)-1-methyl-5-[(1-methyl-2-oxo-4-pyridyl)amino]-3-piperidyl]benzoate

[0794] [ka]

[0795] To a stirred solution of 4-bromo-1-methyl-pyridin-2-one (1.13 g, 6.01 mmol) in 1,4-dioxane:DMSO (1:1, 22 mL) was added methyl 4-[(3R,5R)-5-amino-1-methyl-3-piperidyl]benzoate (1.00 g, 4.00 mmol, from Step 5 of Intermediate 1) followed by Cs2CO3 (4.00 g, 12.30 mmol) at room temperature. To the resulting reaction mixture was added Pd2(dba)3 (0.37 g, 0.40 mmol) and Johnphos (0.24 g, 0.80 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by 100-200 mesh silica gel column chromatography (using 10% MeOH in DCM) to give methyl 4-[(3R,5R)-1-methyl-5-[(1-methyl-2-oxo-4-pyridyl)amino]-3-piperidyl]benzoate (0.08 g, 10%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.91(d,J=7.8Hz,2H), 7.42(d,J=7.3Hz,2H), 7.26(d,J=6.8 Hz,1H), 6.37(d,J=8.3Hz,1H), 5.68(d,J=6.4Hz,1H), 5.24(brs,1H), 3.40(s,3H), 3.2 1(s,3H), 3.17~3.12(m,1H), 3.02(d,J=11.2Hz,2H), 2.90~2.83(m,1H), 2.24(s,3H), 2.10(d,J=16.6Hz,1H), 1.91(t,J=10.5Hz,1H), 1.76~1.65(m,1H), 1.47~1.27(m,1H). LC-MS:m / z 356.26[M+H] + . Step 2: Methyl 4-((3R,5R)-5-((3-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate

[0796] [ka]

[0797] To a stirred solution of (ethyl 4-((3R,5R)-1-methyl-5-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)piperidin-3-yl)benzoate (2.00 g, 5.41 mmol, from step 1) in DCM (20 mL) at −78° C. was added N-bromosuccinimide (0.95 g, 5.23 mmol), and the reaction mixture was stirred at −78° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to −78° C. and cooled to −78° C. for 1 h. The reaction mixture was ... The mixture was quenched with sodium, diluted with water, and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% MeOH / DCM) to give ethyl 4-((3R,5R)-5-((3-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate (2.00 g, 82%) as a grey solid. LC-MS: m / z 448.30 and 450.30 [M+H] + . Step 3: 4-((3R,5R)-5-((3-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid

[0798] [ka]

[0799] To a stirred solution of ethyl 4-((3R,5R)-5-((3-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate (0.95 g, 2.11 mmol, from step 2) in ethanol (10 mL) and water (2 mL) was added lithium hydroxide (0.06 g, 2.46 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 1 hour. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, washed with diethyl ether, and concentrated under reduced pressure to give 4-((3R,5R)-5-((3-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.80 g, 90%) as an off-white solid, which was used directly in the next reaction. LC-MS: m / z 420.0 and 422.0 [M+H] + . Preparation of Intermediate 19: 4-((3R,5R)-5-((3-chloro-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid Step 1: Methyl 4-[(3R,5R)-1-methyl-5-[(1-methyl-2-oxo-4-pyridyl)amino]-3-piperidyl]benzoate

[0800] [ka]

[0801] To a stirred solution of 4-bromo-1-methyl-pyridin-2-one (1.13 g, 6.01 mmol) in 1,4-dioxane:DMSO (22 mL) was added methyl 4-[(3R,5R)-5-amino-1-methyl-3-piperidyl]benzoate (1.00 g, 4.00 mmol, from Step 5 of Intermediate 1). The reaction mixture was stirred at 110° C. for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (10% MeOH in DCM) to give methyl 4-[(3R,5R)-1-methyl-5-[(1-methyl-2-oxo-4-pyridyl)amino]-3-piperidyl]benzoate (0.08 g, 10%) as a pale yellow solid. LC-MS: m / z 356.26 [M+H] + . Step 2: Methyl 4-[(3R,5R)-5-[(3-chloro-1-methyl-2-oxo-4-pyridyl)amino]-1-methyl-3-piperidyl]benzoate

[0802] [ka]

[0803] To a stirred solution of methyl 4-[(3R,5R)-1-methyl-5-[(1-methyl-2-oxo-4-pyridyl)amino]-3-piperidyl]benzoate (0.50 g, 1.40 mmol, from step 1) in DCM (10 mL) was added NCS (0.19 g, 1.40 mmol) and the reaction mixture was stirred at −30° C. for 1 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (10% MeOH in DCM) to give methyl 4-[(3R,5R)-5-[(3-chloro-1-methyl-2-oxo-4-pyridyl)amino]-1-methyl-3-piperidyl]benzoate (0.11 g, 20%) as a liquid. LC-MS: m / z 390.10 [M+H] + .

[0804] The ester was then hydrolyzed to the acid in the same manner as in Intermediate 18, Step 3, to give the desired Intermediate 19:

[0805] [ka]

[0806]

[0336] 1 H NMR(400MHz,DMSO-d6)δ=11.71(brs,1H), 7.95(d,J=8.2Hz,2H), 7.59(d,J=7.6Hz,1H), 7.43(d,J=8.2Hz,2H), 6.24(d ,J=7.8Hz,1H), 6.09(d,J=8.7Hz,1H), 3.46~3.35(m,7H), 2.79(d,J=4.1Hz,3H), 2.43~2.34(m,3H), 2.12~2.04(m,1H). LC-MS:m / z 376.30[M+H] + . Intermediate 20: Preparation of methyl 4-((3R,5R)-5-((3-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate

[0807] [ka]

[0808] Intermediate 20 was prepared from methyl 4-((3R,5R)-5-((3-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate (Step 2 of Intermediate 18) using a Suzuki reaction followed by hydrolysis similar to steps 1 and 2 of Intermediate 17. 1 H NMR(400MHz,DMSO-d6)δ=11.55(brs,1H), 7.95(d,J=7.8Hz,2H), 7.79~7.69(m,1H), 7.49~7.42(m,2H), 6.15(d,J=7.8Hz,1H), 5.60(brs,1H), 4.39 ~4.23(m,1H), 3.48~3.41(m,3H), 3.37~3.31(m,3H), 3.18~3.06(m,2H), 2 .89~2.74(m,4H), 2.14(d,J=11.7Hz,1H), 2.04~1.94(m,1H), 1.84(s,2H). LC-MS: m / z 356.40 [M+H] + . Preparation of compounds General Step 1:

[0809] [ka] Process 1

[0810] To a stirred solution of aniline or dihaloarene (13.00 mmol) in 1,4-dioxane (25 mL), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15.00 mmol) was added, followed by potassium carbonate (25.00 mmol) dissolved in water, and the reaction mixture was purged with argon for 30 minutes. To the resulting reaction mixture, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), Pd(118) (1.30 mmol) was added, and the reaction mixture was purged with argon again for 20 minutes. The reaction mixture was stirred in a sealed tube at 100°C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the desired product. Process 2

[0811] To a stirred solution of the intermediate from step 1 (4.80 mmol) in ACN (40 mL) was added isoamyl nitrite (29.00 mmol) at room temperature and stirred for 10 minutes. To this was added copper(I) iodide (14.00 mmol) at room temperature. The reaction mixture was stirred at 60° C. for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the desired product. Process 3

[0812] [ka]

[0813] To a stirred solution of the intermediate from step 2 (2.30 mmol) in toluene (20 mL) was added tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2.70 mmol) followed by sodium tert-butoxide (3.40 mmol) at room temperature. The reaction mixture was purged with argon for 30 minutes. To the resulting reaction mixture was added 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.23 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.11 mmol) at room temperature, and the reaction mixture was purged with argon again for 20 minutes. The reaction mixture was stirred in a sealed tube at 110°C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the desired product. Process 4

[0814] [ka]

[0815] To a stirred solution of the intermediate from step 3 (0.69 mmol) in 1,4-dioxane (10 mL) was added 10% Pd / C at room temperature. The reaction mixture was stirred in a steel vessel under 50 psi H2 gas pressure at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the desired product. Process 5

[0816] [ka]

[0817] To a stirred solution of the intermediate from step 4 (0.49 mmol) in DCM (5 mL) was added TFA (2 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 5 minutes, followed by room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the desired product. Process 6

[0818] [ka]

[0819] To a stirred solution of the intermediate from step 5 (0.30 mmol) in DMF (4 mL), 1-methylimidazole (1.00 mmol) followed by the benzoic acid intermediate (0.30 mmol) were added, and the reaction mixture was stirred at room temperature for 10 minutes. To this was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.40 mmol), and the reaction mixture was stirred at 80 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the crude compound was purified by preparative HPLC to give the desired product. General Procedure 2: Process 1

[0820] [ka]

[0821] To a stirred solution of 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (0.45 mmol, Intermediate 11) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.54 mmol) in 1,4-dioxane was added NaCO (0.67 mmol) dissolved in HO (1.2 mL) at room temperature. The reaction mixture was purged with argon for 30 minutes. To the resulting reaction mixture was added PdCl(dppf) (0.04 mmol), and the reaction mixture was purged with argon again for 20 minutes. The reaction mixture was stirred in a sealed tube at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure to give the desired product. Process 2

[0822] [ka]

[0823] To a stirred solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.25 mmol, from Step 2) in EtOAc (0.5 mL) and EtOH (0.5 mL) was added 10% Pd / C followed by triethylsilane (2.55 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to give the desired product. Process 3

[0824] [ka]

[0825] To a stirred solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-1-carboxylate (0.16 mmol, from step 3) in DCM (2 mL) was added 30% TFA in DCM (4 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 5 minutes, then at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the desired product. Process 4

[0826] [ka]

[0827] To a stirred solution of 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione (0.22 mmol, from Step 3) in DMF (3 mL) was added the benzoic acid intermediate (0.22 mmol, Intermediate 1, 8, or 17) followed by N-methylimidazole (1.10 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. To the resulting reaction mixture was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.33 mmol) and stirred at 85°C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice-cold water. The precipitated solid was filtered to give the crude compound, which was purified by preparative HPLC to give the desired product. General Step 3:

[0828] [ka]

[0829] To a stirred solution of the amine intermediate (0.34 mmol) in DMF (1 mL) was added triethylamine (1.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. To this was added intermediate 6, 12, or 15 (0.31 mmol) at room temperature, and the reaction mixture was stirred at 100° C. for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with DCM. The combined organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the desired product. Example 1 Preparation of 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)phenyl)-N-methylbenzamide Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione

[0830] [ka]

[0831] To a stirred solution of 4-fluoroisobenzofuran-1,3-dione (1.00 g, 6.02 mmol) and 3-aminopiperidine-2,6-dione (0.99 g, 6.02 mmol) in acetic acid (10 mL) was added NaOAc (0.52 g, 6.30 mmol), and the reaction mixture was stirred at 100° C. for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered and washed with water. The crude compound was dissolved in acetone. Charcoal was added, and the reaction mixture was refluxed for 30 minutes. The reaction mixture was filtered through Celite® and washed with acetone. The filtrate was concentrated to give 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.20 g) as an off-white solid, which was used directly in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ = 11.14 (brs, 1H), 7.96-7.86 (m, 1H), 7.79-7.66 (m, 2H), 5.12 (dd, J = 5.1, 12.5 Hz, 1H), 2.94-2.78 (m, 1H), 2.57 (d, J = 18.6 Hz, 1H), 2.03 (d, J = 5.6, 7.6 Hz, 1H). 1H peak merged with solvent peak. LC-MS: m / z 277.0 [M+H] + . Step 2: 2-(2,6-dioxopiperidin-3-yl)-4-(4-(methylamino)phenoxy)isoindoline-1,3-dione

[0832] [ka]

[0833] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.50 g, 1.81 mmol, from Step 1) and 4-(methylamino)phenol (0.25 g, 1.99 mmol) in DMA (7 mL) was added KF (0.16 g, 2.72 mmol), and the reaction mixture was stirred in a microwave at 170° C. for 1.5 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered, and the residue was washed with water. The crude compound was purified by silica gel column chromatography (30% ethyl acetate in hexane) to give 2-(2,6-dioxopiperidin-3-yl)-4-(4-(methylamino)phenoxy)isoindoline-1,3-dione (0.16 g, 23%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.18–11.05 (m, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.02–6.92 (m, 2H), 6.61 (d, J = 8.8 Hz, 2H), 5.81–5.67 (m, 1H), 5.13 (dd, J = 5.1, 13.0 Hz, 1H), 2.98–2.82 (m, 1H), 2.74–2.66 (m, 3H), 2.65–2.54 (m, 2H), 2.12–2.00 (m, 1H). 1H peak merged with solvent peak. LC-MS: m / z 380.0 [M+H] + . Step 3: 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)phenyl)-N-methylbenzamide

[0834] [ka]

[0835] To a stirred solution of 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.03 g, 0.07 mmol, Intermediate 1) in DMF (1.5 mL) was added N-methylimidazole (0.03 g, 0.35 mmol) followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.03 g, 0.11 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. To the resulting reaction mixture was added 2-(2,6-dioxopiperidin-3-yl)-4-(4-(methylamino)phenoxy)isoindoline-1,3-dione (0.03 g, 0.07 mmol, from Step 2), and the reaction mixture was stirred at 80° C. for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude compound was purified by Combiflash® column (Method D) to give 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)phenyl)-N-methylbenzamide (0.0044 g, 8%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=11.13(brs,1H), 7.86(brs,1H), 7.83~7.69(m,1H), 7.65~7.54(m,1H), 7.35~6.92(m,10H), 5.80(d,J=5.4Hz,1H), 5 .19~5.06(m,1H), 4.00~3.82(m,1H), 3.66(brs,3H), 3.39(brs,3H), 2.99~2.74(m,5H), 2.22(brs,3H), 2.11~1.81(m,4H), 1.74~1.54(m,1H). LC-MS: m / z 782.0 and 783.9 [M+H] + . Example 2 Preparation of 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)-N-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)propyl)phenyl)-N-methylbenzamide Step 1: Methyl 3-(4-aminophenyl)propionate

[0836] [ka]

[0837] To a stirred solution of 3-(4-aminophenyl)propanoic acid (10.00 g, 60.60 mmol) in MeOH (100 mL) was added SOCl (4.50 mL, 60.60 mmol) at 0 °C, and the reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO solution and extracted with DCM. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give methyl 3-(4-aminophenyl)propionate (10.00 g, 92%) as an off-white solid, which was used directly in the next reaction. 1 H NMR (400MHz, DMSO-d6) δ=6.84(d,J=8.3Hz,2H), 6.47(d,J=8.3Hz,2H), 4.84(s,2H), 3.56(s,3H), 2.69~2.61(m,2H), 2.52(s,1H), 2.50~2.47(m,1H). LC-MS:m / z 180.2[M+H] + . Step 2: Methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)propionate

[0838] [ka]

[0839] To a stirred solution of methyl 3-(4-aminophenyl)propionate (10.00 g, 55.80 mmol, from Step 1) in 1,4-dioxane (100 mL) was added Na2CO3 (8.90 g, 83.70 mmol) followed by (Boc)2O (14.60 g, 67.00 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (20% ethyl acetate in hexane) to give methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)propionate (14.00 g, 90%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ=9.23(brs,1H), 7.34(d,J=8.3Hz,2H), 7.08(d,J=7.8Hz,2H), 3.57(s,3H), 2.81~2.71(m,2H), 2.62~2.54(m,2H), 1.46(s,9H). LC-MS:m / z 278.2[MH] + . Step 3: Methyl 3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propionate

[0840] [ka]

[0841] To a stirred solution of methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)propionate (0.10 g, 0.35 mmol, from step 2) in DMF (1 mL) was added NaH (60% in mineral oil, 0.02 g, 0.71 mmol) at 0° C., and the reaction mixture was stirred for 30 min. To the resulting reaction mixture was added MeI (0.11 g, 0.71 mmol), and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude methyl 3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propionate (0.03 g, 28%) as an off-white solid, which was used directly in the next reaction. LC-MS: m / z 238.2 [M+H] - (M-tBu). Step 4: tert-butyl(4-(3-hydroxypropyl)phenyl)(methyl)carbamate

[0842] [ka]

[0843] To a stirred solution of methyl 3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propionate (0.12 g, 0.40 mmol, from step 3) in THF (4 mL) was added LAH (1.00 mL, 1.63 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 2 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl solution, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give tert-butyl (4-(3-hydroxypropyl)phenyl)(methyl)carbamate (0.07 g, 70%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.15 (s, 4H), 3.41 (t, J = 6.4 Hz, 2H), 3.14 (s, 3H), 2.58 (t, J = 7.8 Hz, 2H), 1.74-1.62 (m, 2H), 1.38 (s, 9H), 1H merged with the solvent peak. LC-MS: m / z 210.2 [M+H] + (M-tBu). Step 5: 3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propyl-4-methylbenzenesulfonate

[0844] [ka]

[0845] To a stirred solution of tert-butyl (4-(3-hydroxypropyl)phenyl)(methyl)carbamate (1.10 g, 4.15 mmol, from Step 4) in DCM (20 mL) was added TEA (0.56 mL, 6.20 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 15 minutes. To the resulting reaction mixture was added tosyl chloride (1.10 g, 6.22 mmol), and the reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with ice-cold water and extracted with DCM. The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (20% ethyl acetate in hexane) to give 3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propyl-4-methylbenzenesulfonate (1.50 g, 86%) as a colorless semi-solid. 1 H NMR(400MHz,DMSO-d6)δ=7.78(d,J=7.8Hz,2H), 7.48(d,J=7.8Hz,2H), 7.14~7.09(m,2H), 7.07~6.98(m, 2H), 3.99(t,J=5.9Hz,2H), 3.13(s,3H), 2.56~2.51(m,2H), 2.42(s,3H), 1.90~1.78(m,2H), 1.37(s,9H). LC-MS:m / z 364.0[M+H] + (M-tBu). Step 6: tert-butyl (4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)propyl)phenyl)(methyl)carbamate

[0846] [ka]

[0847] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1.17 g, 4.30 mmol) in DMF (20 mL) was added Na2CO3 (0.91 g, 8.59 mmol) followed by 3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propyl-4-methylbenzenesulfonate (1.80 g, 4.30 mmol) in DMF at room temperature. The reaction mixture was stirred at 90°C for...

Claims

1. Compound of Formula II: 【Chemical 1】 or a pharmaceutically acceptable salt thereof (In the formula, Ring A is 【Chemistry 2】 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 bond or a divalent C １～３ is a straight or branched hydrocarbon chain; Each R １ are independently optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; n is 0, 1, 2, 3, or 4; Z is N or CR ３ and R ２ represents hydrogen, halogen, —CN, optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; Each R ３ are independently hydrogen, halogen, or optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; R ４ is hydrogen, optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; R ５ is hydrogen, halogen, optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic, or R ２ and R ５ are joined together with the atoms to which they are attached to form an optionally substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R ６ is hydrogen, optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; X is O or NR ７ and R ７ is hydrogen or optionally substituted C １～６ aliphatic, or R ４ and R ７ are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R ９ is hydrogen or optionally substituted C １～６ is aliphatic; The linker may be a covalent bond or an optionally substituted bivalent linear or branched saturated or unsaturated C １ ~C ２０ a hydrocarbon chain, wherein 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-; each Cy is independently an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system, said ring system being fully saturated, partially saturated, or aromatic, and said ring system containing 0-6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C １～６ Aliphatic, phenyl, C ３～７ an optionally substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding moiety. And, 【Chemistry 3】 Not a compound.

2. Ring A is 【Chemistry 4】 2. The compound of claim 1, wherein:

3. Ring A is 【Chemistry 5】 3. The compound of claim 2, selected from:

4. Ring A is 【Chemistry 6】 4. The compound of claim 3, selected from:

5. Ring A is 【Chemistry 7】 2. The compound of claim 1, wherein:

6. R ２ and R ５ together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S.

7. Ring A is 【Chemistry 8】 7. The compound of claim 6, wherein:

8. Ring A is 【Chemistry 9】 2. The compound of claim 1, wherein:

9. R ２ and R ５ together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S.

10. Ring A is 【Chemistry 10】 10. The compound of claim 9 selected from:

11. X is NR ７ and R ４ and R ７ together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.

12. Ring A is 【Chemistry 11】 12. The compound of claim 11, wherein:

13. Ring A is 【Chemistry 12】 2. The compound of claim 1, wherein:

14. Ring A is 【Chemistry 13】 14. The compound of claim 13, wherein:

15. R ９ 15. The compound of any one of claims 1 to 14, wherein is hydrogen.

16. The compound of any one of claims 1 to 15, wherein Ring B is a 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S.

17. Ring B is 【Chemistry 14】 17. The compound of claim 16, wherein:

18. Ring B is 【Chemistry 15】 18. The compound of claim 17, wherein:

19. L １ 19. The compound of any one of claims 1 to 18, wherein is a covalent bond.

20. Each R １ are independently optionally substituted C １～６ 20. The compound of any one of claims 1 to 19, wherein the compound is alkyl.

21. Each R １ became independent and C １～６ 21. The compound of claim 20, wherein the compound is alkyl.

22. 22. The compound of any one of claims 1 to 21, wherein n is 0 or 1.

23. R ２ is halogen or C １～６ 23. The compound of any one of claims 1 to 22, which is alkyl.

24. R ２ 24. The compound of any one of claims 1 to 23, wherein is halogen.

25. Each R ３ 25. The compound of any one of claims 1 to 24, wherein is hydrogen.

26. R ４ is optionally substituted C １～６ 26. The compound of any one of claims 1 to 25, which is alkyl.

27. The linker is an optionally substituted divalent linear or branched saturated or unsaturated 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)-, -SO ２ -, -SO ２ N(R)-, -N(R)SO ２ 27. The compound of any one of claims 1 to 26, optionally replaced by - or -Cy-.

28. The linker is an optionally substituted divalent linear or branched saturated or unsaturated C 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 28. The compound of claim 27, wherein said compound is optionally replaced by - or -Cy-.

29. The linker is an optionally substituted divalent linear or branched saturated or unsaturated C １ ~C ２０ 28. The compound of claim 27, which is 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-.

30. The linker is an optionally substituted divalent linear or branched saturated or unsaturated C １ ~C ２０ 30. The compound of claim 29, which is 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-.

31. The linker is an optionally substituted divalent linear or branched saturated or unsaturated C １ ~C ２０ 31. The compound of any one of claims 27 to 30, which is a hydrocarbon chain in which at least one methylene unit is replaced by -C(O)N(R)-.

32. 32. The compound of any one of claims 27 to 31, wherein the linker comprises at least one triple bond.

33. The linker is an optionally substituted divalent linear or branched saturated or unsaturated C １ ~C ２０ 33. The compound of any one of claims 27 to 32, which is a hydrocarbon chain, wherein at least one methylene unit is replaced by -Cy-.

34. The linker 【Chemistry 16】 (In the formula, M １ and M ２ are each independently absent, —CH ２ -, -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-; L ６ and L ７ each independently represents a covalent bond or an optionally substituted divalent linear or branched saturated or unsaturated C １ ~C １０ a hydrocarbon chain, wherein 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-) 34. The compound of any one of claims 1 to 33, wherein

35. The linker 【Chemistry 17】 35. The compound of claim 34, selected from:

36. The linker 【Chemistry 18】 36. The compound of claim 35, wherein:

37. The linker 【Chemistry 19】 35. The compound of claim 34, selected from:

38. L ６ 38. The compound of any one of claims 34 to 37, wherein is a covalent bond.

39. L ７ 39. The compound of any one of claims 34 to 38, wherein is a covalent bond.

40. 40. The compound of any one of claims 27 to 39, wherein each Cy is independently an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, a monocyclic 4- to 7-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and a bicyclic 6- to 11-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S.

41. 41. The compound of claim 40, wherein Cy is optionally substituted phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

42. 41. The compound of claim 40, wherein Cy is an optionally substituted monocyclic 4- to 7-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S.

43. 41. The compound of claim 40, wherein Cy is an optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S.

44. 44. The compound of claim 43, wherein Cy is a spirocyclic 6- to 7-membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S.

45. Each Cy is 【Chemistry 20】 40. The compound of any one of claims 27 to 39, independently selected from:

46. Each R is independently hydrogen or optionally substituted C １～６ 46. ​​The compound of any one of claims 1 to 45, which is alkyl.

47. 47. The compound of any one of claims 1-46, wherein the LBM is a CRBN binding moiety.

48. 47. The compound of any one of claims 1 to 46, wherein the LBM is a VHL binding moiety.

49. 47. The compound of any one of claims 1 to 46, wherein the LBM is an IAP binding moiety.

50. 47. The compound of any one of claims 1 to 46, wherein the LBM is an MDM2 binding moiety.

51. Compound of Formula IIA: 【Chemical 21】 51. The compound of any one of claims 1 to 50, which is: or a pharmaceutically acceptable salt thereof.

52. A compound of formula IIA-1, IIA-2, IIA-3, or IIA-4: 【Chemical 22】 or a pharmaceutically acceptable salt thereof.

53. Compound of Formula IIA-5: 【Chemical 23】 53. The compound of any one of claims 1 to 52, which is: or a pharmaceutically acceptable salt thereof.

54. Compound of Formula IIA-6: 【Chemistry 24】 53. The compound of any one of claims 1 to 52, which is: or a pharmaceutically acceptable salt thereof.

55. Compound of Formula III: 【Chemistry 25】 or a pharmaceutically acceptable salt thereof. (In the formula, Ring C is an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system, said ring system being fully saturated, partially saturated, or aromatic, and said ring system containing 0-6 heteroatoms independently selected from N, O, and S; Each R ａ are independently hydrogen or optionally substituted C １～６ aliphatic or two R ａ the groups, together with the atoms to which they are attached, join to form a 3- to 6-membered saturated or partially unsaturated ring; L ２ is a covalent bond or a linear or branched C １～３ It is a hydrocarbon chain, and one methylene is -O-, -S-, -N(R)-, -SO ２ optionally replaced by —, —C(O)N(R)—, or —N(R)C(O)—; Y is N or CH).

56. Ring C is phenyl, C ５～６ 56. The compound of claim 55, which is an optionally substituted group selected from alicyclic, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S.

57. 57. The compound of claim 56, wherein Ring C is an optionally substituted phenyl or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S.

58. Ring C is 【Chemical 26】 (In the formula, each B is independently selected from N, C, and CH, provided that no more than two B are N; Each R ｃ is halogen, -OR, -N(R) ２ , —CN, and optionally substituted C １～６ independently selected from aliphatic; m is 0, 1, 2, or 3.

58. The compound of claim 57, wherein:

59. Ring C is 【Chemical 27】 59. The compound of claim 58, wherein:

60. Compound of Formula IIIC: 【Chemical formula 28】 60. The compound of any one of claims 55 to 59, which is: or a pharmaceutically acceptable salt thereof.

61. Compound of Formula IIID: 【Chemical 29】 61. The compound of any one of claims 55 to 60, which is: or a pharmaceutically acceptable salt thereof.

62. Ring C is optionally substituted C ３ ~C ７ 56. The compound of claim 55, which is alicyclic or a 3- to 7-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S.

63. 56. The compound of claim 55, wherein Ring C is an optionally substituted 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

64. Ring C is 【Chemistry 30】 (In the formula, each A is independently N, C, or CH, provided that no more than two A groups are N; Each R ｂ is hydrogen, or two R on the same carbon ｂ the groups taken together form oxo or join to form a 3- to 6-membered saturated or partially unsaturated ring; Each R ｃ is halogen, -OR, -N(R) ２ , —CN, and optionally substituted C １～６ independently selected from aliphatic; m is 0, 1, 2, or 3.

64. The compound of claim 63, wherein:

65. Ring C is 【Chemical 31】 65. The compound of claim 64, wherein:

66. L ２ 66. The compound of any one of claims 55 to 65, wherein is a covalent bond.

67. L ２ Ga-CH ２ 66. The compound of any one of claims 55 to 65, wherein the group is -, -O-, or -N(R)-.

68. 68. The compound of any one of claims 55 to 67, wherein Y is N.

69. 68. The compound of any one of claims 55 to 67, wherein Y is CH.

70. Each R ｃ is halogen, -O(C １～６ alkyl), —O(C １～６ haloalkyl), C １～６ Alkyl, and C １～６ 70. The compound of any one of claims 55 to 69, independently selected from haloalkyl.

71. Compound of Formula IIIA: 【Chemical 32】 71. The compound of any one of claims 63 to 70, which is: or a pharmaceutically acceptable salt thereof.

72. Compound of Formula IIIB: 【Chemical 33】 or a pharmaceutically acceptable salt thereof.

73. Compounds of Formula IIIB-1 or IIIB-2: 【Chemical 34】 or a pharmaceutically acceptable salt thereof.

74. Compound of Formula IX: 【Chemical 35】 or a pharmaceutically acceptable salt thereof (In the formula, Ring A is 【Chemical 36】 Selected from: L ３ , L ４ , and L ５ each independently represents a covalent bond or an optionally substituted divalent C １～６ is a straight or branched hydrocarbon chain; Z is N or CR ３ and R ２ represents hydrogen, halogen, —CN, optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; Each R ３ are independently hydrogen, halogen, or optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; R ４ is hydrogen, optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; R ５ is hydrogen, halogen, optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic, or R ２ and R ５ are joined together with the atoms to which they are attached to form an optionally substituted 5-6 membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R ６ is hydrogen, optionally substituted C １～６ Aliphatic or optionally substituted C ３～６ is alicyclic; X is O or NR ７ and R ７ is hydrogen or optionally substituted C １～６ aliphatic, or R ４ and R ７ are joined together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; Each R ８ are independently hydrogen or optionally substituted C １～６ is aliphatic; R ９ is hydrogen or optionally substituted C １～６ is aliphatic; The linker may be a covalent bond or an optionally substituted bivalent linear or branched saturated or unsaturated C １ ~C ２０ a hydrocarbon chain, wherein 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-; each Cy is independently an optionally substituted mono- or polycyclic 3- to 16-membered bivalent ring system, said ring system being fully saturated, partially saturated, or aromatic, and said ring system containing 0-6 heteroatoms independently selected from N, O, and S; Each R is independently hydrogen or C １～６ Aliphatic, phenyl, C ３～７ an optionally substituted group selected from alicyclic, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; LBM is the E3 ubiquitin ligase binding moiety).

75. Compounds of Formula I: PBM-Linker-LBM I (In the formula, PBM is KAT2 protein binding moiety; Linker is an optional linking moiety; LBM is the E3 ubiquitin ligase binding moiety).

76. 76. The compound of claim 75, wherein the PBM is a KAT2A protein binding moiety.

77. 76. The compound of claim 75, wherein the PBM is a KAT2B protein binding moiety.

78. 78. The compound of any one of claims 75 to 77, wherein the linker is less than 14 atoms in length.

79. 79. The compound of any one of claims 75 to 78, wherein the linker is less than 11 atoms in length.

80. 80. The compound of any one of claims 75-79, wherein the LBM is a CRBN binding moiety.

81. 80. The compound of any one of claims 75 to 79, wherein the LBM is a VHL binding moiety.

82. 80. The compound of any one of claims 75 to 79, wherein the LBM is an IAP binding moiety.

83. 80. The compound of any one of claims 75 to 79, wherein the LBM is an MDM2 binding moiety.

84. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

85. 85. A pharmaceutical composition comprising a compound of any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

86. 86. A method for preparing the pharmaceutical composition of claim 85, comprising: Providing a compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof; formulating said compound with suitable excipients to obtain said pharmaceutical composition; A method comprising:

87. 86. A method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 85.

88. 86. A method of treating cancer, comprising administering to a subject in need thereof a compound of any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 85.

89. 89. The method of claim 88, wherein the cancer is selected from acute myeloid leukemia, neuroblastoma, non-small cell lung cancer, small cell lung cancer, colon cancer, melanoma, and prostate cancer.

90. A method for degrading KAT2 in a subject, comprising administering to a subject in need thereof a compound described in any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 85.

91. 85. An in vitro method of degrading KAT2, comprising contacting a biological sample with a compound of any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof.

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